Angiogenin up-regulation correlates with adverse clinicopathological and biological factors, increased microvascular density and poor patient outcome in neuroblastomas.
As new biomarkers are urgently needed to identify children with high-risk neuroblastoma (NB), we studied the contribution of angiogenin (ANG) to angiogenesis and its association with clinicopathological and biological features and patient outcome in NB. Ninety NBs and 12 ganglioneuromas (GNs) were immunostained for ANG and CD31. ANG expression in NB tumoral cells (ANG scores) and vessels [ANG microvascular density (MVD)] and total MVD (CD31 MVD) were determined. The ANG score was significantly greater in NBs than in GNs (P = 0.015) and in NBs from children with stage 4 tumours, high-risk disease, unfavourable pathology (P < 0.001 for each), MYCN amplification (P = 0.003), and 1p deletion (P = 0.002). ANG scores correlated with ANG MVD and CD31 MVD (P < 0.001 for each). Total ANG and CD31 protein levels, measured with a sensitive enzyme-linked immunosorbent assay, were highly correlated (P = 0.003). High ANG scores were associated with decreased overall and event-free survival (log-rank test, P = 0.025 and P = 0.018, respectively). High ANG MVD was associated with decreased overall and event-free survival (log-rank test, P = 0.009 and P = 0.026, respectively). High CD31 MVD was associated with decreased event-free survival (P = 0.045). The strong correlation of ANG up-regulation with total MVD and adverse clinicopathological and biological factors indicates that ANG supports growth and progression in NB.


Demonstration of multiple regulatory factors for purified human leukocyte 5-lipoxygenase.
The human leukocyte 5-lipoxygenase is a unique enzyme in its class because of its involvement in the synthesis of the biologically active leukotrienes. Furthermore, unlike most other lipoxygenases, this enzyme requires multiple stimulatory factors for maximal activity. These include Ca2+, ATP, and three non-dialyzable cellular components, two cytosolic, and one membrane-associated. The mechanism of action of these factors is not yet well understood; however, a Ca2+-dependent association of the enzyme and one of the cytosolic factors with the membrane has been demonstrated. These findings suggest that stimulation of the leukocyte, resulting in an increased intracellular Ca2+ concentration, may result in the translocation of the enzyme and the factor to a membrane site, thereby facilitating the interaction of these two proteins with other enzymes involved in the 20:4 metabolic cascade. The development of a better understanding of these processes should not only help to define the biochemical basis for the regulation of leukotriene formation, but should also yield valuable information concerning the more general aspects of stimulus-response coupling in the leukocyte.


Development of an 241Am applicator for continuous low-dose-rate irradiation of the rat sarcoma BA1112.
An 241Am applicator for continuous low-dose-rate irradiation of the rat sarcoma BA1112 has been developed. The irradiator consists of two disc sources, each containing 800 mCi of 241Am, an isotope which emits primarily 60 keV photons. The disc sources are held in a specially-designed light-weight helmet which surrounds the tumor on the head of the rat. Dose distributions produced by these sources have been measured using an ionization chamber, thermoluminescent dosimeters and Fricke dosimeter. A computerized treatment planning system has been modified to compute dose distributions from 241Am sources, to optimize the design of this applicator. Computed and measured dose distributions for several values of separation between the 241Am discs are presented. A survival curve for cells from tumors irradiated in vivo with this applicator has been determined by an in vitro colony formation technique. The mean lethal dose DO was found to be 720 cGy for an average tumor dose rate of 95 +/- 7 cGy/hr. The major advantages of the 241Am applicator in comparison with the 192Ir applicator used previously for continuous low-dose-rate studies are: a considerably smaller half value layer thickness and the longer half life of the radionuclide. These features make it more suitable for long-term tumor cure studies because of the lower whole body dose to the animal, the availability of relatively constant dose-rate irradiators for many years, the decreased shielding requirements for the animal care facility and the diminished exposure to laboratory personnel involved with the implants on the animals.


The P-300 event-related potential in experimental nitrous oxide exposure.
Without the availability of objective measures of central neurologic dysfunction, neuroepidemiologic investigations of individuals exposed to psychoactive drugs and potential environmental and occupational neurotoxins are extraordinarily difficult, particularly when the central nervous system manifestations are subtle, diffuse, and limited to cognitive deficits. In an attempt to assess and quantitate psychomotor dysfunction, P-300 event-related potentials, Symbol Digit Test, Continuous Performance Test, and Finger Tapping Test were obtained from six subjects sequentially exposed to nitrous oxide at 0%, 10%, 20%, and 40%. With increasing concentration of N2O, there was prolongation of P-300 latency and worsening of Continuous Performance Test and Symbol Digit Test performance; P-300 amplitude and Finger Tapping Test performance were decreased by exposure to N2O. This study demonstrates a dose-dependent reduction in P-300 amplitude and prolongation of P-300 latency in subjects in whom psychomotor impairment was induced by the acute administration of N2O.


Cloning and characterization of the Arabidopsis thaliana lupeol synthase gene.
A 2274 bp Arabidopsis thaliana cDNA was isolated that encodes a protein 57% identical to cycloartenol synthase from the same organism. The expressed recombinant protein encodes lupeol synthase, which converts oxidosqualene to the triterpene lupeol as the major product. Lupeol synthase is a multifunctional enzyme that forms other triterpene alcohols, including beta-amyrin, as minor products. Sequence analysis suggests that lupeol synthase diverged from cycloartenol synthase after plants diverged from fungi and animals. This evolutionary order is the reason that fungi and animals do not make lupeol.


The identification of a cell culture inhibitor in a tumour extract.
An extract of Harding-Passey mouse melanoma was found to inhibit the proliferation of the same cell line grown in culture when measured by both thymidine incorporation and by the increase in cell number. The active ingredient was purified by ultrafiltration, column chromatography and preparative electrophoresis. The purified material was identified by mass spectrometry and by gas chromatography as spermidine. The partially purified material reversed the methylglyoxal Bis-guanyl hydrazone (Methyl-GAG) inhibition of cultured cells to the same extent as spermidine. Very low concentrations of Methyl-GAG were found to suppress the spermidine inhibition of thymidine incorporation into cells. The inhibitor extracted from melanoma tumours behaved in the same way as spermidine at all Methyl-GAG concentrations. Thus, it is unlikely that the active ingredient in the biological extract is anything other than spermidine.


A rheological investigation of the self-assembly and adsorption behavior of a surfactant salt.
The properties of a surfactant salt obtained by neutralizing oleic acid with an ethoxylated stearylamine were determined in blends of water and propylene glycol. The adsorption of this surfactant salt onto the surface of a commercial TiO(2) dispersed in blends of water and propylene glycol was studied using a rheometer. At low propylene glycol content the dispersions exhibited Newtonian behavior, but became shear-thinning fluids with high viscosity at propylene glycol contents above a critical concentration. The observed behavior is consistent with a model involving a surfactant bilayer below the critical point, moving to a monolayer above the critical point. The high viscosity above the critical point is generated by reversible flocculation via hydrophobic forces. The viscosity of the dispersion flocculated by the hydrophobic forces was found to be much higher than that caused by flocculation via van der Waals forces in the absence of surfactant. Changing both the total concentration of the surfactant in the dispersion and the dispersion temperature resulted in a reversible transition between the bilayer and the monolayer. Although the surfactant was always above its critical micelle concentration (CMC) the amount on the particle surface varied appreciably with both propylene glycol and surfactant concentration.


Perceptions of caregivers about special respite services for the elderly.
Questionnaires were circulated to 48 family members who had arranged for respite care for ill elderly relatives. Caregiver families used their respite for vacations, personal business, freedom from caregiving, and surgery. Eighteen (78%) wished to participate in respite again because they thought it the best available arrangement to maintain their mental health during caregiving.


Subvalvular pannus and thrombosis in a mitral valve prosthesis.
A 69-year-old female underwent cardiac CT to evaluate prosthetic valve (PHV) dysfunction detected on echocardiography. A CT coronal and en face views of the mitral annular plane showed a low-density, mass-like lesion on the left atrial side of the PHV and a high-density, plate-like lesion on the left ventricular side of PHV. A repeat of the mitral valve replacement was performed, and preoperative CT findings of both the thrombus on the left atrial side and pannus formation on the LV side were confirmed in the operative findings.


Prox1, master regulator of the lymphatic vasculature phenotype.
In contrast to the extensive molecular and functional characterization of blood vascular endothelium, little is known about the mechanisms that control the formation and lineage-specific differentiation and function of lymphatic vessels. The homeobox gene Prox1, the vertebrate homologue of the Drosophila prospero gene, has been recently identified to be required for the induction of lymphatic vascular development from preexisting embryonic veins, and studies in Prox1-deficient mice have confirmed Florence Sabin's original hypothesis about the origin of the lymphatic vascular system from embryonic veins. The recent establishment of cell culture models for the selective propagation of blood vascular and lymphatic endothelial cells, together with the findings that these cells maintain their lineage-specific differentiation in vitro, has led to the discovery that Prox1 expression is sufficient to induce a lymphatic phenotype in blood vascular endothelium. Ectopic expression of Prox1 downregulated blood vascular-associated genes and also upregulated some of the known lymphatic endothelial cell markers. Together, these studies suggest that the blood vascular phenotype represents the default endothelial differentiation and they identify an essential role of Prox1 in the program specifying lymphatic endothelial cell fate.


The cortical contrast accumulation from brain computed tomography after endovascular treatment predicts symptomatic hemorrhage.
The prognostic value of contrast accumulation from non-contrast brain computed tomography taken immediately after endovascular reperfusion treatment in acute ischaemic stroke patients to predict symptomatic hemorrhage was studied. Between July 2007 and August 2014, acute anterior circulation ischaemic stroke patients who were treated by intra-arterial thrombolysis or thrombectomy were included. Contrast accumulation was defined as a high attenuation area from non-contrast brain computed tomography immediately taken after endovascular reperfusion treatment, and patients were categorized into three groups according to the presence and location of contrast: (i) negative, (ii) cortical involvement and (iii) non-cortical involvement. The rates of symptomatic hemorrhage after 24 h and functional outcome at discharge were compared between patients with and without cortical involvement. Of 64 patients who were treated by endovascular intervention, contrast accumulation was detected in 56, including 33 patients with cortical involvement and 23 patients without cortical involvement. The cortical involvement pattern was more frequently associated with symptomatic hemorrhage (13 vs. 1 patient, P = 0.003) and with grave outcome at discharge with modified Rankin Scale 5 or 6 (14 vs. 4, P = 0.048) than the non-cortical involvement group. Multivariate logistic regression analysis including initial collateral status and occlusion site disclosed that cortical involvement pattern independently predicted symptomatic hemorrhage after endovascular treatment (odds ratio 19.0, confidence interval 1.6-227.6, P = 0.020). Our study provides evidence that the cortical involvement of contrast accumulation is associated with symptomatic hemorrhage after endovascular reperfusion treatment.


Effect of cardioplegic and organ preservation solutions and their components on coronary endothelium-derived relaxing factors.
Cardioplegic (and organ preservation) solutions were initially designed to protect the myocardium (cardiac myocytes) during cardiac operation (and heart transplantation). Because of differences between cardiac myocytes and vascular (endothelial and smooth muscle) cells in structure and function, the solutions may have an adverse effect on coronary vascular cells. However, such effect is often complicated by many other factors such as ischemia-reperfusion injury, temperature, and perfusion pressure or duration. To evaluate the effect of a solution on the coronary endothelial function, a number of points should be taken into consideration. First, the overall effect on endothelium should be identified. Second, the effect of the solution on the individual endothelium-derived relaxing factors (nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor) must be distinguished. Third, the effect of each major component of the solution should be investigated. Lastly, the effect of a variety of new additives in the solution may be studied. Based on available literature these issues are reviewed to provide information for further development of cardioplegic or organ preservation solutions.


Correlation analysis of hysterectomy and ovarian preservation with depression.
The relationship between hysterectomy and ovarian preservation and depression is controversial. This study aimed to determine the association of hysterectomy and ovarian preservation with depression using National Health and Nutrition Examination Survey. To assess the association between hysterectomy with or without ovariectomy and depression, we used 3 methods. Method 1: propensity score model (PSM) was established. Method 2 was logistics regression analysis of hysterectomy and depression before and after PSM. Method 3 was a logistics regression analysis of the relationship between hysterectomy and different depressive symptoms. At the same time, in order to evaluate the association between hysterectomy with or without oophorectomy and depression, we explored the effect of four different surgical procedures on depression using logistic regression equations. We enrolled 12,097 women, of whom 2763 underwent hysterectomy, 34.455% were positive for depression. After weighting, 33.825% of the total sample had a PHQ ≥ 5. Finally, a total of 2778 women were successfully matched by propensity score, and 35.537% of them were positive for depression. The OR for PHQ ≥ 5 was 1.236 after crude adjustment of covariates and 1.234 after exact adjustment. This suggests that Hysterectomy is strongly associated with positive depression. Positive depression (PHQ ≥ 5) was associated with little interest, feeling down and trouble concentrating. It was not associated with trouble sleeping, feeling tired, poor appetite, feeling bad, slow moving or speaking, and suicidal thoughts. Oophorectomy-alone is not associated with depression. Hysterectomy-alone is a risk factor for depression, but Hysterectomy combined with Oophorectomy has a stronger correlation with depression than Hysterectomy-alone. Women who have had a Hysterectomy are at higher risk of depression than women who have not had a Hysterectomy, and this risk may be exacerbated if the uterus and ovaries are removed. When clinically appropriate, surgeons should try to preserve the patient's ovaries.


Replication of a genetic variant for prostate cancer-specific mortality.
Few genetic variants have been confirmed as being associated with prostate cancer-specific mortality (PCSM). A recent study identified 22 candidate single-nucleotide polymorphisms (SNPs) associated with PCSM in a Seattle-based patient cohort. Five of these associations were replicated in an independent Swedish cohort. We genotyped these 22 SNPs in Physicians' Health Study (PHS) participants diagnosed with prostate cancer (PCa). Using the same model that was found to be most significant in the Seattle cohort, we examined the association of these SNPs with lethal disease with Cox proportional hazards models. One SNP, rs5993891 in the ARVCF gene on chromosome 22q11, which had also replicated in the Swedish cohort, was also significantly associated with PCSM in the PHS cohort (hazard ratio (HR)=0.32; P=0.01). When we tested this SNP in an additional cohort (Health Professionals Follow-up Study, HPFS), the association was null (HR=0.95, P=0.90); however, a meta-analysis across all studies showed a statistically significant association with a HR of 0.52 (0.29-0.93, P=0.03). The association of rs5993891 with PCSM was further replicated in PHS and remains significant in a meta-analysis, though there was no association in HPFS. This SNP may contribute to a genetic panel of SNPs to determine at diagnosis whether a patient is more likely to exhibit an indolent or aggressive form of PCa. This study also emphasizes the importance of multiple rounds of replication.


Primary lymphoepithelioma-like carcinoma of salivary gland: sixty-nine cases with long-term follow-up.
Lymphoepithelioma-like carcinoma (LELC) in the salivary glands is a rare but unique malignancy. Sixty-nine patients with salivary gland LELC with long-term follow-up were reviewed for this study. There were 52 cases in the parotid gland and 17 cases in the submandibular gland. All patients underwent complete tumor excision, 41 underwent neck dissection, and 39 received postoperative radiotherapy. The 5-year, 10-year, and 15-year overall survival (OS) rates were 90%, 75%, and 54%, respectively. Patients with higher neutrophil/lymphocyte ratio (NLR ≥ 4.0) and advanced stage (stage III and IV) had significantly poorer OS. Patients who received postoperative radiotherapy had significantly better relapse-free survival (RFS). In multivariate analysis, stage, NLR, and neck dissection were associated independently with OS, whereas stage and postoperative radiotherapy were associated independently with RFS. Salivary gland LELC is a rare malignancy with a better prognosis that partially attributes to surgery with neck dissection and postoperative radiotherapy. Preoperative NLR is an independent prognostic factor.


Twin Legacies: Victor and Vincent McKusick/Twin Studies: Twinning Rates I; Twinning Rates II; MZ Twin Discordance for Russell-Silver Syndrome; Twins' Language Skills/Headlines: Babies Born to Identical Twin Couples; Identity Exchange; Death of Princess Ashraf (Twin); Yahoo CEO Delivers Identical Twins.
The lives of the illustrious monozygotic (MZ) twins, Victor A. and Vincent L. McKusick, are described. Victor earned the distinction as the 'Father of Medical Genetics', while Vincent was a legendary Chief Justice of the Maine Supreme Court. This dual biographical account is followed by two timely reports of twinning rates, a study of MZ twin discordance for Russell-Silver Syndrome (RSS) and a study of twins' language skills. Twin stories in the news include babies born to identical twin couples, a case of switched identity, the death of Princess Ashraf (Twin) and a new mother of twins who is also Yahoo's CEO.


Fetal brain grafts rescue adult retinal ganglion cells from axotomy-induced cell death.
After intraorbital transection of the optic nerve of adult rats, 90% of the retinal ganglion cells die within 30 days. Since fetal brain extracts and cocultured fetal target regions support the survival of retinal ganglion cells in vitro (Nurcombe and Bennett: Exp. Brain Res. 44: 249-258, '81; McCaffery et al.: Exp. Brain Res. 48: 377-386, '82; Armson and Bennett: Neurosci. Lett. 38: 181-186, '83) we investigated whether cell death in the adult retina could be prevented by transplanting fetal (E16) thalamus and tectum to the proximal stump of the optic nerve of adult rats that was completely transected 2-3 mm behind the optic disc. Unoperated eyes contained 119,973 (+/- 939, SEM) retinal ganglion cells, estimated from axon counts of the intact optic nerve. Of these, 11,601 (+/- 1,857) remained in control operated eyes at 30 days postoperation while in the eyes of grafted rats, 35,086 (+/- 2,278) retinal ganglion cells were counted. Thus, 23,485 (= 22% of those normally dying after transection of the optic nerve) ganglion cells were rescued by the fetal grafts from cell death normally following axotomy. These results indicate that fetal target regions of retinal ganglion cells contain and/or produce neurotrophic molecules that promote the survival of adult axotomized retinal ganglion cells.


Association between individual, household, and area-level socioeconomic status indicators and sensorineural hearing loss in adults in southwest Iran: a population-based study.
Hearing loss is the fourth most common chronic disease, but studies on the relationship between hearing loss and socioeconomic factors are limited. We aimed to examine the association between hearing loss and socioeconomic factors among 35-70 year adults in southwest Iran. This population-based cross-sectional study was conducted in the baseline of Hoveyzeh cohort study in adults aged 35-70 in southwest Iran between 2017 and 2021. Information on socioeconomic factors, demographic characteristics, comorbidities, family history of hearing loss, and noise exposure was collected. We assessed the relationship between three levels of socioeconomic factors (individual, household, and area level) with sensorineural hearing loss (SNHL). Multiple logistic regression was used to adjust the potential confounders. Among a total of 1,365 assessed participants, 485 patients were diagnosed as having hearing loss, and the other 880 individuals were diagnosed without hearing loss, which is considered the case and the control group, respectively. At the individual level of socioeconomic, the odds of having hearing loss in the participants with high school education and diploma, [OR = 0.51 (95%CI:0.28-0.92)], and the individuals with university education [OR = 0.44 (95%CI:0.22-0.87)] were significantly lower than the illiterate participants. At the household socioeconomic level, the odds of having hearing loss were lower for those with poor [OR = 0.63 (95%CI:0.41-0.97)] and moderate [OR = 0.62 (95%CI:0.41-0.94)] wealth status vs. those with the poorest wealth status. In the area level socioeconomic, although the odds of hearing loss in the residents of affluent areas were slightly lower than the residents of deprived areas, there was no significant difference among the groups. The individuals with hearing loss may have insufficient education and income.


Myosin light chain kinase is involved in lipopolysaccharide-induced disruption of colonic epithelial barrier and bacterial translocation in rats.
Sepsis is associated with bacterial translocation (BT) and changes in colonic paracellular permeability (CPP), but the link between these effects is unknown. The present study aimed to identify whether changes in CPP after lipopolysaccharide (LPS) administration triggers BT, colonic inflammation, visceral pain, and sickness behavior and to evaluate the role of myosin light chain kinase (MLCK) in colonocyte cytoskeleton contraction. Rats received the MLCK inhibitor ML-7 alone or combined with LPS. CPP was measured for 6 hours after administration. Visceral pain, food intake, BT, electron microscopy of tight junctions of colonocytes, cytokine levels, and Western blotting of phosphorylated MLC from colonic mucosa were assessed in a time range of 0 to 3 hours after treatment. Sepsis increased CPP at 0 to 6 hours after LPS and associated with tight junction morphological changes, increased MLC phosphorylation, and mucosal release of proinflammatory cytokines. Massive BT, visceral hyperalgesia, and reduced food intake were also observed. Addition of ML-7 prevented all LPS-induced effects, except for changes in food intake. In conclusion, LPS-mediated effects on CPP include gut inflammation, BT, and visceral hyperalgesia. Inhibition of MLCK-dependent colonocyte cytoskeleton contraction by ML-7 prevents the LPS-induced alterations of CPP and its subsequent effects.


Hereditary malformation of the toes and fingers in a family with double translocation heterozygosity.
A hereditary malformation of the metatarsophalangeal joints, called here "tear drop" deformity, and a cut off appearance of the distal phalanges of the toes is described in a family with double translocation t (7; 12), t (2; 6) heterozygosity. A bracydactyly E was also found. These disorders seemed unrelated to the chromosomal aberration.


How to perceive the insecticide? The Neotropical termite Nasutitermes corniger (Termitidae: Nasutitermitinae) triggers alert behavior after exposure to imidacloprid.
In eusocial insects, alarm signaling is used to inform nestmates about threats such as predators, competitors, and pathogens. Such behavior is important for the survival of colonies. However, studies evaluating the effect of insecticides on the alarm in termites have not yet been reported. Here, we inspected the effects of insecticide on alarm communication in Nasutitermes corniger. Specifically, we test the following hypotheses: (1) termite groups exposed to insecticide imidacloprid increase the body shaking movements, displaying an alert behavior; and (2) the alert behavior displayed after exposition to insecticide is dose dependent. Bioassays were conducted evaluating the body shaking movements and walking activity of termite groups exposed and non-exposed to insecticide. Thereafter, body shaking movements were evaluated in groups submitted to different doses of insecticide. In general, exposing termite groups to insecticide resulted in significantly higher body shaking movements compared to non-exposed groups. There was a positive effect of imidacloprid doses on the shaking movements. Walking activity, however, decreases in those groups exposed to the insecticide. Our results demonstrate the existence of 'insecticide alert behavior' in N. corniger and it appears to be a previously unrecognized communication mechanism in termites that allows for reducing the intoxication risks in the colony.


Ethnic differences in disease presentation of uterine cancer in New Zealand women.
Little is known about the ethnic differences in disease presentation of uterine cancer in New Zealand women. The objectives of this study were two-fold: (1) to estimate the incidence and mortality of uterine cancer among women in New Zealand and (2) to examine the association of ethnicity and socioeconomic status with tumour stage and grade, at presentation of uterine cancer. Retrospective survey of cancer cases identified from the New Zealand Cancer Registry. The authors analysed all 3203 uterine cancer cases registered with the New Zealand Cancer Registry during the period 1 January 1997 to 31 December 2006. Ethnic groups were defined based on the self-identified ethnicity recorded on the cancer registry: Ma-ori, Pacific and non-Māori non-Pacific women. Socioeconomic status was categorised as quintiles of the New Zealand Deprivation Index 2006. The mortality to incidence ratio was used as a measure of prognosis. Logistic regression was used to estimate age, ethnic and deprivation adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Pacific and Māori women have higher incidence (32.4 and 17.7 per 100 000 women, respectively) and mortality rates of uterine cancer (12.1 and 7.4 per 100 000 women, respectively). Women in the most deprived areas are more likely to present with an advanced stage of uterine cancer (OR 1.64, 95% CI 1.09-2.48). Māori and Pacific women are less likely to present with well-differentiated tumours (OR 0.69, 95% CI 0.52-0.92 and OR 0.72, 95% CI 0.52-0.99, respectively). Māori and Pacific women, and those from lower socioeconomic areas, are more likely to present with advanced uterine cancer.


Long-term follow-up of patients undergoing reoperation for recurrent carotid artery disease.
We examined the perioperative course and long-term fate of individuals who required reoperation for recurrent carotid artery disease. The records of 2289 patients undergoing 2961 consecutive operations during a 22-year period were reviewed. Forty-two patients (1.8%) who underwent reoperations were studied. Forty-seven redo carotid artery reconstructions were performed on these 42 patients for neurologic symptoms or asymptomatic high-grade stenosis. Long-term follow-up was obtained on 41 of 42 patients (mean 54 months; range 9 to 202 months). The forty-seven reoperations consisted of endarterectomy with patch angioplasty (n = 36), saphenous vein or polytetrafluoroethylene interposition graft (n = 7), or simply vein or polytetrafluoroethylene patch angioplasty (n = 4). There were no perioperative strokes or deaths. Three patients had perioperative transient ischemic attacks and two had cranial nerve injuries. The incidence of late failure after secondary surgery was 19.5% (8/41 patients). These failures consisted of one stroke, three transient ischemic attacks, and four asymptomatic occlusions. One tertiary carotid artery reconstruction was performed for a restenosis at the site of the secondary reconstruction. The factors responsible for the high incidence of late failures after secondary carotid artery reconstruction are unclear. Reoperation for recurrent carotid artery disease appears less durable than primary carotid endarterectomy. Close postoperative surveillance is recommended after carotid artery reoperation.


Transcript levels of major MMPs and ADAMTS-4 in relation to the clinicopathological profile of patients with lumbar disc herniation.
The involvement of matrix metalloproteinases (MMPs) in both the pathogenesis of intervertebral disc (ID) herniation and the spontaneous regression of herniated ID fragments remains only partially elucidated. The purpose of the present study was to simultaneously examine the transcript levels of a large number of MMPs (-1, -3, -8, -9, -13 and -14) and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs) and to investigate their correlation with the clinicopathologic profile of patients suffering from symptomatic lumbar ID herniation. mRNA expression levels were determined by means of the real-time polymerase chain reaction in 63 herniated and 10 control ID specimens. Our results showed multiple positive correlations among all MMPs and ADAMTS-4 mRNA in herniated samples, indicating their possible synergistic effect in ID herniation. MMP-9 and -13 mRNA levels were significantly elevated in patients with chronic pain, presumably as a consequence of neovascularization and chronic inflammation. Smoking habits were found to have a negative dose-dependent effect on the transcript levels of MMP-3 and MMP-13 and a positive correlation with pain intensity, suggesting an unfavorable role for smoking in the regression process of herniated disc fragments. Our findings provide evidence of the molecular portrait of MMPs and ADAMTS-4 in lumbar ID herniation, as well as of its association with the clinicopathological profile of the patients included in this study, reinforcing the hypothesis of MMPs involvement in the natural history of ID herniation. However, further studies are necessary to elucidate the exact role of MMPs in the resorption process of herniated lumbar discs.


Algae-containing raw water treatment and by-products control based on ClO2 preoxidation-assisted coagulation/precipitation process.
Eutrophication has become a great concern in recent years with the algae blooms in source water resulting in a serious threat posing to the safety of drinking water. Chlorine dioxide (ClO2) has been served as an alternative oxidant for preoxidation or disinfection during drinking water treatment process due to its high oxidation efficiency and low risk of organic by-products formation. However, the generation of inorganic by-products including chlorite (ClO2-) and chlorate (ClO3-) has become a potential problem when applied in drinking water treatment. In this study, ClO2 preoxidation-assisted coagulation/precipitation process was applied to improve the raw water quality, especially algae, turbidity, chemical oxygen demand (CODMn), and UV254, and explore the formation mechanisms of inorganic by-products. It was found that the polymeric aluminum chloride (PAC) and ClO2 have shown the best raw water treatment performance with the optimal dosage of 10 mg/L and 0.8 mg/L, respectively. Moreover, the initial pH also has exhibited a notable influence on pollutants treatment and by-products generation. Due to the adverse influence of algae and natural organic matters (NOM) and the generation of by-products, it was significant to investigate their inhibition effect on the water quality and the production of ClO2- and ClO3- in the ClO2 preoxidation-assisted coagulation/precipitation process. Moreover, it was applicable of this process to apply for the algae-containing raw water (calculated as Chl.a lower than 50 μg/L) treatment with the ClO2 dosage of less than 0.8 mg/L to achieve optimum treatment performance and minimum by-products generation.


[Trendsetting Ideas of the Children's Hospital "Kinderklinik Glanzing" Since 1915].
Since its foundation in 1915, the Children's Hospital Glanzing has had many innovative medical directors, whose careers and scientific activities are described here in chronological order. Leopold Moll established substantial socio-pediatric initiatives such as "Kriegspatenschaften" ("war sponsorship organizations") and vacations for poor children, as well as counseling centers for mothers in Vienna. August Reuss founded baby care wards and pediatrics departments. He established his own training for pediatricians. Alfred Rosenkranz established in 1974 the first Neonatal Intensive Care Unit in Austria.In 1992, Andreas Lischka successfully introduced quality management (QM) to the Children's Hospital Glanzing, one of the first hospitals in Europe, involving all hospital staff. The Children's Hospital Glanzing was the second European center to participate in the Vermont Oxford Neonatal Network (VONN) for the quality assurance of neonatal care. In 2000 in Wilhelminen Hospital, the first "baby hatch" was established for the anonymous abandonment of newborns without legal prosecution in order to give these unwanted babies a chance of survival (in addition to the possibility of an anonymous birth).Since 1999, music therapy has been offered at the neonatal intensive care unit in cooperation with the University of Music and Performing Arts, Vienna (mdw).Publications on the toxicity of the plasticizer diethylhexyl phthalate (DEHP) in polyvinyl chloride (PVC)-containing medical products constituted the opportunity to establish a PVC-free neonatal intensive care unit. Promotion of breast-feeding especially for premature born babies has always been a particular concern of the Children's Hospital Glanzing. Pollution with polychlorinated biphenyls (PCBs), dioxins, and furan in breast milk cannot be avoided; only a legal ban would lead to a reduction in these pollutants.To reduce the fear of hospitals in children, in 1994 the Children's Hospital Glanzing established a yearly summer children's festival before the end of the school term, with more than 2,500 parents and children attending in 2007. Great importance was attached to the comprehensive education of prospective pediatricians in all areas of our specialty, which could be taught by rotation in our own department with many focal points.The current situation of the Covid-19 pandemic indicates the great importance not only of intensive care beds but also the training of sufficient medical and supporting staff.


Using machine learning to predict antibody response to SARS-CoV-2 vaccination in solid organ transplant recipients: the multicentre ORCHESTRA cohort.
The study aim was to assess predictors of negative antibody response (AbR) in solid organ transplant (SOT) recipients after the first booster of SARS-CoV-2 vaccination. Solid organ transplant recipients receiving SARS-CoV-2 vaccination were prospectively enrolled (March 2021-January 2022) at six hospitals in Italy and Spain. AbR was assessed at first dose (t0), second dose (t1), 3 ± 1 month (t2), and 1 month after third dose (t3). Negative AbR at t3 was defined as an anti-receptor binding domain titre <45 BAU/mL. Machine learning models were developed to predict the individual risk of negative (vs. positive) AbR using age, type of transplant, time between transplant and vaccination, immunosuppressive drugs, type of vaccine, and graft function as covariates, subsequently assessed using a validation cohort. Overall, 1615 SOT recipients (1072 [66.3%] males; mean age±standard deviation [SD], 57.85 ± 13.77) were enrolled, and 1211 received three vaccination doses. Negative AbR rate decreased from 93.66% (886/946) to 21.90% (202/923) from t0 to t3. Univariate analysis showed that older patients (mean age, 60.21 ± 11.51 vs. 58.11 ± 13.08), anti-metabolites (57.9% vs. 35.1%), steroids (52.9% vs. 38.5%), recent transplantation (<3 years) (17.8% vs. 2.3%), and kidney, heart, or lung compared with liver transplantation (25%, 31.8%, 30.4% vs. 5.5%) had a higher likelihood of negative AbR. Machine learning (ML) algorithms showing best prediction performance were logistic regression (precision-recall curve-PRAUC mean 0.37 [95%CI 0.36-0.39]) and k-Nearest Neighbours (PRAUC 0.36 [0.35-0.37]). Almost a quarter of SOT recipients showed negative AbR after first booster dosage. Unfortunately, clinical information cannot efficiently predict negative AbR even with ML algorithms.


[If a patient has never experienced depression, should we tell him he has bipolar disorder? An updated systematic review on recurrent mania].
Bipolar disorder (BD) is a severe and recurrent mood disorder. It is characterized by episodic changes in mood and energy/activity levels that are increased during mania/hypomania or decreased during depression. Recurrent mania (RM) is a mood disorder, which would be defined by at least two manic/hypomanic without depressive episodes. Despite a rich body of clinical descriptions, RM is still not integrated into the latest editions of disease classifications and continues to be subsumed under BD in clinical practice. We conducted a systematic review of the literature to pool data about RM prevalence within BD groups, identify differences between RM and BD and develop reliable knowledge about specificities of RM. Furthermore, we sought to identify the methodological bias inherent to RM studies. Relevant publications were identified by a systematic search of PubMed, Embase, ScienceDirect and PsychInfo databases according to PRISMA criteria, with no limitation of date. The following MESH terms were used: (mania OR manic) AND (unipolar) NOT (depress*) OR ("unipolar mania" OR "unipolar manic" NOT "depress*"). Twenty-three (23) of 186identified studies met eligibility criteria for our systematic review. The total sample included 1118RM subjects among 4796BD subjects. The weighted mean of RM prevalence was 23.2%. Compared to BD, RM was characterized by a predominance of men, an earlier age at illness onset, less rapid cycles and seasonal variations, longer manic episodes, less specific clinical features (suicide attempts, anxious disorders, catatonic symptoms, irritability, hyperactivity, racing thoughts), less family history of depression, more addictive comorbidities and worse response to lithium prophylaxis (P<0.05). However, many studies failed to replicate these significant differences. RM studies were mainly retrospective. The major bias of RM studies were the lack of consensus on the defining criteria for RM and the risk of unreported depressive episodes, both in charts that were reviewed in retrospective studies and in prospective studies with insufficient follow-up duration. Although the literature on RM remains sparse, many authors agree that RM should be distinguished from BD. RM would concern almost 1 in 4 BD patients. Furthermore, several clinical variables could differentiate this mood disease from BD and may orient the specific therapeutic choice. However, clinical criteria are still not reliable enough to make a diagnosis of RM. Further studies are required to replicate the results of existing studies and to adjust for the effect of methodological biases.


Direct bovine leukocyte migration inhibition assay: standardization and comparison with skin testing.
A direct leukocyte migration inhibition (LMI) assay under agarose was standardized for use in cattle. The procedure included maintenance of culture conditions at pH 7.4 in a humidified, 39 C incubator with 98% air and 2% CO2. Optimum demonstration of incubation was obtained using a 9-hour incubation period. The LMI assay was used to detect reactivity to keyhold limpet hemocyanin (KLH) and horseshoe crab hemocyanin (HCH). Calves sensitized to KLH had specific reactivity for KLH and occasional reactivity for HCH. Similarly, calves sensitized to HCH showed reactivity for HCH and occasional reactivity for KLH. The nonspecific reactivity in the LMI was more frequent after skin testing with both antigens. Specific association of LMI reactivity and DTH reactivity was found in 8 of 10 animals. There were no nonspecific skin test responses. The results suggest that consecutive LMI assays are required to establish trends in reactivity and these should be used in conjunction with other in vitro assays of cellular immune reactivity.


Ureteral stent extraction strings in children: Stratifying the risk of post operative urinary tract infection.
Ureteral stents facilitate recovery and avoid external drains in pediatric ureteral reconstruction. Extraction strings avoid the need for a secondary cystoscopy and anesthetic. Due to concerns regarding febrile UTIs in children with extraction strings, we retrospectively assessed the relative risk of UTI in children with extraction strings. Our hypothesis was that stents with extraction strings do not increase the risk of UTI after pediatric ureteral reconstruction. Records of all children undergoing pyeloplasty and ureteroureterostomy (UU) from 2014 to 2021 were reviewed. The incidences of UTI, fever, and hospitalization were recorded. 245 patients mean age 6.4 years (163M:82F) underwent pyeloplasty (n = 221) or UU (n = 24). 42% (n = 103) received prophylaxis. Of these, 15% developed UTI versus 5% of those not receiving prophylaxis (p < 0.05). 42 females had prior history of UTI, compared to 20 males (p < 0.05). 49 patients had an extraction string. Stents with extraction strings were removed on average 0.6 months post-op while others underwent cystoscopic removal on average 1.26 months post-op (p < 0.05). 9 (18.4%) required hospitalization for febrile UTI while the stent with extraction string was in place, while only 13 (6.6%) of those without extraction string did (p < 0.02). Of the 9 children with a febrile UTI in the extraction string group, 6 had history of prior UTI (46.1%), compared to only 3 (8.3%) without a prior UTI (p < 0.05). With no prior UTI, there was no difference in UTI risk between those with (3, 8.3%) and without (8, 6.4%) extraction string (p = 0.71). Females with prior UTI and extraction string were more likely to develop UTI than those with prior UTI and no extraction string (p = 0.01). There were not enough males with history of UTI to analyze alone. There were 5 (10%) stent dislodgements in the extraction string group, 2 required further intervention with cystoscopy or percutaneous drainage. Extraction strings provide the assurance of drainage while avoiding the need for a second general anesthetic procedure. There is not an increased risk of UTI with extraction string in those without prior history of UTI, but we no longer routinely leave extraction strings if there is history of UTI. Children, particularly females, with prior history of UTI have a significantly increased risk of febrile UTIs associated with the use of extraction strings. Prophylaxis does not seem to reduce this risk. Patients with no prior UTI had no higher risk of UTI with extraction string use for pyeloplasty or UU.


Government funding of cancer research in Brazil.
Cancer research is a prominent theme on national and international development agendas. In many developed countries, funding for this area comes mainly from government sources. This article analyzes government funding of cancer research in Brazil, identifying the main funding instruments and examining the regional distribution of resources, research project and researcher profiles. Exploratory study of government funding of cancer research in Brazil between 2007 and 2016. The primary data were federal and state funding agencies. A total of 8565 research awards were identified for the period 2007-2016. Amounting to almost US$489 million, these awards were linked to 7622 research projects and 3068 researchers. The proportion of grants awarded to women was slightly higher. It is noteworthy that just 3% of researchers received 20 % of the grants. The multiple-grant history of individual researchers seemed to be a conditioning factor for obtaining new grants/fellowships. Funding was highly concentrated in the Southeast region, accounting for 84.4 % of total awards. There was a positive correlation between number of awards and amount awarded. The most frequently studied cancers were breast (11.8 %), head and neck (9.0 %) and skin cancer (5.3 %). Studies that did not specify the type of cancer accounted for 36.8 % of grants and 45.1 % of funding. The findings show a fall in the share of cancer research funding in the three largest funders. Cuts in government spending triggered by the country's political and economic crisis, highlight the vulnerability of science and technology. Greater transparency through access to information on funding, researcher, and research profiles is key to obtaining a better understanding the cancer research funding landscape in Brazil and reducing regional inequalities. A more centralized management of public cancer research funding and constant investment and monitoring is needed to ensure the effective implementation of funding policy.


The distribution of isoelectric points of human soluble proteins and in particular of the enzyme products of 88 human gene loci.
The isoelectric points of the 'primary' isozymes coded for by 88 human gene loci have been determined. The distribution was found to be bimodal with an antimode at the 'physiological pH'. Soluble human proteins have the same distribution and this appears to be characteristic of soluble mammalian proteins in general. There may be some correlation with function, mitochondrial enzymes being more basic and hydrolytic enzymes being more acidic than other classes of enzymes. The bimodal distribution can be explained in terms of the buffering effects of the charged amino acids. Most proteins would thus appear to be charged at neutral pH values.


Implementation and outcomes of a standard dose dextrose gel protocol for management of transient neonatal hypoglycemia.
The use of oral dextrose gel (DG) reduces IV dextrose use. Prior studies used weight-based dosing (WD), though barriers exist, and are mitigated using standard dosing (SD). Our outcomes include IV dextrose use, NICU admissions, breastfeeding, adverse events, and assessment of WD vs SD. Retrospective chart review comparing pre-DG, WD, and SD in 16490 newborns (1329 hypoglycemic) ≥ 35 weeks admitted to the nursery over 3 years. There was reduction in IV dextrose use 10.9% vs 6.5% (p = 0.004) and NICU admissions 27.9% vs 16.1% (p < 0.001) associated with DG use, and increased rate of breastfed infants 33.8% vs 43.5% (p = 0.001), with no difference between WD and SD. No difference noted in adverse events across the study period. DG utilization is associated with reduced IV dextrose use, NICU admissions, and improved breastfeeding rates without changes in adverse events. We offer SD as a safe alternative to WD.


Spread mixed monolayers of deoxycholic and dehydrocholic acids at the air-water interface, effect of subphase pH. Characterization by axisymmetric drop shape analysis.
Bile acids (deoxycholic and dehydrocholic acids) spread mixed monolayers behavior at the air/water interface were studied as a function of subphase pH using a constant surface pressure penetration Langmuir balance based on the Axisymmetric Drop Shape Analysis (ADSA). We examined the influence of electrostatic, hydrophobic and hydration forces on the interaction between amphiphilic molecules at the interface by the collapse area values, the thermodynamic parameters and equation of state virial coefficients analysis. The obtained results showed that at neutral (pH=6.7) or basic (pH=10) subphase conditions the collapse areas values are similar to that of cholanoic acid and consistent with the cross-sectional area of the steroid nucleus (approximately 40 A(2)). The Gibbs energy of mixing values (DeltaG(mix)<0) and the first virial coefficients of the equation of state (b(0)<1) indicated that a miscible monolayer with laterally structured microdomains existed. The aggregation number (1/b(0)) was estimated within the order of 6 (pH=6.7) and 3 (pH=10). At pH=3.2, acidic subphase conditions, no phase separation occurs (DeltaG(mix)<0) but a high expanded effect of the monolayer could be noted. The mixed monolayer behavior was no ideal and no aggregates were formed (b(0)> or =1). Such behavior indicates that the polar groups of the molecules interacts each other more strongly by repulsive electrostatic forces than with the more hydrophobic part of the molecule.


The impact of screening for social risks on OBGYN patients and providers: A systematic review of current evidence and key gaps.
Increasingly, policymakers and professional organizations support screening for social assets and risks during clinical care. Scant evidence exists on how screening impacts patients, providers, or health systems. To systematically review published literature for evidence of the clinical utility of screening for social determinants of health in clinical obstetric and gynecologic (OBGYN) care. We systematically searched Pubmed (March 2022, 5,302 identified) and identified additional articles using hand sorting (searching articles citing key articles (273 identified) and through bibliography review (20 identified)). We included all articles that measured a quantitative outcome of systematic social determinants of health (SDOH) screening in an OBGYN clinical setting. Each identified citation was reviewed by two independent reviewers at both the title/abstract and full text stages. We identified 19 articles for inclusion and present the results using narrative synthesis. The majority of articles reported on SDOH screening during prenatal care (16/19) and the most common SDOH was intimate partner violence (13/19 studies). Overall, patients had favorable attitudes towards SDOH screening (in 8/9 articles measuring attitudes), and referrals were common following positive screening (range 5.3%-63.6%). Only two articles presented data on the effects of SDOH screening on clinicians and none on health systems. Three articles present data on resolution of social needs, with inconsistent results. Limited evidence exists on the benefits of SDOH screening in OBGYN clinical settings. Innovative studies leveraging existing data collection are needed to expand and improve SDOH screening.


Perception, practices, and understanding related to teenage pregnancy among the adolescent girls in India: a scoping review.
Teenage pregnancy is a concerning public health problem in India. Misperception and misunderstanding about pregnancy and its preventive methods lead to pregnancy when adolescents are involved in unsafe sexual intercourse. This scoping review aims to discuss the evidence on the perception, practices, and understanding related to teenage pregnancy among adolescent girls in the Indian context. The Arksey and O'Malley scoping review framework and Joanna Briggs Institute Reviewers' Manual were used for the scoping review. The Population, Concept, and Context strategy (PCC) ensured the review questions, eligibility criteria, and search strategy. The Systematic Review and Meta-analysis: Extension for Scoping Review (PRISMA-ScR) was used. A literature search was done using electronic databases by specific keywords such as "teenage", "adolescences", "pregnancy", "perception", "knowledge", "awareness", etc. Relevant grey literature was identified through further searching. The review included studies that fulfil inclusion criteria having female adolescent groups aged from 10 to 19 years in the Indian context between the years 2000 and 2021. We found 40 eligible studies; more than half of these were from southern (35%) and northern (27.5%) regions, and studies from the rest of India were very sporadically distributed. Most studies (72.5%) were published in the last 10 years. The relevant extracted data from individual studies were synthesized and presented in the two major sections, perception, practices, and the second one, understanding and experiences among teenage girls. The understanding of pregnancy and teenage pregnancy-related preventive methods was detailed analysis in about 72% of papers whereas other aspects, such as perception (22.5%), practices (25%), and experiences (7.5%) were discussed in the remaining papers related to pregnancy among adolescent girls. Evidence in the selected studies shows that understanding and practices are the major areas that were primarily explored, where perception, practices and experiences are the topics that are relatively less investigated. Literature synthesis derives misconception, lack of understanding, and practices without knowing the consequences are the key factors responsible for early pregnancies. Future interventions like increasing awareness, providing comprehensive reproductive knowledge, convenient health care aids, and proper counselling are adequate measures for minimalising the problem. The present analysis showed that studies are limited in their scope concerning various aspects of teenage pregnancy in India, so this scoping review gives essential perspectives on future research and implementation plans and policies in this field.


The location of collapse and its effect on survival from cardiac arrest.
Survival from cardiac arrest is higher when the collapse occurs outside the home. Of 781 patients collapsing at home, 101 (13%) survived to hospital discharge. This compared with 66 survivors among 248 (27%) patients arresting outside the home (P less than .001). Patients collapsing outside the home were younger and more frequently were men. Cardiac arrests outside the home were more often witnessed, more likely to have bystander CPR, less often preceded by symptoms, and the collapsing rhythm was more frequently ventricular fibrillation. Mean time to CPR was shorter. Multivariate logistic regression showed that the effect of location on survival was still statistically significant, although diminished, after adjusting for the above variables (P less than .01). We speculate that comorbidity, underlying etiology, and activity level may explain the remaining difference. Because 76% of arrests occur in the home, efforts to increase the frequency of bystander-CPR through targeted and dispatcher-assisted CPR programs are warranted.


Competitive exclusion of clonal subpopulations in heterogeneous tumours after stromal injury.
Xenografted artificial heterogeneous tumours (AHTs) were created by admixing, in a ratio of 9:1 or 1:9, two clonal subpopulations (designated as clones A and D) obtained from a heterogeneous human colon adenocarcinoma. In unperturbed AHTs these percentages remain constant with increasing tumour size. At average volumes of 250 mm3, AHTs were X-irradiated (15 Gy) and changes in growth rate and composition assayed. A and D cells exhibited equivalent levels of survival after in vivo irradiation as determined by excision assay procedures. At about 2-3 weeks post-irradiation AHTs exhibited a significant enrichment of the majority population in both the 1:9 or 9:1 A:D AHTs. Additional studies were concomitantly performed to determine whether these changes were mostly a function of normal tissue damage or of parenchymal tumour cell killing. In these studies, the normal tissue only was irradiated, tumour cells were implanted one day after irradiation, and the composition of AHTs assayed as a function of time post-irradiation. In these studies, similar shifts in composition with similar kinetics to that seen in the in situ irradiations were found. We therefore propose that these compositional shifts are mainly a reflection of radiation damage to the stromal microenvironment, which is consequently unable to support tumour growth adequately leading to competitive exclusion of the minority subpopulation.


Intraoperative release of troponin T in coronary venous and arterial blood and its relation to recovery of left ventricular function and oxidative metabolism following coronary artery surgery.
To investigate the intraoperative release of troponin T during uncomplicated coronary artery surgery and to determine its relation to ischaemic time and to recovery of left ventricular function and oxidative metabolism. A prospective observational study. Cardiac surgical unit in a tertiary referral centre. Troponin T, creatine kinase, and lactate were analysed from arterial and coronary sinus samples taken before operation, and 1, 4, 6, 10, 20, 35, and 45 minutes after cross clamp release. Net myocardial troponin T release and lactate extraction were derived from their respective arteriovenous differences. Haemodynamic measurements were made using a thermodilution pulmonary artery catheter. 45 patients, mean (SD) age 62 (9) years, with two or three vessel coronary artery disease and chronic stable angina undergoing routine coronary artery surgery. Before operation, troponin T concentrations were not raised, but within one minute of cross clamp release they increased progressively in both coronary sinus and arterial blood for the entire 45 minutes of reperfusion studied. Coronary sinus troponin T concentrations were consistently higher than arterial concentrations at all time points (p < 0.001), indicating net troponin T release by the myocardium. Peak net troponin T release and area under the curve of net troponin T release correlated closely with ischaemic time (r = 0.58 and r = 0.61, p < 0.0001 for both). Area under the curve of arterial troponin T concentration was also significantly correlated with ischaemic time (r = 0.44, p < 0.01). Patients with cross clamp times longer than 72 minutes (upper quartile for ischaemic time) had greater troponin T release, delayed reversion to lactate extraction, and lower left ventricular stroke work index three hours after surgery, compared with patients who had short (< 50 minutes, lower quartile) and intermediate (51-71 minutes, interquartile) cross clamp times. Peak net troponin T release and area under the curve of arterial troponin T concentration were inversely correlated with left ventricular stroke work index three hours after surgery (r = -0.57, r = -0.38, p < 0.01). Troponin T concentrations increased in every patient after cross clamp release, and were consistently higher in coronary sinus blood than in arterial blood, indicating net myocardial release of troponin T during the period of reperfusion. Intraoperative net troponin T release has functional significance, as it is closely related to ischaemic time and reflects delayed recovery of left ventricular function and oxidative metabolism; therefore, its measurement may contribute to the perioperative assessment of myocardial injury sustained during coronary artery surgery.


A Pronectin™ AXL-targeted first-in-class bispecific T cell engager (pAXLxCD3ε) for ovarian cancer.
Pronectins™ are a new class of fibronectin-3-domain 14th-derived (14Fn3) antibody mimics that can be engineered as bispecific T cell engager (BTCE) to redirect immune effector cells against cancer. We describe here the in vitro and in vivo activity of a Pronectin™ AXL-targeted first-in-class bispecific T cell engager (pAXLxCD3ε) against Epithelial Ovarian Cancer (EOC). pAXLxCD3ε T-cell mediated cytotoxicity was evaluated by flow cytometry and bioluminescence. pAXLxCD3ε mediated T-cell infiltration, activation and proliferation were assessed by immunofluorescence microscopy and by flow cytometry. Activity of pAXLxCD3ε was also investigated in combination with poly-ADP ribose polymerase inhibitors (PARPi). In vivo antitumor activity of pAXLxCD3ε was evaluated in immunocompromised (NSG) mice bearing intraperitoneal or subcutaneous EOC xenografts and immunologically reconstituted with human peripheral blood mononuclear cells (PBMC). pAXLxCD3ε induced dose-dependent cytotoxicity by activation of T lymphocytes against EOC cells, regardless of their histologic origin. The addition of PARPi to cell cultures enhanced pAXLxCD3ε cytotoxicity. Importantly, in vivo, pAXLxCD3ε was highly effective against EOC xenografts in two different NSG mouse models, by inhibiting the growth of tumor cells in ascites and subcutaneous xenografts. This effect translated into a significantly prolonged survival of treated animals. pAXLxCD3ε is an active therapeutics against EOC cells providing a rational for its development as a novel agent in this still incurable disease. The preclinical validation of a first-in-class agent opens the way to the development of a new 14Fn3-based scaffold platform for the generation of innovative immune therapeutics against cancer.


Thrombus originating from frayed distal edge of an aortic stent-graft.
An 87-year-old woman who had undergone a stent-graft repair of a descending aortic aneurysm had additional stent-graft implantation for endoleak. The postoperative course was eventful reflecting her preexisting multiple organ disorder, and despite intensive treatment over a span of 2 months, she died of disseminated intravascular coagulation due to intestinal ischemia. Autopsy revealed a thrombus originating from the frayed distal edge of the graft. Although the relation between intestinal ischemia and the thrombus remains to be proven, this is considered a vital finding.


CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells.
CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8+/-) vs isogenic controls (CHD8+/-), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8+/- neuronal cells. In the current study, RNA-seq was carried out on CHD8+/- and isogenic control (CHD8+/+) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon. TCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/β-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8+/- DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/β-catenin signaling in a subgroup of affected individuals. Overall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets-an important consideration for developing novel therapeutics in genetically heterogeneous complex traits.


Vitamin D improves hepatic alterations in ACE1 and ACE2 expression in experimentally induced metabolic syndrome.
Metabolic Syndrome (MetS) is a term used to describe a cluster of pathophysiological, biochemical, and metabolic criteria; including high Blood Pressure (BP), high cholesterol, dyslipidaemia, central obesity and Insulin Resistance (IR). The Renin Angiotensin System (RAS) has a regulatory function in BP, hydroelectrolyte balance, and cardiovascular function. RAS is composed of angiotensinogen (AGT), (Ang I), (Ang II), (ACE1), (ACE2), (AT1R), (AT2R), and (Ang 1-7). Vitamin D had been proved to act as a protective factor against MetS. Therefore, the study is pursued to explore vitamin D supplementation roles on hepatic RAS in MetS experimental model. At first, 36 males Albino rats were separated into 4 groups and induced to MetS under controlled circumstances for 3 months. Then, data were collected from blood samples, whereas RNA extracted from liver were analyzed using biochemical and statistical analysis tests. As a result, the major finding was proving that vitamin D can balance the expression of ACE1 and ACE2. Also, confirming that it can improve MetS components by elevating HDL and insulin levels while reducing the levels of BP, cholesterol, LDL, TG, GLU, ALT, AST, and IR. These outcomes may give a new insight into the RAS pathways associated with MetS.


Extensive sorption of Amoxicillin by highly efficient carbon-based adsorbent from palm kernel: Artificial neural network modeling.
In the present study, a new sorbent was fabricated from Palm kernel (PK) by dry thermochemical activation with NaOH and characterized by FTIR, X-ray diffraction, FE-SEM and BET, which was used for the Amoxicillin (AMX) sorption from aqueous solution. The influence of effective parameters such as pH, reaction time, adsorbent dosage, AMX concentration and ionic strength on the sorption efficacy of AMX removal were evaluated. The main functional groups on the surface of the magnetic activated carbon of Palm Kernel (MA-PK) were C-C, C-O, C[bond, double bond]O and hydroxyl groups. The specific surface of char, activated carbon Palm Kernel (AC-PK) and MA-PK were 4.3, 1648.8 and 1852.4 m2/g, respectively. The highest sorption of AMX (400 mg/L) was obtained by using 1 g/L of sorbent at solution pH of 5 after 60 min contact time, which corresponding to 98.77%. Non-linear and linear models of isotherms and kinetics models were studied. The data fitted well with Hill isotherm (R2 = 0.987) and calculated maximum sorption capacity were 719.07 and 512.27 mg/g from Hill and Langmuir, respectively. A study of kinetics shows that the adsorption of AMX follows the Elovich model with R2 = 0.9998. Based on the artificial neural network (ANN) modeling, the MA-PK dosage and contact time showed the most important parameters in the removal of AMX with relative importance of 36.5 and 25.7%, respectively. Lastly, the fabricated MA-PK was successfully used to remove the AMX from hospital wastewater.


Expression of the HB9 homeobox gene concomitant with proliferation accompanying epidermal stratification during development of chick embryonic tarsometatarsal skin.
A homeobox gene, HB9, has been isolated from the tarsometatarsal skin of 13-day-old chick embryos using a degenerate RT-PCR-based screening method. In situ hybridization analysis revealed that, during development of chick embryonic skin, the HB9 gene was expressed in epidermal basal cells of the placodes, but not in those of interplacodes, and in the dermal cells under the placodes at 9 days before addition of an intermediate layer by proliferation of the basal cells in the placodes. With the onset of epidermal stratification, the direction of the basal cell mitosis changed, with the axis becoming vertical to the epidermal surface. Placodes and interplacodes form outer and inner scales, respectively, after they have elongated distally (Tanaka S, Kato Y (1983b) J Exp Zool 225: 271-283). During scale ridge elongation at 12-15 days, HB9 was strongly expressed in the epidermis of the outer scale face, where the cell proliferation is more active than in the epidermis of the inner scale face; hence, stratification of the outer scale face is more prominent than that of the inner scale face. After 16 days, when mitotic activity in the epidermal basal cells decreases and the thickness of the epidermis is maintained at a constant level, the HB9 expression decreases with the onset of epidermal keratinization. These results suggest that HB9 may be involved in the proliferation of the epidermal basal cells that accompanies epidermal stratification.


Vascular reconstruction using autologous vs synthetic graft for patients with extremity soft-tissue sarcoma involving the major vessels.
Arterial reconstruction after radical limb-sparing resection of extremity soft-tissue sarcoma (STS) involving great vessels is necessary. However, there is no agreement upon the optimal vascular substitute. This study prospectively evaluated the major vascular reconstructions in extremity STS surgery with vascular involvement. Between June 2017 and August 2019, 29 patients having extremity STS with major vascular reconstruction were enrolled. Recurrent, metastatic STSs or STSs of vascular origin were excluded. Patients were non-randomly divided into two groups according to the type of arterial substitute: group I, autologous graft (16 patients) and group II, synthetic graft (13 patients). Graft patency, postoperative morbidity, and patient and limb survival were analyzed. The mean follow-up was 12 months (range, 6-26). Early postoperative complications and overall survival were nonsignificantly different between groups. The 1-year primary patency was 92.85% vs 90% in groups I vs II, respectively, P = .704. Graft occlusion was nonsignificantly greater in the synthetic group, P = .107. Limb salvage was 93.75% in group I compared with 92.3% in group II, P = .87. Graft choice should be based on autologous vein suitability regarding its length and caliber. If such requirements are not available, synthetic substitutes can be used with close surveillance of patency.


Combining layer-by-layer assembly with electrodeposition of silver aggregates for fabricating superhydrophobic surfaces.
Taking advantage of the stability and penetrability of layer-by-layer (LbL) films, we develop a novel method to fabricate a branchlike structure of Ag aggregates on the matrix of a LbL polyelectrolyte multilayer by an electrodeposition technique. The morphology of Ag aggregates can be adjusted by electrodeposition time and potential. Moreover, after further chemisorption of a self-assembled monolayer of n-dodecanethiol, the as-prepared surface becomes superhydrophobic with a contact angle as high as 154 degrees and a tilt angle lower than 3 degrees.


Development and Validation of the Sleep Inertia Questionnaire (SIQ) and Assessment of Sleep Inertia in Analogue and Clinical Depression.
Sleep inertia is the transitional state from sleep to wake. Research on sleep inertia is important in depression because many people with depression report having difficulty getting out of bed, which contributes to impairment and can impede the implementation of interventions. The first aim was to develop and validate the first self-report measure of sleep inertia, the Sleep Inertia Questionnaire (SIQ). The second aim was to compare reports of sleep inertia across three groups: (1) No-to-Mild-Depression, (2) Analogue-Depression, and (3) Syndromal-Depression. The SIQ demonstrates strong psychometric properties; it has good to excellent internal consistency, strong construct validity, and SIQ severity is associated with less prior sleep duration. Sleep inertia is more severe in the Analogue-Depression and Syndromal-Depression groups compared to the No-to-Mild-Depression group. In conclusion, the SIQ is a reliable measure of sleep inertia and has potential for improving the assessment of sleep inertia in clinical and research settings.


Changes in liver biochemistry and tacrolimus levels following the introduction of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and liver transplant.
Elevated liver function tests (LFTs) are reported in individuals with cystic fibrosis (CF) starting elexacaftor/tezacaftor/ivacaftor (ETI). We report our experience with ETI in CF liver transplant patients. All CF liver transplant patients under the care of the Leeds CF team were commenced on ETI. Liver biopsies were performed when ALT >3 times upper limit of normal with or without bilirubin elevation. Treatment was guided by transplant hepatology and CF teams. Clinical data including lung function, LFTs and tacrolimus levels were collected. Four patients (3 male, 1 female) on tacrolimus were commenced on ETI. Median time post liver transplantation was 6.5 years. Three patients underwent liver biopsy. One biopsy was abnormal with immune-mediated liver injury, which responded to increased immunosuppression. Management of tacrolimus levels proved straightforward. ETI therapy in CF post liver transplant recipients was encouraging. Normal liver biopsy provides re-assurance to continue treatment despite elevated LFTs.


A clinicopathologic study of prosthetic valve endocarditis in 22 patients: morphologic basis for diagnosis and therapy.
Although endocarditis is a frequently lethal complication of prosthetic valve replacement, there is little pathological information on which to base diagnosis and treatment. We have studied the clinical and pathological features of 22 patients with prosthetic valve endocarditis seen at The Johns Hopkins Hospital over the past 17 years. Five patients developed endocarditis within two months of operation and 17 between two and 48 months (average 12) after operation. Patients dying early had a more fulminant course and their endocarditis was less often recognized during life. Late deaths, tending to present with fever and bacteremia unmasked by postoperative problems, were more readily recognized. Mitral and aortic prosthetic endocarditis generally led to a different type of prosthetic valve dysfunction: nine of 14 aortic valve prostheses with endocarditis developed incompetence and one other stenosis; five of seven patients with mitral valve prostheses developed stenosis and one, a homograft, developed incompetence. Prosthetic valve dysfunction led to death in 10 patients (45 per cent) and embolic events in five (23 per cent), including four cerebrovascular accidents. Ring infection, often believed to be universally present, and a contraindication to surgery, was found only in 50 per cent of these patients. In four patients (18 per cent) the endocarditis was sterilized by antibiotics but death occurred from valve dysfunction or emboli. These findings suggest that early surgical intervention combined with antibiotics has a chance of providing effective therapy for prosthetic valve endocarditis.


Tanshinone IIA ameliorated endothelial dysfunction in rats with chronic intermittent hypoxia.
Chronic intermittent hypoxia (CIH) during repetitive airflow cessations may cause endothelial dysfunction. Tanshinone IIA (Tan IIA) has been used to treat various circulatory disturbance-related diseases because of its pharmacological actions, including vasodilation. However, the mechanism of the effect of its vasodilation is not well established. The objective of this study was to explore the effect of Tan IIA in endothelium-dependent contracting factors and endothelin receptors in aortic endothelial dysfunction in CIH rats. Aortas of rats were retrieved for use in in vitro experiments (isometric force measurement), histological analysis, immunohistochemistry, and Western blotting. Tan IIA treatment increased the expression of endothelial nitric oxide synthase (eNOS) and formation of nitric oxide (NO), inhibited the production of endothelin-1 (ET-1), down-regulated ETA receptor expression, and up-regulated ETB receptor expression. In conclusion, Tan IIA protects endothelial function by inhibiting strain-induced ET-1 expression, decreasing ETA receptors, increasing ETB receptors, increasing the formation of NO, and up-regulating eNOS in CIH.


Hydrodynamic modeling: the solution conformation of macromolecules and their complexes.
Hydrodynamic bead modeling (HBM) is the representation of a macromolecule by an assembly of spheres (or beads) for which measurable hydrodynamic (and related) parameters are then computed in order to understand better the macromolecular solution conformation. An example-based account is given of the main stages in HBM of rigid macromolecules, namely: model construction, model visualization, accounting for hydration, and hydrodynamic calculations. Different types of models are appropriate for different macromolecules, according to their composition, to what is known about the molecule or according to the types of experimental data that the model should reproduce. Accordingly, the construction of models based on atomic coordinates as well as much lower resolution data (e.g., electron microscopy images) is described. Similarly, several programs for hydrodynamic calculations are summarized, some generating the most basic set of solution parameters (e.g., sedimentation and translational diffusion coefficients, intrinsic viscosity, radius of gyration, and Stokes radius) while others extend to data determined by nuclear magnetic resonance, fluorescence anisotropy, and electric birefringence methods. An insight into the topic of hydrodynamic hydration is given, together with some practical suggestions for its satisfactory treatment in the modeling context. All programs reviewed are freely available.


Effects of bee venom melittin on the order and dynamics of dimyristoylphosphatidylcholine unilamellar and multilamellar vesicles.
The effects of bee venom melittin on the order and dynamics of dimyristoylphosphatidylcholine unilamellar and multilamellar vesicles at a protein-to-lipid molar ratio of 1:60 have been investigated by employing the techniques of nanosecond emission anisotropy with 1,6-diphenyl-1,3,5-hexatriene as the fluorescent probe, enhancement by polar groups of the weakly allowed 0-0 vibronic transition in the fluorescence spectrum of pyrene, and Raman spectroscopy. The emission anisotropy results, which are found to be consistent with the wobble-in-cone model, show that the protein induces an increase in the order parameter, S, of the acyl chains of unilamellar vesicles below, at, and above their phase transition temperature, Tt, and it decreases strongly the diffusion rate, Dw, only below Tt. On the other hand, for multilamellar vesicles, the protein induces a decrease in S only at Tt and does not affect Dw. These effects are consistent with the observed changes in the degree of enhancement of the 0-0 vibronic transition of pyrene. Moreover, the protein broadens the thermal transition profile of multilamellar vesicles but sharpens dramatically that of unilamellar vesicles and fuses them without changing significantly the Tt in either case. On the other hand, the Raman data detect a decrease in the inter- and intramolecular order of the acyl chains of multilamellar vesicles below Tt and a decrease of only the former Tt. This disparity between the Raman and the nanosecond emission anisotropy data is discussed in terms of differences in the time scales of the two techniques and in the state of aggregation of the lipid-bound melittin. The data for the enhancement of the 0-0 vibronic transition of pyrene suggest that, for a melittin-to-lipid ratio of 1:60, the size or structure of channels formed in the bilayer by melittin does not allow the penetration of a neutral molecule the size of pyrene deeply into the bilayer.


Indications and classes of outpatient antibiotic prescriptions in Japan: A descriptive study using the national database of electronic health insurance claims, 2012-2015.
To evaluate condition-specific antibiotic prescription rates and the appropriateness of antibiotic use in outpatient settings in Japan. Using Japan's national administrative claims database, all outpatient visits with infectious disease diagnoses were linked to reimbursed oral antibiotic prescriptions. Prescription rates stratified by age, sex, prefecture, and antibiotic category were determined for each infectious disease diagnosis. The proportions of any antibiotic prescription to all infectious disease visits and the proportions of first-line antibiotic prescriptions to all antibiotic prescriptions were calculated for each infectious disease diagnosis. Of the 659 million infectious disease visits between April 2012 and March 2015, antibiotics were prescribed in 266 million visits (704 prescriptions per 1000 population per year). Third-generation cephalosporins, macrolides, and quinolones accounted for 85.9% of all antibiotic prescriptions. Fifty-six percent of antibiotic prescriptions were directed toward infections for which antibiotics are generally not indicated. The diagnoses with frequent antibiotic prescription were bronchitis (184 prescriptions per 1000 population per year), viral upper respiratory infections (166), pharyngitis (104), sinusitis (52), and gastrointestinal infection (41), for which 58.3%, 40.6%, 58.9%, 53.9%, and 26.1% of visits antibiotics were prescribed, respectively. First-line antibiotics were rarely prescribed for pharyngitis (8.8%) and sinusitis (9.8%). More antibiotics were prescribed for children aged 0-9 years, adult women, and patients living in western Japan. Antibiotic prescription rates are high in Japan. Acute respiratory or gastrointestinal infections, which received the majority of the antibiotics generally not indicated, should be the main targets of antimicrobial stewardship intervention.


Determinants of emergency medical services use in a Brazilian population with acute ischemic stroke.
Emergency medical services (EMS) plays a key role in the recognition and treatment of stroke. This study evaluates the determinants of EMS use in a Brazilian population with acute ischemic stroke. We performed a post hoc analysis of prospectively collected data of consecutive patients admitted to a Brazilian tertiary hospital with acute ischemic stroke. Groups were compared according to their mode of arrival to the hospital: those brought by EMS and those arriving at the hospital by their own means. Among 165 patients evaluated between January and December 2009, 17.6% arrived by EMS and 82.4% arrived by their own means. After multivariate adjustment, individuals with higher National Institutes of Health Stroke Scale score at presentation (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.06-1.23 for each point on the National Institutes of Health Stroke Scale score) were more likely to use EMS, as were those with atrial fibrillation (OR, 5.8; 95% CI, 1.41-24.07) and with lower blood pressure at hospital admission (OR, 0.72; 95% CI, 0.56-0.93 for each mm Hg). Patients brought by EMS had trends toward a lower door-to-neuroimaging time and a higher frequency of thrombolysis therapy (13% in EMS users vs 5% in patients arriving by their own means; P = .10). Our data demonstrate that in a Brazilian population with acute ischemic stroke, the patients with more severe stroke, those with atrial fibrillation, and those with lower blood pressure at hospital presentation were more likely to use EMS. EMS use was associated with trends toward a lower door-to-neuroimaging time and a higher frequency of thrombolysis therapy.


Design, microwave synthesis, and molecular docking studies of catalpol crotonates as potential neuroprotective agent of diabetic encephalopathy.
Catalpol has gained increasing attention for its potential contributions in controlling glycolipid metabolism and diabetic complications, which makes used as a very promising scaffold for seeking new anti-diabetic drug candidates. Acylation derivatives of catalpol crotonate (CCs) were designed as drug ligands of glutathione peroxidase (GSH-Px) based on molecular docking (MD) using Surfex-Docking method. Catalpol hexacrotonate (CC-6) was synthesized using microwave assisted method and characterized by FT-IR, NMR, HPLC and HRMS. The MD results indicate that with the increasing of esterification degree of hydroxyl, the C log P of CCs increased significantly, and the calculated total scores (Total_score) of CCs are all higher than that of catalpol. It shows that CCs maybe served as potential lead compounds for neuroprotective agents. It was found that the maximum Total_score of isomers in one group CCs is often not that the molecule with minimum energy. MD calculations show that there are five hydrogen bonds formed between CC-6 and the surrounding amino acid residues. Molecular dynamics simulation results show that the binding of CC-6 with GSH-Px is stable. CC-6 was screened for SH-SY5Y cells viability by MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, the result indicates CC-6 can effectively reverse SZT induced cells apoptosis with dose-dependent manner, which can indirectly show that CC-6 is a potential neuroprotective agent.


Localization of glutamine accumulation and tubular reabsorption in rat nephron.
Glutamine accumulation in rat kidney was investigated by giving large loads of gluta, mate and aspartate and measuring glutamine changes in seven completely defined portions of the nephron and in small patches from the thin limb area and from the papilla. Both glutamate and aspartate (which is partly coverted to glutamate) caused increases up to sixfold in glutamine which were mainly confined to the proximal straight tubule. Plasma glutamine is minimally affected. In contrast, large glutamine loads doubled plasma glutamine and caused about a doubling of glutamine concentrations in all parts of the nephron, but resulted in no greater change in the proximal straight tubule than elsewhere. Simultaneous inulin and glutamine measurements make it seem likely that the proximal convoluted tubule is a major site of glutamine reabsorption. The low glutamine concentrations in these cells (only 40% higher than that in plasma) indicate a very small gradient at the antiluminal surface. We suggest that the proximal straight tubule is the major site of glutamine synthesis but that it may not be an important site of glutamine breakdown.


Mutual potentiation of antinociceptive effects of morphine and clonidine on motor and sensory responses in rat spinal cord.
Clonidine and morphine depress nociceptive reflex responses when given alone; when given in combination, the effect of each is potentiated by the other. The present study was designed to test if activity in ascending axons evoked by electrical stimulation of afferent C-fibers in the sural nerve of the rat also exhibits potentiation of the depressant effects of clonidine and morphine when both drugs are administered in combination by intrathecal (i.t.) injection to the lumbar spinal cord. For comparison, experiments were also carried out on the tail-flick response in rats. The results show that clonidine produced a dose-dependent inhibition of the tail-flick response (Ed50 20 micrograms); a combination of ineffective doses of clonidine (0.3 microgram) and morphine (2 micrograms) significantly inhibited the tail-flick response; clonidine (35 micrograms) reduced spontaneous, C-fiber-evoked and, due to co-activation, A delta-fibre-evoked activity in ascending axons; and clonidine at a threshold (0.3 microgram) or higher (3 micrograms) dose administered together with morphine at a dose (2 micrograms) that caused only a moderate inhibition produced a supra-additive effect in significantly depressing spontaneous. A delta- and C-fiber-evoked ascending activity. The dose-response curve of depression by morphine alone of C-fiber-evoked activity (ED50 8 micrograms) is significantly shifted by clonidine to the left (ED50 0.9 microgram). Naloxone (0.2 mg/kg) injected intravenously did not affect the inhibition of ascending activity caused by clonidine at the highest dose (35 micrograms), but it reduced the depressant effect of combined i.t. administration of clonidine and morphine. The potentiation of the antinociceptive effects of clonidine and morphine given in combination are possibly due to actions of the two drugs at different sites between the nociceptive afferents and the neurons sending their axons to the brain.


Contemporary management of 'Inguinal disruption' in the sportsman's groin.
This article helps define the basic principles to diagnosis and manage one of the surgically correctable causes of the 'painful groin', which is commonly described as the sportsman's groin. Often many surgeons will describe a single pathology for the sportsman's groin such as a 'hernia' but often other coexisting etiologies may be present. Management relies on a multidisciplinary approach with a diagnosis initially made by a history of pain in the groin on exercise. Physiotherapy is the recommended first line treatment and is designed to concentrate on strengthening of the abdominal wall muscle and tendon groups around the groin area. Surgery does have a role in the sportsman's groin but only once all conservative measures have been exhausted or if there is a clear identified pathology causing the groin symptoms such as posterior wall defect. Surgical principles for an inguinal disruption include either open or laparoscopic techniques reinforcing the inguinal canal with a mesh or suture repair followed by an active rehabilitation programme. Once an accurate diagnosis has been achieved, contemporary guidance for inguinal disruption requires a multidisciplinary approach including a specially designed physiotherapy regime and possibly surgery.


Experiment Degree Heating Week (eDHW) as a novel metric to reconcile and validate past and future global coral bleaching studies.
Coral bleaching has increasingly impacted reefs worldwide over the past four decades. Despite almost 40 years of research into the mechanistic, physiological, ecological, biophysical and climatic drivers of coral bleaching, metrics to allow comparison between ecological observations and experimental simulations still do not exist. Here we describe a novel metric - experimental Degree Heating Week (eDHW) - with which to standardise the persistently variable thermal conditions employed across experimental studies of coral bleaching by modify the widely used Degree Heating Week (DHW) metric used in ecological studies to standardise cumulative heat loading.


P-glycoprotein does not actively transport nicotine and cotinine.
The ABCB1 gene transporter P-glycoprotein (P-gp) exists in the blood-brain barrier (BBB) and placenta and limits many drugs passing through the BBB and placenta. Several recent studies have raised confounding results regarding the roles of P-gp in nicotine disposition. To ascertain this question, we examined the effects of nicotine and its major oxidative metabolite, cotinine, on ATPase activity using P-gp containing membranes, in which nicotine and cotinine-stimulated inorganic Pi was used as a marker of the binding affinity of nicotine and cotinine to P-gp. At concentrations ranging from 5 to 1000 microm, both nicotine and cotinine produced modest stimulative effects on ATPase activity in the P-gp containing membrane. The Clint values of nicotine and cotinine were 0.01 and 0.007 minute(-1) x 10(-3), respectively. The positive control, verapamil, at concentrations ranging from 1 to 100 microm, created apparent stimulative effects on ATPase activity, with a Clint value of 1.7 minute(-1) x 10(-3), consistent with previously reported results. The results of the current study suggest that nicotine and cotinine were not actively transported by P-gp out of the cells. The observed carrier-mediated nicotine transport in various cell lines may be mediated by other transporter proteins but not P-gp.


Optimum primary tone level setting for measuring high amplitude DPOAEs in guinea pigs.
A special stimulus paradigm needs to be applied when distortion product otoacoustic emission (DPOAE) input/output functions are used to investigate the loss of sensitivity and loss of compression of outer hair cell cochlear amplifiers during noise exposure, drug treatment, etc. This stimulus paradigm should be able to reflect cochlear non-linear compressive sound processing known from direct basilar membrane measurements. Such a paradigm has already been established for humans that accounts for the different compression of the primary tones at the DPOAE generation site at f2 with L1 = 0.4 L2 + 39 dB SPL ('scissor paradigm'). The purpose of the present study was to develop an equivalent parameter setting for guinea pigs. Ninety-six different L1 - L2 combinations were presented to 24 ears in 18 pigmented guinea pigs at seven f2 frequencies between 2 and 16 kHz. L2 ranged from 20 to 60 dB SPL, L1 from 20 to 65 dB SPL. An extreme value analysis was performed to achieve the maximum DPOAE level for L1 in relation to L2. Linear regression analysis yielded a scissor paradigm specific to guinea pigs (L1 = 0.46 L2 + 41 dB SPL) which is similar to that of humans.


Perinatal asphyxia, hyperthermia and hyperferremia as factors inducing behavioural disturbances in adulthood: a rat model.
Alertness was studied in adult male Wistar rats after neonatal critical anoxia applied under three different thermal conditions: (i) at physiological neonatal body temperature of 33 degrees C, (ii) at body temperature elevated to 37 degrees C, and (iii) at body temperature elevated to 39 degrees C (both during anoxia and for 2 h postanoxia). To elucidate the effect of iron-dependent postanoxic oxidative damage to the brain, half of the group (iii) was injected with deferoxamine, a chelator of iron. Postanoxic behavioural disturbances were recorded in open-field, elevated plus-maze, and sudden silence tests when the rats reached the age of 4 month. Moreover, spontaneous motor activity of the rats was recorded radiotelemetrically in their home-cages. Both open-field stress-induced and spontaneous motor activity were reduced in rats subjected to neonatal anoxia under hyperthermic conditions. In contrast, these rats were hyperactive in the plus-maze test. Both the plus-maze and sudden silence tests revealed that these rats show reduced alertness to external stimuli signalling potential dangers. The behavioural disturbances were prevented by the body temperature of 33 degrees C and by postanoxic administration of deferoxamine. These data support the conclusion that permanent postanoxic behavioural disturbances are due to iron-dependent oxidative damage to the brain, which can be prevented by the reduced neonatal body temperature.