Evidence for male-biased effective sex ratio and recent step-by-step colonization in the bivalve Pinctada mazatlanica.
This paper presents a comparison of the geographical distribution of genetic variability at mitochondrial and nuclear loci among pearl oyster populations from the tropical American Pacific coast (Pinctada mazatlanica). Surprisingly, both mitochondrial and nuclear gene variability decreased regularly from north to south of the studied area, which, altogether with a significant correlation between genetic and geographical distances for mtDNA, suggests a recent colonization or re-colonization of the southern areas. However, the loss of diversity between north and south was much more important for mitochondrial than for nuclear DNA, and this did not translate into measurable fixation index at nuclear loci (theta = 0.03, n.s.), contrary to the mitochondrial data (theta = 0.18*). Smaller effective size of mtDNA accentuated by a strong male-biased effective sex ratio and step-by-step colonization from northern areas can explain this discrepancy among natural populations of this protandric species.


Kisspeptin-10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback.
Does sex-steroid feedback influence gonadotrophin responses to kisspeptin-10? Gonadotrophin response to kisspeptin-10 is enhanced in sex-steroid deficient post-menopausal women and suppressed in women taking pharmacological doses of exogenous estrogen and progestogen. Kisspeptin, a novel hypothalamic neuropeptide, stimulates gonadotrophin secretion by stimulating GnRH secretion and has been shown in animal models to play a pivotal role in mediating sex steroid feedback. As estrogen feedback occurs at both the hypothalamus and the pituitary levels, we hypothesized that the stimulatory effect of kisspeptin-10 in women would be dependent on prevailing sex steroid milieu. An experimental study of a novel neuropeptide in women-10 in the early follicular phase, 6 post-menopausal and 8 taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Gonadotrophin secretion was followed for 60 min after kisspeptin administration. The gonadotrophin response to intravenous kisspeptin-10 (0.3 µg/kg) in women in the early follicular phase was compared with that in the presence of low endogenous sex steroids/high gonadotrophin secretion (post-menopausal women) and in women taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Area under the curve (AUC) of gonadotrophin secretion sampled at 15 min intervals over 60 min before and after kisspeptin-10 was analysed. Kisspeptin-10 stimulated LH secretion in follicular (ΔAUC 2.3 ± 0.8 IU/l h, P = 0.009), post-menopausal (5.3 ± 0.9 IU/l h P 0.002) and progestogen (2.6 ± 0.8 IU/l h P 0.05) groups but not in women taking combined pill (0.9 ± 0.4 IU/l h P 0.13). FSH secretion was significantly increased only in post-menopausal women (ΔAUC 2.6 ± 0.8 IU/l h P = 0.03) with changes of <0.5 IU/l h observed in the other three groups. Both LH and FSH responses in post-menopausal women were significantly larger than the other groups (one-way ANOVA analysis of ΔAUC; LH (P = 0.012) and FSH (P = 0.001)]. This study only assessed acute responses to an intravenous bolus of kisspeptin-10 administration, and the impact of continuous exposure to kisspeptin-10 on LH pulse frequency in women remains to be studied to fully understand the translational potential. Gonadotrophin secretion in women is stimulated by kisspeptin-10. These results suggest that the pituitary gonadotrope is a functionally important locus of estrogen feedback in women and also inform potential translational applications of kisspeptin in reproductive endocrine disorders. Medical Research Council (UK). None.


[Syndrome of inappropriate antidiuretic hormone secretion following adjuvant CDDP and 5-FU administration in a patient with esophageal carcinoma].
A case of hyponatremia following the first course of systemic adjuvant chemotherapy with cisplatin (CDDP) and 5-FU in a previously treated patient with esophageal cancer is reported. A 61-year-old man was admitted to our hospital for adjuvant chemotherapy after transthoracic esophagectomy and 3-field lymphadenectomy for esophageal cancer. Six days following chemotherapy, his serum sodium concentration was found to be 118 mEq/L, without edema or dehydration. This hyponatremic state was diagnosed as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) induced by CDDP, based on the hypo-osmolality of his serum and urine, and an inappropriate level of plasma vasopressin.


Repair or replacement of defective direct resin-based composite restorations: contemporary teaching in U.S. and Canadian dental schools.
Opportunities exist to promote minimally invasive dentistry by repairing rather than replacing defective and failing direct resin-based composite restorations. The authors conducted a study to investigate the current teaching of such techniques in U.S. and Canadian dental schools. In late 2010, the authors, with the assistance of the Consortium of Operative Dentistry Educators, invited 67 U.S. and Canadian dental schools to participate in an Internet-based survey. The response rate was 72 percent. Eighty-eight percent of the dental schools taught repair of defective direct resin-based composite restorations. Of these schools, 79 percent reported providing both didactic and clinical teaching. Although teaching repair of defective resin-based composite restorations was included in the didactic curricula of most schools, students in some schools did not gain experience in minimally invasive management of defective resin-based composite restorations by means of performing repair procedures. The American Dental Association's Code on Dental Procedures and Nomenclature does not have a procedure code for resin-based composite restoration repairs, which may limit patients' access to this dental treatment. Teaching dental students minimally invasive dentistry procedures, including restoration repair, extends the longevity of dental restorations and reduces detrimental effects on teeth induced by invasive procedures, thereby serving the interests of patients.


Dynamic Buffering of Extracellular Chemokine by a Dedicated Scavenger Pathway Enables Robust Adaptation during Directed Tissue Migration.
How tissues migrate robustly through changing guidance landscapes is poorly understood. Here, quantitative imaging is combined with inducible perturbation experiments to investigate the mechanisms that ensure robust tissue migration in vivo. We show that tissues exposed to acute "chemokine floods" halt transiently before they perfectly adapt, i.e., return to the baseline migration behavior in the continued presence of elevated chemokine levels. A chemokine-triggered phosphorylation of the atypical chemokine receptor Cxcr7b reroutes it from constitutive ubiquitination-regulated degradation to plasma membrane recycling, thus coupling scavenging capacity to extracellular chemokine levels. Finally, tissues expressing phosphorylation-deficient Cxcr7b migrate normally in the presence of physiological chemokine levels but show delayed recovery when challenged with elevated chemokine concentrations. This work establishes that adaptation to chemokine fluctuations can be "outsourced" from canonical GPCR signaling to an autonomously acting scavenger receptor that both senses and dynamically buffers chemokine levels to increase the robustness of tissue migration.


Blood group isoantigen deletion in carcinoma in situ of the urinary bladder.
Blood group isoantigens A and H (O) were measured by the Secific Red Cell Adherence (SRCA) Test in nine radical cystectomy specimens removed from patients with extensive carcinoma in situ of the urinary bladder. All bladders had areas of histologically normal epithelium and areas of epithelial atypia in addition to the carcinoma in situ. In eight cases, tissue-associated blood group isoantigens were deleted in areas showing either atypia or carcinoma in situ. Isoantigens were present in these areas in the ninth case. Blood group isoantigens were absent in approximately half of the sections of histologically normal epithelium. We propose that areas of epithelium which appear benign according to conventional histological criteria but in which the blood group isoantigens are absent may represent areas of low grade carcinoma in situ.


Intra-abdominal abscess in regional enteritis.
Intra-abdominal abscess (IAA) developed in 129 of 610 patients (21.2%) with Crohn's disease confined to the small bowel. The location of the abscess was intraperitoneal (IPA) in 109 (17.9%) and retroperitoneal (RPA) in 20 (3.3%). There was a marked preponderance of male patients in the retroperitoneal group (ratio, 18:2) (p less than 0.0001). All 129 patients were operated on. Thirteen of one hundred nine patients (12%) with IPA were reoperated on for recurrent abscess, and nine (8.2%) for other reasons. External fistula developed in 24 patients (22%) after simple incision and drainage. Four (3.7%) died; one from hepatitis, and three from sepsis 5, 14, and 90 days after surgery. Of the 20 patients with RPA, two (10%) were reoperated on for recurrent abscess and four (20%) for other reasons. External fistula developed in two patients (10%). There were no deaths in this group. A small number of patients with IAA complicating regional enteritis had persistent sepsis causing postoperative death, which is, however, six times lower than in our comparable series of Crohn's (ileo)colitis.


Development and evaluation of the SPeeding Research-tested INTerventions (SPRINT) training program.
The National Cancer Institute established a dissemination and implementation accelerator program called SPeeding Research-tested INTerventions (SPRINT) to improve the uptake of evidence-based interventions. The purpose of this study was to describe the origin, structure, and goals of the SPRINT program, and present evaluation results from the first two cohorts of the program. Qualitative (focus group) and quantitative (survey) data collected from participants were used to evaluate the course and inform program improvement efforts. The majority of the participants (over 90% in both cohorts) rated the course highly, and over 80% would recommend the course to other researchers. Most participants indicated knowing relatively little about business model concepts before SPRINT, but after SPRINT, nearly all respondents felt that they had at least "some" knowledge of each business model component. Participants also indicated that they learned about the product-market fit of their intervention and gained insights from customer discovery interviews that would enable them to make their intervention more "stakeholder focused". Participants also indicated that they plan to use the knowledge and skills they gained during the SPRINT program in their future work. Feedback from participants was used by the management team to implement various program improvements to better serve the next cohort of participants. While behavioral researchers face significant barriers to commercializing their interventions, they recognize the importance of translating their research into practice. Training researchers to consider scale-up, implementation, and commercialization from the outset can help reduce the number of proven interventions that are never used in practice.


Alkyl-imidazolium glycosides: non-ionic-cationic hybrid surfactants from renewable resources.
A series of surfactants combining carbohydrate and imidazolium head groups were prepared and investigated on their assembly behavior. The presence of the imidazolium group dominated the interactions of the surfactants, leading to high CMCs and large molecular surface areas, reflected in curved rather than lamellar surfactant assemblies. The carbohydrate, on the other hand, stabilized molecular assemblies slightly and reduced the surface tension of surfactant solutions considerably. A comparative emulsion study discourages the use of pure alkyl imidazolium glycosides owing to reduced assembly stabilities compared with APGs. However, the surfactants are believed to have potential as component in carbohydrate based surfactant mixtures.


Dysregulation of dimethylargininedimethylaminohydrolase/asymmetric dimethylarginine pathway in rat type II diabetic nephropathy.
An impaired generation of nitric oxide has been associated with diabetic renal disease. In order to elucidate the underlying molecular mechanisms into how nitric oxide synthesis is impaired in diabetic renal disease, we examined changes in activities and expressions of some renal enzymes involved in nitric oxide production during the development of diabetic nephropathy in type II diabetic Otsuka Long-Evans Tokushima Fatty rats. Ten-week old Otsuka Long-Evans Tokushima Fatty (n = 40) and control Long-Evans Tokushima Otsuka rats (n = 20) were given drinking water containing 20% sucrose to accelerate the development of diabetic nephropathy. Otsuka Long-Evans Tokushima Fatty rats developed diabetic nephropathy in an age-dependent manner. Renal nitric oxide synthase activities in Otsuka Long-Evans Tokushima Fatty rats gradually declined with the progression of diabetic mellitus and were significantly lower than those of age-matched Long-Evans Tokushima Otsuka rats after 22 weeks of age. The lower activities of renal nitric oxide synthase in Otsuka Long-Evans Tokushima Fatty rats were correlated with relatively higher levels of renal free asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, and were also correlated with decreased activities of dimethylargininedimethylaminohydrolase which metabolizes asymmetric dimethylarginine to citrulline. These results imply that dimethylargininedimethylaminohydrolase dysregulation may play an important role in the development of diabetic nephropathy by increasing asymmetric dimethylarginine levels, which leads to inhibition of renal nitric oxide synthesis.


LONG-TERM PROTECTIVE RABIES ANTIBODIES IN THAI CHILDREN AFTER PRE-EXPOSURE RABIES VACCINATION.
Rabies is a viral zoonosis affecting around 16,000-39,000 people annually. Pre-exposure vaccination should be offered to individuals at high risk of rabies exposure and is suggested for children living in rabies endemic areas.The incidence rate of dog bite in the test group was 14.1/1,000 person-years. Intradermal (ID) route of administration is considered an alternative to the standard intramuscular (IM) administration, and reduces vaccination cost. A 3-year clinical study of a rabies vaccine administered IM or ID to 12–18-month-old Thai children, simultaneously with a Japanese encephalitis (JE) vaccine (M49P2 study), revealed that all regimens used elicited an adequate immune response. In order to determine the long-term (4-8 years) rabies neutralizing antibody titers induced by the pre-exposure regimens, blood was collected annually from 68 from the M49P2 study and analyzed using a rapid fluorescence focus inhibition test. Full- IM(three doses of 1 ml/dose), half-IM(three doses of 0.5 ml/dose), and 3-ID(three doses of 0.1 ml/dose) regimens induced antibody titers above the seroprotective level throughout the study period. However, the 2-ID(two doses of 0.1 ml/dose) group had sub-seroprotective titer of 6.7%, 13.4%, 25.0%, and 36.4% in year 5, 6, 7, and 8, respectively. A secondary immune response was induced by rabies booster vaccination. This study demonstrates a reduced-dose rabies regimen may lower the cost of long-term protection against rabies for vulnerable populations, thus improving the cost-effectiveness of pre-exposure rabies vaccination in children.


Intensification of doxorubicin-related oxidative stress in the heart by hypothyroidism is not related to the expression of cytochrome P450 NADPH-reductase and inducible nitric oxide synthase, as well as activity of xanthine oxidase.
Cytochrome P450 NADPH-reductase (P450R), inducible synthase (iNOS) and xanthine oxidase play an important role in the antracycline-related cardiotoxicity. The expression of P450R and iNOS is regulated by triiodothyronine. The aim of this study was to evaluate the effect of methimazole-induced hypothyreosis on oxidative stress secondary to doxorubicin administration. 48 hours after methimazole giving cessation, rats were exposed to doxorubicin (2.0, 5.0 and 15 mg/kg). Blood and heart were collected 4, 48 and 96 h after the drug administration. Animals exposed exclusively to doxorubicin or untreated ones were also assessed. The hypothyreosis (0.025% of methimazole) significantly increased the doxorubicin effect on the cardiac carbonyl group and they may increase the glutathione level. An insignificant effect of methimazole was noticed in case of the cardiac lipid peroxidation product, the amount of DNA oxidative damages, iNOS and xanthine oxidase-enzymes responsible for red-ox activation of doxorubicin. However, the concentration of P450R was affected by a lower dose of methimazole in rats administered with doxorubicin. Since in rats receiving doxorubicin changes in oxidative stress caused by methimazole were not accompanied by elevation of bioreductive enzymes, it may be concluded that these changes in the oxidative stress were not related to the tested enzymes.


Activation of estrogen receptor α by raloxifene through an activating protein-1-dependent tethering mechanism in human cervical epithelial cancer cells: a role for c-Jun N-terminal kinase.
Nuclear estrogen receptor α (ERα) regulates target gene expression in response to ligands through two distinct mechanisms: direct binding to DNA and indirect tethering through other DNA-bound transcription factors, such as AP-1. In the studies described herein, we examined the molecular mechanisms underlying the activation of ERα in the AP-1 tethering pathway by the selective estrogen receptor modulator (SERM) raloxifene (Ral). Our results with the MMP1 and PRUNE genes indicate that the c-Fos component of the AP-1 tethering factor and the c-Jun N-terminal kinase 1 (JNK1) are constitutively bound at the promoter regions prior to Ral exposure. Ral then promotes the binding of ERα at the promoter in a c-Fos-dependent manner. Interestingly, we found that JNK1 enzymatic activity is required for Ral-dependent gene activation through ERα. Our results suggest that one role for Ral-dependent recruitment of ERα to the AP-1 binding site is to stimulate JNK1 enzymatic activity. Alternatively, Ral-occupied ERα might recruit protein substrates to promoter-bound JNK1 without any change in JNK1 activity. Collectively, our studies have revealed a new role for JNK1 in determining gene regulatory outcomes by ERα.


Shigella dysenteriae type 1-specific bacteriophage from environmental waters in Bangladesh.
Shigella dysenteriae type 1 is the causative agent of the most severe form of bacillary dysentery, which occurs as epidemics in many developing countries. We isolated a bacteriophage from surface water samples from Bangladesh that specifically lyses strains of S. dysenteriae type 1. This phage, designated SF-9, belongs to the Podoviridae family and has a 41-kb double-stranded DNA genome. Further screening of water samples for the prevalence of the phage revealed 9 of 71 (12.6%) water samples which were positive for the phage. These water samples were also positive in PCR assays for one or more S. dysenteriae type 1-specific genes, including ipaBCD and stx1, and live S. dysenteriae type 1 was isolated from three phage-positive samples. The results of this study suggest that phage SF-9 may have epidemiological applications in tracing the presence of S. dysenteriae type 1 in environmental waters.


[Clinical assessment of physical dependence potential of dihydroetorphine hydrochloride (DHE)].
This paper reports the DHE substitution clinical trial in 38 heroin addicts. The CINA (Clinical Institute Narcotic Assessment) scale was used to assess physical dependence potential. The CINA scale contains 10 opioid withdrawal signs (nausea, vomiting, gooseflesh, sweating, restlessness, tremor, larcrimation, nasal congestion, yawning, changes in heart rate and systolic blood pressure) and 3 opiate withdrawal symptoms (abdominal pain, muscle pain and feeling hot or cold). For each subject admitted to the Drug Detoxification and Treatment Center his (her) status on each of the 13 items of CINA were immediately rated. Then, naloxone 0.4 mg was injected iv to precipitate withdrawal symptoms and at 5, 10, 15 min after the naloxone injection, the CINA score of each patient was rated again. The differences among the scores of pre- and post-naloxone injection is a measurement of the degree of withdrawal symptoms. Then, a single dose of DHE was administered sublingually to each patient, all withdrawal symptoms disappeared. These results show that DHE can compete with naloxone for opioid receptors. A good dose-response relationship was found between the 100% suppressive withdrawal sign doses of DHE and the degree of withdrawal sign in heroin addicts. The physical dependence potential of DHE given to heroin addicts sublingually was probably more than that of methadone given to heroin addicts orally by making reference to the report of Dr. Peachy.


Role of contact system activation in hemodialyzer-induced thrombogenicity.
The contact system is generally believed to be the main trigger of the coagulation cascade during extracorporeal circulation. However, the extent of contact activation, its role for intradialytic thrombin generation as well as the influence of different dialyzer membranes have not been well established. In a novel full-scale ex vivo recirculation dialysis model, we investigated the thrombogenicity of three widely used hemodialyzers (Cuprophan Renak RA15-U, Polysulfone F6HPS and AN69XT Nephral 200). The activation of the contact system was evaluated using a newly developed ELISA for factor XIIa-C1-inhibitor complexes. Additionally, we determined free FXIIa (ELISA), thrombin-antithrombin (TAT) complexes, platelet factor 4 (PF4), complement activation (C5a), granulocyte elastase and blood cell counts. The findings in blood from normal volunteers were compared with factor XII-deficient blood. With normal blood AN69 exhibited the highest thrombogenicity in comparison to Cuprophan and Polysulfone, as assessed by TAT generation and platelet consumption. AN69 caused a rapid increase of the FXIIa-C1-inhibitor complexes and of free FXIIa. Despite significant TAT generation with Cuprophan and Polysulfone free FXIIa remained unchanged and the FXIIa-C1-inhibitor complexes stayed below the detection limit. With factor XII-deficient blood Polysulfone exhibited the same TAT generation, whereas the thrombogenicity of AN69 was greatly reduced. Our data challenge the common assumption that activation of the contact system with generation of FXIIa is the main trigger for coagulation and thrombus formation in hemodialysis. Only the negatively charged AN69 membrane with enhanced thrombogenicity strongly induced contact activation.


Podophyllum toxicity: a report of a fatal case and a review of the literature.
A 59-yr-old male ingested 10 g of podophyllum in a fatal suicide attempt. Previously unreported nuclear and cytoplasmic changes were observed in circulating leukocytes. Symptoms did not occur until 10 h after ingestion with loss of reflexes, coma, and a marked lactic acidosis. Despite hemoperfusion, the patient expired 39 h after ingestion. The literature on podophyllum toxicity is reviewed.


Integrating research integrity into the history of science.
This introductory essay frames our special issue by discussing how attention to the history of research integrity and fraud can stimulate new historical and methodological insights of broader import to historians of science.


The Effects of Suffering in Chronically Ill Older Adults on the Health and Well-Being of Family Members Involved in Their Care: The Role of Emotion-Related Processes.
A large literature shows that caregivers of chronically ill older adults have a higher risk for impaired health and decreased longevity. In this paper we review research that addresses pathways through which family members experience negative health consequences from exposure to a partner's suffering. We first provide a conceptualization of suffering and describe how it can be measured, then review empirical evidence that exposure to suffering uniquely influences caregivers' health, and discuss individual differences in caregivers' emotional reactions to partners' suffering using three emotion theories (Gross' process model of emotion regulation, attachment theory, and a functionalist perspective on emotion). Finally, we discuss implications of the effects of suffering for the health and well-being of family caregivers.


Modern dosimetric tools for (60)Co irradiation at high containment laboratories.
To evaluate an innovative photo-fluorescent film as a routine dosimetric tool during (60)Co irradiations at a high containment biological research laboratory, and to investigate whether manufacturer-provided chamber exposure rates can be used to accurately administer a prescribed dose to biological specimens. Photo-fluorescent, lithium fluoride film dosimeters and National Institutes of Standards and Technology (NIST) transfer dosimeters were co-located in a self-shielded (60)Co irradiator and exposed to γ-radiation with doses ranging from 5-85 kGy. Film dose-response relationships were developed for varying temperatures simulating conditions present when irradiating infectious biological specimens. Dose measurement results from NIST transfer dosimeters were compared to doses predicted using manufacturer-provided irradiator chamber exposure rates. The film dosimeter exhibited a photo-fluorescent response signal that was consistent and nearly linear in relationship to γ-radiation exposure over a wide dose range. The dosimeter response also showed negligible effects from dose fractionization and humidity. Significant disparities existed between manufacturer-provided chamber exposure rates and actual doses administered. This study demonstrates the merit of utilizing dosimetric tools to validate the process of exposing dangerous and exotic biological agents to γ-radiation at high containment laboratories. The film dosimeter used in this study can be utilized to eliminate potential for improperly administering γ-radiation doses.


Who benefits from hormone therapy?
Not all hormone receptor (HR)-positive tumors respond to hormone therapy, although hormone therapy has brought significant benefits to breast cancer patients. In order to improve the efficacy of hormone therapy, a variety of new approaches are currently being tested in such as extended adjuvant therapy, selection of responders using array-based techniques and combination therapy with signal transduction inhibitors. It is therefore necessary to distinguish between highly hormone responsive tumors and relatively less hormone sensitive tumors. Through reviewing recent outcomes of clinical trials, these issues are summarized and discussed in this review.


[Effects of cell cycle regulatory genes on breast cancer neo-adjuvant chemotherapy by M-FISH].
Objective: The dysregulation of cell cycle could influence cell proliferation, differentiation and response to medicine. The purpose of this study is to explore the correlation between cell cycle regulatory genes and breast cancer neo-adjuvant chemotherapy (NAC) in patients with local advanced breast cancer, and thus to find some predictors of NAC to provide guidance for clinical treatment. Methods: Ninety five cases of local advanced breast cancer were collected, which were treated with NAC of TAC (Taxanes/Anthracycline/Cyclophosphamide) regimen. Multi-gene fluorescence in situ hybridization (M-FISH) was used to study the correlation between copy number variations of cell cycle regulatory genes (c-myc, Mdm2, CCND1, CHEK2, Rb1, p53, p16, p21) and clinical effect of NAC. Results: In the effective group, there were 18 cases of c-Myc amplification and 52 cases of no amplification. There were 11 cases of CCND1 amplification and 59 cases of no amplification; 12 cases of p53 deletion and 58 cases without deletion; 11 cases of p16 deletion and 59 cases without deletion. In the ineffective group, there were 12 cases of c-Myc amplification and 13 cases of no amplification; CCND1 amplification in 9 cases, no amplification in 16 cases; p53 deletion in 10 cases, no deletion in 15 cases; p16 deletion in 10 cases and no deletion in 15 cases. The copy number of the above four genes was statistically different between the two groups. C-Myc gene amplification (P=0.040), CCND1 gene amplification (P=0.033), p53 gene deletion (P=0.020) and p16 gene deletion (P=0.012) were significant correlation with poor effect of NAC. Among them, the effect of NAC in patients with two or more genes copy number variations of c-Myc, CCND1, p53, p16 were poorer than that in patients with one or not gene copy number variations (P=0.000). In addition, the copy number variations of CCND1 (P=0.049), c-Myc (P=0.049), and p16 (P=0.008) were correlated with neo-adjuvant chemotherapeutic effect respectively in Luminal breast cancer, Her-2 positive breast cancer, and triple-negative breast cancer. Conclusion: These results indicated that the copy number variations of c-Myc, CCND1, p53, and p16 in patients were significant correlation with poor effect of NAC.


Curcumin ameliorates acute thioacetamide-induced hepatotoxicity.
Increased production of reactive oxygen species and nitric oxide and activation of nuclear factor kappa B are implicated in the pathogenesis of various liver diseases, including fulminant hepatic failure. Curcumin is a naturally occurring anti-oxidant that reduces oxidative stress and inhibits nuclear factor kappa B and nitric oxide formation. The aim of the present study is to assess curcumin's therapeutic potential in acute thioacetamide hepatotoxicity, a rat model of fulminant hepatic failure. Fulminant hepatic failure was induced by two intraperitoneal (i.p.) injections of 300 mg/kg thioacetamide (TAA) at 24-h intervals. The experimental groups received a low-dose (200 mg/kg per day, i.p.) or a high-dose (400 mg/kg per day) of curcumin, initiated 48 h prior to the first TAA injection. A fourth group was administered neither TAA nor curcumin and served as a control. The survival rate was higher in both curcumin-treated groups compared to the TAA only treated group. Biochemical parameters of liver injury, blood ammonia and hepatic necroinflammation were lower in the low-dose curcumin group compared to TAA controls, and were further reduced in the high-dose group (P < 0.05 and P < 0.01, respectively). Curcumin treatment also reduced the TAA-induced elevated hepatic levels of thiobarbituric acid-reactive substances (TBARS), and inhibited the nuclear binding of nuclear factor kappa B (NFkappaB) and inducible nitric oxide (iNOS) protein expression. Curcumin improved survival and minimized oxidative stress, hepatocellular injury and hepatic necroinflammation, NFkappaB binding and iNOS expression in a rat model of FHF. These findings support the role of ROS, NFkappaB and iNOS in mediating liver insult due to TAA, and that of curcumin as a hepato-protectant.


Developing a parent vocabulary checklist for young Indigenous children growing up multilingual in the Katherine region of Australia's Northern Territory.
Purpose: The aim of this study was to develop a checklist to assess vocabulary development in Indigenous Australian children, with a local focus on Indigenous Australian children growing up in the towns and communities of the Katherine Region in the Northern Territory of Australia. In this region, many families are multilingual and/or multidialectal and children's home languages include varieties of Aboriginal English, Kriol, traditional Aboriginal languages, and/or other languages.Method: Over four years, a checklist was iteratively developed from parent interviews, comparisons of potential items to the content and structure of the Communicative Development Inventories (CDI): Words & Gestures (Short Form), team discussions and pilot testing with 33 parents of infants aged 0-4 years.Result: The Early Language Inventory (ERLI) checklist offers new content compared with the CDI: Words & Gestures (short form) and the OZI (Australian English CDI, long form). Initial data from 33 parents suggests the checklist has desirable features: scores correlated positively with age and related to word combining, reaching ceiling around 3 years of age for many children. Infants whose parents had concerns tended to have lower scores.Conclusion: ERLI is a new local adaptation of the CDI (Words & Gestures) for assessing early communication among Indigenous infants growing up in the Katherine region of the Northern Territory, Australia.


Electropalatographic specification of Croatian fricatives /s/ and /z/.
Electropalatographic specification of alveolar fricatives in Croatian is aimed at providing speech therapists with normative data about the range of acceptable productions of /s/ and /z/ in adult speakers of Croatian. Four variables were analysed: place of articulation, total contact, groove width and hold phase duration. Intra- and inter-speaker variability for each variable was analysed. Lingual palatal cues for voicing difference were also quantified and discussed. Results show that Croatian /s/ and /z/ are alveolar and not dental as previously reported. The comparison between the voiced and the voiceless fricative shows that durational measures provide the best differentiation. The voiceless counterpart is significantly longer. The difference between voiced and voiceless is also found in the total contact, with /z/ having more contact in the anterior four rows of electrodes, while /s/ has more contact in the posterior four rows of electrodes. This difference is also reflected in the anterior and the posterior groove widths. Possibilities of using these results as normative data for the diagnosis and treatment of atypical articulation of /s/ and /z/ are discussed.


Tetra-kis(μ-penta-fluoro-benzoato-κO:O')bis-[(tetra-hydro-furan-κO)molybdenum(II)].
In the asymmetric unit of the title compound, [Mo(2)(C(7)F(5)O(2))(4)(C(4)H(8)O)(2)], two independent half-mol-ecules are present, which are completed by a crystallographically imposed center of inversion between the individual Mo atoms. In each mol-ecule, four penta-fluoro-benzoate anions bridge the quadruply bonded Mo(2) (4+) unit that is, in addition, axially coordinated by two O atoms of tetra-hydro-furan (THF) mol-ecules. In the two independent mol-ecules, the mean Mo-Mo bond length is 2.110 Å. Since the THF mol-ecules are equally disordered over two sets of sites, there are four different Mo-O distances in both half-mol-ecules with an overall mean of 2.542 Å. A zigzag chain is formed by π-π stacking inter-actions between penta-fluoro-phenyl rings, indicated by a centroid-centroid distance of 3.7054 (11) Å and a centroid-to-plane distance of 3.4169 (3) Å. The extension of the unit gives a three-dimensional network structure with the THF mol-ecules located in the voids.


microRNA-532 suppresses the PI3K/Akt signaling pathway to inhibit colorectal cancer progression by directly targeting IGF-1R.
Substantial evidence has shown that numerous microRNAs (miRNAs) are deregulated in colorectal cancer (CRC) and that their dysregulation is involved in CRC formation and progression. miRNA-based targeted therapy that inhibits or restores expression may be a promising therapeutic approach for anti-cancer therapy. Therefore, a comprehensive investigation of the mechanisms underlying CRC occurrence and development may help identify effective therapeutic targets for the therapy of CRC, thus improving the prognosis of patients with this disease. This study showed that miRNA-532 (miR-532) was significantly down-regulated in CRC tissues and cell lines. Low miR-532 expression strongly correlated with aggressive clinicopathological characteristics, including tumor size, lymphatic metastasis and TNM stage. Exogenous expression of miR-532 restricted cell proliferation, colony formation, migration and invasion; promoted cell apoptosis in vitro; and reduced tumor growth in vivo. Mechanistically, insulin-like growth factor 1 receptor (IGF-1R) was determined to be a novel direct target gene of miR-532 in CRC. In clinical CRC tissues, the expression of miR-532 was inversely correlated with that of IGF-1R, which was clearly overexpressed in CRC tissues. Furthermore, IGF-1R silencing simulated the tumor-suppressing roles of miR-532 in CRC. Moreover, recovered IGF-1R expression antagonized the inhibitory effects of miR-532 overexpression on CRC cells. Notably, miR-532 overexpression inhibited activation of the PI3K/Akt signaling pathway in CRC, both in vitro and in vivo. These results indicate that miR-532 plays an important role in CRC development, partly by directly targeting IGF-1R and regulating the PI3K/Akt signaling pathway. Thus, the miR-532/IGF-1R axis has clinical significance in the therapy of patients with CRC.


Threats to Site Occupation of Carnivores: A Spatiotemporal Encroachment of Non-native Species on the Native Carnivore Community in A Human-dominated Protected Area.
Interspecific interactions of commensal non-native species such as domestic dogs and livestock with native wildlife are evident issues in protected areas (PAs). We studied spatiotemporal interactions by combining camera trap photographic sampling over three years. We used a generic multiseason occupancy and co-occurrence analysis and kernel density estimates of temporal activity. We accumulated a total of 1,305 and 1,557 independent photo-captures respectively for non-native and carnivore species during 26,216 trap nights. We found that non-native and carnivore species did not show substantial changes in occupancy rate over time. Yet both kinds of species were frequently detected. Carnivores had lower values of occupancy equilibrium than non-native species in seasons one and two. Domestic dogs directly occurred with native carnivores (except with leopards in season one), while the human and livestock presence displayed direct (Species Interaction Factors > 1) and indirect (Species Interaction Factors close to 1) co-occurrence, respectively, with the leopard and two mesocarnivores. The leopard cat was the least spatially influenced carnivore by the non-native species interactions. Furthermore, the leopard had higher temporal overlap (high Δ4) with all non-native species than the leopard cat and red fox (low Δ4). Our study exposes the negative impact of free-ranging non-native species across this protected area on native carnivore occupancy. An evaluation of the interconnections among non-native and carnivore species across diverse PA management regimes is crucial to develop robust landscape-scale conservation strategies.


Acute post-streptococcal glomerulonephritis in Central Australia.
To determine the incidence, clinical presentation and progress of acute post-streptococcal glomerulonephritis in Central Australia. Retrospective observational analysis. Paediatric inpatient admission at Alice Springs Hospital. Patients admitted to Alice Springs Hospital under 14 years of age meeting diagnostic criteria for acute post-streptococcal glomerulonephritis between January 2010 and December 2014. Incidence of acute post-streptococcal glomerulonephritis in central Australia. Biochemical abnormalities associated with acute post-streptococcal glomerulonephritis. Co-occuring conditions. Sixty-nine out of the 174 cases reviewed were identified as having either acute post-streptococcal glomerulonephritis (63) or probable acute post-streptococcal glomerulonephritis (6). We calculate the incidence of APSGN admission to be higher than previously reported and the highest reported incidence globally in children. Clinical evidence of skin infection was frequently documented. Co-occurring infections were common, including scabies/head lice, urinary tract infection and pneumonia. Fifty-three patients showed biochemical evidence of acute kidney injury. Aboriginal children in Central Australia have the highest incidence of acute post-streptococcal glomerulonephritis reported worldwide. Urgent action is required to improve housing and reduce overcrowding in Central Australian towns and communities to reduce the burden of disease of skin infection and Group A Streptococcus related diseases. Without effective change in living conditions, it is unlikely that there will be a significant change in the morbidity related to these conditions.


Crohn's disease of the appendix.
Crohn's disease limited to the appendix is uncommon. The disease may mimic acute appendicitis with fever, leukocytosis, right lower quadrant pain, and occasionally a palpable mass. When Crohn's disease affects the appendix, it typically has a longer clinical period in which the patient has symptoms than do most cases of acute appendicitis. The most common preoperative diagnoses are acute appendicitis and appendiceal abscess. A review of the literature is presented along with our experience in three additional cases of Crohn's disease limited to the appendix. We suggest that Crohn's disease be included in the preoperative differential diagnosis and that extensive intraoperative examination of the gastrointestinal tract be made in any case of suspected appendicitis that has had a protracted preoperative course.


Adipose-Derived Mesenchymal Stromal Cells Treated with Interleukin 1 Beta Produced Chondro-Protective Vesicles Able to Fast Penetrate in Cartilage.
The study of the miRNA cargo embedded in extracellular vesicles (EVs) released from adipose-derived mesenchymal stromal cells (ASC) preconditioned with IL-1β, an inflammatory stimulus driving osteoarthritis (OA), along with EVs-cartilage dynamic interaction represent poorly explored fields and are the purpose of the present research. ASCs were isolated from subcutaneous adipose tissue and EVs collected by ultracentrifugation. Shuttled miRNAs were scored by high-throughput screening and analyzed through bioinformatics approach that predicted the potentially modulated OA-related pathways. Fluorescently labeled EVs incorporation into OA cartilage explants was followed in vitro by time-lapse coherent anti-Stokes Raman scattering; second harmonic generation and two-photon excited fluorescence. After IL-1β preconditioning, 7 miRNA were up-regulated, 4 down-regulated, 37 activated and 17 silenced. Bioinformatics allowed to identify miRNAs and target genes mainly involved in Wnt, Notch, TGFβ and Indian hedgehog (IHH) pathways, cartilage homeostasis, immune/inflammatory responses, cell senescence and autophagy. As well, ASC-EVs steadily diffuse in cartilage cells and matrix, reaching a plateau 16 h after administration. Overall, ASCs preconditioned with IL-1β allows secretion of EVs embedded with a chondro-protective miRNA cargo, able to fast penetrate in collagen-rich areas of cartilage with tissue saturation in a day. Further functional studies exploring the EVs dose-effects are needed to achieve clinical relevance.


Hesitant 2-tuple fuzzy linguistic multi-criteria decision-making method based on correlation measures.
Correlation is considered the most important factor in analyzing the data in statistics. It is used to measure the movement of two different variables linearly. The concept of correlation is well-known and used in different fields to measure the association between two variables. The hesitant 2-tuple fuzzy linguistic set (H2FLS) comes out to be valuable in addressing people's reluctant subjective data. The purpose of this paper is to analyze new correlation measures between H2FLSs and apply them in the decision-making process. First and foremost, the ideas of mean and variance of hesitant 2-tuple fuzzy linguistic elements (H2FLEs) are introduced. Then, a new correlation coefficient between H2FLSs is established. In addition, considering that different H2FLEs may have different criteria weights, the weighted correlation coefficient and ordered weighted correlation coefficient are further investigated. A practical example concerning the detailed procedure of solving problems is exemplified to feature the reasonableness and attainability of the proposed technique in situations where the criteria weights are either known or unknown. When the weight vector is unknown, the best-worst method (BWM) is used to acquire the criteria weights in the context of a hesitant 2-tuple fuzzy linguistic environment. Furthermore, a comparative study is undertaken with current techniques to provide a vision into the design decision-making process. Finally, it is verified that the proposed correlation coefficient between H2FLSs is more satisfactory than the extant ones, and the correlation coefficient with the weights of criteria being either known or unknown is applicable.


[Forensic expertise of thoracic aorta, heart and pericardial injuries in car-occupant fatalities].
Forensic expertise has not specified with certainty any specific injury among fatally injured frontal car-occupants in frontal car collisions. To establish if blunt injuries of thoracic aorta, heart, and pericardium could be used as predictors where the fatally injured car-occupant was at the moment of car-collision. A retrospective autopsy study was performed. The subjects were fatally injured car-drivers, front-seat and rear-seat passengers in head-on car collisions. In each of them we analyzed the injuries of thoracic aorta, heart and pericardium. 492 subjects were analysed (378 male and 104 female): 239 car-drivers, 194 front-seat and 49 rear-seat passengers. The isthmus of aorta was the commonest site of simple blunt rupture among car-drivers and front-seat passengers. Among more than half of the observed subject, there was aortic blunt rupture as concomitant injury with heart and pericardium injuries. Heart and pericardium ruptures were most common among fatally injured car-drivers. Most frequently injured part of the heart was the right atrium. Injuries of thoracic aorta, heart and pericardium indicated a higher probability that the fatally injured would be the car-driver (lambda = 0.818; df = 2; p = 0.011, lambda = 0.906; df = 2; p = 0.000, and lambda = 0.951; df = 2; p =0.000); this was also pointed out by the rupture of the right atrium and multiple ruptures of the thoracic aorta (lambda = 0.966; df = 2; p = 0.000 and lambda = 0.918; df = 2; p = 0.009). The concomitant injuries of the thoracic aorta with thoracic spine, sternum and heart pointed out that the injured person was the car-driver (lambda = 0.971; df = 4; p = 0.007, lambda = 0.974; df = 4; p = 0.013 and lambda = 0.958; df = 4; p = 0.000), as well as the concomitant injuries of heart and sternal fracture (lambda = 0.960; df = 4; p = 0.001). The probability of about 80% that the fatally injured person in head-on collisions was a car-driver was pointed out by concomitant blunt thoracic aorta rupture with fractured sternum and ribs (Wald. coeff. = 8.611; df = 1; p = 0.003, and Wald. coeff. = 3.875; df = 1; p = 0.049). The basic mechanism of the injury of thoracic organs is deceleration, as well as anteroposterior compression with caudorostral hyperextension. That is why thoracic organ injuries are mostly concomitant. Fatally injured car-drivers suffered more often of these injuries than other car-occupants. The probability that the fatally injured was the car-driver rises with the number of concomitant injuries of thoracic aorta, heart and pericardium, as well as with the fractured thoracic-cage bones.


Studies on effects of calcineurin inhibitor withdrawal on arterial distensibility and endothelial function in renal transplant recipients.
Whether withdrawal of calcineurin inhibitors has a beneficial effect on disturbed endothelial function and large artery distensibility in renal transplant recipients is not clear. We studied the effects of cyclosporine A (CsA) withdrawal on arterial compliance and endothelium-dependent flow-mediated vasodilatation (FMD) in a prospective, randomized trial; 24 renal transplant recipients receiving mycophenolate mofetil were randomized to withdrawal (n=12) or continuation of CsA (n=12). At baseline and after 6 months, carotid and brachial artery distensibility coefficients and brachial FMD were measured. Brachial distensibility coefficients increased in both groups (withdrawal: 11.1+/-1-14.9+/-2 10(-3)/kPa, continuation: 10.7+/-1-15.2+/-3 10(-3)/kPa, P<0.05, respectively). However, there was no significant effect of treatment on carotid artery distensibility coefficients, FMD, or graft function. Withdrawal of CsA failed to improve carotid artery distensibility or brachial FMD in patients after renal transplantation. Our data indicate that CsA treatment does not contribute significantly to endothelial dysfunction observed in renal transplant recipients.


Analysis of DNA looped domains organization during Triturus cristatus spermatogenesis.
Chromatin from eukaryotes is organized in DNA loops with sequential attachments to a nucleoskeleton named nuclear matrix. This organization plays major roles in replication, transcription, recombination, DNA repair, chromosome condensation and segregation. During spermatogenesis, chromatin undergoes several dynamic transitions, which are often associated with important changes not only in its physical conformation but even in its compositions and structure. To understand the periodical change in the functional organization of chromatin during spermatogenesis, the higher order organization of chromatin in different testicular cell types (pachytene spermatocytes, round spermatids) and the epididymal sperm of Triturus cristatus have been investigated. The expansion and the contraction of nucleoid DNA were measured with a fluorescence microscope following exposure of nucleoids to increasing concentrations of ethidium bromide (EtBr) (2.5-200 μg/ml) as an intercalating dye to induce DNA-positive supercoils. Nucleoids from all studied cell types exhibited a biphasic change (condensed-relaxed-condensed) in size as a consequence of exposure to increasing concentrations of EtBr, indicating that they contained negatively supercoiled DNA. At higher EtBr concentrations, maximum positive supercoiling occurred in pachytene DNA loops. Our data suggest that pachytene DNA is the most open chromatin conformation in terms of EtBr intercalation.


The use of zeolites to generate PET phantoms for the validation of quantification strategies in oncology.
In recent years, segmentation algorithms and activity quantification methods have been proposed for oncological (18)F-fluorodeoxyglucose (FDG) PET. A full assessment of these algorithms, necessary for a clinical transfer, requires a validation on data sets provided with a reliable ground truth as to the imaged activity distribution, which must be as realistic as possible. The aim of this work is to propose a strategy to simulate lesions of uniform uptake and irregular shape in an anthropomorphic phantom, with the possibility to easily obtain a ground truth as to lesion activity and borders. Lesions were simulated with samples of clinoptilolite, a family of natural zeolites of irregular shape, able to absorb aqueous solutions of (18)F-FDG, available in a wide size range, and nontoxic. Zeolites were soaked in solutions of (18)F-FDG for increasing times up to 120 min and their absorptive properties were characterized as function of soaking duration, solution concentration, and zeolite dry weight. Saturated zeolites were wrapped in Parafilm, positioned inside an Alderson thorax-abdomen phantom and imaged with a PET-CT scanner. The ground truth for the activity distribution of each zeolite was obtained by segmenting high-resolution finely aligned CT images, on the basis of independently obtained volume measurements. The fine alignment between CT and PET was validated by comparing the CT-derived ground truth to a set of zeolites' PET threshold segmentations in terms of Dice index and volume error. The soaking time necessary to achieve saturation increases with zeolite dry weight, with a maximum of about 90 min for the largest sample. At saturation, a linear dependence of the uptake normalized to the solution concentration on zeolite dry weight (R(2) = 0.988), as well as a uniform distribution of the activity over the entire zeolite volume from PET imaging were demonstrated. These findings indicate that the (18)F-FDG solution is able to saturate the zeolite pores and that the concentration does not influence the distribution uniformity of both solution and solute, at least at the trace concentrations used for zeolite activation. An additional proof of uniformity of zeolite saturation was obtained observing a correspondence between uptake and adsorbed volume of solution, corresponding to about 27.8% of zeolite volume. As to the ground truth for zeolites positioned inside the phantom, the segmentation of finely aligned CT images provided reliable borders, as demonstrated by a mean absolute volume error of 2.8% with respect to the PET threshold segmentation corresponding to the maximum Dice. The proposed methodology allowed obtaining an experimental phantom data set that can be used as a feasible tool to test and validate quantification and segmentation algorithms for PET in oncology. The phantom is currently under consideration for being included in a benchmark designed by AAPM TG211, which will be available to the community to evaluate PET automatic segmentation methods.


Fast atom bombardment mass spectrometry of glycosphingolipids. Glycosphingolipids containing neutral sugars.
Natural and synthetic glycosphingolipids containing neutral sugars have been analyzed by positive and negative ion fast atom bombardment mass spectrometry. Basic structural characterization including saccharide size and sequence and ceramide composition is possible on the basis of the fragment ions observed. The degree of fragmentation could be increased by using higher sample concentrations and lower fast atom beam energies. Commercially available synthetic compounds that had been presumed to be pure were shown to contain homologous fatty acids. Mixtures of glycosphingolipids such as those obtained from Gaucher's spleen and from human erythrocytes can be characterized and quantitated.


Foot Pain and Morphofunctional Foot Disorders in Patients with Rheumatoid Arthritis: A Multicenter Cross-Sectional Study.
Foot problems are highly prevalent in people with rheumatoid arthritis. This study aims to explore the foot morphology, pain and function in rheumatoid arthritis patients and the relation with the time of disease debut. A cross-sectional study was designed. Footprint, the Foot Posture Index, the hallux valgus prevalence, foot pain and function in 66 rheumatoid arthritis patients and the association with time since diagnosis, were recorded. The Foot Function Index, the Manchester Foot Pain and Disability Index, the Visual Analogic Scale, and the Manchester Scale for hallux valgus were administered and analyzed in two groups, with less and more than 10 years of diagnosis of the disease. A high prevalence of pronated (right 36.8% and left 38.6%) and highly pronated (right 15.8% and left 15.8%) feet was observed, as well as an elevated percentage of low arched footprints (right 68.4 and left 66.7%) and hallux valgus (right 59.6% and left 54.4%). Hallux valgus prevalence, toe deformities and Foot Function Index (Functional limitation) factors were significantly associated with the time since RA diagnosed adjusted for the other factors. The adjusted odds ratio of Hallux valgus prevalence was 4.9 (1.2-19.7). In addition, the foot function was diminished, and foot pain was present in most participants. In conclusion, rheumatoid arthritis patients' feet showed altered morphology and function, and with longer rheumatoid arthritis history, metatarsophalangical stability and foot function, but not pain and global foot posture, were likely to deteriorate.


The Influence of Single Nucleotide Polymorphism Microarray-Based Molecular Karyotype on Preimplantation Embryonic Development Potential.
In order to investigate the influence of the molecular karyotype based on single nucleotide polymorphism (SNP) microarray on embryonic development potential in preimplantation genetic diagnosis (PGD), we retrospectively analyzed the clinical data generated by PGD using embryos retrieved from parents with chromosome rearrangements in our center. In total, 929 embryos from 119 couples had exact diagnosis and development status. The blastocyst formation rate of balanced molecular karyotype embryos was 56.6% (276/488), which was significantly higher than that of genetic imbalanced embryos 24.5% (108/441) (P<0.001). No significant difference was detected in blastocyst formation rates in the groups of maternal age <30, 30-35 and >35 respectively. Blastocyst formation rates of male and female embryos were 44.5% (183/411) and 38.8% (201/518) respectively, with no significant difference between them (P>0.05). The rates of balanced molecular karyotype embryos vary from groups of embryos with different cell numbers at 68 hours after insemination. The blastocyst formation rate of embryos with 6-8 cells (48.1%) was significantly higher than that of embryos with <6 cells (23.9%) and with >8 cells (42.9%) (P<0.05). As for the unbalanced embryos, there was no significant difference of the distribution of abnormal molecular karyotypes in the subgroup of the arrest, morula and blastocyst. Thus, we conclude that embryos with balanced molecular karyotype have significant higher development potential than those with imbalanced molecular karyotype whilst maternal age, embryo gender and types of abnormal molecular karyotype have no significant influence on blastocyst formation. Compared with embryos with <6 and >8 cells, embryos with 6-8 blastomeres have higher rate of balanced molecular karyotype and blastocyst formation.


Macrolane for breast enhancement: 12-month follow-up.
Stabilized hyaluronic acid–based gel of nonanimal origin (NASHA-based gel) is well established for use in aesthetic facial procedures. A new formulation (Macrolane VRF30, Q-Med AB, Uppsala, Sweden) may be suitable for patients seeking breast enhancement. The aim of this study was to develop a reproducible technique for injecting NASHA-based gel posterior to the mammary gland (subglandular injection) and to assess treatment safety and efficacy. The feasibility of dual-plane submuscular injection was also explored. Nonpregnant, nonbreastfeeding women with small breasts were recruited for this open-label, noncomparative study. Patients were treated in groups of four to enable step-wise revision of the injection technique. Safety and efficacy assessments (12-month follow-up) included adverse event reporting and the Global Aesthetic Improvement Scale, respectively. Twenty-four women (mean age, 37 years) were recruited, 20 of whom underwent subglandular injection. A reproducible injection technique was successfully developed that could be performed under local anesthesia. High subject improvement rates for breast appearance (38 of 46 breasts; 83 percent) were observed for at least 6 months after treatment. At 12 months, 69 percent of breasts were still considered improved. Similar trends were observed with patient satisfaction levels. NASHA-based gel was generally well tolerated, with no inflammatory reactions or serious adverse events. Capsular contracture was the most commonly reported adverse event. NASHA-based gel is a new option for patients who desire aesthetic improvement of the breast but who do not want to undergo surgery. Further studies to confirm these findings in larger numbers of patients are warranted.


[Correlation between colonoscopy and histopathology of the colon in diverticular disease and the irritable colon syndrome].
In this study 29 patients were carriers of diverticular disease of the colons (DDC) and 29 patients with irritable bowel syndrome (IBS). The patients were diagnosed by means of a directed anamnesis standardized by the radiologic study of the colons. The methodology included, radiologic study of the colons, endoscopic examination of the colon (colonoscopy with biopsy) and anatomic pathologic examination of the fragments obtained in the endoscopy. It was tried, by means of colonoscopy with biopsy and anatomic pathological examination, to demonstrate, classify and relate, in agreement with pre-established criterion, the degree of intensity of the inflammatory process in the colic mucosa. According to the results we may conclude that: 1) colonoscopy in the studied inflammatory diseases is important for diagnosis, evaluation of the inflammatory process, identification of associated illness and material obtention for the anatomic pathological examination; 2) there is always a chronic inflammatory process, in variable degrees, of the colic mucosa in DDC and in IBS; 3) colonoscopy with biopsy and the anatomic pathological examination are adequate to diagnose with precision the degree of intensity of the chronic inflammatory process of the colic mucosa and the presence of associated disease in DDC and in IBS.


Revisiting a classic approach to the Aspidosperma alkaloids: an intramolecular Schmidt reaction mediated synthesis of (+)-aspidospermidine.
[reaction: see text] A total synthesis of (+)-aspidospermidine (1) is described. The key reactions used in the synthesis of this pentacyclic Aspidosperma alkaloid were a deracemizing imine alkylation/Robinson annulation sequence, a selective "redox ketalization", and an intramolecular Schmidt reaction. A Fischer indolization step carried out on a tricyclic ketone mirrored the sequence reported by Stork and Dolfini in their classic aspidospermine synthesis.


Structural and Magnetic Studies of ABO4-Type Ruthenium and Osmium Oxides.
Oxides of the form ABO4 with A = K, Rb, Cs and B = Ru and Os have been synthesized and characterized by diffraction and magnetic techniques. For A = K the oxides adopted the tetragonal (I41/a) scheelite structure. RbOsO4, which crystallizes as a scheelite at room temperature, underwent a continuous phase transition to I41/amd near 550 K. RbRuO4 and CsOsO4 were found to crystallize in the orthorhombic (Pnma) pseudoscheelite structure, and both displayed discontinuous phase transitions to I41/a at high temperatures. CsOsO4 was determined to undergo a phase transition to a P21/c structure below 140 K. CsRuO4 crystallizes with a baryte-type structure at room temperature. Upon heating CsRuO4 a first order phase transition to the scheelite structure in I41/a is observed at 400 K. A continuous phase transition is observed to P212121 below 140 K. DC magnetic susceptibility data is consistent with long-range antiferromagnetic ordering at low temperatures for all compounds except for CsOsO4, which is paramagnetic to 2 K. The effective magnetic moments are in agreement with the spin only values for an S = 1/2 quantum magnet. Effective magnetic moments calculated for Os compounds were lower than their Ru counterparts, reflective of an enhanced spin orbit coupling effect. A magnetic structure is proposed for RbRuO4 consisting of predominately antiferromagnetic (AFM) ordering along the 001 direction, with canting of spins in the 100 plane. A small ordered magnetic moment of 0.77 μB was determined.


3D technology to measure dental arches and create a template for lingual brackets technique.
This study aims at identifying anatomical dimensions of dental arches, based on landmarks currently used in the lingual orthodontic technique, and create an archwire form template to be used in orthodontic clinics. Maxillary and mandibular dental casts of 140 Caucasian individuals with natural and normal occlusion were digitized (3D), and the images were analyzed with Delcam Power ShapeTM 2010 software. The dental arch shapes and sizes were obtained from 14 landmarks selected on the lingual surface of the teeth. Points and segments defined by the software were used to create an archwire form template. Various dental arch patterns were found for both maxilla and mandible. The smallest sizes were found in females, and the largest were found in male subjects. Six categories were defined for each gender, three for the maxilla and three for the mandible (Small, Medium and Large). A template was created with eighteen anatomic lingual archwire designs, nine for the maxilla and nine for the mandible, for both genders. Landmarks evaluated in this study showed dental arch differences between genders. This information enables making orthodontic lingual archwires that are more compatible with the anatomical forms and sizes of the maxilla and mandible. The findings also allowed the creation of a template for an anatomic lingual metallic archwire form to be used in the lingual technique.


Modulating serine palmitoyl transferase (SPT) expression and activity unveils a crucial role in lipid-induced insulin resistance in rat skeletal muscle cells.
Saturated fatty acids, such as palmitate, promote accumulation of ceramide, which impairs activation and signalling of PKB (protein kinase B; also known as Akt) to important end points such as glucose transport. SPT (serine palmitoyl transferase) is a key enzyme regulating ceramide synthesis from palmitate and represents a potential molecular target in curbing lipid-induced insulin resistance. In the present study we explore the effects of palmitate upon insulin action in L6 muscle cells in which SPT expression/activity has been decreased by shRNA (small-hairpin RNA) or sustained incubation with myriocin, an SPT inhibitor. Incubation of L6 myotubes with palmitate (for 16 h) increases intramyocellular ceramide and reduces insulin-stimulated PKB activation and glucose uptake. PKB inhibition was not associated with impaired IRS (insulin receptor substrate) signalling and was ameliorated by short-term treatment with myriocin. Silencing SPT expression (approximately 90%) by shRNA or chronic cell incubation with myriocin (for 7 days) markedly suppressed SPT activity and palmitate-driven ceramide synthesis; however, challenging these muscle cells with palmitate still inhibited the hormonal activation of PKB. This inhibition was associated with reduced IRS1/p85-PI3K (phosphoinositide 3-kinase) coupling that arises from diverting palmitate towards greater DAG (diacylglycerol) synthesis, which elevates IRS1 serine phosphorylation via activation of DAG-sensitive PKCs (protein kinase Cs). Treatment of SPT-shRNA cells or those treated chronically with myriocin with PKC inhibitors antagonized palmitate-induced loss in insulin signalling. The findings of the present study indicate that SPT plays a crucial role in desensitizing muscle cells to insulin in response to incubation with palmitate. While short-term inhibition of SPT ameliorates palmitate/ceramide-induced insulin resistance, sustained loss/reduction in SPT expression/activity promotes greater partitioning of palmitate towards DAG synthesis, which impacts negatively upon IRS1-directed insulin signalling.


One-pot exfoliation of graphite and synthesis of nanographene/dimesitylporphyrin hybrids.
A simple one-pot process to exfoliate graphite and synthesize nanographene-dimesitylporphyrin hybrids has been developed. Despite the bulky mesityl groups, which are expected to hinder the efficient π-π stacking between the porphyrin core and graphene, the liquid-phase exfoliation of graphite is significantly favored by the presence of the porphyrins. Metallation of the porphyrin further enhances this effect. The resulting graphene/porphyrin hybrids were characterized by spectroscopy (UV-visible, fluorescence, and Raman) and microscopy (STEM, scanning transmission electron microscopy).


[Role of carbonic acid in regulation of metabolism and physiological functions in fish].
Experiments with carp showed the metabolic interrelations between exogenic carbonic acid and the fish organism. An increase in the concentration of carbonic acid solved in water causes a rise in its concentration in plasma and a simultaneous compensatory accumulation of HCO3- in blood. When there is a threat of the acidemia development there occurs a rise in the content of bicarbonates in plasma due to the reaction of the carbonic acid hydrogen ions exchange with the blood buffer systems (protein and phosphate ones) accompanied by the compensatory intensification of their reabsorption in the renal tubules and by a total decrease in the intensity of excretion from the kidneys. The dependence of the level of carbonic acid solved in water on its concentration in blood determines the metabolic character of interrelations between the gas regime of water bodies and indexes of their growth and development.


The correlation between HLA-DRB1 and HLA-DQB1 gene polymorphisms and cytokines in HPV16 infected women with advanced cervical cancer.
To analyze the distribution of HLA-DRB1 and HLA-DQB1 alleles and its correlation with IFN-γ, IL-2, IL-6, IL-10 in HPV16 infected women with advanced cervical carcinoma. We collected 137 blood samples of cervical carcinoma patients diagnosed by pathology as cervical cancer in stage IIb-IVb before the treatment, and we gathered 175 blood samples of healthy women living in the local. We determined the genetic subtypes of HLA-DRB1 and HLA-DQB1, and we measured the concentration of IFN-γ, IL-2, IL-6 and IL-10. We compared the difference of cytokines in patients with different clinical stages and the healthy in the control group. According to genetic subtypes of HLA-DRB1 and HLA-DQB1, we also compared the concentration of cytokine (CK) in different genetic subtypes. Eight HLA-DRB1 alleles and four HLA-DQB1 alleles were found. There were not significant differences between each allele in the concentration of IFN-γ, IL-2, IL-6, and IL-10. HLA-DRB1*07, HLA-DQB1*02 and HLA-DQB1*03 were the differentially expressed gene in HPV16 infected patients with advanced cervical cancer. There may be correlations between the occurrence, development of cervical cancer and IFN-γ, IL-2, IL-6, IL-10.


National decision-making on adopting new vaccines: a systematic review.
In recent years numerous new vaccines have been developed, offering potential reductions in the morbidity and mortality caused by a range of diseases. This has led to increased interest in decision-making about the adoption of new vaccines into national immunization programmes. This paper aims to systematically review the literature on national decision-making around the adoption of new vaccines. A thematic framework was developed inductively through analysis of the vaccine adoption decision-making frameworks included in the review. This thematic framework was then applied to the remaining studies included in the review. In total, 85 articles were included in the review: 39 articles describing examples of vaccine adoption decision-making, 26 presenting vaccine decision-making frameworks, 21 empirical articles of decision-making relating to vaccine adoption and 19 theoretical essays. An analysis of vaccine adoption decision-making frameworks identified nine broad categories of criteria: the importance of the health problem; vaccine characteristics; immunization programme considerations; acceptability; accessibility, equity and ethics; financial/economic issues; impact; alternative interventions and the decision-making process. The quality of the empirical studies was varied. Although some of the issues included in the frameworks were similar to those considered in the studies, there were also some notable differences. On the whole, the frameworks were more comprehensive than the studies, including a greater range of criteria. The existing literature provides a good foundation for further research into vaccine adoption decision-making. The current review, in pulling together what is already known and by identifying strengths, weaknesses and gaps in the existing evidence base, aims to encourage a more focused and rigorous approach to the topic in future. This could help to identify the most appropriate ways to develop vaccine adoption decision-making, so as to improve decisions and, ultimately, health outcomes.


Reproducibility of linear tumor measurements using PACS: comparison of caliper method with edge-tracing method.
The aim of this study was to evaluate inter- and intra-observer reproducibility when making electronic caliper linear tumor measurements on picture archiving and communications systems (PACS) and compare them with linear measurements obtained from circumferential tracing of tumor perimeter. Three radiologists measured 64 masses from 30 patients on body CT scans in two separate settings. Long axis and perpendicular short axis were measured using electronic calipers. The edge of each tumor was traced electronically and the long and short axes were calculated by computer software. The reproducibility of a measurement was evaluated by computing and comparing the absolute value of the mean difference between initial and subsequent measurements. The mean differences +/-95% confidence interval (CI) between two measurements of the long by short axis were 3.8+/-2.6x3.1+/-1.8 mm when the caliper method was used and 3.5+/-2.0x3.2+/-1.5 mm when the tumor tracing method was used. There was no statistically significant difference in individual intra-observer reproducibility of tumor axes measurements. Neither long- nor short-axis single-dimension measurements resulted in significantly greater or lesser intra-observer reproducibility. When comparing caliper and tracing measurements, the overall mean difference (3.42+/-1.8 vs 3.38+/-1.4 mm) was not statistically significant. There was close correlation between the individual measurements made by each observer whether these were made by electronic calipers and when these were calculated from electronic tracings (Pearson correlations between 0.79 and 0.949). Current PACS systems allow reproducible linear, long or short axis, tumor measurements. There is no significant difference in reproducibility of measurements whether these are made directly with electronic calipers or calculated from tumor edge tracings.


Childhood idiopathic hypereosinophilic syndrome: report of a case.
We described a 15-year-old girl who presented with persistent fever, bilateral flank pain, and worsening dyspnea. The peripheral blood cell count showed remarkable eosinophilia at the time of admission. Severe pleural effusion with eosinophilic Infiltrations as well as pericardial effusion were noted thereafter. Bone marrow examination disclosed markedly increased eosinophils. Bilateral ectasia of the renal pelvis was found in an ultrasonographic study of the kidneys. Spiking fever and progressive shortness of breath persisted despite treatment with empiric antibiotics for infection. Based on the clinical course and histological findings, a tentative diagnosis of idiopathic HES was made. After treatment with oral prednisolone daily (1 mg/kg/day) for one week, there was a rapid improvement in her clinical condition. She was discharged a few days later and the steroids were withdrawn gradually when she was asymptomatic. The absolute eosinophil count (AEC) was monitored during follow-up. At 3 weeks, the AEC had fallen from 8,060/mm3 to 4,792/mm3 and it further fell to 1,591/mm3 at 5 months, and to 855/mm3 at 8 months during follow-up. There is no evidence of any other organ involvement until now. The clinical manifestations, diagnosis and management of idiopathic HES in children are also reviewed.


Brain Changes Linked to Cognitive Symptomatology in Homeless Youth.
Youth impacted by homelessness experience diminished cognition due to a variety of reasons including mental health symptoms, alcohol and substance use, and adverse childhood experiences. However, the status of specific brain regions which could impact important cognitive functions in homeless youth remains unclear. In this pilot comparative and correlational study, a series of demographic, psychological, cognitive assessments, and brain magnetic resonance imaging were performed in 10 male youth experiencing homelessness and 9 age-matched healthy male controls (age range: 18-25 years). Participants experiencing homelessness had significantly decreased regional brain gray matter tissue in comparison to the controls. Moreover, there were strong inverse correlations between the brain regions classically associated with executive decision-making (prefrontal cortices), depression (insular lobes), and conflict resolution (anterior cingulate), and the level of the symptoms detected by their questionnaires.


Building surgical capacity in developing countries: lessons from Haiti and Honduras.
The unmet burden of surgical disease in developing countries is large and growing. We successfully initiated two surgical field hospitals in austere environments. Similar problems were encountered in the areas of facility development, operations, and social considerations. A literature review was performed to contextualize our experience and compare it with that of others.


Automated external defibrillators: selection and use.
Although sudden cardiac death is rare in sports, having an automated external defibrillator (AED) available facilitates early defibrillation and increases the chance of survival for an athlete in cardiac arrest. The decision to buy an AED involves many factors, and physicians and other personnel who work with athletes should be familiar with the use of such devices given their increasing availability and the widespread acceptance of the principle of early defibrillation.


Nerve endoneurial microstructure facilitates uniform distribution of regenerative fibers: a post hoc comparison of midgraft nerve fiber densities.
Despite their inferiority to nerve autograft, clinical alternatives are commonly used for reconstruction of peripheral nerve injuries because of their convenient off-the-shelf availability. Previously, our group compared isografts with NeuraGen(®) (Integra, Plainsboro, NJ) nerve guides, which are a commercially available type I collagen conduit and processed rat allografts comparable to Avance(®) (AxoGen, Alachua, FL) human decellularized allograft product. From this study, qualitative observations were made of distinct differences in the pattern of regenerating fibers within conduits, acellular allografts, and isografts. In the current post hoc analysis, these observations were quantified. Using nerve density, we statistically compared the differential pattern of regenerating axon fibers within grafts and conduit. The conduits exhibited a consistent decrease in midgraft density when compared with the isograft and acellularized allografts at two gap lengths (14 mm and 28 mm) and time points (12 and 22 weeks). The decrease in density was accompanied by clustered distribution of nerve fibers in conduits, which contrasted the evenly distributed regeneration seen in processed allografts and isografts. We hypothesize that the lack of endoneurial microstructure of conduits results in the clustering regenerating fibers, and that the presence of microstructure in the acellularized allograft and isografts facilitates even distribution of regenerating fibers.


Psychosocial Factors in End-Stage Kidney Disease Patients at a Tertiary Hospital in Australia.
Aim. This study seeks to review the psychosocial factors affecting patients with end-stage kidney disease (ESKD) from a tertiary hospital in Australia. Methods. We audited patients with ESKD, referred to social work services from January 2012 to December 2014. All patients underwent psychosocial assessments by one, full-time renal social worker. Patient demographics, cumulative social issues, and subsequent interventions were recorded directly into a database. Results. Of the 244 patients referred, the majority were >60 years (58.6%), male (60.7%), born in Australia (62.3%), on haemodialysis (51.6%), and reliant on government financial assistance (88%). Adjustment issues (41%), financial concerns (38.5%), domestic assistance (35.2%), and treatment nonadherence (21.3%) were the predominant reasons for social work consultation. Younger age, referral prior to start of dialysis, and unemployment were significant independent predictors of increased risk of adjustment issues (p = 0.004, <0.001, and =0.018, resp.). Independent risk factors for treatment nonadherence included age and financial and employment status (p = 0.041, 0.052, and 0.008, resp.). Conclusion. Psychosocial and demographic factors were associated with treatment nonadherence and adjustment difficulties. Additional social work support and counselling, in addition to financial assistance from government and nongovernment agencies, may help to improve adjustment to the diagnosis and treatment plans as patients approach ESKD.


[Atypical computed tomographic features of meningioma: a case report].
Diagnosis of intracranial meningiomas with computed tomography (CT) is usually easy. However, some authors have reported cases preoperatively misdiagnosed because of atypical computed tomographic features. We report a case of non-cystic meningioma presenting a ring enhanced mass lesion, with CT scan. A 48-year-old male was admitted to our hospital on January 5, 1987, because of progressive monoparesis of his left lower limb. This had continued for 1 1/2 years. Neurological examination revealed monoparesis, hypesthesia and decreased deep sensation of the left lower limb. X-ray films of the skull appeared normal. A CT scan demonstrated a ring-like high density mass attached to the falx in the right frontoparietal area with perifocal low density. The ring-like high density was irregularly increased with contrast enhancement. Right carotid angiograms showed a doughnut like tumor stain without meningeal blood supply. Brain scintigrams revealed a dense round hot lesion in the frontoparietal area at 5 minutes, and the hot lesion was still visualized after 90 minutes. We diagnosed a cystic parasagittal meningioma. A right frontoparietal craniotomy was performed, and total removal of the parasagittal tumor was made. The center of the tumor was very soft but it could not be said that it was not cystic. Histologically the tumor was a meningotheliomatous meningioma. The center of the tumor, which was very soft, was necrotic with arteriolar hyalinization. The meningioma cells survived around the patent vessels. These intact meningioma cells were scattered like islands in extensive necrosis. This is so called "oasis phenomenon" indicating that the necrosis of the tumor was caused by intratumoral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)


CTNNA3 (α-catenin) gene variants are associated with diisocyanate asthma: a replication study in a Caucasian worker population.
Recently, a genome-wide association study (GWAS) conducted in Korean subjects identified four CTNNA3 (alpha-T catenin) single nucleotide polymorphisms (SNPs) (rs10762058, rs7088181, rs1786929, and rs4378283) associated with diisocyanate-induced occupational asthma (DA). The CTNNA3 gene codes for a cadherin involved in formation of stretch-resistant cell-cell adhesions. We conducted a candidate gene association study to replicate these findings in Caucasian workers. Genotyping was performed on DNA using a 5' nuclease PCR assay collected from 410 diisocyanate-exposed and predominantly Canadian workers including 132 workers with DA confirmed by a specific inhalation challenge (DA+); 131 symptomatic workers in whom DA was excluded by a negative challenge (DA-); and 147 hexamethylene diisocyanate-exposed asymptomatic workers (AWs). As in the Korean study, highly linked CTNNA3 rs7088181 and rs10762058 SNPs (but not rs4378283 and rs1786929) were significantly associated with DA+ when compared with AWs but not in comparison with DA- workers (p ≤ 0.05). After adjusting for potentially confounding variables of age, smoking status, and duration of exposure, minor allele homozygotes of rs7088181 and rs10762058 SNPs were at increased risk for DA compared with AWs (OR = 9.05 [95% CI: 1.69, 48.54] and OR = 6.82 [95% CI: 1.65, 28.24], respectively). In conclusion, we replicated results from the only reported GWAS study of DA demonstrating an association between two closely linked CTNNA3 gene SNPs and DA. These findings lend further support to the clinical relevance of these genotypes in predicting susceptibility to DA and the potential importance of catenins in the disease process.


Structures of covalent adducts between DNA and ochratoxin a: a new factor in debate about genotoxicity and human risk assessment.
The potent renal carcinogenicity of ochratoxin A (OTA) in rats, principally in the male, raises questions about mechanism. Chromatographic evidence of DNA adducts after (32)P-postlabeling analysis contrasts with experimental attempts to demonstrate the absence of OTA in such adducts. Proffered schemes for alternative epigenetic mechanisms in OTA carcinogenicity remain unsatisfying, while structural data substantiating DNA-OTA adducts has also been lacking. We report refined (32)P-postlabeling methodology revealing one principal adduct isolated in small amounts from the kidneys of all five Fischer and five Dark Agouti rats to which OTA had been given on four consecutive days. We also describe structural data for the principal adduct from OTA/DNA interaction in vitro and its subsequent preparative isolation by the postlabeling methodology (as C-C8 OTA 3'dGMP), essentially creating an ochratoxin B-guanine adduct. Reasoning for the unsuitability of experimental protocols in published evidence claiming nongenotoxicity of OTA is given. In vivo exposure of renal DNA to cycles of adduction with OTA, necessarily protracted for carcinogenesis to occur, can reasonably explain an occasional focal neoplasm from which metastasizing carcinoma could develop.


Allograft-prosthesis composite reconstruction for the management of failed elbow replacement with massive structural bone loss: a medium-term follow-up.
We studied, ten patients (11 elbows) who had undergone 14 allograft-prosthesis composite reconstructions following failure of a previous total elbow replacement with massive structural bone loss. There were nine women and one man with a mean age of 64 years (40 to 84), who were reviewed at a mean of 75 months (24 to 213). One patient developed a deep infection after 26 months and had the allograft-prosthesis composite removed, and two patients had mild pain. The median flexion-extension arc was 100° (95% confidence interval (CI) 76° to 124°). With the exception of the patient who had the infected failure, all the patients could use their elbows comfortably without splints or braces for activities of daily living. The mean Mayo Elbow Performance Index improved from 9.5 (95% CI 4.4 to 14.7) pre-operatively to 74 (95% CI 62.4 to 84.9) at final review. Radiologically, the rate of partial resorption was similar in the humeral and ulnar allografts (three of six and four of eight, respectively; p > 0.999). The patterns of resorption, however, were different. Union at the host-bone-allograft junction was also different between the humeral and ulnar allografts (one of six and seven of eight showing union, respectively; p = 0.03). At medium-term follow-up, allograft-prosthesis composite reconstruction appears to be a useful salvage technique for failed elbow replacements with massive bone loss. The effects of allograft resorption and host-bone-allograft junctional union on the longevity of allograft-prosthesis composite reconstruction, however, remain unknown, and it is our view that these patients should remain under long-term regular review.


[Ketotifene: experimental and clinical data].
Some important pharmacodynamic and clinical data on ketotifen, a benzocycloheptathiophene used in the prophylaxis of allergic asthma, are provided as an introduction to papers discussing the therapeutic use of this substance in adults and children. Ketotifen, which is active when administered orally, has a therapeutic efficacy comparable to that of cromoglycate but characterized by a somewhat different mechanism of action. The therapeutic efficacy of ketotifen appears to be associated with a progressive diminution of bronchial hyper-reactivity to various specific or nonspecific spasmogenic factors (allergens, histamine, exercise). An antagonistic action to, and an inhibitory effect on, the activation and release of the principal mediators of anaphylactic hypersensibility (SRS-A, histamine) have been demonstrated in several experimental models both in animals and in man.


Applying lean: implementation of a rapid triage and treatment system.
Emergency department (ED) crowding creates issues with patient satisfaction, long wait times and leaving the ED without being seen by a doctor (LWBS). Our objective was to evaluate how applying Lean principles to develop a Rapid Triage and Treatment (RTT) system affected ED metrics in our community hospital. Using Lean principles, we made ED process improvements that led to the RTT system. Using this system, patients undergo a rapid triage with low-acuity patients seen and treated by a physician in the triage area. No changes in staffing, physical space or hospital resources occurred during the study period. We then performed a retrospective, observational study comparing hospital electronic medical record data six months before and six months after implementation of the RTT system. ED census was 30,981 in the six months prior to RTT and 33,926 after. Ambulance arrivals, ED patient acuity and hospital admission rates were unchanged throughout the study periods. Mean ED length of stay was longer in the period before RTT (4.2 hours, 95% confidence interval [CI] = 4.2-4.3; standard deviation [SD] = 3.9) than after (3.6 hours, 95% CI = 3.6-3.7; SD = 3.7). Mean ED arrival to physician start time was 62.2 minutes (95% CI = 61.5-63.0; SD = 58.9) prior to RTT and 41.9 minutes (95% CI = 41.5-42.4; SD = 30.9) after. The LWBS rate for the six months prior to RTT was 4.5% (95% CI = 3.1-5.5) and 1.5% (95% CI = 0.6-1.8) after RTT initiation. Our experience shows that changes in ED processes using Lean thinking and available resources can improve efficiency. In this community hospital ED, use of an RTT system decreased patient wait times and LWBS rates.


Current aspects of hearing loss from occupational and leisure noise.
Hearing loss from occupational and leisure noise numbers amongst the most frequent causes of an acquired sensorineural hearing loss. Here we present a review of up-to-date findings on the pathophysiology of acoustic injury to the inner ear, with special attention being paid to its molecular-biological and genetic aspects. Epidemiological aspects shall also be dealt with, as shall the roles of lacking recovery from occupational noise due to additional exposure by leisure noise and the combined exposure of noise and chemicals. Based on the epidemiological and pathophysiological findings and against the background of published animal-experimental, pre-clinical and clinical findings, the various approaches for prevention, protection and therapeutic intervention with acoustic trauma are discussed. Pharmacological strategies involving anti-oxidative, anti-excitotoxic and anti-apoptotic substances as well as non-pharmacological strategies like "sound conditioning" are given attention. Furthermore, systemic and local substance application as well as the therapy of acute acoustic trauma and chronic hearing problems (including modern therapy forms for comorbidities such as tinnitus) shall be delved into.


Wegener's granulomatosis presenting as temporal arteritis.
A granulomatous giant cell vasculitis of the temporal artery was observed in a biopsy specimen from a patient with corresponding clinical symptoms. Within weeks, the new onset of pulmonary infiltrates and renal failure prompted biopsy of the patient's kidney. A necrotizing glomerulonephritis, compatible with a diagnosis of Wegener's granulomatosis, was present. Vasculitis of the temporal artery may be a feature of Wegener's granulomatosis.


LC-MS/MS-based multiplex antibacterial platform for therapeutic drug monitoring in intensive care unit patients.
Empirically prescribed standard dosing regimens of antibacterial agents may result in insufficient or excess plasma concentrations with persistently poor clinical outcomes, especially for patients in intensive care units (ICUs). Therapeutic drug monitoring (TDM) of antibacterial agents can guide dose adjustments to benefit patients. In this study, we developed a robust, sensitive, and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform for the quantification of 14 antibacterial and antifungal agents (beta-lactams piperacillin, cefoperazone, and meropenem; beta-lactamase inhibitors tazobactam and sulbactam; antifungal agents fluconazole, caspofungin, posaconazole, and voriconazole; and daptomycin, vancomycin, teicoplanin, linezolid, and tigecycline) that can be used for patients with severe infection. This assay requires only 100 µL of serum with rapid protein precipitation. Chromatographic analysis was performed using a Waters Acquity UPLC C8 column. Three stable isotope-labeled antibacterial agents and one analogue were used as internal standards. Calibration curves ranged from 0.1-100 μg/mL, 0.1-50 μg/mL, and 0.3-100 μg/mL for different drugs, and all correlation coefficients were greater than 0.9085. Intra- and inter-day imprecision and inaccuracy values were below 15%. After validation, this new method was successfully employed for TDM in routine practice.


[Isolation, assay and biotyping of lactobacillary flora of the vagina].
The results of the isolation, quantitation and biotyping of 120 strains of vaginal Lactobacillus are presented. The more effective culture media for isolation and different methods of pH measurement were investigated. Five different species of Lactobacillus were isolated in vaginal specimens (Lactobacillus acidophilus 88.8%). The size limits found in the 120 Lactobacillus acidophilus strains were 0.8 to 6,0 mu length and 0.3 to 0.8 mu width. The effort to correlate number of Lactobacillus to pH and weight of vaginal fluid did not give satisfactory results because of difficulties in collecting homogeneous samples. Biochemical investigation of 120 vaginal strains of Lactobacillus did not show any peculiar biotype. The A.A. suggested the "routine" detection of vaginal lactobacillar flora as a usefull marker of ecological status in the choice of the therapy.


Topography and distribution of sympathetic nerve fibers in the rat temporomandibular joint: immunocytochemistry and ultrastructure.
The distribution and fine structure of nerve fibers containing neuropeptide Y (NPY), tyrosine hydroxylase (TH), and vasoactive intestinal polypeptide (VIP) in the temporomandibular joint were investigated by both the avidin-biotin complex method and an indirect immunofluorescence technique. The innervation pattern of NPY- and TH-positive fibers differed from that of VIP-positive fibers. Specifically, the former was distributed in both the superficial and deep sublining layers, while the latter was mostly located in the deep sublining layer. NPY- and TH-immunoreactive fibers were largely confined to vascular elements; occasional fibers were observed in the synovial lining layer close to the joint cavity. More nerves with NPY and TH immunoreactivity were observed close to the upper joint compartment than near the lower compartment NPY and TH immunoreactivity was dramatically reduced in the TMJ of superior cervical ganglionectomized animals, indicating the sympathetic origin of these nerves. NPY immunoreactivity was found only in unmyelinated axons, which were located in the adventitia and adventitia-medial border of arteries or arterioles. Occasionally, axons were near the joint cavity, in areas free of vascular structures. These observations show that abundant sympathetic nerves supply the temporomandibular joint of the rat and provide a morphological basis for the involvement of different neuropeptides in vascular regulatory and modulatory functions in physiological and pathophysiological conditions.


Structural Mechanism for the Fidelity Modulation of DNA Polymerase λ.
The mechanism of DNA polymerase (pol) fidelity is of fundamental importance in chemistry and biology. While high-fidelity pols have been well studied, much less is known about how some pols achieve medium or low fidelity with functional importance. Here we examine how human DNA polymerase λ (Pol λ) achieves medium fidelity by determining 12 crystal structures and performing pre-steady-state kinetic analyses. We showed that apo-Pol λ exists in the closed conformation, unprecedentedly with a preformed MgdNTP binding pocket, and binds MgdNTP readily in the active conformation in the absence of DNA. Since prebinding of MgdNTP could lead to very low fidelity as shown previously, it is attenuated in Pol λ by a hydrophobic core including Leu431, Ile492, and the Tyr505/Phe506 motif. We then predicted and demonstrated that L431A mutation enhances MgdNTP prebinding and lowers the fidelity. We also hypothesized that the MgdNTP-prebinding ability could stabilize a mismatched ternary complex and destabilize a matched ternary complex, and provided evidence with structures in both forms. Our results demonstrate that, while high-fidelity pols follow a common paradigm, Pol λ has developed specific conformations and mechanisms for its medium fidelity. Structural comparison with other pols also suggests that different pols likely utilize different conformational changes and microscopic mechanisms to achieve their catalytic functions with varying fidelities.