[Study of surplus cost of robotic assistance for radical hysterectomy, versus laparotomy and standard laparoscopy].
The study purpose was to compare the costs among robotic, laparoscopic and open radical hysterectomy for cervical cancer. Thirty-seven patients underwent robotic radical hysterectomy for cervical cancer. Cases were performed by three surgeons, at two institutions, and were retrospectively reviewed to perform a cost comparison between all three modalities. We included costs for edible materials in anesthesia and surgery, but costs for staff and indirect financial expenses were excluded. Those data are compared to open and laparoscopic radical hysterectomy data. The average cost for robotic assistance presented a surplus of 1796 euros compare to laparotomy and 1313 euros compare to standard laparoscopy in 2008, and 1320 and 837 euros respectively. The average cost for radical hysterectomy was highest for robotic, followed by standard laparoscopy, and least for laparotomy. However, over only 2 years of use, this difference tends to decrease. Medico-economic impact is the main restraint for robotic assistance development, and needs to be assessed permanently.


Stratification of yeast cells during chronological aging by size points to the role of trehalose in cell vitality.
Cells of the budding yeast Saccharomyces cerevisiae undergo a process akin to differentiation during prolonged culture without medium replenishment. Various methods have been used to separate and determine the potential role and fate of the different cell species. We have stratified chronologically-aged yeast cultures into cells of different sizes, using centrifugal elutriation, and characterized these subpopulations physiologically. We distinguish two extreme cell types, very small (XS) and very large (L) cells. L cells display higher viability based on two separate criteria. They respire much more actively, but produce lower levels of reactive oxygen species (ROS). L cells are capable of dividing, albeit slowly, giving rise to XS cells which do not divide. L cells are more resistant to osmotic stress and they have higher trehalose content, a storage carbohydrate often connected to stress resistance. Depletion of trehalose by deletion of TPS2 does not affect the vital characteristics of L cells, but it improves some of these characteristics in XS cells. Therefore, we propose that the response of L and XS cells to the trehalose produced in the former differs in a way that lowers the vitality of the latter. We compare our XS- and L-fraction cell characteristics with those of cells isolated from stationary cultures by others based on density. This comparison suggests that the cells have some similarities but also differences that may prove useful in addressing whether it is the segregation or the response to trehalose that may play the predominant role in cell division from stationary culture.


MiR-548 K regulatory effect on the ABCG2 gene expression in MDR breast cancer cells.
multidrug resistance (MDR) is One of the foremost challenges in overcoming breast cancer. Various molecular processes are involved in the development of MDR in breast cancer cells, including over expression of ABC transporters such as ABCG2 (BCRP), increase breast cancer stem cells drug resistance, and epithelial mesenchymal transition. In the present study, we used bioinformatics and experimental analysis to investigate the role of miR-548 K, in the modulating of ABCG2, in MDR breast cancer cells. In silico inspections introduce 14 microRNAs targeting 3'-UTR region of ABCG2 transcripts, which are probably involved in breast cancer drug resistance. An association was highlighted between miR-548 k with ABC transporter family. The expression level of ABCG2 gene in MCF7-MX cell lines was significantly more than MCF7 cell lines. On the other hand, we increased the expression of miR-548 K in MCF7-MX and MCF7 cell lines through its transfection, which dramatically coincided with decreasion in the ABCG2 transcripts level. Additional studies on patient samples revealed that the expression of ABCG2 showed an increase in ABCG2 level in neoadjuvant chemotherapy drugs resistance (NCDR) patients compared to primary pre-operative chemotherapy drugs response (PCDR) patients. Also, a reduction in the expression of miR-548 K in NCDR patients was revealed. The results of our study suggest that miR-548 K may be involved in modulating the expression of ABCG2 in MDR breast cancer cells.


[Studies of climatic factors influencing the performance of cattle in the Syrian Arab Republic. 3. Assessment of the factors effective in 1969/70--comparison with those of 1968/69].
Continuing previous investigations (1968/69), the values of temperature and humidity (inside and outside the cowsheds) were determined for the period October 1969 to September 1970. They were related to the physiological compatibility ranges established for dairy cattle and discussed in connection with a cowshed scheme in the Animal Experimental Station at Deir el Hajar in the Syrian Arab Republic. The values obtained in the two years of investigation largely agreed. The means of the temperature in both years was 27.7% inside and 30.5% outside the cowsheds above the physiologically compatible range of 0 to 24 degrees C for the whole period. Only in 47.6% and 46.7%, respectively, of the overall hours the temperature inside and outside the cowsheds was within the optimum compatibility range for dairy cattle. 43.5% of the relative humidity outside the cowshed was in the too dry and 21.7% was in the too moist compatibility range.


Repair of truncus arteriosus in the neonate and young infant.
Infants with truncus arteriosus present a difficult management issue. Because of the high operative mortality, repair is often delayed beyond the first 3 to 6 months of age. We reviewed our experience with 11 neonates and young infants with truncus arteriosus undergoing repair (median age, 21 days). Five patients also had major truncal valve insufficiency, and 2 required valve replacement. Right ventricle-pulmonary artery continuity was established with a porcine valved conduit in 3 patients and an aortic or pulmonary homograft in 8. There was 1 operative death (9%; 70% confidence limits, 3%-22%) and 1 late death over a mean follow-up of 21 months (range, 4 to 32 months). Eight of the 9 late survivors are growing normally. Echocardiographic examination revealed normal ventricular function in all patients (mean shortening fraction, 39%). Doppler assessment demonstrated trivial prosthetic or homograft valve regurgitation in 7 patients and mild to moderate obstruction in 5 patients. This recent experience with repair of truncus arteriosus indicates that the operative risk is low even in the neonate. Repair in the first month of life should be recommended before the development of critical congestive heart failure or irreversible pulmonary vascular disease.


An indirect technique for assuring simplicity and marginal integrity of provisional restorations during full mouth rehabilitation.
Full mouth rehabilitation with fixed prosthodontics can be a time- and labor-intensive process. The use of provisional restorations allows the treating clinician to determine the functional and esthetic requirements of the definitive prostheses. However, in the case of full mouth rehabilitation, the individual preparation of provisional restorations for multiple teeth may complicate the provisional phase and increase the treatment time. This article describes a method to simplify the indirect fabrication of provisional restorations for full mouth reconstruction. Provisional restorations may be easily achieved by splinting the provisional restorations in sextants, trimming them according to red pencil marks around the prepared margins as guidelines, and fitting them in the laboratory, utilizing a second set of solid casts for the prepared teeth.


Regulation of choline kinase activity by Ras proteins involves Ral-GDS and PI3K.
Ras proteins are molecular switches that control signaling pathways critical in the onset of a variety of human cancers. The signaling pathways activated by Ras proteins are those controlled by its direct effectors such as the serine-threonine protein kinase Raf-1, the exchange factor for other GTPases Ral-GDS, and the lipid kinase PI3K. As a consequence of Ras activation, a number of additional enzymes are affected, including several members of the serine-threonine intracellular proteins kinases as well as enzymes related to phospholipid metabolism regulation such as phospholipases A2 and D, and choline kinase. The precise mechanisms by which ras oncogenes impinge into these later molecules and their relevance to the onset of the carcinogenic process is still not fully understood. Here we have investigated the mechanism of regulation of choline kinase by Ras proteins and found no direct link between PLD and choline kinase activation. We provide evidence that Ras proteins regulate the activity of choline kinase through its direct effectors Ral-GDS and PI3K, while the Raf pathways seems to be not relevant in this process. The importance of Ras-dependent activation of choline kinase is discussed.


Characterization of juvenile play in rats: importance of sex of self and sex of partner.
Juvenile social play is observed in many mammalian species, and its disruption in several neuropsychiatric disorders has greatly increased interest in understanding the origins and sources of variability in this behavior. We quantified social play behavior in juvenile rats and investigated the impact of sex and familiarity of the play partner. Sex differences in play behavior were investigated by comparing males and females from either same- or mixed-sex pairs with data pooled over 12 days of analysis. Whether play was altered based on the sex of the play partner was assessed using a paired analysis to compare play with a same- or opposite-sex play partner for both males and females. Additionally, a repeated measures design was utilized to determine whether play changed with increasing age. On postnatal day 33, a novel play partner was introduced. We used a repeated measures analysis to compare postnatal day 33 with the previous day. These approaches were used to assess the effects of age, sex, sex of partner, and familiarity of partner on total social play behavior as well as how play was broken down into components, such as pouncing, pinning, chasing, and boxing. There were sex differences in total frequency of play, and specific parameters of play behavior, such as chasing, pouncing, pinning, and boxing. Additionally, males significantly altered their play behavior in response to the sex of their play partner, whereas females were more sensitive to the familiarity of the play partner. This study provides critical groundwork for uncovering factors that regulate social play behavior and can be used to guide future mechanistic based work.


The ranging of amino acids substitution matrices of various types in accordance with the alignment accuracy criterion.
The alignment of character sequences is important in bioinformatics. The quality of this procedure is determined by the substitution matrix and parameters of the insertion-deletion penalty function. These matrices are derived from sequence alignment and thus reflect the evolutionary process. Currently, in addition to evolutionary matrices, a large number of different background matrices have been obtained. To make an optimal choice of the substitution matrix and the penalty parameters, we conducted a numerical experiment using a representative sample of existing matrices of various types and origins. We tested both the classical evolutionary matrix series (PAM, Blosum, VTML, Pfasum); structural alignment based matrices, contact energy matrix, and matrix based on the properties of the genetic code. This study presents results for two test set types: first, we simulated sequences that reflect the divergent evolution; second, we performed tests on Balibase sequences. In both cases, we obtained the dependences of the alignment quality (Accuracy, Confidence) on the evolutionary distance between sequences and the evolutionary distance to which the substitution matrices correspond. Optimization of a combination of matrices and the penalty parameters was carried out for local and global alignment on the values of penalty function parameters. Consequently, we found that the best alignment quality is achieved with matrices corresponding to the largest evolutionary distance. These matrices prove to be universal, i.e. suitable for aligning sequences separated by both large and small evolutionary distances. We analysed the correspondence of the correlation coefficients of matrices to the alignment quality. It was found that matrices showing high quality alignment have an above average correlation value, but the converse is not true. This study showed that the best alignment quality is achieved with evolutionary matrices designed for long distances: Gonnet, VTML250, PAM250, MIQS, and Pfasum050. The same property is inherent in matrices not only of evolutionary origin, but also of another background corresponding to a large evolutionary distance. Therefore, matrices based on structural data show alignment quality close enough to its value for evolutionary matrices. This agrees with the idea that the spatial structure is more conservative than the protein sequence.


Caregiver Preferences for Three-Dimensional Printed or Augmented Reality Craniosynostosis Skull Models: A Cross-Sectional Survey.
Recent advances in three-dimensional (3D) printing and augmented reality (AR) have expanded anatomical modeling possibilities for caregiver craniosynostosis education. The purpose of this study is to characterize caregiver preferences regarding these visual models and determine the impact of these models on caregiver understanding of craniosynostosis. The authors constructed 3D-printed and AR craniosynostosis models, which were randomly presented in a cross-sectional survey. Caregivers rated each model's utility in learning about craniosynostosis, learning about skull anatomy, viewing an abnormal head shape, easing anxiety, and increasing trust in the surgeon in comparison to a two-dimensional (2D) diagram. Furthermore, caregivers were asked to identify the fused suture on each model and indicate their preference for generic versus patient-specific models. A total of 412 craniosynostosis caregivers completed the survey (mean age 33 years, 56% Caucasian, 51% male). Caregivers preferred interactive, patient-specific 3D-printed or AR models over 2D diagrams (mean score difference 3D-printed to 2D: 0.16, P < 0.05; mean score difference AR to 2D: 0.17, P < 0.01) for learning about craniosynostosis, with no significant difference in preference between 3D-printed and AR models. Caregiver detection accuracy of the fused suture on the sagittal model was 19% higher with the 3D-printed model than with the AR model (P < 0.05) and 17% higher with the 3D-printed model than with the 2D diagram (P < 0.05). Our findings indicate that craniosynostosis caregivers prefer 3D-printed or AR models over 2D diagrams in learning about craniosynostosis. Future craniosynostosis skull models with increased user interactivity and patient-specific components can better suit caregiver preferences.


Switching carbon metabolic flux for enhancing the production of sesquiterpene-based high-density biofuel precursor in Saccharomyces cerevisiae.
Sesquiterpenes are designated as a large class of plant-derived natural active compounds, which have wide applications in industries of energy, food, cosmetics, medicine and agriculture. Neither plant extraction nor chemical synthesis can meet the massive market demands and sustainable development goals. Biosynthesis in microbial cell factories represents an eco-friendly and high-efficient way. Among several microorganisms, Saccharomyces cerevisiae exhibited the potential as a chassis for bioproduction of various sesquiterpenes due to its native mevalonate pathway. However, its inefficient nature limits biosynthesis of diverse sesquiterpenes at industrial grade. Herein, we exploited an artificial synthetic malonic acid-acetoacetyl-CoA (MAAC) metabolic pathway to switch central carbon metabolic flux for stable and efficient biosynthesis of sesquiterpene-based high-density biofuel precursor in S. cerevisiae. Through investigations at transcription and metabolism levels, we revealed that strains with rewired central metabolism can devote more sugars to β-caryophyllene production. By optimizing the MVA pathway, the yield of β-caryophyllene from YQ-4 was 25.8 mg/L, which was 3 times higher than that of the initial strain YQ-1. Strain YQ-7 was obtained by introducing malonic acid metabolic pathway. Combing the optimized flask fermentation process, the target production boosted by about 13-fold, to 328 mg/L compared to that in the strain YQ-4 without malonic acid metabolic pathway. This designed MAAC pathway for sesquiterpene-based high-density biofuel precursor synthesis can provide an impressive cornerstone for achieving a sustainable production of renewable fuels.


Factors influencing the effect of surgical treatment in secondary proliferative disease with lung involvement.
Surgical treatment of neoplastic lung metastases is a big therapeutic problem, at the stage of qualifying for the procedure, in the surgical technique itself, and in the tactics of managing subsequent disease relapses. The most doubtful aspect is determining which factors influence the prolongation of survival in patients with such a diagnosis. To determine which factors influence the effectiveness of surgical treatment of neoplastic metastases to the lungs. A group of 577 patients was subjected to the study. An analysis of all performed operations (1009) was also carried out according to the set goals. Statistical analysis was performed using the estimates of the χ2 test, Kaplan-Meier estimator, and log-rank test. It was established what statistically significant factors may improve the treatment effectiveness. It was found that the lack of radicalism was influenced by: the number of lung metastases, the presence of changes in the lymph nodes, age, histology of the primary tumor and its location, and the number of treatments. Nodal metastases are more common in non-radical procedures, depend on the patient's age, are more often found in unilateral procedures, and depend on the location and histology of the primary tumor. It was found that the radical nature of the procedure did not affect the progression of the disease, but it did have an impact on survival. Relapses are more common in bilateral procedures, reducing survival. Lymph node metastases worsen the prognosis.


Cat-scratch disease manifesting as uveitis and binocular fundus nodular lesions: a case report.
Cat-scratch disease typically presents with various ocular manifestations such as uveitis, vitritis, retinitis, retinochoroiditis, and optic neuritis. However, fundus nodular lesions was rarely reported. In our study, we reported a case of Cat-Scratch disease with binocular fundus nodular lesions. An 11-year old male presented with uveitis in the right eye and bilateral fundus nodular lesions after indirect contact with unvaccinated cats. Comprehensive ancillary examinations including wide-angle fundus photography, ultrasonography, fluorescein fundus angiography, optical coherence tomography, and orbital magnetic resonance imaging were performed to elucidate the multidimensional features of the binocular lesions. Metagenomics next-generation sequencing was utilized to confirm the diagnosis of Cat-scratch disease. The patient's condition showed improvement after a 6-month combination treatment regimen involving systemic administration of doxycycline hyclate and methylprednisolone tablets, as well as local application of mydriatic and corticosteroid eye drops. We firstly reported a case of Cat-scratch disease presenting simultaneously with uveitis and fundus nodular lesions caused by Bartonella henselae infection in a child. Timely diagnosis and treatment with antibiotics and corticosteroids showed promising outcomes for the prognosis of these ocular disorders.


Combined education and patient-led goal setting intervention reduced chronic low back pain disability and intensity at 12 months: a randomised controlled trial.
One model of care that has not been tested for chronic low back pain (LBP) is patient-led goal setting. We aimed to compare the clinical effectiveness and healthcare use of a patient-led goal setting approach (intervention) with simple advice to exercise (control) over 12 months. An assessor-blinded randomised controlled trial. Intervention was education combined with patient-led goal setting compared with a control group receiving a standardised exercise programme. The primary outcomes were back pain disability and pain intensity. Secondary outcomes were quality of life, kinesiophobia, self-efficacy, depression, anxiety and stress. Outcomes and healthcare use were assessed immediately post-treatment (2 months) and after 4 and 12 months. Analysis was by intention to treat. Seventy-five patients were randomly assigned to either the intervention (n=37) or the control (n=38) group. Using linear mixed model analyses, adjusted mean changes in primary outcomes of disability and pain intensity were greater in the intervention group than in the control group (disability post-treatment: p<0.05). These differences were clinically meaningful. Mean differences in all secondary measures were greater in the intervention group than in the control group (p<0.05). There was no difference in healthcare use between groups over 12 months. A patient-led goal setting intervention was significantly more effective than advice to exercise for improving outcomes in disability, pain intensity, quality of life, self-efficacy and kinesiophobia in chronic LBP. These improvements were maintained at 12 months. Smaller effects were seen in measures of depression, anxiety and stress. ACTRN12614000830695.


Impact of Number of Vessels Targeted on Outcomes of Fenestrated-Branched Endovascular Repair for Complex Abdominal Aortic Aneurysms.
The aim of this study was to investigate the impact of number of vessels targeted by fenestrations or branches on early outcomes of fenestrated-branched endovascular aortic repair (F-BEVAR) for complex abdominal aortic aneurysms (cAAAs). The clinical data of 260 patients (209 men; mean, 74 ± 7 years) treated for cAAAs in four academic centers using fenestrated-branched stent grafts with one to five fenestrations or branches were entered into prospectively maintained databases (2010-2015). Data were analyzed in patients treated with ≤2-vessel (group 1, n = 124), 3-vessel (group 2, n = 80), or ≥4 fenestrations or directional branches (group 3, n = 56). For group definition, only vessels incorporated by fenestrations or directional branches were accounted. End points were technical success, procedural variables, 30-day mortality, and major adverse events (MAEs). A total of 830 vessels (mean, 3.19 ± 0.8 vessels/patient) were targeted by fenestrations (n = 672), scallops (n = 136), or branches (n = 22). Two-vessel designs were used more often in the early experience (64%), whereas ≥3-vessel design (groups 2 and 3) was preferred in the late experience (68%, P < 0.05). Patients with ≥4-vessel designs had longer operating and fluoroscopy time (+78 min, P < 0.0001 and + 27 min, P < 0.001), higher volume of contrast use (+31 mL, P = 0.03), and longer hospital stay (+3 days, P = 0.007) of those who had ≤2-vessel designs. Technical success, estimated blood loss, mortality, MAEs, and rate of spinal cord injury were similar in all three groups (P > 0.05). F-BEVAR for complex abdominal aortic aneurysms was associated with high technical success and low 30-day mortality and morbidity. Increasing complexity was associated with longer operating and fluoroscopy time, more contrast use, and longer hospital stay but did not affect technical success and MAEs of the procedure.


Correction to 'Adaptive responses and transgenerational plasticity of a submerged plant to benthivorous fish disturbance'.
[This corrects the article DOI: 10.1002/ece3.10398.].


Targeting regulated cell death in aortic aneurysm and dissection therapy.
Regulated cell death (RCD) is a basic biological phenomenon associated with cell and tissue homeostasis. Recent studies have enriched our understanding of RCD, and many novel cell death types, such as ferroptosis and pyroptosis, have been discovered and defined. Aortic aneurysm and dissection (AAD) is a life-threatening condition, but the pathogenesis remains largely unclear. A series of studies have indicated that the death of smooth muscle cells, endothelial cells and inflammatory cells participates in the development of AAD and that corresponding interventions could alleviate disease progression. Many treatments against cell death have been used to impede the process of AAD in vitro and in vivo, which provides strategies to protect against this condition. In this review, we focus on various types of regulated cell death and provide a framework of their roles in AAD, and the information contributes to further exploration of the molecular mechanisms of AAD.


Te hauora karu o te iwi Māori: A comprehensive review of Māori eye health in Aotearoa/New Zealand.
This article provides a summary of available data on Māori ocular health, highlighting significant disparities between Māori and non-Māori populations. Māori are more likely to develop diabetes, sight-threatening retinopathy and keratoconus, and present for cataract surgery earlier with more advanced disease. Limited data exists for macular degeneration and glaucoma, but there is some suggestion that Māori may have lower prevalence rates. The article emphasises the urgent need for robust national data on Māori ocular health to enable targeted interventions and funding allocation. Achieving equity for Māori in all aspects of health, including ocular health, requires concerted efforts from all stakeholders.


Characterization of periprosthetic environment microbiome in patients after total joint arthroplasty and its potential correlation with inflammation.
Periprosthetic joint infection (PJI) is one of the most serious complications after total joint arthroplasty (TJA) but the characterization of the periprosthetic environment microbiome after TJA remains unknown. Here, we performed a prospective study based on metagenomic next-generation sequencing to explore the periprosthetic microbiota in patients with suspected PJI. We recruited 28 patients with culture-positive PJI, 14 patients with culture-negative PJI, and 35 patients without PJI, which was followed by joint aspiration, untargeted metagenomic next-generation sequencing (mNGS), and bioinformatics analysis. Our results showed that the periprosthetic environment microbiome was significantly different between the PJI group and the non-PJI group. Then, we built a "typing system" for the periprosthetic microbiota based on the RandomForest Model. After that, the 'typing system' was verified externally. We found the periprosthetic microbiota can be classified into four types generally: "Staphylococcus type," "Pseudomonas type," "Escherichia type," and "Cutibacterium type." Importantly, these four types of microbiotas had different clinical signatures, and the patients with the former two microbiota types showed obvious inflammatory responses compared to the latter ones. Based on the 2014 Musculoskeletal Infection Society (MSIS) criteria, clinical PJI was more likely to be confirmed when the former two types were encountered. In addition, the Staphylococcus spp. with compositional changes were correlated with C-reactive protein levels, the erythrocyte sedimentation rate, and the synovial fluid white blood cell count and granulocyte percentage. Our study shed light on the characterization of the periprosthetic environment microbiome in patients after TJA. Based on the RandomForest model, we established a basic "typing system" for the microbiota in the periprosthetic environment. This work can provide a reference for future studies about the characterization of periprosthetic microbiota in periprosthetic joint infection patients.


Bis(indole) alkaloids as sortase A inhibitors from the sponge Spongosorites sp.
A new bis(indole) alkaloid (9) of the hamacanthin class along with the previously reported compounds of the related structural classes, topsentin class (1-4) and hamacanthin class (5-8), was isolated from the marine sponge Spongosorites sp. and their inhibitory activities toward sortase A (SrtA) that play key roles in cell-wall protein anchoring and virulence in Staphylococcus aureus were evaluated. Our studies have identified a series of SrtA inhibitors, providing the basis for further development of potent inhibitors. The preliminary structure-activity relationship, to elucidate the essential structural requirements, has been described. The fibronectin-binding activity data highlight the potential of these compounds for the treatment of S. aureus infections via inhibition of SrtA activity.


Posterior subcapsular cataract in endogenous Cushing syndrome: an uncommon manifestation.
Posterior subcapsular cataract is a well-known complication of longstanding glucocorticoid therapy (exogenous Cushing syndrome). The purpose of this study was to examine the effect of chronic endogenous hypercortisolism (endogenous Cushing syndrome) on the human lens. Sixty consecutive patients (8 to 67 years of age, 46 females, 14 males) with endogenous Cushing syndrome were studied. The exposure to cortisol was estimated based on the duration of the disease and measurements of the 24-hour urine free cortisol excretion. Complete ocular examination included biomicroscopy of the lens after dilation. Duration from the onset of endogenous Cushing syndrome ranged from 1 to 20 years (mean +/- SD, 5.5 +/- 3.7). Urine free cortisol excretion ranged from 250 to 3065 micrograms/24 hr (mean +/- SD, 693 +/- 547; normal values, 20 to 90 micrograms/24 hr). Only two of the 60 patients (3.3%) had posterior subcapsular cataract. This low prevalence contrasts to the high prevalence attributed to glucocorticoid therapy with grossly equivalent total dosage of glucocorticoids. It was concluded that posterior subcapsular cataract is an infrequent complication of endogenous hypercortisolism compared to exogenous Cushing syndrome. Because the total exposure to endogenous glucocorticoids was not lower than that of exogenous glucocorticoid therapy, a potential explanation for this difference might be the exposure of the lens to the natural (cortisol) rather than a synthetic glucocorticoid or pharmacokinetic differences of glucocorticoids between the two forms of Cushing syndrome.


Gynecologic oncology fellowship leadership trends by gender.
Our objective was to examine the educational, research, and leadership trends among gynecologic oncology (GYO) fellowship program directors (PD) and how these vary by gender. PDs were identified using the Society of Gynecologic Oncology Fellowship Directory. Surveys were sent to PDs' emails to obtain information about demographics, education, and research background. Publicly available data and institutional biographies were used to supplement primary survey data for incomplete responses or survey non-responders. Scopus was used to determine the h-index and number of publications and citations for each PD. Parametric data were compared using unpaired two-tailed t-tests. Chi-square and Fisher's exact tests were performed for categorical data. The significance level was p < 0.05. Approximately one-half of PDs were female (50.8%). Female PDs had a younger mean age than male PDs (46.4 years vs 51.9 years, p = 0.0014). The average overall h-index was 22 (SD = 14.5) and the average number of publications was 71.2 (SD = 63.3). The average h-index was higher in male PDs than females (27.8 vs 16.3, p = 0.0012), as were the number of publications (97.3 vs 45.8, p = 0.0008). Differences exist among GYO PDs by gender. While research productivity may be reflective of age, gender-based equity in research time should be further explored.


Lifestyle treatment in women with polycystic ovary syndrome: predictors of weight loss and dropout.
Polycystic ovary syndrome (PCOS) affects 5%-10% of women in their reproductive years. Most women with PCOS struggle with obesity during their entire life. Knowing which determinants contribute to a successful lifestyle change is important to optimize treatment options for women with PCOS. This analysis of secondary outcome measures aimed to determine factors of ≥5% weight loss and dropout in all arms of the study and separately in the lifestyle intervention (LI) and control (care as usual [CAU]) groups. Women diagnosed with PCOS (N = 183) and a Body Mass Index (BMI) above 25 kg/m2 were included. Participants were assigned to (1) 20 lifestyle sessions involving cognitive behavioral therapy (CBT), (2) 20 lifestyle sessions involving CBT with additional short message service (SMS), or (3) to control (CAU). A generalized linear regression was performed to identify determinants of ≥5% weight loss. Logistic regression was performed to identify determinants of dropout. All models were corrected by including baseline weight as a covariate. LI (OR 4.906, p = .001) was associated with ≥5% weight loss, while higher depression scores (OR 0.549, p = .013) had a negative association. Restraint eating was a positive factor for ≥5% weight loss in LI but a negative in CAU. Higher baseline weight (OR 1.033, p = .006), LI with SMS (OR 4.424, p = .002), and higher levels of androstenedione (OR 1.167, p = .026) were associated with dropout. Depression and eating behavior were associated with ≥5% weight loss. Women with PCOS should be screened for depression and eating behavior before a LI.


Allosteric inhibition of the nonMyristoylated c-Abl tyrosine kinase by phosphopeptides derived from Abi1/Hssh3bp1.
Here we report c-Abl kinase inhibition mediated by a phosphotyrosine located in trans in the c-Abl substrate, Abi1. The mechanism, which is pertinent to the nonmyristoylated c-Abl kinase, involves high affinity concurrent binding of the phosphotyrosine pY213 to the Abl SH2 domain and binding of a proximal PXXP motif to the Abl SH3 domain. Abi1 regulation of c-Abl in vivo appears to play a critical role, as demonstrated by inhibition of pY412 phosphorylation of the nonmyristoylated Abl by coexpression of Abi1. Pervanadate-induced c-Abl kinase activity was also reduced upon expression of the wild type Abi1 but not by expression of the Y213 to F213 mutant Abi1 in LNCaP cells, which are naturally deficient in the regulatory pY213. Our findings suggest a novel mechanism by which Abl kinase is regulated in cells.


Catheter-based septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: follow-up results of the TASH-registry of the German Cardiac Society.
In late 1997, the German Cardiac Society set up a multicenter registry to evaluate the acute and mid-term course of all patients (pts.) treated with septal ablation for symptomatic hypertrophic obstructive cardiomyopathy (HOCM). An analysis of the acute results has already been published. We now report on the mid-term course (3-6 months) of 242 pts. registered through September 1999. Follow-up was 92% complete (n=222). During follow-up (mean: 4.9+/-2.3 months), an additional 3 pts. died (in-hospital mortality: 3 pts.). A satisfactory clinical effect was reported by 195 pts. (88%); 27 pts. (12%) remained in NYHA classes III and IV. Overall symptomatic improvement (NYHA class: from 2.8+/-0.7 to 1.7+/-0.7) paralleled the outflow gradient (LVOTG) reduction which was further accentuated as compared with the acute result (Doppler measurement at rest: from 57+/-31 to 25+/-25 mmHg to 20+/-21 mmHg; with provocation: from 107+/-53 to 49+/-40, to 44+/-40 mmHg, p<0.001, resp.). Left atrial (LA) diameter (from 46+/-8 to 44+/-7 mm) and septal thickness (from 20+/-5 to 15+/-5 mm; p<0.001, resp.) were also reduced. Comparing the methods for target vessel selection (i.e., with contrast echo monitoring vs pressurefluoroscopy guidance), at followup clinical improvement and hemodynamic measurements were comparable. Clinical success can be achieved by septal ablation, both with the echocontrast guided and gradient-fluoroscopy guided method, in 88% of highly symptomatic HOCM pts. At mid-term follow-up, symptoms, left atrial size and septal thickness are reduced, and outflow gradients are further improved as compared to the acute result.


AGK2 ameliorates mast cell-mediated allergic airway inflammation and fibrosis by inhibiting FcεRI/TGF-β signaling pathway.
Asthma is characterized by airway hyperresponsiveness and allergic inflammation, detrimentally affecting the patients' quality of life. The development of new drugs for the treatment of asthma is warranted to alleviate these issues. Recent studies have demonstrated that sirtuin2 (SIRT2) aggravates asthmatic inflammation by up-regulation of T-helper type 2 responses and macrophage polarization. However, effects of SIRT2 on mast cell activation remain obscure. In this study, we investigated the effects of AGK2, an inhibitor for SIRT2, on mast cell-mediated allergic airway inflammation. Pre-treatment with AGK2 inhibited degranulation of mast cells by suppressing the FcεRI signaling pathway and intracellular calcium influx. The expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-4, IL-5, IL-6, and IL-8, was inhibited via regulation of transcription factors such as NF-κB and NRF2. These effects of AGK2 were verified in passive cutaneous anaphylaxis and acute lung injury animal models. AGK2 attenuated Evans blue pigmentation by inhibiting mast cell activation and lung barrier dysfunction by inhibiting inflammatory responses in these animal models. In the ovalbumin (OVA)-induced allergic airway inflammation murine model, AGK2 alleviated allergic asthma symptoms such as lung histological changes (immune cell and mast cell infiltration, collagen deposition, and α-smooth muscle actin expression) and serum immunoglobulins (Ig) levels (IgE, OVA-specific IgE, IgG1, and IgG2a). Moreover, AGK2 reduced the levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-4, IL-5, and IL-6) and inflammatory mediators (myeloperoxidase, eosinophil peroxidase, and tumor growth factor-α) in the bronchoalveolar lavage fluid and lung tissues. In addition, the anti-fibrotic effects of AGK2 were verified using lung epithelial cells and TGF-β/Smad reporter stable cells. In conclusion, our findings suggest that SIRT2 plays a role in mast cell-mediated airway inflammatory disease. Therefore, AGK2 is a good potential candidate for treating allergic asthma and lung inflammation.


Production of antibodies against bradykinin.
High-titer antibodies against bradykinin were raised in rabbits. 2 different conjugates of bradykinin were used for immunization: bradykinin coupled to human serum albumin via 1,5-difluoro-2,4-dinitrobenzene and bradykinin coupled to edestin via 1-ethyl-3(3-dimethyl-aminopropyl)-carbodiimide. The sensitivity of the radioimmunoassay method is in the range of 1-50 pg of bradykinin. Cross-reaction of anti-bradykinin antisera occurred with kallidin and met-lys-bradykinin.


Functional anatomy and ultrasound examination of the canine penis.
The aim of this study was to identify the functional-anatomical structures of the canine penis during and after erection to demonstrate the respective changes to provide a basis for further examinations of pathological conditions like priapism. Additionally, a gray-scale analysis was performed to quantify results from the ultrasound examination. In total, 80 dogs were examined. In group (Gr.) A, 44 intact or castrated dogs were examined, and in Gr. B, 36 dogs were examined during erection and after complete detumescence of the penis. The following parameters were assessed: (1) using physical measurements: length of the Pars longa glandis [Plg] and length of the Bulbus glandis [Bg]; and (2) using ultrasound: total penile diameter, width of the erectile tissue of the Plg, diameter of the Corpus spongiosum [Cs] including the penile bone and urethra, vertical diameter, circumference of the penis, cross-sectional area, and area of the Cs including the urethra. The mentioned parameters could be assessed in all dogs of Gr. A and Gr. B with the only exception being the urethra that could be visualized using ultrasound in some dogs only and predominantly in the erected penis (Gr. B). Concomitantly, the erectile tissue of the Plg and the Cs was more heterogenous and hypo- to anechoic during erection compared with dogs in Gr. A and Gr. B after detumescence. Comparing the results in Gr. B, the length of the Plg and the Bg were decreased approximately 40.6% and 38.0%, the total width of the penis 40.5%, the total width of the erectile tissue of the Plg 48.0%, and the width of the Cs 15.6% during detumescence compared with erection. Comparing the decrease in size at the different locations (apex penis, middle of Plg, middle of Bg) for vertical diameter, total circumference, and cross-section area, it was largest at the Bg. B-mode ultrasound is a suitable tool to investigate not only the morpho-functional structures of the resting canine penis, but also of the erected and detumescent penis, and to investigate the underlying changes during erection and detumenscence.


Mechanical ventilation with positive end-expiratory pressure preserves arterial oxygenation during prolonged pneumoperitoneum.
Laparoscopic surgery usually requires a pneumoperitoneum by insufflating the abdominal cavity with carbon dioxide (CO2). Increased intraabdominal pressure causes diaphragmatic displacement resulting in compressed lung areas, which leads to formation of atelectasis, especially during mechanical ventilation. Application of positive end-expiratory pressure (PEEP) can maintain pulmonary gas exchange. The objective of this study was to investigate the effect of abdominal gas insufflation on arterial oxygenation during mechanical ventilation with and without PEEP in rats. In experiment 1, two groups of six rats were continuously insufflated with CO2 at 12 mmHg for 180 min. Group 1 was ventilated with 8 cm H2O PEEP and group 2 had 0 cm H2O PEEP. Group 3 served as a control. This group had abdominal wall lifting and was ventilated with 0 cmH2O PEEP. In experiment 2, two groups of six rats had abdominal CO2 insufflation and were ventilated with or without PEEP during 180 min (group 4 and 5). In this experiment, abdomens were desufflated in both groups for 5 min at 60 and 120 min. Blood pressure monitoring and measurement of arterial pO2 was performed by placement of an indwelling carotid artery catheter in both experiments. In both experiments, paO2 values decreased significantly in insufflation groups that were ventilated with 0 cmH2O PEEP (groups 2 and 5). Insufflation groups ventilated with 8 cmH2O PEEP had paO2 values comparable to these of control group. There were no significant differences in mean arterial pressure between insufflation groups ventilated with or without PEEP. PEEP preserves arterial oxygenation during prolonged pneumoperitoneum in rats with minimal adverse hemodynamic effects.


Effects of hydrodynamic shear stress on sludge properties, N2O generation, and microbial community structure during activated sludge process.
Sludge properties are critical to the treatment performance and potentially correlate with nitrous oxide (N2O) generation during activated sludge processes. The hydrodynamic shear stress induced by aeration has a significant influence on sludge properties and is inevitable for wastewater treatment plants (WWTPs). In this study, the effects of aerobic induced hydrodynamic shear stress on sludge properties, N2O generation, and microbial community structure were investigated using three parallel sequencing batch reactors (SBRs) with identical dissolved oxygen (DO) concentrations. Results showed that with a shear stress increase from 1.5 × 10-2 N/m2 to 5.0 × 10-2 N/m2, the COD and NH4+-N removal rates were enhanced from 89.4% to 94.0% and from 93.9% to 98.0%, respectively, while the TN removal rate decreased from 66.0% to 56.5%. Settleability of the activated sludge flocs (ASFs) also increased with the enhancement of shear stress, due to variation in sludge properties including particle size, regularity, compactibility, and EPS (extracellular polymeric substances) composition. The increase in shear stress promoted oxygen diffusion within the ASFs and mitigated NO2--N accumulation, leading to a decrease in the N2O-N conversion rate from (4.8 ± 0.3)% to (2.2 ± 0.6)% (based on TN removal). Microbial analysis results showed that the functional bacteria involved in the biological nitrogen removal was closely related with shear stress. The increase in shear stress favored the enrichment of nitrite oxidizing bacteria (NOB) while suppressed the accumulation of ammonia-oxidizing bacteria (AOB) and denitrifying bacteria (DNB).


Evaluation of the clinical chemistry tests analytical performance with Sigma Metric by using different quality specifications - Comparison of analyser actual performance with manufacturer data.
The interest in quality management tools/methodologies is gradually increasing to ensure quality and accurate results in line with international standards in clinical laboratories. Six Sigma stands apart from other methodologies with its total quality management system approach. However, the lack of standardization in tolerance limits restricts the advantages for the process. Our study aimed both to evaluate the applicability of analytical quality goals with Roche Cobas c 702 analyser and to determine achievable goals specific to the analyser used. The study examined under two main headings as Sigmalaboratory and Sigmaanalyser. Sigmalaboratory was calculated using internal and external quality control data by using Roche Cobas c 702 analyser for 21 routine biochemistry parameters and, Sigmaanalyser calculation was based on the manufacturer data presented in the package inserts of the reagents used in our laboratory during the study. Sigma values were calculated with the six sigma formula. Considering the total number of targets achieved, Sigmaanalyser performed best by meeting all CLIA goals, while Sigmalaboratory showed the lowest performance relative to biological variation (BV) desirable goals. The balance between the applicability and analytical assurance of "goal-setting models" should be well established. Even if the package insert data provided by the manufacturer were used in our study, it was observed that almost a quarter of the evaluated analytes failed to achieve even "acceptable" level performance according to BV-based goals. Therefore, "state-of-the-art" goals for the Six Sigma methodology are considered to be more reasonable, achievable, and compatible with today's technologies.


The urethral catheter--a review of its implication in urinary-tract infection.
The research into acquisition of urinary-tract infection over the last few decades has established three ways in which organisms may gain access to the urinary tract of the catheterized patients: Firstly, during the process of passing the catheter into the bladder should complete asepsis not be observed; secondly by travelling along the urethra in the small, fluid-filled cavity between catheter and mucosa; Thirdly following contamination of the drainage system, along the inside of the catheter directly into the bladder. The relative importance of each route is not clear and is still the subject of much controversy but it would seem that all these routes have a part to play in allowing infection to develop. The risk of catheterized patients acquiring urinary-tract infection is so great that where possible catheterization should be avoided. The most important preventive measure which may be taken is to limit the duration of indwelling catheterization. In addition, a considerable amount of research has attempted to distinguish other factors which might affect the rate at which urinary-tract infection in the catheterized patient becomes established so that high-risk patients may be identified. The evidence indicates that the risk increases with duration of catheterization, age, length of hospital stay, immunosuppressant treatment, that it is greater in female than male patients and that a patient with a serious or fatal underlying disease is also more likely to develop bacteriuria. Finally, properties of the urine and the host defence mechanisms may affect the susceptibility of the individual to urinary-tract infection. Identification of the routes of infection and patients at risk is only part of the problem. The next stage is to formulate criteria for the care of catheterized patients which reduce the risk of infection to the absolute minimum and will hopefully go some way towards diminishing the unsatisfactory high levels of urinary-tract infection that are currently associated with indwelling catheterization.


Shoulder and elbow pathology in the female athlete: sex-specific considerations.
Unique biologic and biomechanical aspects of the female body make women more prone to certain orthopedic injuries. Sex differences are well understood with regard to certain orthopedic pathologies such as anterior cruciate ligament injury, hallux valgus, carpal tunnel, and carpometacarpal joint arthritis; however, sex differences are less commonly discussed with regard to shoulder and elbow pathology. The purpose of this review is to elucidate sex differences specific to sports-related shoulder and elbow injuries in the female athlete population.


Streptomyces lactacystinicus sp. nov. and Streptomyces cyslabdanicus sp. nov., producing lactacystin and cyslabdan, respectively.
Correction to: The Journal of Antibiotics (2015) 68, 322–327; doi:10.1038/ja.2014.162; published online 10 December 2014. The authors of the above article noticed following error in the publication of this paper. In the Abstract and the "Description of Streptomyces lactacystinicus sp. nov." sub-section under the Results and Discussion section, DSM number for strain OM-6519T was wrong. It should have been read OM-6519T (=NBRC 110082T, DSM 42136T). Authors apologize for this mistake.


Particulate untransformed glucocorticoid-receptor complexes from HeLa cells crosslinked in vivo.
When control HeLa cells were incubated at 2 degrees C in the presence of tritiated dexamethasone, most glucocorticoid-receptor complexes were found in cytosolic extracts as untransformed forms. Chemical crosslinking of intact HeLa cells resulted in the immobilization of 50% of the total cellular glucocorticoid-receptor complexes in the nuclear fraction. Under these conditions the redistribution of total protein, RNA and lactate dehydrogenase activity between cytosol and nuclei was negligible, indicating that glucocorticoid binding in the nuclear fraction was not due to a methodological artifact. High levels of glucocorticoid receptor were also found in the nuclear fraction of crosslinked cells which were not exposed to glucocorticoids. Nuclear receptor complexes could be released in soluble forms by DNase I and sonication. Evaluations of DNA binding and ionic properties of glucocorticoid receptors prepared from control and crosslinked cells maintained at 2 degrees C revealed that most of the hormone-receptor complex in cytosols and nuclear extracts behaved as untransformed forms. As opposed to glucocorticoid receptors prepared from control cells, heat treatment of extracts obtained from crosslinked cells did not result in increased DNA binding and changes in ionic properties of receptor complexes. I conclude that untransformed glucocorticoid receptors are present in both cytosol and nuclei of intact cells.


Immunotherapy in Gastrointestinal Malignancies.
Gastrointestinal (GI) cancers represent a heterogeneous group of malignancies, each with a unique tumor biology that in turn affects response to treatment and subsequent prognosis. The interplay between tumor cells and the local immune microenvironment also varies within each GI malignancy and can portend prognosis and response to therapy. Treatment with immune checkpoint inhibitors has changed the treatment landscape of various solid tumors including (but not limited to) renal cell carcinoma, melanoma, and lung cancer. Advances in the understanding between the interplay between the immune system and tumors cells have led to the integration of immunotherapy as standard of care in various GI malignancies. For example, immunotherapy is now a mainstay of treatment for tumors harboring defects in DNA mismatch repair proteins and tumors harboring a high mutational load, regardless of primary site of origin. Data from recent clinical trials have led to the integration of immunotherapy as standard of care for a subset of gastroesophageal cancers and hepatocellular carcinoma. Here, we outline the current landscape of immunotherapy in GI malignancies and highlight ongoing clinical trials that will likely help to further our understanding of how and when to integrate immunotherapy into the treatment of various GI malignancies.


A candidate molecular signature associated with tamoxifen failure in primary breast cancer.
Few markers are available that can predict response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancers. Identification of such markers would be clinically useful. We attempted to identify molecular markers associated with tamoxifen failure in breast cancer. Eighteen initially ER-positive patients treated with tamoxifen requiring salvage surgery (tamoxifen failure [TF] patients) were compared with 17 patients who were disease free 5 years after surgery plus tamoxifen adjuvant therapy (control patients). cDNA microarray, real-time quantitative PCR, and immunohistochemistry on tissue microarrays were used to generate and confirm a gene signature associated with tamoxifen failure. An independent series of 33 breast tumor samples from patients who relapsed (n = 14) or did not relapse (n = 19) under tamoxifen treatment from a different geographic location was subsequently used to explore the gene expression signature identified. Using a screening set of 18 tumor samples (from eight control patients and 10 TF patients), a 47-gene signature discriminating between TF and control samples was identified using cDNA arrays. In addition to ESR1/ERalpha, the top-ranked genes selected by statistical cross-analyses were MET, FOS, SNCG, IGFBP4, and BCL2, which were subsequently validated in a larger set of tumor samples (from 17 control patients and 18 TF patients). Confirmation at the protein level by tissue microarray immunohistochemistry was observed for ER-alpha, gamma-synuclein, and insulin-like growth factor binding protein 4 proteins in the 35 original samples. In an independent series of breast tumor samples (19 nonrelapsing and 14 relapsing), reduced expression of ESR1/ERalpha, IGFBP4, SNCG, BCL2, and FOS was observed in the relapsing group and was associated with a shorter overall survival. Low mRNA expression levels of ESR1/ERalpha, BCL2, and FOS were also associated with a shorter relapse-free survival (RFS). Using a Cox multivariate regression analysis, we identified BCL2 and FOS as independent prognostic markers associated with RFS. Finally, the BCL2/FOS signature was demonstrated to have more accurate prognostic value for RFS than ESR1/ERalpha alone (likelihood ratio test). We identified molecular markers including a BCL2/FOS signature associated with tamoxifen failure; these markers may have clinical potential in the management of ER-positive breast cancer.


Effect of intranasal oxytocin on palatable food consumption and c-Fos immunoreactivity in relevant brain areas in rats.
Peripheral and central injections of oxytocin (OT) in laboratory animals decrease eating for energy and palatability, but the hypophagic response is dependent on the administration route. Human studies rely on intranasal (IN) administration of the peptide, the route underutilized in OT animal feeding studies thus far. Therefore, we examined the effect of IN OT on various aspects of food consumption in rats: (a) overnight deprivation-induced standard chow intake, (b) episodic (2-h) consumption of calorie-dense and palatable high-fat high-sugar (HFHS) chow, (c) 2-h episodic intake of palatable and calorie-dilute sucrose and Intralipid solutions, and (d) 2-h sucrose solution intake in rats habituated to ingesting this solution daily for several weeks. Finally, we assessed c-Fos changes in response to the acute IN OT administration in rats habituated to daily sugar consumption. We found that IN 20μg OT decreased deprivation-induced intake of standard chow and HFHS chow in nondeprived rats without affecting water consumption. IN OT also reduced 2-hour episodic fluid consumption of sucrose, but not Intralipid. In the habitual sugar consumption paradigm, acute IN OT diminished sucrose solution intake in animals accustomed to the 2-hour/day sucrose meal regimen. In rats habitually consuming sucrose, IN OT altered c-Fos immunoreactivity in brain areas related to energy homeostasis and reward, including the central nucleus of the amygdala, the hypothalamic paraventricular and the arcuate nuclei. We conclude that IN OT is an effective appetite suppressant for carbohydrate/sugar diets in rats and its effects involve feeding-related brain circuits.


Vibration insensitivity of a short latency reflex linking the lower leg and the active knee extensor muscles in humans.
The study indirectly investigated the afferent source of a human lower limb reflex that spans two joints and may link limb muscular activity during movement. Low threshold (motor nerve threshold (MT) to 1.6 MT) single, 1 msec, pulses were delivered to the common peroneal nerve at caput fibula. Heteronymous excitatory responses were observed in the elctromyogram of the knee extensor muscle vastus medialis (VM), when the latter was prior contracted. The briefest latency for the VM reflex was 24.2 msec. The distal belly and tendon of the tibialis anterior muscle were vibrated for 20 min at a frequency of 105 Hz, amplitude 1-2 mm, to inhibit the reflex potential evoked by group Ia afferent fibres from that muscle. This significantly reduced the amplitude of the group Ia mediated Hoffmann (H) reflex in TA. Such vibration did not depress the amplitude of the heteronymous reflex to VM, when initially the latter was at peak amplitude or at its mid-range for amplitude. Reflex latency, threshold, and stimulation current for peak expression suggested that group II fibres were unlikely to be the major initiators of the reflex. The results support the view that this human reflex is primarily Ib mediated.


Macrophages are involved in DNA degradation of apoptotic cells in murine thymus after administration of hydrocortisone.
In the present study, we undertook kinetic analyses of DNA degradation and acid DNase activity in murine thymus after administration of hydrocortisone. Hydrocortisone induced apoptosis in thymocytes, and a large number of cortical thymocytes became TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labelling)-positive (TUNEL+). F4/80+ macrophages infiltrated through the cortico-medullay junction into the cortical region, and thereafter engulfed apoptotic cells in the cortex of thymus. The distribution of acid DNase-active cells appeared to be similar to that of F4/80+ macrophages. Eighteen hours after the injection, although the foci of apoptotic cells were situated within massively distended F4/80+ macrophages, oligonucleosomal DNA fragments on an agarose gel were undetectable. Our results showed that macrophages were involved in the disappearance of oligonucleosomal DNA fragments in apoptotic thymocytes. Taken together, macrophages play a role in the hydrolysis of DNA in apoptotic cells upon their phagocytosis of the dead cells.


Hydroxycholesterols in serum from hypercholesterolaemic patients with and without bile acid sequestrant therapy.
To assess the effect of bile acid sequestrant therapy on bile acid precursors in plasma, we determined hydroxycholesterols in serum from patients with primary hypercholesterolaemia. Compared with a group of 5 male and 12 female patients without any lipid-lowering drug therapy, which has normal to slightly elevated 7 alpha-hydroxycholesterol, normal 7 beta-hydroxycholesterol and high normal to elevated 26-hydroxycholesterol levels, a group of 5 male and 9 female patients, using colestipol had higher 7 alpha-hydroxycholesterol without overlap, and higher 7 beta-hydroxycholesterol levels, but similar levels of 26-hydroxycholesterol. In the latter group, the ratio between 7 alpha-hydroxycholesterol and total cholesterol in serum was also higher without overlap. Both groups did not differ for age, body weight, body mass index and serum lipid levels. In the group of patients without lipid-lowering drug therapy, 7 alpha-hydroxycholesterol correlated positively with total and low-densitylipoprotein cholesterol, 7 beta-hydroxycholesterol negatively with body weight and body mass index, and 26-hydroxycholesterol positively with body weight. In both groups, 7 alpha-hydroxycholesterol correlated positively with 7 beta-hydroxycholesterol. These results suggest that (1) bile acid sequestrants enhance bile acid synthesis via the 7 alpha-hydroxylation but not via the 26-hydroxylation pathway, (2) serum 7 alpha-hydroxycholesterol level and the ratio between this hydroxycholesterol and total cholesterol in serum might be suitable parameters to check intake of bile acid sequestrants irrespective of dose, and (3) 7 beta-hydroxycholesterol is unlikely to be the result of cholesterol auto-oxidation in vitro.


Alternatives to total splenectomy: two case reports.
Postsplenectomy sepsis is a serious problem with high morbidity and high mortality. Surgical alternatives to total splenectomy are being sought. This paper describes two cases where, after splenectomy, some splenic tissue was either reimplanted or was left in situ and remains functional.


Topography of dolichyl phosphate synthesis in rat liver microsomes. Transbilayer arrangement of dolichol kinase and long-chain prenyltransferase.
The topography of the dolichyl phosphate biosynthetic enzymes within the plane of rat liver microsomes was investigated by the use of two impermeant inhibitors of enzyme activity: trypsin and mercury-dextran. Mercury-dextran was found to inactivate over 50% of the activities of the CTP-dependent dolichol kinase and the long-chain prenyltransferase. Trypsin caused over 90% inactivation of the long-chain prenyltransferase and 60% inactivation of the dolichol kinase. In addition, the CTP-dependent dolichol kinase was inhibited over 90% by CDP applied externally to sealed microsomes. Inactivation of the dolichyl phosphate biosynthetic enzymes by the impermeant probes occurred under conditions where the mannose-6-phosphatase activity was highly latent. It was concluded that the active sites of these two enzymes are located on the external surface of the microsomal membranes and that dolichyl phosphate biosynthesis occurs asymmetrically on the cytoplasmic surface of the endoplasmic reticulum.


A novel model measuring the harm of transplanting hepatocellular carcinoma exceeding Milan criteria.
No empirical studies have defined the posttransplant survival that would justify expansion of the Milan criteria for liver transplantation of hepatocellular carcinoma. We created a Markov model comparing the survival benefit of transplantation for a patient with >Milan HCC, versus the harm caused to other patients on the waiting list. In the base-case analysis, the strategy of transplanting the patient with >Milan HCC resulted in a 44% increased risk of death and a utility loss of 3 quality-adjusted years of life across the pre- and posttransplant periods for a nationally representative cohort of patients on the waiting list. This harm outweighed the benefit of transplantation for a patient with >Milan HCC having a 5-year posttransplant survival of less than 61%. This survival threshold was most sensitive to geographic variations in organ shortage, with the threshold varying from 25% (Region 3) to >72% (Regions 1, 5, 7 and 9). In conclusion, expansion of the Milan criteria will require demonstrating high survival rates for the newly eligible patients-approximately 61% at 5 years after transplantation. In regions with less severe organ shortage, a more aggressive approach to transplanting these patients may be justified.


HIV in youth prevention in the emergency department initiative: A survey of pediatric emergency medicine providers.
The incidence of HIV among adolescents remains high, and adolescents are known to participate in sexual behaviors that increase their risk for HIV, such as unprotected sex and sex with multiple partners. HIV pre-exposure prophylaxis (PrEP) has been shown to be effective at preventing HIV when taken daily and is approved by the FDA for use in adolescents. Efforts to screen patients in adult emergency departments and connect them with PrEP services have been validated. We surveyed pediatric emergency medicine (PEM) providers to determine their knowledge of PrEP, prescribing practices, willingness to prescribe, and barriers to a screening protocol in the pediatric emergency department (PED). We administered a survey to a multidisciplinary group of PEM providers to measure knowledge, use, willingness, and implementation barriers to PrEP as well as elements needed for a successful referral system. A total of 87 responses were included for analysis. While 79.1% of all providers had heard of PrEP, only 14.8% of prescribing providers had ever discussed PrEP with a patient, and none had ever prescribed PrEP. Overall, 76.3% of all providers were knowledgeable about PrEP based on answers to true/false questions, with prescribing providers significantly more likely to be knowledgeable compared to nurses (p = 0.005). Knowledgeable providers had higher willingness scores to refer for PrEP compared to providers who were not knowledgeable. Ninety-two percent of providers felt a PrEP referral process from the PED would be feasible. Creation of an eligibility algorithm and educational materials were the most common efforts providers preferred to make them more likely to refer for PrEP. The most notable barriers perceived by providers included patient noncompliance with therapy (20.9%), acceptance of PrEP discussion among patients and parents (19.8%), and cost of therapy (15.1%). PEM providers are knowledgeable about PrEP but have little experience with discussing or prescribing PrEP. Their willingness to refer for PrEP and anticipated feasibility of a PrEP referral system is encouraging. These results support the need for future educational efforts among PEM providers and creation of referral systems for PrEP services from the PED.


Biochemical aspects of the visual process. XXXVII. Evidence for lateral aggregation of rhodopsin molecules in phospholipase C-treated bovine photoreceptor membranes.
Photoreceptor membranes derived from isolated bovine rod outer segments, are subjected to treatment with phospholipase C (Bacillus cereus). This results in varying degrees of hydrolysis of the membrane phospholipids into diglycerides and water soluble phosphate esters without loss of rhodopsin. Electron microscopic observations of thin sections and freeze-fractured preparations indicate extrusion of diglycerides from the membranes and their coalescence to lipid droplets, beginning at 20% hydrolysis of phospholipids. After 90% hydrolysis of phospholipids membranous structures are still present. The rhodopsin is located in these structures, presumably in the form of two-dimensional lateral aggregates. This explains the cross-fracturing of the membranous structures, regularly observed upon freeze-fracturing of the phospholipase-treated photoreceptor membranes.


HLA-DRB1*08:48, a novel allele identified in a Brazilian donor.
The new allele presents a point mutation at codon 67.1 (ATC→CTC) resulting in a conservative change from isoleucine to leucine.


Extrafloral nectaries: ants, herbivores and fecundity in Cassia fasciculata.
Extrafloral nectaries of Cassia fasciculata attract nectar feeding ants which protect the plant against leaf herbivores. High ant visitation in late July coincided with high herbivore densities at two sites in east central Iowa. The highest level of leaf herbivory occurred during the time of flowering and early fruit filling, just after the peak of herbivore and ant activity. Results of ant exclusion experiments at the two sites showed that ant visitation resulted in decreased herbivore numbers, decreased leaf area loss, increased growth, and at one site decreased plant mortality. However, this reduction in leaf area loss and increase in growth did not translate into seed set differences between plants with and without ants at either site. Initial plant size was more important than the presence or absence of ants in determining fecundity for this temperate annual during a year of summer drought.


Acute and chronic bacterial infections and sarcoidosis.
Pathogen-induced inflammatory diseases mostly involving, but sometimes exclusively affecting, the central nervous system (CNS) manifest with a plethora of signs and symptoms. The different diseases are still difficult to cure despite modern diagnostic, preventive, and therapeutic advances, and this is mainly due to the host inflammatory response, leading to irreversible tissue damage. Knowledge about underlying pathomechanisms is constantly growing, and numerous studies on humans, human material, and animal models as well as in vitro systems have considerably increased our understanding of molecular mechanisms; however, there are still enormous uncertainties with respect to host-pathogen interaction and treatment. There are important regional variations as to prevalence and susceptibility of diseases, reflecting the importance of environmental factors, and immunogenetic peculiarities of different ethnicities. In addition, the opportunistic infections of the CNS are becoming very relevant, not only in the context of human immunodeficiency virus (HIV), but also in the context of modern, highly specific immunosuppressive or immunomodulatory treatments, evoking new and unmet diagnostic and therapeutic challenges. This chapter summarizes up-to-date knowledge about bacterial CNS infections, as well as cerebral sarcoidosis, focussing on morphologic aspects.


Study of the idiotypy of lipopolysaccharide-specific polyclonal and monoclonal antibodies.
The monoclonal antibodies produced by a variety of hybridomas making antibody specific for E. coli 0113 lipopolysaccharide (LPS) were purified by affinity chromatography and their fine specificity studied. All reacted specifically with the polysaccharide moiety of LPS from E. coli 0113 and from Neisseria lactamica; two reacted with LPS from Pseudomonas aeruginosa and one reacted with LPS from Klebsiella pneumoniae. Polyclonal and monoclonal syngeneic and semi-syngeneic anti-idiotypic antisera were produced to study the idiotypy of LPS-specific monoclonal antibodies which express a complex cross-reactive idiotype (IdX) as well as individual idiotypes. E. coli 0113 LPS-specific antibodies produced by BALB/c mice express this IdX and the kinetics for its expression was examined using mice either primed or hyperimmunized with LPS; idiotypic maturation was observed, but we were unable to detect an auto-anti-idiotypic antibody response. This IdX was expressed on E. coli 0113 LPS-specific antibodies from all strains of mice examined, indicating that its expression is not restricted by genes linked to the IgCH locus.


Neural network-based performance assessment of one- and two-liquid phase biotrickling filters for the removal of a waste-gas mixture containing methanol, α-pinene, and hydrogen sulfide.
The performance of one- and two-liquid phase biotrickling filters (OLP/TLP-BTFs) treating a mixture of gas-phase methanol (M), α-pinene (P), and hydrogen sulfide (H) was assessed using artificial neural network (ANN) modeling. The best ANN models with the topologies 3-9-3 and 3-10-3 demonstrated an exceptional capacity for predicting the performance of O/TLP-BTFs, with R2 > 99%. The analysis of causal index (CI) values for the model of OLP-BTF revealed a negative impact of M on P removal (CI = -2.367), a positive influence of P and H on M removal (CI = +7.536 and CI = +3.931) and a negative effect of H on P removal (CI = -1.640). The addition of silicone oil in TLP-BTF reduced the negative impact of M and H on P degradation (CI = -1.261 and CI = -1.310, respectively) compared to the OLP-BTF. These findings suggested that silicone oil had the potential to improve P availability to the biofilm by increasing the concentration gradient of P between the air/gas and aqueous phases. Multi-objective particle swarm optimization (MOPSO) suggested an optimum operational condition, i.e. inlet M, P, and H concentrations of 1.0, 1.1, and 0.3 g m-3, respectively, with elimination capacities (ECs) of 172.1, 26.5, and 0.025 g m-3 h-1 for OLP-BTF. Likewise, one of the optimum operational conditions for TLP-BTF is achievable at inlet concentrations of 4.9, 1.7, and 0.8 g m-3, leading to the optimum ECs of 299.7, 52.9, and 0.072 g m-3 h-1 for M, P, and H, respectively. These results provide important insights into the treatment of complex waste gas mixtures, addressing the interactions between the pollutant removal characteristics in OLP/TLP-BTFs and providing novel approaches in the field of biological waste gas treatment.


No differences in the pharmacodynamics and pharmacokinetics of the thrombin receptor antagonist vorapaxar between healthy Japanese and Caucasian subjects.
Vorapaxar, a novel antiplatelet agent in advanced clinical development for the prevention and treatment of atherothrombotic disease, is a potent, orally bioavailable thrombin receptor antagonist selective for the protease-activated receptor 1 (PAR-1). Since race/ethnicity may affect the safety, efficacy and dosage of drugs, this study was conducted to evaluate potential differences in the pharmacodynamics, pharmacokinetics and safety of vorapaxar after single (5, 10, 20, or 40 mg) or multiple (0.5, 1, or 2.5 mg once daily) doses in healthy Japanese and matched (gender, age, height, and weight) Caucasian volunteers. Vorapaxar was well tolerated in both Japanese and Caucasian subjects. Pharmacodynamic and pharmacokinetic profiles of vorapaxar in the two racial/ethnic groups were similar. In both racial groups, complete inhibition of platelet aggregation was achieved most rapidly with vorapaxar 40 mg and was consistently achieved and maintained with a 2.5 mg daily maintenance dose. There were no substantial differences in the safety, pharmacokinetics or pharmacodynamics of vorapaxar between Japanese and Caucasian subjects.


The NMR structure of the engineered halophilic DnaE intein for segmental isotopic labeling using conditional protein splicing.
Protein trans-splicing catalyzed by split inteins has been used for segmental isotopic labeling of proteins for alleviating the complexity of NMR signals. Whereas inteins spontaneously trigger protein splicing upon protein folding, inteins from extremely halophilic organisms require a high salinity condition to induce protein splicing. We designed and created a salt-inducible intein from the widely used DnaE intein from Nostoc punctiforme by introducing 29 mutations, which required a lower salt concentration than naturally occurring halo-obligate inteins. We determined the NMR solution structure of the engineered salt-inducible DnaE intein in 2 M NaCl, showing the essentially identical three-dimensional structure to the original one, albeit it unfolds without salts. The NMR structure of a halo-obligate intein under high salinity suggests that the stabilization of the active folded conformation is not a mere result of various intramolecular interactions but the subtle energy balance from the complex interactions, including the solvation energy, which involve waters, ions, co-solutes, and protein polypeptide chains.


Using pure protein to build a multiple reaction monitoring mass spectrometry assay for targeted detection and quantitation.
Multiple reaction monitoring (MRM) is an increasingly popular mass spectrometry-based method to simultaneously detect and quantify multiple proteins. MRM is particularly useful for validating biomarkers discovered with a mass spectrometer and any analite discovered by MS can be monitored by MR because an MRM assay can be developed without the need to generate specific antibodies. In this chapter, we present a robust and systematic procedure to rapidly build a high-sensitivity MRM assay using purified protein as the starting material. Theoretical digestion of the protein with trypsin is used to identify mass spectrometry--compatible peptides and to generate preliminary MRM transitions to detect these peptides. Peptides generated by trypsin cleavage of the actual protein are then run on a liquid chromatography column coupled to a triple quadrupole mass spectrometer, which is programmed with the preliminary transitions. Whenever a transition is detected, it triggers dissociation of the corresponding peptide and collection of a full mass range scan of the resulting fragment ions. From this scan, fragment ions yielding the strongest and most reproducible signals are utilized to design empirical MRM transitions. The assay is further refined by optimizing the collision energy and creating a standard curve to measure sensitivity. Once MRM transitions have been established for a particular protein, they can be combined with transitions for other target proteins to create multiplex assays and used to quantify proteins in samples arising from serum, urine, subcellular fractions, or any other specemen of interest.


Visual classification of banded human chromosomes ii. classification and karyotyping of integrated density profiles.
Visual classification and karyotyping of 897 integrated density profiles generated from straight and non-overlapping chromosomes from 22 trypsin-banded metaphases of average quality was carried out and evaluated. The results were compared with visual classification of photographic prints of the same 897 chromosomes. The experiments were carried out by one observer. About 5% errors were made in classification of isolated profiles; 0-5% errors were made in karyotyping profiles and about 3% errors were made in classification of isolated chromosome prints. The reason for the small error rate obtained by karyotyping profiles as compared to the error rate when classifying isolated profiles was assumed to be the use of a priori knowledge of the composition of (normal) metaphases and the possibility of making appropriate comparisons between the individual profiles within the metaphase. Comparison between classification of isolated prints and of profiles showed different error patterns on the basis of which it was assumed that prints constitute a better basis for visual classification than profiles. The results seemed to indicate two ways of improving computer classification of banded chromosomes: (1) information of value in the chromosomes (band pattern, shape etc.) should be extracted from the digitized chromosome image in a manner superior to the simple integration by which profiles are produced; (2) computer karyotyping should simulate the human method, thus taking advantage of a priori knowledge of the composition of the metaphases and being able to make appropriate comparisons between individual chromosomes.


[Protein motors: structure and generation of mechanical force].
Recent data about the structural and functional features of protein motors (myosin, dynein, kinesin) are presented. The mechanism by which the chemical energy of ATP is transduced into mechanical work is discussed.


An alternative interpretation of "intensive" PTSD treatment failures.
An evaluation of program failures in the treatment of combat-related posttraumatic stress disorder has led some reviewers to conclude that the focus of treatment should be shifted away from combat trauma and directed toward other problems. A more detailed examination of these programs reveals that they rarely involve the systematic use of the most soundly-validated PTSD treatment, trauma-focused therapy.


Pathways for Carotenoid Biosynthesis, Degradation, and Storage.
Carotenoids are isoprenoid compounds synthesized de novo in all photosynthetic organisms as well as in some nonphotosynthetic bacteria and fungi. In plants, carotenoids are essential for light harvesting and photoprotection. They contribute to the vivid color found in many plant organs. The cleavage of carotenoids produces small molecules (apocarotenoids) that serve as aroma compounds, as well as phytohormones and signals to affect plant growth and development. Since carotenoids provide valuable nutrition and health benefits for humans, understanding of carotenoid biosynthesis, catabolism and storage is important for biofortification of crops with improved nutritional quality. This chapter primarily introduces our current knowledge about carotenoid biosynthesis and degradation pathways as well as carotenoid storage in plants.


Acute medullar compression secondary to a septic arthritis of a thoracic facet joint: a case report and review of literature.
Septic arthritis of a facet joint (SAFJ) is a rare entity and frequently underdiagnosed. It is most frequently localised in the lumbar segment. A 48-year-old woman presented at our emergency room with a chief complaint of lumbar pain and perineal hypoesthesia. An urgent lumbar Magnetic Resonance Imaging (MRI) was performed showing no signs of compressive pathology. Intravenous painkillers were administered improving her clinical symptoms, so she was discharged from the emergency department to be followed at our out-patient clinic. After 12 h, the patient presented again referring an acute loss of strength in her lower limbs and paresthesias at a T10 sensitive level. Due to the severity of the symptoms, we performed an urgent dorsal MRI that showed a septic arthritis of the left T8-T9 facet joint and an epidural abscess causing a medullar compression. Blood cultures were performed before surgical treatment. An urgent laminectomy of T8 and debridement of the abscess were performed. Intraoperative microbiology and blood cultures were positive for Streptococcus constellatus. After surgery, the patient presented a progressive improvement of her symptomatology. Physicians should have in mind and rule out this clinical entity to avoid severe consequences that a misdiagnosed SAFJ could develop.


Oral manifestations of non-Hodgkin's lymphoma in HIV-infected patients.
The incidence of non-Hodgkin's lymphomas (NHL) in patients infected with human immunodeficiency virus (HIV) is relatively high. However, there have been few reports on the clinical and histopathological features of oral manifestations of NHL in these patients. The lesions reported so far were all tumorous swellings with or without ulceration, as in non-HIV-infected patients. In this report 3 cases are presented of HIV-infected patients with solitary, primary oral NHL. These lesions showed a striking resemblance to acute, necrotizing gingivitis, a common finding in these patients, thus making the diagnosis more difficult.


Transcoding sound to spelling: single or multiple sound unit correspondence?
We report a detailed analysis of the written spelling of an aphasic patient, KT, in whom no viable comprehension could be demonstrated despite accurate repetition and fluent speech (transcortical sensory aphasia). His spelling conformed in all respects with the definition of an orthographic/lexical dysgraphic such that his writing of regular, orthographically unambiguous words and nonsense syllables was entirely satisfactory. Lexical variables such as word class or word frequency had no effect on his performance. Irregular or ambiguously spelled words were selectively impaired. An independent measure of orthographical ambiguity was defined in relation to the frequency with which a phoneme was represented by a particular grapheme and the number of alternative graphemes for the same sound. For the majority of sounds studied, KT was able to demonstrate the use of all the most frequent alternative transcoding units for each sound but he did not use them in the same frequency with which they occurred in written English. Thus his performance bore little or no relationship to predictions based on single phoneme/grapheme counts and there was unequivocal evidence for his ability to use multiple sound-unit correspondences.


Mitochondrial DNA mutations cause resistance to opening of the permeability transition pore.
The age-related accumulation of mitochondrial DNA mutations has the potential to impair organ function and contribute to disease. In support of this hypothesis, accelerated mitochondrial mutagenesis is pathogenic in the mouse heart, and there is an increase in myocyte apoptosis. The current study sought to identify functional alterations in cell death signaling via mitochondria. Of particular interest is the mitochondrial permeability transition pore, opening of which can initiate cell death, while pore inhibition is protective. Here, we show that mitochondria from transgenic mice that develop mitochondrial DNA mutations have a marked inhibition of calcium-induced pore opening. Temporally, inhibited pore opening coincides with disease. Pore inhibition also correlates with an increase in Bcl-2 protein integrated into the mitochondrial membrane. We hypothesized that pore inhibition was mediated by mitochondrial Bcl-2. To test this hypothesis, we treated isolated mitochondria with Bcl-2 antagonistic peptides (derived from the BH3 domain of Bax or Bid). These peptides released the inhibition to pore opening. The data are consistent with a Bcl-2-mediated inhibition of pore opening. Thus, mitochondrial DNA mutations induce an adaptive-protective response in the heart that inhibits opening of the mitochondrial permeability pore.


Histocompatibility antigen-activated cytotoxic T lymphocytes. I. Estimates of the absolute frequency of killer cells generated in vitro.
A sensitive procedure employing limiting dilution of activated lymphocytes and 51Cr release from highly labeled target cells was used to derive minimal estimates of the absolute frequency of cytotoxic T lymphocytes (CTL) present in a population of mouse lymphocytes activated to alloantigens of the major histocompatibility complex in bulk mixed lymphocyte cultures. From this figure (0.7-1.2%), the maximal rate of target cell killing could be calculated to be approximately 4 targets/CTL/hour.


Safety of coronary stenting early after thrombolysis in patients with acute myocardial infarction: one- and six-month clinical and angiographic evolution.
To determine the feasibility and safety of early posthrombolysis coronary stenting and the incidence of further reocclusion, we followed 99 consecutive patients with acute myocardial infarction thrombolyzed with rt-PA 2.0 +/- 0.8 hr after onset. Culprit artery was stented 14.0 +/- 7.0 hr after thrombolysis. All patients underwent clinical and angiographic follow-up at 1 and 6 months. Angiographic success was achieved in 99% of cases. Neither major cardiac events nor bleeding or vascular complications occurred during hospital stay. At 30 days, no events occurred and normal flow persisted in all stented arteries. At 6 months, only one artery reoccluded (1%), resulting in a nonfatal reinfarction. Restenosis rate was 21%. Contribution of the infarcted area to left ventricular function significantly increased from baseline to 30-day and to 6-month evaluations. Thus, early posthrombolysis stenting is a safe strategy with a low reocclusion rate, which seems to allow functional recovery of the infarcted area. Further studies are necessary to define its impact on survival and cost-effectiveness.


Effects of heavy metals on fish physiology - A review.
The pollution by heavy metals poses a serious threat to the aquatic environment and to the organisms if the concentration of heavy metals in the environment exceeds the safe limits. Due to their non-biodegradable and long persistence nature in the environment, heavy metals cause toxicity in fish by producing oxygen reactive species through oxidizing radical production. In this review, we investigated the effects of heavy metals on fish physiology with special emphasis on hemato-biochemical properties, immunological parameters especially hormones and enzymes, histopathology of different major organs and underlying molecular mechanisms. All those parameters are significantly affected by heavy metal exposure and are found to be important bio-monitoring tools to assess heavy metal toxicity. Hematological and biochemical alterations have been documented including cellular and nuclear abnormalities in different fish species exposed to different concentrations of heavy metals. Major fish organs (gills, liver, kidneys) including intestine, muscles showed different types of pathology specific to organs in acute and chronic exposure to different heavy metals. This study also revealed the expression of different genes involved in oxidative stress and detoxification of heavy metals. In a nutshell, this article shades light on the manipulation of fish physiology by the heavy metals and sought attention in the prevention and maintenance of aquatic environments particularly from heavy metals contaminations.


Imaging of P-glycoprotein of H69/VP small-cell lung cancer lines by scanning near-field optical microscopy and confocal laser microspectrofluorometer.
Chemoresistance remains the major obstacle to successful therapy of the lung cancer. The multi-drug resistance (MDR) is generally associated with altered expression of drug transporter proteins, such as P-glycoprotein (P-gp). So the distribution of P-gp on the membrane is of great importance to further study the interaction between drug and P-gp. In the present work, the P-gp of the H69/VP small-lung cancer cells was detected using monoclonal antibody UIC2. A secondary goat-anti mouse antibody coupled with biotin was used. The fluorescence emission was detected from a streptavidin-Texas Red. Results were investigated by a homemade scanning near-field optical microscope (SNOM) coupled to a confocal laser microspectrofluorometer (CLMF). Topographical images and localized spectra were obtained at the level of one cell membrane. It was found that the distribution of P-gp is not homogeneous and this observation is basically in accord with the fluorescent images obtained by classical microscopy. The distribution of P-gp would be localized in a higher region on a cell surface. This methodology would also enhance our understanding of MDR under physiological conditions.


[Results of treatment in patients with destructive pulmonary tuberculosis without consideration of drug sensitivity in Mycobacterium tuberculosis].
Treatment of 63 patients having infiltrative and disseminated pulmonary tuberculosis attended by decay and bacterial excretion with 4 essential drugs (isoniazid, rifadine, pyrazinamide, ethambutol) and, in disseminated processes, additionally with streptomycin without determining their drug sensitivity contributed to the cessation of sputum acid-resistant mycobacteria in 96.8% and to cavity cicatrisation in 77.8%. Irregular use of izoniazid and rifadine during continued treatment is one of the reasons for the low rates of cavity resolution.


Risk factors for ischemic stroke: a prospective study in Rochester, Minnesota.
A cohort of 1,804 residents of Rochester, Minnesota, who were at least 50 years old, free of stroke, and who underwent examination at the Mayo Clinic in 1960, was followed for 13 years. During this period, there were 110 first ischemic strokes and 616 deaths without stroke. The time of onset, if available, or the time of diagnosis of potential risk factors was determined for all patients during the study and was used to construct a proportional hazards model of time to occurrence of stroke with time-dependent risk factors. The model included 8 risk factors (2 fixed and 6 time-dependent). For these, the individual relative risks are: 1.6 for age (per 10 years), 2.0 for males, 4.0 for definite hypertension, 3.9 for transient ischemic attacks, 2.2 for hypertensive heart disease, 2.2 for coronary heart disease, 1.7 for congestive heart failure, and 1.7 for diabetes mellitus. Atrial fibrillation was not a significant risk factor using time-dependent multivariate analysis.


Evaluation of the suitability of chromatographic systems to predict human skin permeation of neutral compounds.
Several chromatographic systems (three systems of high-performance liquid chromatography and two micellar electrokinetic chromatography systems) besides the reference octanol-water partition system are evaluated by a systematic procedure previously proposed in order to know their ability to model human skin permeation. The precision achieved when skin-water permeability coefficients are correlated against chromatographic retention factors is predicted within the framework of the solvation parameter model. It consists in estimating the contribution of error due to the biological and chromatographic data, as well as the error coming from the dissimilarity between the human skin permeation and the chromatographic systems. Both predictions and experimental tests show that all correlations are greatly affected by the considerable uncertainty of the skin permeability data and the error associated to the dissimilarity between the systems. Correlations with much better predictive abilities are achieved when the volume of the solute is used as additional variable, which illustrates the main roles of both lipophilicity and size of the solute to penetrate through the skin. In this way, the considered systems are able to give precise estimations of human skin permeability coefficients. In particular, the HPLC systems with common C18 columns provide the best performances in emulating the permeation of neutral compounds from aqueous solution through the human skin. As a result, a methodology based on easy, fast, and economical HPLC measurements in a common C18 column has been developed. After a validation based on training and test sets, the method has been applied with good results to the estimation of skin permeation of several hormones and pesticides.


2-Arylalkyl-substituted anthracenones as inhibitors of 12-lipoxygenase enzymes. 2. Structure-activity relationships of the linker chain.
A series of 2-arylalkyl-substituted anthracenones were tested as inhibitors of three types of 12-lipoxygenase isoforms in epidermal homogenate of mice, bovine platelets and porcine leukocytes. Their inhibitory activities were compared with those to inhibit the 5-lipoxygenase enzyme in bovine leukocytes. The compounds were synthesised by Marschalk, Wittig or Horner-Emmons reaction at the anthracenedione stage and then reduced to the anthracenones. Structure-activity relationship for the chain linking the anthracenone nucleus and the phenyl ring terminus was investigated. The 2-phenylethyl analogues were among the most potent inhibitors, and 3,4-dimethoxy-substituted 10f was identified as a selective inhibitor of the 12-LO enzymes over 5-LO. Selectivity for 12-LO isoforms was observed with an increase in the overall lipophilicity of the inhibitors. However, none of the linker chains of the 2-substituted anthracenones provided inhibitors that were able to discriminate between the 12-LO isoforms.


Rotavirus vaccine clinical trials: a cross-sectional analysis of clinical trials registries.
Rotavirus is a primary infectious virus causing childhood diarrhoea and is associated with significant mortality in children. Three African countries (Nigeria, the Democratic Republic of Congo, and Angola) are among the five countries that account for 50% of all diarrheal-related deaths worldwide. This indicates that much needs to be done to reduce this burden. The World Health Organization International Clinical Trial Registry Platform (WHO ICTRP) is a global repository for primary registries reporting on clinical trials. This study aimed to identify and describe planned, ongoing, and completed rotavirus vaccine trials conducted globally. We searched WHO-ICTRP on 17 June 2021 and conducted a cross-sectional analysis of rotavirus studies listed in the database. Data extraction included trial location, participant age, source of the trial record, trial phase, sponsor, and availability of results. We used the Microsoft Excel 365 package to generate descriptive summary statistics. We identified 242 rotavirus vaccine trials registered from 2004 to 2020. Most of these trials were registered retrospectively, with only 26% of the rotavirus vaccine trials reporting the availability of results in their registries. Most of the trials are studying children aged less than 5 years. The recruitment status for these trials is currently shown in the WHO-ICTRP as "not recruiting" for 80.17% of trials, "recruiting" for 11.57% of trials recruiting, and unknown for 6.61% of trials. The continents in which these rotavirus vaccine trials have recruitment sites in Asia (41%) and North America (20%), with the maximum number of trials in the clinical trial registries coming from India (21%) and the USA (11%) with most being sponsored by the pharmaceutical industry. Our analysis shows that only 26% of the rotavirus vaccine trials report the availability of results in their registries. Mapping rotavirus vaccine clinical trial activity using data from the WHO ICTRP beneficial provides valuable information on planned, ongoing, or completed trials for researchers, funders, and healthcare decision-makers. Despite the high rotavirus disease burden in low- and middle-income countries, including Africa, there is minimal clinical trial activity related to the condition on the continent. The clinical trial registries as a valuable tool to share interim results of the trials.