Dorsal root ganglia in vivo morphometry and perfusion in female patients with Fabry disease.
To examine dorsal root ganglia and the proximal nerve segments in female patients with Fabry disease by functional and morphometric magnetic resonance neurography. In this prospective multicenter study the lumbosacral dorsal root ganglia and proximal sciatic nerve were examined in ten female patients with Fabry disease by a standardized magnetic resonance neurography protocol at 3 T. Volumes of dorsal root ganglia L3-S2, permeability of dorsal root ganglia L5 and S1 and the spinal nerve L5 as well as the cross-sectional area of the proximal sciatic nerve were compared to 16 gender-matched healthy controls. Dorsal root ganglia were symmetrically enlarged by 54% (L3), 79% (L4), 60% (L5), 94% (S1), and 106% (S2) (p < 0.001). Additionally, permeability of the blood-tissue interface was decreased by 47% (p < 0.001). This finding was most pronounced in the peripheral zone of the dorsal root ganglia, where the cell bodies of the primary sensory neurons are located (p < 0.001). While spinal nerve permeability showed no differences compared to healthy controls, proximal sciatic nerve cross-sectional area was mildly increased by 6% (p < 0.01). Although heterozygous, Fabry females show severe enlarged dorsal root ganglia with a concomitant dysfunctional perfusion, even in patients with minor disease progression and in patients who are not considered for enzyme replacement therapy yet. Alterations in dorsal root ganglia volume and perfusion might serve as a very early in vivo marker for involvement of the peripheral nervous system in Fabry disease, even in patients with residual enzyme activity.


Preoperative chemotherapy for hypopharyngeal carcinoma.
Twenty patients with advanced squamous cell carcinoma of the hypopharynx received two courses of chemotherapy with cisplatinum, vincristine and bleomycin before undergoing surgery. The chemotherapy was well tolerated, with minimal toxicity and no intra or postoperative complications attributable to it. The response to the chemotherapy was dramatic with all but 2 patients exhibiting a greater than 50% tumor shrinkage. Only 3 patients, all with positive surgical margins, received postoperative radiation therapy. Surgical salvage of recurrent lesions was performed on 2 patients who are now free of disease. With a median follow-up of 20 months, 1 patient has died of recurrent disease, 3 have died of other causes, all others remain free of disease.


Changes in characteristics of rat skeletal muscle after experimental allergic encephalomyelitis.
Experimental allergic encephalomyelitis (EAE) serves as an animal model for certain neuroinflammatory diseases of the central nervous system, in particular multiple sclerosis (MS). EAE is accompanied by transient weakness or paralysis of hind limbs. We have investigated the effect of partial and transient conduction failure in the central nervous system on skeletal muscle function. At approximately 2.5 days after development of maximal clinical signs, body and medial gastrocnemius muscle mass were lower (by approximately 21 and 33%, respectively; P < 0.05) in EAE rats compared with controls. Fiber cross-sectional area was lower by 40-50% in all fiber types. Maximal force and power were substantially lower (by 58% and 73%) in EAE rats, as was the force normalized for muscle mass (35%). However, no such weakness was found when lower stimulation frequencies were used. Generation of similar submaximal forces was attributable to a slower relaxation in EAE muscles. This advantage for the EAE muscles was lost during repeated exercise. While fatigability was similar, the difference in relaxation rate between EAE and control disappeared in fatigue. Our data suggest that, as a result of central neuroinflammatory diseases, maximal performance of skeletal muscle is impaired but submaximal performance is relatively well maintained.


The fate of the split thickness skin graft in neovaginas. A pathologic study of 21 cases and a review of the literature.
Twenty-one cases of congenital absence of the vagina corrected by McIndoe's procedure were examined. The longest follow-up was 21 years (average 10.5 years). Vaginal biopsies showed a spectrum of changes, ranging from an almost normal vaginal mucous membrane to a skin-like mucous membrane. Neither hormonal status nor postoperative complication, nor the time the graft had been in place, correlated to histology, and we suggest that the varied appearance of the graft epithelium depends on the amount of corium included in the transplant.


Pregnancy imparts distinct systemic adaptive immune function.
Pregnancy represents a state of systemic immune activation that is primarily driven by alterations in circulating innate immune cells. Recent studies have suggested that cellular adaptive immune components, T cells and B cells, also undergo changes throughout gestation. However, the phenotypes and functions of such adaptive immune cells are poorly understood. Herein, we utilized high-dimensional flow cytometry and functional assays to characterize T-cell and B-cell responses in pregnant and non-pregnant women. Peripheral blood mononuclear cells from pregnant (n = 20) and non-pregnant (n = 25) women were used for phenotyping of T-cell and B-cell subsets. T-cell proliferation and B-cell activation were assessed by flow cytometry after in vitro stimulation, and lymphocyte cytotoxicity was evaluated by using a cell-based assay. Statistical comparisons were performed with linear mixed-effects models. Pregnancy was associated with modestly enhanced basal activation of peripheral CD4+ T cells. Both CD4+ and CD8+ T cells from pregnant women showed increased activation-induced proliferation; yet, a reduced proportion of these cells expressed activation markers compared to non-pregnant women. There were no differences in peripheral lymphocyte cytotoxicity between study groups. A greater proportion of B cells from pregnant women displayed memory-like and activated phenotypes, and such cells exhibited higher activation following stimulation. Maternal circulating T cells and B cells display distinct responses during pregnancy. The former may reflect the unique capacity of T cells to respond to potential threats without undergoing aberrant activation, thereby preventing systemic inflammatory responses that can lead to adverse perinatal consequences.


Different lethal effects by enzyme-generated triplet indole-3-aldehyde in different Escherichia coli strains.
Strains of Escherichia coli which lack 4-thiouridine (S4U) exhibit a higher survival rate than their wild-type parents which contain S4U after treatment with enzyme-generated triplet indole-3-aldehyde. In a similar manner to results obtained with monochromatic 334 nm UV light, the survival is related to single-strand breakage of DNA in E. coli containing the pBR 322 plasmid. The effects of the excited states generated by an enzymatic system suggest that S4U is an important chromophore in the lethal effects observed. The results also suggest that the energy transferred from triplet indole-3-aldehyde to S4U may also be passed from S4U of t-RNA to DNA, possibly through a singlet oxygen intermediate generated by excited S4U, resulting in a decrease in the survival rate of E. coli containing S4U. These results emphasize the importance of excited states in biological systems.


Alkaloids isolated from Tropaeolum tuberosum with cytotoxic activity and apoptotic capacity in tumour cell lines.
Two alkaloids were isolated and identified for the first time in the black tubers of Tropaeolum tuberosum, collected from the Titicani-Taca, Ingavi province in La Paz, Bolivia. Their structures were elucidated by extensive NMR and MS spectroscopic analyses. The isolated compounds were evaluated for their cytotoxicity and apoptotic capacity against four human cancer cell lines. 2-Benzyl-3-thioxohexahydropyrrolo[1,2-c]imidazole-1-one (1) showed slight cytotoxic activity against all the cancer cell lines which were tested, with IC50 values ranging from 27.45 ± 0.80 to 31.07 ± 0.87 μM. Moreover, N-(4-acetyl-5-methyl-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl) acetamide (2) showed significant anti-cancer potential, with IC50 values between 1.26 ± 0.57 μM and 1.37 ± 0.09 μM against all human cancer cell lines which were tested. Treatment of tumour cell lines with the compounds caused an increase in the apoptotic rate of these cells, observing that compound 2 presented an apoptotic effect which was double with respect to the control (Dimethylenastron).


Extrapolating Evidence-Based Medicine of AIT Into Clinical Practice in the United States.
Allergy/immunology specialists in the United States prescribing allergy immunotherapy (AIT) have placed a heavy value on practical experience and anecdotal evidence rather than research-based evidence. With the extensive research on AIT conducted in the last few decades, the time has come to better implement evidence-based medicine (EBM) for AIT. The goal of this review was to critically assess EBM for debated concepts in US AIT practice for respiratory allergies in the context and quality of today's regulatory standards. Debated topics reviewed were the efficacy and safety of AIT in various subgroups (eg, polyallergic patients, older patients, patients with asthma, and pregnant women), diagnosis topics (eg, skin prick test vs allergen-specific serum IgE, factors affecting skin prick tests, use of nasal or conjunctival allergen challenges, and telemedicine for diagnosis), and dosing topics (eg, optimal dosing for subcutaneous immunotherapy and sublingual immunotherapy tablets, US liquid allergen extract history, duration of treatment, and biomarkers of efficacy). In addition, EBM for patient-centered AIT issues (eg, adherence, use of practice guidelines, and pharmacoeconomics) and the approach to implementation of AIT EBM in future clinical practice were addressed. The EBM for each concept was briefly summarized, and when possible, a practical, concise recommendation was given.


Contribution of laryngeal size to differences between male and female voice production.
In this study we investigated the effect of sex- and age-related differences in vocal fold length, thickness, and depth on voice production in a three-dimensional vocal fold model. The results showed that the cause-effect relationships between vocal fold physiology and voice production previously identified in an adult male-like vocal fold geometry remained qualitatively the same in vocal folds with geometry representative of adult females and children. We further showed that the often-observed differences in voice production between adult males, adult females, and children can be explained by differences in length and thickness. The lower F0, higher flow rate, larger vocal fold vibration amplitude, and higher sound pressure level (SPL) in adult males as compared to adult females and children can be explained by differences in vocal fold length. In contrast, the thickness effect dominated and contributed to the larger closed quotient of vocal fold vibration, larger normalized maximum flow declination rate, and lower H1-H2 in adult males as compared to adult females and children. The effect of differences in vocal fold depth was generally small. When targeting a specific SPL, adult males experienced a lower peak vocal fold contact pressure during phonation than adult females and children.


A Novel Approach to Managing Post Retropubic Vaginal Sling Pain.
To describe a novel technique of using peripheral nerve neuromodulation (PNNM) for the treatment of refractory, mesh-induced chronic pelvic pain. Chronic pelvic pain associated with mesh can be a debilitating complication and there is currently no consensus on treatment. PNNM has been shown to be successful in the treatment of post-traumatic neuralgias but has yet to be studied in mesh complications. We present a case of a 50-year-old woman who had unrelenting pelvic pain after retropubic sling placement. She failed multiple therapies including medications, mesh removal, pelvic floor physical therapy, pudendal neuromodulation, and pelvic floor onabotulinumtoxinA trigger point injections. The only treatment that provided temporary relief of this patient's pain was transvaginal trigger point injections along with a right pudendal nerve block using 40 mg triamcinolone and 0.5% ropivacaine. To help define if treatment at the site of her pain would provide relief, a series of blocks were done by advancing a needle retropubically to her area of pain and injecting triamcinolone and 0.5% ropivacaine. This injection, which corresponded to the previous tract of her retropubic sling, provided temporary, but profound, relief. PNNM was then done with placement of the electrode in the retropubic space at the site of her pain. This provided instantaneous relief of almost all of her pain symptoms. Twelve months postoperatively, the patient continued to have >90% improvement in her pain. Focused PNNM is a simple procedure and can provide symptomatic relief for refractory postvaginal mesh pain.


Histamine inhibition of mixed function oxidase activity in rat and human liver microsomes and in the isolated perfused rat liver.
The imidazole ring is a common structural feature of some xenobiotics that inhibit cytochrome P-450-catalysed reactions. Histamine is a 4-substituted imidazole and a preliminary study has shown it to be an inhibitor of rat liver microsomal drug oxidation. This work has now been extended. Histamine appears to be a competitive inhibitor of the alpha-hydroxylation (HM) (Ki = 164 microM; IC50 at 20 microM = 308 microM) and O-demethylation (ODM) (Ki = 243 microns; IC50 at 20 microM = 400 microM) of metoprolol in rat liver microsomes. Of the metabolites of histamine only N-acetylhistamine showed comparable inhibitory potency to that of the parent compound. Histamine impaired the disappearance of lignocaine when incubated with rat liver microsomes. This was accompanied by a corresponding inhibition of 3-hydroxy-lignocaine appearance. Histamine produced a type II spectral interaction with rat liver microsomes (lambda max = 432 nm, lambda min = 408 nm; Ks = 0.11 mM). When histamine was incubated alone with rat liver microsomes no loss of substrate was observed. The oxidation of metoprolol by human liver microsomes was impaired by histamine (IC50 values for ODM appearance at 25 microM: liver HL1 greater than 10, HL3 = 3.8 and HL4 = 3.7 mM). In comparison, cimetidine had an IC50 value of 1.5 mM using microsomes from liver HL3. Addition of histamine impaired the elimination of metoprolol by the isolated perfused rat liver in a dose-dependent manner (P less than 0.001, one-way analysis of variance). These data demonstrate that histamine can enter hepatocytes, interact with cytochrome P-450 and inhibit some drug oxidation reactions. The physiological relevance of inhibition of drug metabolism by histamine remains to be determined.


Right Heart Adaptation to Exercise in Pulmonary Hypertension: An Invasive Hemodynamic Study.
Right heart failure (RHF) is associated with a dismal prognosis in patients with pulmonary hypertension (PH). Exercise right heart catheterization may unmask right heart maladaptation as a sign of RHF. We sought to (1) define the normal limits of right atrial pressure (RAP) increase during exercise; (2) describe the right heart adaptation to exercise in PH owing to heart failure with preserved ejection fraction (PH-HFpEF) and in pulmonary arterial hypertension (PAH); and (3) identify the factors associated with right heart maladaptation during exercise. We analyzed rest and exercise right heart catheterization from patients with PH-HFpEF and PAH. Right heart adaptation was described by absolute or cardiac output (CO)-normalized changes of RAP during exercise. Individuals with noncardiac dyspnea (NCD) served to define abnormal RAP responses (>97.5th percentile). Thirty patients with PH-HFpEF, 30 patients with PAH, and 21 patients with NCD were included. PH-HFpEF were older than PAH, with more cardiovascular comorbidities, and a higher prevalence of severe tricuspid regurgitation (P < .05). The upper limit of normal for peak RAP and RAP/CO slope in NCD were >12 mm Hg and ≥1.30 mm Hg/L/min, respectively. PH-HFpEF had higher peak RAP and RAP/CO slope than PAH (20 mm Hg [16-24 mm Hg] vs 12 mm Hg [9-19 mm Hg] and 3.47 mm Hg/L/min [2.02-6.19 mm Hg/L/min] vs 1.90 mm Hg/L/min [1.01-4.29 mm Hg/L/min], P < .05). A higher proportion of PH-HFpEF had RAP/CO slope and peak RAP above normal (P < .001). Estimated stressed blood volume at peak exercise was higher in PH-HFpEF than PAH (P < .05). In the whole PH cohort, the RAP/CO slope was associated with age, the rate of increase in estimated stressed blood volume during exercise, severe tricuspid regurgitation, and right atrial dilation. Patients with PH-HFpEF display a steeper increase of RAP during exercise than those with PAH. Preload-mediated mechanisms may play a role in the development of exercise-induced RHF.


Initial three years' experience with laparoscopic cholecystectomy in a district hospital: evaluation of early results and operative measures.
The article describes results of cholelithiasis treatment by laparoscopic cholecystectomy in a district hospital in the face of rising controversy surrounding the incidence of complications related to the widespread use of this operating technique. Laparoscopic cholecystectomy may be safely applied into the routine district hospital surgical ward activities, taking advantage of its effectiveness, low incidence of complications and low postoperative mortality rate.


Changes in corneal curvature in accommodation.
To determine the changes in corneal curvature in accommodation. Department of Ophthalmology, St. Luke's International Hospital, Tokyo, Japan. Twenty-eight eyes of 14 healthy volunteers with a mean age of 38.9 years (range 28 to 65 years) were enrolled in this prospective study. Corneal topographies were taken before and during accommodation. Subjects achieved maximal accommodation by gazing at a target letter "A" in front of the eye. Keratometric values (K-values) obtained by topographies before and during accommodation were compared. Steepened corneal curvatures during accommodation were observed with the difference-plot view. Maximum K-values for the central 3.0 mm, 5.0 mm, and 7.0 mm corneal diameters significantly increased by a mean of 0.62 diopters (D) +/- 0.83 (SD) (P =.0005, paired t test), 0.60 +/- 0.90 D (P =.0015), and 0.72 +/- 0.65 D (P<.0001), respectively. Respective minimum K-values significantly increased by a mean of 0.62 +/- 0.83 D (P=.0005), 0.67 +/- 0.68 D (P<.0001), and 0.64 +/- 0.62 D (P<.0001). No statistically significant relationship was found between age and change in K-values. The results suggest that changes in corneal curvature in accommodation participate in the mechanism of accommodation.


Neighborhood size in a beetle pollinated tropical aroid: effects of low density and asynchronous flowering.
Genetic neighborhood size and area were estimated from pollinator movements over 3 years in a scarab beetle-pollinated clonal herb, Dieffenbachia longispatha (Araceae) at the La Selva Biological Station, Costa Rica. This species was characterized by low densities of reproductive individuals and asynchronous flowering within the population. The pollinator flight distributions were characterized by relatively long mean distances between consecutive visits to inflorescences (83 m) and movements to the nearest neighboring inflorescence in the appropriate phase of flowering. Pollinator movement distributions between consecutive visits to inflorescences were significantly leptokurtic in 2 of the 3 years. I calculated neighborhood sizes incorporating the levels of kurtosis and found minimal estimates of N e to be 227-611 ramets and neighborhood area to be 88 000-180 000 m2. The three beetle species that made 94% of the visits (Cyclocephala gravis, C. amblyopsis, and Erioscelis columbica) varied in their flight distributions and in their contributions to the estimates of neighborhood size. Cyclocephala amblyopsis exhibited the greatest degree of kurtosis in its movement patterns, and neighborhood size based on its movement was large relative to N e calculated from movement distributions of the other two beetle species. Long-distance movements of C. amblyopsis (>300 m) accounted for 68% of the neighborhood size.


Pelvic floor muscle training for stress urinary incontinence: a randomized, controlled trial comparing different conservative therapies.
Pelvic floor muscle training (PFMT) is an effective therapy for stress urinary incontinence (SUI). There is little and inconsistent data about different strategies of PFMT. Finding the right, patient-oriented treatment decision seems to be essential in order to achieve good results in conservative management of SUI. It was the aim of this prospective randomized controlled trial (RCT) to compare three different strategies using electromyography (EMG) biofeedback-assisted PFMT with and without electrical stimulation (ES) for treatment of SUI in women capable of voluntarily contracting the pelvic floor when a home-training device with vaginal electrode was used. Three-arm RCT comparing 1) EMG biofeedback-assisted PFMT and conventional ES; 2) EMG biofeedback-assisted PFMT and dynamic ES; and 3) EMG biofeedback-assisted PFMT. Primary outcome measures were quality of life (King's Health Questionnaire) and degree of suffering (rated on a visual analogue scale from 1 to 10). Secondary outcome measures were number of pads used, pad weight test, contractility of the pelvic floor measured by digital palpation and intra-vaginal EMG. The quality of life significantly increased over the 12-week training. The number of pads used was reduced, the pad weight test and the contractility of the pelvic floor significantly improved. There were no significant differences between the three groups. This RCT shows significant improvement in patients' quality of life for conservative therapy of SUI. Differences between the three therapeutic options analyzed could not be found. Additional ES showed no benefit for patients with SUI, capable of voluntary pelvic floor contraction.


The effects of intracerebroventricular infusion of prolactin in luteinizing hormone, testosterone and growth hormone secretion in male sheep.
This study tested a hypothesis that the enhancement of the prolactin (PRL) concentration within the central nervous system (CNS) disturbs pulsatile luteinizing hormone (LH) and growth hormone (GH) secretion in rams that are in the natural breeding season. A 3h long intracerebroventricular (icv.) infusion of ovine PRL (50 microg/100 microl/h) was made in six rams during the daily period characterized by low PRL secretion in this species (from 12:00 to 15:00 h); the other six animals received control infusions during the same time. Blood samples were collected from 9:00 to 18:00 h at 10 min intervals. A clear daily pattern of LH secretion was shown in control animals, with the lowest concentration at noon and an increasing basal level around the time of sunset (P < 0.001). No significant changes in LH concentration occurred in PRL-infused animals and the concentration noted after infusion of PRL was significantly (P < 0.05) lower than after the control infusion. The frequency of LH pulses tended to decrease in rams after PRL treatment. The changes in LH secretion clearly carried over to the secretion of testosterone in the rams of both groups. The GH concentrations changed throughout the experiment in both groups of rams, being higher after the infusions (P < 0.001). However, the mean GH concentration and GH pulse amplitude noted after PRL infusion were significantly lower (P < 0.001 and P < 0.05, respectively) from those recorded in the control. The continued fall in PRL secretion observed in rams following PRL infusion (P < 0.05 to P < 0.001) indicates a high degree of effectiveness of exogenous PRL at the level of the CNS. In conclusion, maintenance of an elevated PRL concentration within the CNS leads to disturbances in the neuroendocrine mechanisms responsible for pulsatile LH and GH secretion in sexually active rams.


Anti-correlation between longevity gene SirT1 and Notch signaling in ascending aorta biopsies from patients with bicuspid aortic valve disease.
About 1-2% of the population present with bicuspid aortic valves (BAV), a defect of the aortic valve resulting in the formation of two leaflets instead of three. This disease leads to an abnormal aorta, altered in strength and size, which in turn is a high risk factor for potentially lethal events such as aortic dissection and aneurysm formation. BAV is inheritable, with a demonstrated association with Notch1, a member of the Notch intercellular signaling pathway that is implicated in various cardiovascular disorders. Sirtuin 1 (SirT1) is a protein deacetylase of the sirtuin family, whose activation appears beneficial for cardiac diseases. A recent study has shown that SirT1 can limit Notch signaling in model systems of vascular growth. If a concomitant dysregulation in Notch and SirT1 signaling pathways can cause the phenotypic form of human BAV is unknown. To address this issue, we analyzed human ascending aorta biopsies from BAV and control patients obtained at the time of cardiac surgery. RNA and proteins were extracted from formalin-fixed and paraffin-embedded specimens, and quantitative real-time PCR and immunoblotting were used to determine the expression of sirtuins and members of the Notch family of proteins. We found a significant increase in SirT1 expression that correlates with a decreased expression of the Notch signaling effectors detected. We put forward the idea that an altered interaction between SirT1 and Notch signaling could participate in BAV pathogenesis and that these molecules could be used as potential clinical markers.


South African health financing reform 2000-2010: understanding the agenda-setting process.
Governments around the world are struggling to address persistent disparities in health care access. However, this priority competes with many others for support in moving onto and up the political agenda. In this paper, a novel method of agenda-setting analysis is developed by merging and modifying the Hall and Kingdon models. As a case study, this method is used to explore how health financing reform reached the policy agenda in South Africa between the years 2000 and 2010. Certain factors are identified that could have determined the agenda-setting process: a change in government, increase in the cost of private medical schemes, and increase in support for reform from various stakeholders. Further analysis, using a conceptual framework of interacting trends and shocks, identifies the growing middle class, the private sector, and workers unions as powerful actors and outlines further factors that may have contributed to the process: a broad political shift in the second half of the decade and the changing prioritisation of HIV/AIDS. Study findings have relevance to academics and policy makers in South Africa and beyond.


Streptococcus pyogenes bacteraemia: an old enemy subdued, but not defeated.
Bacteraemia with Streptococcus pyogenes (Group A haemolytic streptococci) was reviewed in patients admitted to University Hospital, Nottingham over a period of 7 years. Altogether, 40 cases were encountered, representing 2% of all cases of bacteraemia. Mortality was 35%. Most cases were community-acquired and 28% of patients were less than 40 years of age. A third of the patients were previously fit. The most common sources of bacteraemia were the skin and soft tissue (23 patients) and the respiratory tract (eight patients). Shock was recorded in 40% of cases and carried a 60% mortality. This feature of streptococcal bacteremia has not received sufficient attention in the past. Despite its unique susceptibility to penicillin, S. pyogenes continues to pose a challenge to the physician.


Differential sensitivity of barley (Hordeum vulgare L.) to chlorpyrifos and propiconazole: Morphology, cytogenetic assay and photosynthetic pigments.
The present investigation was performed to evaluate the effects of an insecticide and fungicide, namely, chlorpyrifos (CP) and propiconazole (PZ) on barley (Hordeum vulgare L. variety Karan-16). The seeds were treated with three concentrations of CP and PZ, i.e., 0.05%, 0.1% and 0.5% for 6 hours after different pre-soaking durations of 7, 17 and 27 hours. Different pre-soaking durations (7, 17 and 27 h) represent three phases of the cell cycle i.e., G1, S and G2, respectively. Double distilled water and ethyl methane sulfonate were used as negative and positive controls, respectively. As compared to their respective controls, treated root tip meristematic cells of barley showed significant reductions in the germination percentage, seedling height, mitotic index and comparative increase in chromosomal aberrations against both the pesticides, and the magnitude was higher in CP. After treatment with the pesticides, chlorophyll and carotenoid contents increased up to 0.1% but reduced at 0.5% and the decrease was more prominent in CP as compared to PZ. In treated cells, fragmentation, stickiness, bridges, multipolar anaphase and diagonal anaphase were observed as aberrations. As compared to control, chromosomal aberrations were higher in CP as compared to PZ. The results of the present study concluded that CP induced chromosomal aberrations were more frequent than PZ; hence it has higher probability to cause genotoxicity in barley.


Compliance and barriers to implementing the sepsis resuscitation bundle for patients developing septic shock in the general medical wards.
This two-part study aimed to investigate compliance with the sepsis resuscitation bundle (SRB) and the barriers to its implementation for patients developing septic shock in the general medical wards. In the first part, medical records of patients who were admitted to the intensive care unit from the general medical wards due to septic shock were reviewed. Compliance rates with the six SRB components were assessed. In the second part, responsible junior physicians (first-year and second-year residents) in the general wards and senior physicians (third-year residents and fellows) were randomly invited for questionnaire-based interviews. In the first part, during the 6-month study period, 40 patients were included. Overall compliance with the SRB within 6 h was only 2.5%, mainly due to femoral catheterization (42.5%) and the lack of measuring central venous oxygen saturation (ScvO₂). Delayed completion of SRB components contributed little to the low compliance rate. In the second part, based on the questionnaire results of 71 junior physicians and 64 senior physicians, the junior physicians were less familiar with the SRB guidelines, particularly regarding the meaning of ScvO₂ (p = 0.01) and management of low ScvO₂ (p = 0.04). Junior physicians were also more reluctant to measure the central venous pressure (CVP; p = 0.04) and the ScvO₂ (p = 0.01), and were also less confident with internal jugular vein or subclavian vein catheterization (p < 0.001). Compliance with the SRB for patients developing septic shock in the general medical wards is very low. Besides providing educational programs to improve awareness and acceptance of the SRB, measures to help in central venous catheterization and completion of SRB may be considered.


Gastropericardial fistula: a late complication of esophageal reconstruction.
Esophageal replacement for both benign and malignant diseases commonly uses gastric tube reconstruction. A rare but potentially life-threatening late complication is the formation of a gastropericardial fistula. We describe a case of gastropericardial fistula occurring more than 20 years after esophageal reconstruction for congenital esophageal atresia. We report our surgical strategy and review the key concepts in the management of this complication.


[Study on a sensitive setup of capillary electrophoresis with laser induced fluorescence detector and its application].
To develop a setup of capillary electrophoresis with laser induced fluorescence detector for separating and detecting DNA fragments and protein. The setup is assembled of He-Ne Laser with 543.5 nm as the excitation light, filter, monochromator, photomultiplier tube and a computer for controlling the system and collecting the electropherograms. The design of the setup and the analytical parameters were optimized. The electropherograms with high Signal-to-Noise were obtained by the laser induced fluorescence detector-capillary electrophoretic setup. For Sulforhdamine B, the detection limit was 10(-9) mol/L, and the linear range from 1 x 10(-6) mol/L to 1 x 10(-9) mol/L. The PCR products, the digested products by Hae III and BstE of mycobacterium DNA, and the human serum albumin were determined by the successful application of this setup. The setup is characterized by simple structure, low cost and high sensitivity. Compared with traditional agarose gel electrophoresis, capillary electrophoresis with laser induced fluorescence detector is more remarkable in resolution and detection time. It can be applied as a more effective means for analysis of DNA fragments and protein.


The significance of MUM1/IRF4 protein expression and IRF4 translocation of CD30(+) cutaneous T-cell lymphoproliferative disorders: a study of 53 cases.
Current laboratory technics, clinicopathologic findings cannot always reliably distinguish primary cutaneous CD30(+) lymphoproliferative disorders (LPD), such as lymphomatoid papulosis (LyP), primary cutaneous CD30(+) anaplastic large cell lymphoma (PCALCL), transformed mycosis fungoides (T-MF) and systemic ALK(-) anaplastic large cell lymphoma (ALCL) with skin involvement. We investigated the presence of IRF4 translocation with break apart DNA-FISH method of these entities according to the recent studies of Feldman et al. In our study group with 53 cases, the detection of IRF4 translocation had a specificity and positive predictive value for PCALCL of 100%. In contrast MUM1/IRF4 protein expression was distributed widely without any predictive value.


The functional expression of TLR3 in EPCs impairs cell proliferation by induction of cell apoptosis and cell cycle progress inhibition.
Toll-like receptor 3 (TLR3), a member of the TLR family that recognizes double-stranded RNA (dsRNA), plays an important role in antiviral immunity. TLR3 is widely expressed in various cells and the activation of TLR3 induces cell apoptosis in some cells. However, the effect of TLR3 on cell proliferation in endothelial progenitor cells (EPCs) is unclear. In this study, we found that EPCs expressed high levels of TLR1, 3, 4, and 6 and low levels of TLR2, 5, 7, 8, and 10. The treatment of EPCs with TLR3 agonist Poly I:C up-regulated the expression of cytokines IL-1β, IL-6, IL-8, TNF-α, IFN-α, and IFN-β, indicating that EPCs expressed functional TLR3. Moreover, Poly I:C treatment induced cell cycle progress inhibition and cell apoptosis, leading to the inhibition of cell proliferation. Further studies indicated that IL-1β was involved in TLR3-induced cell proliferation inhibition, as IL-1β inhibited cell proliferation in a dose-dependent manner, and the IL-1β receptor type I (IL-1R1)-neutralizing antibody ameliorated Poly I:C-induced cell proliferation inhibition. Taken together, these results suggest that Poly I:C impairs cell proliferation by inducing cell cycle progress inhibition and cell apoptosis via TLR3 in EPCs.


Treatment options for juvenile-onset systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an inflammatory chronic disease characterized by the presence of activated helper T-cells that induce a B-cell response, resulting in the secretion of pathogenic autoantibodies and the formation of immune complexes. SLE in children is a disease of low prevalence with a wide range of clinical manifestations, which means that the number of randomized controlled studies are few and usually involve a small number of patients. In recent years, new therapeutic agents have appeared and the role of older treatments has been clarified. Many of these treatments are designed to reduce inflammation. The spectrum is broad and ranges from traditional nonsteroidal anti-inflammatory drugs (NSAIDs) to cytotoxic agents that have anti-inflammatory effects. The current treatment of children or adults depends on the clinical expression of the disease. Minor manifestations usually respond to the administration of NSAIDs, low doses of corticosteroids, hydroxychloroquine, or methotrexate. Thalidomide could be used for refractory skin lesions. Major manifestations can endanger the patient's life and require early, aggressive treatment. Kidney disease and other manifestations have been related to the formation or deposit of tissular immune complexes. Therefore, for years the main aim of treatment has been to suppress the immune response. The immunosuppressant treatments used in children with SLE include high doses of corticosteroids, azathioprine, methotrexate, cyclosporine, and cyclophosphamide. Several combinations of medications have been used to obtain a rapid remission or to reduce the risk of toxicity of prolonged administration of cytotoxic agents. Intravenous gamma-globulin has been successfully used in the treatment of lupus nephritis, vasculitis, and acute thrombocytopenia. In spite of numerous published studies, the use of these drugs is still controversial. The immunosuppression achieved with these treatments is nonspecific, not always effective, and associated with significant toxicities; the most significant being growth retardation, accelerated atherosclerosis and severe infectious complications. The purpose of new biological therapies is to achieve specific immunosuppression, which makes it possible to design more effective and less toxic therapeutic strategies. Mycophenolate mofetil is a promising alternative in patients who do not respond to high doses of cyclophosphamide or azathioprine. Some recently developed monoclonal antibodies such as anti-CD40L or anti-IL-10, or other molecules such as LJP394 may prove useful in the near future. Finally, stem cell transplantation may be proposed in patients with severe juvenile-onset SLE who do not respond to any treatment.


Effects of prenatal education on complaints during pregnancy and on quality of life.
The study was conducted to determine the effects of prenatal education on quality of life and complaints during pregnancy. This study is a quasi-experimental research with a control group. Personal Information Form and Scale of Complaints during Pregnancy and their Effects on Quality of Life (SCPEQL) were used to collect the data. Thirty participants were included in both the control and the intervention groups (N = 60). The mean scores of SCPEQL of the intervention group was 46.2 ± 21.1 and the mean scores of SCPEQL of the control group was 99.8 ± 21.6 in 2nd trimester. In the 3rd trimester, the mean score of SCPEQL of the intervention group was 43.5 ± 16.4, and the mean score of SCPEQL of the control group was 108.0 ± 16.8. The difference between the groups was statistically significant in 2nd and 3rd trimesters (p < 0.05). Findings of the study suggest that providing prenatal education reduces complaints and increases quality of life of pregnant women. Assessing complaints during pregnancy by nurses is a part of the prenatal care. Therefore, nurses should evaluate pregnancy-related complaints. Quality of life should be increased by giving effective education about complaints during pregnancy.


Genome-Wide Association Study for Milk Fatty Acids in Holstein Cattle Accounting for the DGAT1 Gene Effect.
The identification of genomic regions and candidate genes associated with milk fatty acids contributes to better understand the underlying biology of these traits and enables breeders to modify milk fat composition through genetic selection. The main objectives of this study were: (1) to perform genome-wide association analyses for five groups of milk fatty acids in Holstein cattle using a high-density (777K) SNP panel; and (2) to compare the results of GWAS accounting (or not) for the DGAT1 gene effect as a covariate in the statistical model. The five groups of milk fatty acids analyzed were: (1) saturated (SFA); (2) unsaturated (UFA); (3) short-chain (SCFA); (4) medium-chain (MCFA); and (5) long-chain (LCFA) fatty acids. When DGAT1 was not fitted as a covariate in the model, significant SNPs and candidate genes were identified on BTA5, BTA6, BTA14, BTA16, and BTA19. When fitting the DGAT1 gene in the model, only the MGST1 and PLBD1 genes were identified. Thus, this study suggests that the DGAT1 gene accounts for most of the variability in milk fatty acid composition and the PLBD1 and MGST1 genes are important additional candidate genes in Holstein cattle.


Late Silurian trilete spores from northern Jiangsu, China.
The Late Silurian is generally considered to a particular significant key period in the study of early land vascular plants. A trilete spore assemblage of the Upper Silurian is described from northern Jiangsu, China. This assemblage comprises 11 genera and 20 species of trilete spores (including laevigate, apiculate, perinotrilite, patinate, rarely distally murornate and equatorially crassitate, and three indeterminate trilete miospores forms). It has similarities to those described from coeval assemblages from around the world (e.g., England and South Wales; Tripolitania, Libya; Cornwallis Island, Canadian Arctic; Northwest Spain). The rare cryptospore, only one specimen (Tetrahedraletes sp.) had been found to be associated with the Chinese trilete spore assemblage. The discovery of the trilete spores from Late Silurian rocks indicates the existence of early land plants, some possibly vascular, at that time in northern Jiangsu, China.


[Diagnostic procedure for bladder cancer. Standards and current developments].
Urinary cytology and white light endoscopy have been the gold standard for initial diagnosis of bladder cancer for decades. Furthermore the use of imaging techniques, such as ultrasound or CT scanning can be necessary in certain cases. This article gives an overview on standard diagnostic techniques and introduces new optical diagnostic technologies, such as Raman spectroscopy, optical coherence tomography, narrow band imaging and confocal laser microscopy, which could play a role in the diagnosis of bladder cancer in the future. Furthermore the current indications for photodynamic diagnoses are discussed.


Domain mapping of a claudin-4 modulator, the C-terminal region of C-terminal fragment of Clostridium perfringens enterotoxin, by site-directed mutagenesis.
A C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) is a modulator of claudin-4. We previously found that upon deletion of the C-terminal 16 amino acids, C-CPE lost its ability to modulate claudin-4. Tyrosine residues in the 16 amino acids were involved in the modulation of claudin-4. In the present study, we performed functional domain mapping of the 16-amino acid region of C-CPE by replacing individual amino acids with alanine. To evaluate the ability of the alanine-substituted mutants to interact with claudin-4, we carried out a competition analysis using claudin-4-targeting protein synthesis inhibitory factor. We found that Tyr306Ala, Tyr310Ala, Tyr312Ala, and Leu315Ala mutants had reduced binding to claudin-4 compared to C-CPE. Next, we investigated effects of each alanine-substituted mutant on the TJ-barrier function in Caco-2 monolayer cells. The TJ-disrupting activity of C-CPE was reduced by the Tyr306Ala and Leu315Ala substitutions. Enhancement of rat jejunal absorption was also decreased by each of these mutations. The double mutant Tyr306Ala/Leu315Ala lost the ability to interact with claudin-4, modulate TJ-barrier function, and enhance jejunal absorption. These data indicate that Tyr306 and Leu315 are key residues in the modulation of claudin-4 by C-CPE. This information should be useful for the development of a novel claudin modulator based on C-CPE.


Prognostic value of TCBI for short-term outcomes in ATAD patients undergoing surgery.
Nutritional status has been reported to be associated with the prognosis of cardiovascular diseases. The study aimed to investigate the prognostic value of Triglycerides-total Cholesterol-Body weight-Index (TCBI) for short-term mortality in acute type A aortic dissection (ATAD) patients undergoing surgery. Totally, the data of 290 ATAD patients undergone surgery were, retrospectively, analyzed. After logistic regression analysis, TCBI was identified as an independent predictor of short-term mortality in ATAD surgery. The development of receive operating characteristic (ROC) curve demonstrated that TCBI (AUC = 0.745, P < 0.001) could provide well prognostic value for short-term mortality. Accordingly, the optimal cut-off value was identified as 883.5 and patients were divided into high TCBI (> 883.5) and low TCBI (≤ 883.5) groups. Furthermore, Kaplan-Meier analysis illustrated that short-term mortality increased significantly in the low TCBI group than in the high TCBI group (P < 0.0001). In addition, the incidence of postoperative renal failure was also elevated in the low TCBI group (P = 0.0011). Malnutrition by preoperative TCBI presented strong prognostic value for patients following ATAD surgery. And TCBI could be applied for risk stratification and therapeutic strategy-making in ATAD.


Initial findings using the V8 hourglass-shaped valvuloplasty balloon for postdilatation in treating paravalvular leaks associated with transcatheter self-expanding aortic valve prosthesis.
The aim of this study was to assess the effect of a novel hourglass-shaped balloon on reduction of paravalvular leak (PVL) in patients undergoing transcatheter aortic valve replacement (TAVR) with self-expanding prostheses. An important limitation of TAVR compared with surgical aortic valve replacement remains the higher incidence of PVL. A commonly used strategy to treat PVL is balloon postdilatation (BPD); however, the optimal technique for treating PVL after TAVR is unknown. We examined consecutive patients with severe, symptomatic aortic stenosis who underwent TAVR with the Medtronic CoreValve followed by BPD with an InterValve V8 balloon for PVL grade ≥2+. Data from echocardiographic, multidetector computed tomographic, and angiographic images were reviewed. The primary endpoint was successful reduction in PVL to grade 1+ or less as assessed by intraprocedural echocardiography. Eleven patients were studied (median age, 82 years; 64% female). Ten patients (91%) demonstrated successful reduction in PVL after V8 BPD. In three patients, PVL was reduced to zero or trace. PVL remained unchanged in one patient (2+). Two patients had complete heart block associated with valve deployment and received permanent pacemakers. There were no occurrences of annular injury or major adverse clinical events. BPD with the V8 hourglass-shaped balloon was feasible in reducing PVL from self-expanding TAVR prostheses. © 2016 Wiley Periodicals, Inc.


Long-term achievement of the therapeutic objectives of lipid-lowering agents in primary prevention patients and cardiovascular outcomes: an observational study.
Lowering elevated cholesterol levels reduces cardiovascular (CV) morbidity and mortality. Nonetheless, most patients treated with lipid-lowering agents (LLA) do not reach recommended therapeutic objectives. In a setting of primary care in France, we investigated the association between LDL-cholesterol goal attainment and the occurrence of CV events in primary prevention patients with multiple CV risk factors (> or = 3). According to national guidelines, the therapeutic objective (TO) for such patients is an LDL-cholesterol value below 130 mg/dL. 579 patients treated with LLA and with LDL-cholesterol values documented at least once a year over a period of at least 3 years (2000-2002) were allocated to three groups based on the number of years the TO was attained during the follow-up period: in all 3 years (TO+++: n=145), only part of the time (TO intermediate: n=256), and never (TO---: n=178). CV events (angina pectoris, myocardial infarction, heart failure, stroke, peripheral artery disease) occurring during the last year of observation (2002) were retrospectively collected. The occurrence risk (OR) of CV events was assessed based on TO status, with a logistic regression model to adjust for baseline differences in CV risk factors. Only a quarter of patients attained TO during all 3 study years. CV events during the third year of observation occurred in 5.5%, 10.5% and 12.9% of patients in the TO+++, TO intermediate and TO--- groups, respectively. Compared with TO+++ patients, the risk of CV events increased significantly in TO intermediate (OR=2.34, 95% CI=[1.01-5.39]) and TO--- patients (OR=2.99, 95% CI=[1.26-7.08]). In real practice, a prolonged attainment of TO is rarely observed in high CV risk patients treated with LLA as primary prevention. Therapeutic failure is related to an increased incidence of cardiovascular morbidity. Our data strongly support the need to improve adherence to treatment guidelines to achieve effective cardiovascular prevention.


Characterization of 9-fatty acid hydroperoxide lyase-like activity in germinating barley seeds that transforms 9(S)-hydroperoxy-10(E),12(Z)-octadecadienoic acid into 2(E)-nonenal.
Previously, we reported that 2(E)-nonenal, having a low flavor threshold (0.1 ppb) and known as the major contributor to a cardboard flavor (stale flavor) in stored beer, is produced by lipoxygenase-1 and a newly found factor named 9-fatty acid hydroperoxide lyase-like (9-HPL-like) activity in malt. To assess the involvement of 9-HPL-like activity in beer staling, we compared the values of the wort nonenal potential, an index for predicting the staleness of beer, with the lipoxygenase and 9-HPL-like activity of 20 commercial malts. There was a significant correlation between the malt 9-HPL-like activity and the values of wort nonenal potential (r=0.53, P<0.05), while the correlation between malt lipoxygenase activity and the wort nonenal potential was statistically insignificant. Analysis of the partially purified 9-HPL-like activity from embryos of germinating barley seeds indicated that 9-HPL-like activity consisted of fatty acid hydroperoxide lyase and 3Z:2E isomerase.


Accidental intrathecal vincristine administration. Report of a case.
A case is described of accidental intrathecal administration of vincristine, with detailed clinical observations over a 17-day period. The clinical picture resembled that seen with toxicity from intravenously administered vincristine, but was rapidly progressive and resulted in death. The onset was characterised by opisthotonos, followed by ascending paralysis and finally bulbar and cerebral involvement. The specific changes in the brain at autopsy were masked by those due to prolonged artificial respiration prior to death. The accidental drug administration occurred owing to procedural errors, which can be avoided by strict attention to rules.


Diagnostic value of PD-1 mRNA expression combined with breast ultrasound in breast cancer patients.
This study explored the value of measuring programmed death 1 (PD-1) in peripheral blood, combined with breast ultrasound using the Breast Imaging Reporting and Data System (BI-RADS) classification, for differentiation between benign and malignant breast tumors. We enrolled 113 patients with breast cancer and 66 patients with benign breast tumors who were admitted to Hangzhou First People's Hospital from September 2014 to August 2017. The mRNA level of PD-1 was detected by quantitative real-time polymerase chain reaction. The mRNA levels of PD-1 were significantly higher in the peripheral blood of patients with breast cancer than those in patients with benign breast tumors. The diagnostic sensitivity of PD-1 mRNA expression was 0.805, the specificity was 0.788, and the area under the curve (AUC) was 0.848 (P < 0.001); the sensitivity of breast ultrasound-based BI-RADS classification was 0.752, the specificity was 0.909, and the AUC was 0.906 (P < 0.001); and the combined sensitivity, specificity, and AUC of the two assays were 0.920, 0.879, and 0.938, respectively (P < 0.001). Progesterone receptor-positive breast cancer patients exhibited high levels of PD-1 expression (P < 0.001). This study suggests that the measurement of PD-1 combined with breast ultrasound-based BI-RADS classification represents a significant improvement for breast cancer diagnosis compared with diagnoses based on either method alone.


Rates of onset and offset of action of narcotic analgesics in isolated preparations.
In isolated preparations of the myenteric plexus--longitudinal muscle of the guinea-pig ileum and the mouse vas deferens, the rates of onset and offset of action of narcotic analgesics are inversely related to lipid solubility; this effect is probably due to drug binding at secondary lipid-rich binding sites. These findings are in contrast to observations in vivo by A. Herz and his colleagues, who showed that the rates of onset of action and of recovery are directly related to lipid solubility because of the presence of lipid-rich barriers. In view of the opposite effects, an optimum may be expected when a drug has a degree of lipid solubility which ensures rapid penetration of the blood--brain barrier without seriously slowing down of receptor association and dissociation. From the interaction of rapidly acting quaternary antagonists, e.g. N-methylnalorphinium, with slowly acting agonists, e.g. methadone, it is concluded that at least a part of the receptor site is on the surface of the cell membrane, and the possibility of an allosteric agonist--antagonist interaction is considered.


Development of microbial fuel cell integrated constructed wetland (CMFC) for removal of paracetamol and diclofenac in hospital wastewater.
Hospital wastewater management has become a significant concern across the globe due to the presence of pharmaceutically active compounds (PhACs) and other toxic substances, which can potentially disrupt ecosystems. The presence of recalcitrant PhACs in hospital wastewater increases the difficulty level for conventional wastewater treatment systems. Furthermore, incorporating advanced oxidation-based treatment systems increase capital and operation costs. To reduce treatment costs, low-cost innovative technology, i.e., composite constructed wetland and microbial fuel cell system (CMFC), has been developed for higher treatment efficiency of PhACs in hospital wastewater along with simultaneous bioelectricity generation as an additional outcome. In this study, influencing operating parameters, such as initial chemical oxygen demand (COD), electrode spacing, and substrate-to-water-depth ratio, were optimized for two plant species: water hyacinth (WH) and duckweed (DW). The optimized systems were run in batch and continuous mode for WH-CMFC and DW-CMFC to treat synthetic hospital wastewater with paracetamol and diclofenac, and the bioelectricity generation was monitored. DW-CMFC system depicted better treatment efficiency and voltage generation as compared to WH-CMFC. In continuous mode, the DW-CMFC system exhibited a removal of 95.3% COD, 97.1% paracetamol, and 87.5% diclofenac. WH-CMFC and DW-CMFC achieved power densities of around 21.26 mW/m2 and 42.93 mW/m2, respectively. The fate of PhACs during and after treatment and toxicity analysis of the transformation products formed were also carried out. Higher bio-electricity generation and efficient wastewater treatment of the DW-CMFC make it a sustainable option for hospital wastewater management.


Effects of moderate-intensity resistance exercise on blood glucose and pregnancy outcome in patients with gestational diabetes mellitus: A randomized controlled trial.
To investigate the effects of a structured moderate-intensity resistance exercise program on blood glucose levels and other health-related indicators in patients with GDM. A total of 99 patients with GDM in a tertiary class A general hospital were randomly divided into an experimental group and a control group. GDM patients in the control group received routine prenatal care, online education, and a personalized diabetes diet intervention. The experimental group was treated in the same way as the control group with the addition of a moderate intensity resistance exercise program. The blood glucose levels in both groups were lower after the intervention compared with before intervention (P < 0.05). After intervention, the average fasting blood glucose, the 2 h postprandial blood glucose, the utilization rate of insulin, the amount of insulin, gestational weight gain and blood pressure (P < 0.05) in the experimental group were lower than the control group. In addition, there was no statistical significance in the incidence of adverse pregnancy outcomes between the two groups after intervention (P > 0.05). Moderate intensity resistance exercise was helpful for improvement of blood glucose control and insulin use, gestational weight gain and blood pressure in patients with GDM. In the future, long-term follow-up of both maternal and newborn infants should be performed to assess the long-term effects of exercise intervention on maternal and child health. The impact on the risk of obesity and diabetes may need to be further clarified. The trial was approved by the registration of the Chinese Clinical Trial Registry, and registration number: ChiCTR1900027929.


Modulating the phonological similarity effect: the contribution of interlist similarity and lexicality.
The classical phonological similarity effect (PSE) was studied with words and nonwords in two immediate serial recall (ISR) tasks. The relative contributions of intralist and interlist interference were compared, and differential effects on item and order memory were observed. PSE occurred with words and was reversed with nonwords. In addition, PSE was modulated by interlist similarity, which enhanced recall of rhyme items and impaired recall of distinct items. Finally, interlist similarity reduced item recall of words, whereas it improved serial recall of nonwords. The latter finding rules out the hypothesis that the reverse PSE for nonwords is due to interlist interference. It is concluded that two opposing effects of phonological intralist similarity cause the interaction between PSE and lexicality in ISR. With words, the positive effect on item recall is usually masked by a much more disruptive effect on position accuracy. With nonwords, however, the positive effect often masks the negative one. These findings are discussed in relation to current models of verbal short-term memory.


Estrogen-induced efflux of endogenous catecholamines from the hypothalamus in vitro.
Short-term organ cultures of the intact hypothalamus were used to study the effects of various estrogenic compounds on catecholamine release. Estradiol-17 beta (0.1--20 microM) produced a concentration-dependent efflux of norepinephrine and dopamine while its biologically inactive enantiomer, estradiol-17 alpha, was ineffective at concentrations up to 20 microM. Diethylstilbestrol, a potent non-steroidal estrogen, was as effective as estradiol-17 beta in inducing catecholamine efflux. In contrast, weakly or non-estrogenic steroids such as estrone, estriol, and corticosterone were without effect. The time course of the estrogen-induced efflux of hypothalamic catecholamines was similar to that previously reported for the estrogen-induced accumulation of hypothalamic cAMP, providing further evidence for the involvement of catecholamines in this effect. Theses results suggest that estrogen may facilitate the release of catecholamines within the hypothalamus.


Lateral presynaptic inhibition mediates gain control in an olfactory circuit.
Olfactory signals are transduced by a large family of odorant receptor proteins, each of which corresponds to a unique glomerulus in the first olfactory relay of the brain. Crosstalk between glomeruli has been proposed to be important in olfactory processing, but it is not clear how these interactions shape the odour responses of second-order neurons. In the Drosophila antennal lobe (a region analogous to the vertebrate olfactory bulb), we selectively removed most interglomerular input to genetically identified second-order olfactory neurons. Here we show that this broadens the odour tuning of these neurons, implying that interglomerular inhibition dominates over interglomerular excitation. The strength of this inhibitory signal scales with total feedforward input to the entire antennal lobe, and has similar tuning in different glomeruli. A substantial portion of this interglomerular inhibition acts at a presynaptic locus, and our results imply that this is mediated by both ionotropic and metabotropic receptors on the same nerve terminal.


Can a periarticular levobupivacaine injection reduce postoperative opiate consumption during primary hip arthroplasty?
Several reports have confirmed the ability of intraoperative periarticular injections to control pain after THA. However, these studies used differing combinations of analgesic agents and the contribution of each, including the local anesthetic agent, is uncertain. Understanding the independent effects of the various agents could assist in improved pain management after surgery. We therefore determined the ability of intraoperative periarticular infiltration of levobupivacaine to (1) reduce postoperative pain, (2) reduce postoperative morphine requirements, and (3) reduce the incidence of nausea and urinary retention. A double-blinded, randomized, placebo-controlled trial of patients undergoing primary THAs was performed. Patients were randomized to receive a periarticular infiltration of 150 mg levobupivacaine in 60 mL 0.9% saline (n = 45) or a placebo consisting of 60 mL 0.9% saline (n = 46). We obtained a short-form McGill pain score, visual analog scale (VAS), and morphine requirements via patient-controlled analgesia (PCA) as primary measures. Postoperative antiemetic requirements and need for catheterization for urinary retention were determined as secondary measures. Subjectively reported pain scores and the overall intensity scores were similar for both groups in the postoperative period. At the same time the mean morphine consumption was less in the levobupivacaine group, most notable in the first 12 hours after surgery: treatment group 11.5 mg vs control group 21.2 mg. We observed no differences in the frequency of postoperative nausea and vomiting or urinary retention. Our observations suggest periarticular injection of levobupivacaine can supplement available postoperative analgesic techniques and reduce postoperative morphine requirements after THA. Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.


A review of 450 stabwounds of the spinal cord.
Patients with spinal cord stabwounds accounted for over one-quarter of the more than 1 600 patients with spinal cord injury admitted to this unit during 13 years. Over half the lesions were of the Brown-Séquard type. Functional recovery was good in nearly two-thirds of patients. The principles of treatment are discussed.


Penile Tuberculosis in a Bull.
We describe a case of penile tuberculosis in a bull. The prepuce was thickened, firm and pale with multifocal to coalescent caseous nodules, and the inguinal and mesenteric lymph nodes were moderately enlarged. Lesions in the prepuce, penis and lymph nodes were characterized by multifocal to coalescent areas of caseous necrosis and marked granulomatous inflammation. Acid-fast bacilli were seen within necrotic foci and Langhans giant cells. Mycobacteriumtuberculosis var. bovis was identified in inguinal lymph nodes by the polymerase chain reaction technique and by bacterial isolation. Although rare, tuberculosis should be considered in the differential diagnosis of granulomatous lesions in the genital tract of bulls.


Benefits and Risks of Testosterone Treatment in Men with Age-Related Decline in Testosterone.
The substantial increase in life expectancy of men has focused growing attention on quality-of-life issues associated with reproductive aging. Serum total and free testosterone levels in men, after reaching a peak in the second and third decade of life, decline gradually with advancing age. The trajectory of age-related decline is affected by comorbid conditions, adiposity, medications, and genetic factors. Testosterone treatment of older men with low testosterone levels improves overall sexual activity, sexual desire, and erectile function; improves areal and volumetric bone density, as well as estimated bone strength in the spine and the hip; corrects unexplained anemia of aging; increases skeletal muscle mass, strength and power, self-reported mobility, and some measures of physical function; and modestly improves depressive symptoms. The long-term effects of testosterone on major cardiovascular events and prostate cancer risk remain unclear. The Endocrine Society recommends against testosterone therapy of all older men with low testosterone levels but suggests consideration of treatment on an individualized basis in men who have consistently low testosterone levels and symptoms or conditions suggestive of testosterone deficiency.


Computed tomography characteristics of primary pulmonary lymphoepithelioma-like carcinoma in 41 patients.
To assess the computed tomography (CT) findings of primary pulmonary lymphoepithelioma-like carcinoma (LELC). Clinical information and CT findings of 41 patients with pulmonary LELC were reviewed. CT images of 2 or 5mm thickness were obtained with a pre-treatment CT and were jointly evaluated by two radiologists. Thirty central tumors and 11 peripheral tumors with diameters ranging from 1.0 to 8.7cm (mean, 4.1±1.9cm) were identified. Central tumors appeared to be larger than peripheral tumors (P=0.017). Tumors occurred more frequently in right middle lobe (31.7%) and left lower lobe (29.3%). CT findings of patients with early stage were similar to those observed in patients with advanced stage except that lymphadenopathy was significantly more common in patients with advanced stage. CT findings of pulmonary LELC consisted of well defined border (63.4%), lobulation (78.0%), vascular or bronchial encasement (43.9%), obstructive pneumonia (41.5%), pleural effusion (12.2%) and calcification (4.9%). On contrast-enhanced CT scans, inhomogeneously enhanced tumors were significantly larger than homogeneously enhanced tumors (P<0.001). Lymphadenopathy was seen in 28 patients, and lymph nodes with homogeneous enhancement were observed in 24/28 patients. Enlarged lymph nodes were more frequently occurred in peribronchial or hilar nodes (53.7%), subcrinal nodes (39.0%), right lower paratracheal nodes (31.7%) and right upper paratracheal nodes (22.0%). Pulmonary LELC usually appeared as a large, central, well defined and lobulated tumor with vascular or bronchial encasement and obstructive pneumonia. Calcification was rare in pulmonary LELC. Lymphadenopathy was common, usually with homogeneous enhancement.


Metacarpal epiphyseal fractures.
Five cases of injuries to the distal metacarpal physis and epiphysis are reviewed. Axially applied loads may result in growth disturbances. The extent of the physeal injury is not always evident on the initial radiographs. Decreased longitudinal growth of the metacarpal occurs in those injuries in which the physis has been damaged.


Comparative diagnostic accuracy of contrast-enhanced MRI and (18)F-FDOPA PET-CT in recurrent glioma.
To compare the diagnostic accuracy of contrast enhanced magnetic resonance imaging (Ce-MRI) and (18)F-fluorodopa ((18)F-FDOPA) positron emission tomography (PET)-computed tomography (CT) for detecting recurrent glioma. In this prospective study, 35 patients (age, 36.62 ± 0.86 years; 80 % male) with histopathologically proven glioma with clinical suspicion of recurrence were evaluated using Ce-MRI and (18)F-FDOPA PET-CT. (18)F-FDOPA PET-CT images were evaluated qualitatively and semi-quantitatively. Combination of clinical follow-up (minimum 1 year), repeat imaging and/or biopsy (when available) was taken as the reference standard. Based on the reference standard, 26 patients were positive and nine were negative for recurrence. The sensitivity, specificity and accuracy of Ce-MRI were 92.3 %, 44.4 % and 80 % respectively, whereas those of (18)F-FDOPA PET-CT were 100 %, 88.89 % and 97.1 % respectively. Results of Ce-MRI and (18)F-FDOPA PET-CT were concordant in 74.3 % (29/35) and discordant in 17.1 % of patients (6/35). On McNemar analysis the difference was not statistically significant overall (P = 0.687), for high-grade tumour (P = 0.5) or low-grade tumours (P = 1.0). However, (18)F-FDOPA PET-CT was more specific than Ce-MRI overall (P = 0.0002), for high-grade tumour (P = 0.006) and low-grade tumours (P = 0.004). F-FDOPA PET-CT shows a high but comparable diagnostic accuracy to Ce-MRI for the detection of recurrent glioma. However, it is more specific than Ce-MRI. • Recurrent glioma in the postoperative site remains a diagnostic dilemma. • (18) F-FDOPA PET-CT shows high diagnostic accuracy for detecting recurrent glioma. • Diagnostic accuracies for (18) F-FDOPA PET-CT and contrast enhanced MRI are comparable. • However, (18) F-FDOPA PET-CT is more specific than Ce-MRI for recurrent glioma.


Biodistribution and safety studies of hDel-1 plasmid-based gene therapy in mouse and rabbit models.
A plasmid encoding the human developmentally regulated endothelial locus-1 (hDel-1) protein formulated with poloxamer 188 is a potential gene therapy for peripheral arterial disease in man. As a prelude to clinical trials, the biodistribution and safety of this therapy were evaluated after intramuscular and intravenous administration in mice and rabbits. In mice, plasmid DNA persisted at the intramuscular injection site for at least 28 days, but was barely detectable in distal tissues by 24 h and essentially cleared by 28 days. By 24 h after intravenous administration, plasmid DNA was readily detected in blood, muscle, and lungs but sporadically and at low levels in other tissues. At 28 days, plasmid DNA was readily detectable only at the intravenous injection site (tail) after low- and high-dose administration, and sporadically in blood and muscle after high-dose administration. In rabbits, the highest intramuscular (4.2 mg kg(-1)) or intravenous (3.7 mg kg(-1)) dose caused no deaths; no treatment-related clinical signs; no changes in body weight, clinical pathology parameters, ophthalmology, ECG, or histopathology; and no detectable increase in antinuclear antibodies by 28 days. The results supported testing of hDel-1 plasmid-based gene therapy in phase I clinical trials.


Antiphospholipid syndrome and recurrent miscarriage: A systematic review and meta-analysis.
Antiphospholipid syndrome (APS) is an autoimmune condition that is associated with thrombosis and morbidity in pregnancy. The exact mechanisms by which these associations occur appear to be heterogeneous and are not yet well understood. The aim of this study was to identify and analyze publications in recent years to better understand the diagnosis and its contribution to monitoring APS among women with recurrent miscarriage (RM). This systematic review and meta-analysis was conducted using the PubMed and Web of Knowledge databases, with articles published between 2010 and 2014, according to the PRISMA statement. Of the 85 identified studies, nine were selected. Most of the studies reported an association between recurrent miscarriage and specific antiphospholipid antibodies, as anticardiolipin antibodies (aCL), lupus anticoagulant (LA), anti-β2-glycoprotein I antibodies (aβ2GPI) and antiphosphatidylserine (aPS), which showed a relationship with RM. The main result of the meta-analysis revealed association between antiphospholipid antibodies (aPLs) and/or APS compared to the patients with RM (OR: 0.279; 95% CI: 0.212-0.366) and APS cases compared to the patients with RM (OR: 0.083; 95% CI: 0.036-0.189). High heterogeneity among these studies (I2=100.0%, p <0.001) was observed. In addition, there was no significant publication bias across studies according to Begg's test (p=0.230), although Egger's test (p=0.037) suggests significant publication bias. The funnel plot was slightly asymmetrical. Systematic review and meta-analysis demonstrated a positive association between antiphospholipid antibodies and/or antiphospholipid syndrome in patients with recurrent miscarriage.


Catalpol coordinately regulates phase I and II detoxification enzymes of Triptolide through CAR and NRF2 pathways to reduce Triptolide-induced hepatotoxicity.
Triptolide (TP), as the main component of Tripterygium Wilfordii (TW), can induce obvious liver injury when exerting the therapeutic effect. However, in our previous study, Catalpol (CAT), the main active ingredient of Rehmannia Glutinosa (RG), was shown to increase the drug clearance rate of TP and to attenuate TP-induced hepatotoxicity. Thus the present study aims to address the roles of phase I and II metabolic enzymes and the nuclear receptors in the detoxification process of TP, to analyze the mechanism of CAT reducing hepatotoxicity. For this purpose, SD rats and human liver cell line L-02 and HepG2 cells were selected, and treated with TP or the combination of TP and CAT in our study. Then the effect of CAT on detoxification of TP was analyzed, and the roles of phase I metabolic enzymes cytochrome P450 3A2/4 (CYP3A2/4) and phase II metabolic enzyme UDP-glucuronosyltransferase 1A6 (UGT1A6) and their related nuclear receptor regulations were evaluated. It was found that TP inhibited the transcription of CYP3A2/4. And through the constitutive androstane receptor (CAR) pathway, CAT not only significantly changed this inhibition and increased the expression of CYP3A2/4 but also increased the expression of CYP2C9, both of which are phase I detoxification enzymes of TP. And with the gene-silenced experiment, it was confirmed that this regulation was CAR-dependent. We also found that CAT could continue to exert a certain protective effect after CAR was silenced, with UGT1A6, the phase II detoxification enzyme of TP, significantly induced. And this was closely related to the enhanced transcriptional regulation of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway. In conclusion, our results reveal that CAT can induce TP's phase I detoxification enzymes CYP3A2/4 and CYP2C9 through the CAR pathway, and induce TP's phase II detoxification enzyme UGT1A6 via the NRF2 pathway when CAR is strongly inhibited. And this coordinate regulation of CAT may be an important source of the effect for CAT to increase TP metabolic conversion and reduce TP hepatotoxicity.


Assessing the utility of gene co-expression stability in combination with correlation in the analysis of protein-protein interaction networks.
Gene co-expression, in the form of a correlation coefficient, has been valuable in the analysis, classification and prediction of protein-protein interactions. However, it is susceptible to bias from a few samples having a large effect on the correlation coefficient. Gene co-expression stability is a means of quantifying this bias, with high stability indicating robust, unbiased co-expression correlation coefficients. We assess the utility of gene co-expression stability as an additional measure to support the co-expression correlation in the analysis of protein-protein interaction networks. We studied the patterns of co-expression correlation and stability in interacting proteins with respect to their interaction promiscuity, levels of intrinsic disorder, and essentiality or disease-relatedness. Co-expression stability, along with co-expression correlation, acts as a better classifier of hub proteins in interaction networks, than co-expression correlation alone, enabling the identification of a class of hubs that are functionally distinct from the widely accepted transient (date) and obligate (party) hubs. Proteins with high levels of intrinsic disorder have low co-expression correlation and high stability with their interaction partners suggesting their involvement in transient interactions, except for a small group that have high co-expression correlation and are typically subunits of stable complexes. Similar behavior was seen for disease-related and essential genes. Interacting proteins that are both disordered have higher co-expression stability than ordered protein pairs. Using co-expression correlation and stability, we found that transient interactions are more likely to occur between an ordered and a disordered protein while obligate interactions primarily occur between proteins that are either both ordered, or disordered. We observe that co-expression stability shows distinct patterns in structurally and functionally different groups of proteins and interactions. We conclude that it is a useful and important measure to be used in concert with gene co-expression correlation for further insights into the characteristics of proteins in the context of their interaction network.


Dataset for understanding the effort and performance of external auditors during the COVID-19 crisis: A remote audit analysis.
The onset of the COVID-19 pandemic at the end of 2019 has dramatically changed the life of both individuals and corporate businesses. Besides the health fears of the pandemic, there are sizable challenges for some jobs that habitually deliver their services face-to-face, disrupting the quality of service. In particular, external auditors, the most critical and reliable accreditors of financial reports, are in an unprecedented situation to conduct audit works and collect sufficient and appropriate audit evidence. To capture how COVID-19 affects auditors in Saudi Arabia, an online questionnaire was developed and distributed from April to August 2021 via email to all 417 auditors/audit firms registered with the Saudi Organization for Chartered and Professional Accountants (SOCPA). This dataset contains responses from 193 auditors, in four major sections: demographic information (7 items); audit effort during COVID-19 (3 items); auditor performance during COVID-19 (7 items); and remote audit proficiency (6 items). It may serve for theoretical and practical assessment for auditors in the time of COVID-19, for example, evaluating how auditors conduct their work during the lockdown and how remote audit proficiency impacts the effort and performance of auditors. In addition, it can be used to assess the differences between auditors by considering the moderating effect of their personal characteristics on the impact of remote audit proficiency on both effort and performance.


Sortilin promotes glioblastoma invasion and mesenchymal transition through GSK-3β/β-catenin/twist pathway.
High aggressiveness is a hallmark of glioblastoma and predicts poor prognosis of patients with glioblastoma. The expression level of sortilin has been preliminarily reported to be elevated in high-grade glioma; however, the potential significance of sortilin in glioblastoma progression has not been elucidated. In this study, we investigated the oncogenic effect of sortilin in glioblastoma. Increased levels of sortilin were noted in the mesenchymal subtype of glioblastoma and highly aggressive subtypes of glioblastoma tissues and cell lines. In addition, high levels of sortilin predicted poor prognoses in patients with glioblastoma. Sortilin knockdown or inhibition with AF38469 (an orally bioavailable inhibitor of sortilin) significantly suppressed migration and invasion by inhibiting EMT-like mesenchymal transition in glioblastoma cells. Furthermore, we proved that sortilin promoted cell invasion mainly via Glycogen synthase kinase 3 beta (GSK-3β)/β-catenin/Twist-induced EMT-like mesenchymal transition in glioblastoma. Taken together, our results demonstrate a critical role of sortilin in glioblastoma invasion and EMT-like mesenchymal transition, indicating that sortilin contributes to glioblastoma progression. These data also highlight the dramatic antitumor effects of AF38469 in glioblastoma, suggesting that AF38469 is a potentially powerful antitumor agent for sortilin-overexpressing human glioblastoma.


Effect of pericardial fluid pro-inflammatory cytokines on hemodynamic parameters.
We investigated the effects of pro-inflammatory cytokines of pericardial fluid on hemodynamic parameters in patients undergoing coronary artery surgery. Seventy-eight patients were included in the study and they were allocated to three groups: group 1, stable angina pectoris (SAP, n = 15); group 2, unstable angina pectoris (USAP, n = 34); group 3, post-myocardial infarction (PMI, n = 29). Pericardial fluid and arterial blood samples were obtained from all patients and interleukin (IL)-1beta, IL-2 receptor, IL-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) levels were measured. Pericardial IL-1beta concentration (pg/mL) was significantly higher in the USAP group (26.6 +/- 10.9) compared to the SAP (5.0 +/- 0.1) and PMI (5.8 +/- 1.0) groups. IL-2R, IL-6, IL-8 and TNF-alpha concentrations of pericardial fluid were significantly higher than serum in all groups; difference was more prominent in the PMI group compared to the SAP and the USAP groups. Serum IL-1beta concentrations (pg/mL) were significantly higher in the USAP group (21.8 +/- 3.4) compared to the SAP group (5.0 +/- 0.1) and the PMI group (5.4 +/- 1.6). Cardiac index (CI) before opening the pericardial sac was found to be lower in the USAP group (1.6 +/- 0.3 L/min/m2) compared to the SAP (2.2 +/- 0.5 L/min/m2) and the PMI (2.1 +/- 0.5 L/min/m2) groups (p = 0.028 and p = 0.011, respectively). In the USAP group, there was a relationship between reduction of CI and increase of IL-1beta levels in serum and pericardial fluid.


Geometric constraints alter cell arrangements within curved epithelial tissues.
Organ and tissue formation are complex three-dimensional processes involving cell division, growth, migration, and rearrangement, all of which occur within physically constrained regions. However, analyzing such processes in three dimensions in vivo is challenging. Here, we focus on the process of cellularization in the anterior pole of the early Drosophila embryo to explore how cells compete for space under geometric constraints. Using microfluidics combined with fluorescence microscopy, we extract quantitative information on the three-dimensional epithelial cell morphology. We observed a cellular membrane rearrangement in which cells exchange neighbors along the apical-basal axis. Such apical-to-basal neighbor exchanges were observed more frequently in the anterior pole than in the embryo trunk. Furthermore, cells within the anterior pole skewed toward the trunk along their long axis relative to the embryo surface, with maximum skew on the ventral side. We constructed a vertex model for cells in a curved environment. We could reproduce the observed cellular skew in both wild-type embryos and embryos with distorted morphology. Further, such modeling showed that cell rearrangements were more likely in ellipsoidal, compared with cylindrical, geometry. Overall, we demonstrate that geometric constraints can influence three-dimensional cell morphology and packing within epithelial tissues.


[HDL level or HDL function as the primary target in preventive cardiology].
The risk for myocardial infarction can be reduced by almost 50% solely by lowering LDL cholesterol. Despite success reducing LDL and cholesterol, atherosclerosis and myocardial infarction remain significant challenges. However, mechanisms of the reverse cholesterol transport system might be used more effectively in the foreseeable future. Although the benefit of high HDL cholesterol appears to be obvious, most clinical trials aimed at increasing HDL cholesterol failed to generate convincing results. Therefore, the question arises as to whether indeed only HDL level or perhaps rather more HDL function is of considerable therapeutic relevance. If function is the crucial issue drugs such as CETP (cholesteryl ester transfer protein) activators or SR-B1 (scavenger receptor type B-1) upregulators could be beneficial. These types of drugs could improve HDL metabolism and might have beneficial effects despite the fact that they lower HDL levels. Ongoing studies on next generation CETP inhibitors and nicotinic acid will clarify this question and might help in our struggle against atherosclerosis.


Draeculacephala robinsoni Hamilton, 1967 (Hemiptera: Auchenorrhyncha: Cicadellidae), a newly introduced species and genus in Europe with comments on its identification.
For the first time in the Palaearctic Region, the New World leafhopper genus Draeculacephala Ball (Hemiptera: Cicadellidae: Cicadellinae) has been recorded in France (Pyrenes-Orientales) and Spain (Catalonia). The species present in both countries is Draeculacephala robinsoni Hamilton 1967, among the most common and widespread species of the genus Draeculacephala in eastern North America. Comments on the identification of this species are presented. The species already seems to be firmly established in the region since it has been found in 11 different sites with a maximum distance of 86 km between them. Since the genus has been reported to be a vector of plant pathogens including Xylella fastidiosa its further spread in Europe should be closely monitored.


Downregulating NHE-1 decreases the apoptosis of hippocampal cells in epileptic model rats based on the NHE-1/calpain1 pathway.
Seizure is associated with pathological changes of hippocampus, but the mechanism by which hippocampal neuronal apoptosis promotes epilepsy is unclear. Our previous study showed that the expression of NHE-1 was increased in epileptic model rats. Therefore, this study further explores the effect of NHE-1 on hippocampal cells apoptosis and seizure in lithium chloride-pilocarpine epileptic model rats. First, we established a lithium chloride-pilocarpine induced epileptic rat model and detected the expression of NHE-1, calpain1 and apoptosis in the hippocampus. Then, we further down-regulated NHE-1 to observe the expression of calpain1 and apoptosis in the hippocampus, as well as its effect on seizures in rats. We found that the expression of NHE-1 and calpain1 and apoptosis in the hippocampus was significant increased in the model group. After down-regulating NHE-1, the expression of calpain1 was decreased, and hippocampal cell apoptosis was alleviated. In addition, down-regulation of NHE-1 reduced the frequency and duration of seizures in epileptic rats. Therefore, hippocampal NHE-1 overexpression is closely related to the development of neuronal apoptosis in a rat model of epilepsy, and downregulating NHE-1 expression can reduce cell apoptosis. Moreover, the NHE-1/calpain1 signaling pathway may be an important mechanism leading to hippocampal cell apoptosis.


Longitudinal ethnic differences in multiple cardiovascular risk factor control in a cohort of US adults with diabetes.
To examine longitudinal differences in multiple cardiovascular risk factor control (glycemia, blood pressure, and lipids) by race/ethnicity. Data were analyzed on a cohort of 11,203 veterans with type 2 diabetes. Primary outcome was odds of none of the risk factors out of control vs. having at least one out of control (HbA1c>8.0%, BP>140/90 mmHg, and LDL>100mg/dL). Secondary outcome was odds of having none out of control vs. having one, two or three risk factors out of control, respectively. Generalized linear mixed models assessed the relationship between race/ethnicity and multiple risk factor control adjusted for covariates. Adjusted models for primary outcome showed that NHB had two-fold (95%CI 1.8-2.3) and Hispanics had 48% higher (95%CI 1.3-1.7) odds of multiple risk factors out of control over time compared to NHW. Adjusted models for secondary outcome showed that NHB and Hispanics also had higher odds of having one, two, and three risk factors out of control over time compared to NHW. Ethnic minority veterans with diabetes are less likely to have multiple cardiovascular risk factor control over time compared to whites. Thus, greater risk reduction efforts are needed to reduce the heavier disease burden among ethnic minorities.


Polymorphisms within the metabotropic glutamate receptor 1 gene are associated with depression phenotypes.
Glutamate has been implicated in the pathophysiology and treatment of mood disorders possibly by affecting the regulation of the hypothalamus-pituitary-adrenocortical (HPA) axis. Growing evidence suggests an important role of the metabotropic glutamate receptor 1 (mGlu1) in depression-related phenotypes. To test whether these findings can also be supported by human genetics data, we explored polymorphisms within the metabotropic glutamate receptor 1 gene (GRM1) for their association with unipolar depression (UPD) as well as with biological phenotypes of this disorder. We first tested the association of 43 tag-SNPs covering the GRM1 locus with UPD in 350 patients and 370 matched controls. We then investigated the effects of the associated SNPs on hippocampal glutamate levels estimated using ¹H-MR-spectroscopy (¹H-MRS) and on endocrine measures from the combined dexamethasone-suppression/CRH stimulation (dex/CRH) test. Within the GRM1 locus, 22 SNPs showed nominally significant association with UPD, of which 6 withstood corrections for multiple testing (rs2268666 with best allelic p=7.0×10⁻⁵). Supportive evidence for an association with UPD was gained from a second independent sample with 904 patients and 1012 controls. Furthermore, patients homozygous for the non-risk genotypes showed reduced hippocampal glutamate levels as measured by ¹H-MRS, a more pronounced normalization of HPA-axis hyperactivity as well as a better antidepressant treatment outcome. These results suggest that the combination of genetic and biological markers may allow to subgroup patients into etiopathogenetically more relevant subcategories which could guide clinicians in their antidepressant treatment choices.


Sustained anti-osteoporotic action of risedronate compared to anti-RANKL antibody following discontinuation in ovariectomized mice.
Bisphosphonates and the anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody denosumab are effective anti-resorptive drugs commonly prescribed for osteoporosis. Both drugs may, however, have intolerable side effects; so, it is critical to examine their residual efficacy such as maintenance of bone mass following cessation. Therefore, we compared the changes in bone histology following discontinuation of the aminobisphosphonate risedronate and anti-RANKL antibody in ovariectomized (OVX) mice. Twelve-week-old female C57BL/6 N mice were OVX or sham operated. Four weeks after surgery, mice were treated with vehicle, a single injection of anti-RANKL antibody (5 mg/kg), or risedronate (5 μg/kg/day, s.c.) for 4 weeks (the treatment period), followed by vehicle treatment for an additional 4 weeks (discontinuation period). The lumbar spine and proximal tibia were evaluated by micro-computed tomography. In addition, the lumbar spine, proximal tibia, and the femoral shaft were examined by bone histomorphometry. After 4 weeks of discontinuation, OVX mice initially treated with the anti-RANKL antibody exhibited a trend of bone loss associated with increased turnover in both trabecular and cortical bones, although the difference was not significant. By contrast, OVX mice treated with risedronate exhibited maintained or even increased bone mass and suppressed bone turnover. Patients discontinuing denosumab should be carefully monitored for recurrent osteoporosis symptoms, and a replacement drug should be considered.


CETP expression ameliorates endothelial function in female mice through estrogen receptor-α and endothelial nitric oxide synthase pathway.
Endothelial dysfunction is an early manifestation of atherosclerosis. The cholesteryl ester transfer protein (CETP) has been considered proatherogenic by reducing plasma HDL levels. However, CETP may exhibit cell- or tissue-specific effects. We have previously reported that male mice expressing the human CETP gene show impaired endothelium-mediated vascular relaxation associated with oxidative stress. Although sexual dimorphisms on the metabolic role of CETP have been proposed, possible sex differences in the vascular effects of CETP were not previously studied. Thus, here we investigated the endothelial function of female CETP transgenic mice as compared with nontransgenic controls (NTg). Aortas from CETP females presented preserved endothelium-dependent relaxation to acetylcholine and an endothelium-dependent reduction of phenylephrine-induced contraction. eNOS phosphorylation (Ser1177) and calcium-induced NO levels were enhanced, whereas reactive oxygen species (ROS) production and NOX2 and SOD2 expression were reduced in the CETP female aortas. Furthermore, CETP females exhibited increased aortic relaxation to 17β-estradiol (E2) and upregulation of heat shock protein 90 (HSP90) and caveolin-1, proteins that stabilize estrogen receptor (ER) in the caveolae. Indeed, CETP females showed an increased E2-induced relaxation in a manner sensitive to estrogen receptor-α (ERα) and HSP90 inhibitors methylpiperidinopyrazole (MPP) and geldanamycin, respectively. MPP also impaired the relaxation response to acetylcholine in CETP but not in NTg females. Altogether, the study indicates that CETP expression ameliorates the anticontractile endothelial effect and relaxation to E2 in females. This was associated with less ROS production, and increased eNOS-NO and E2-ERα pathways. These results highlight the need for considering the sex-specific effects of CETP on cardiovascular risk.NEW & NOTEWORTHY Here we demonstrated that CETP expression has a sex-specific impact on the endothelium function. Contrary to what was described for males, CETP-expressing females present preserved endothelium-dependent relaxation to acetylcholine and improved relaxation response to 17β-estradiol. This was associated with less ROS production, increased eNOS-derived NO, and increased expression of proteins that stabilize estrogen receptor-α (ERα), thus increasing E2-ERα signaling sensitivity. These results highlight the need for considering the sex-specific effects of CETP on cardiovascular risk.


[Pathway of synthesis of the aldehyde factor - a basic substrate of luciferase].
The stimulation of luminescence and cell aldehyde factor during the growth of one-aldehyde-dependent mutant in the condition medium by other aldehyde-dependent mutants was studied. It was shown that the aldehyde factor is synthesized in five successive steps, thus suggesting the participation of five enzymes in aldehyde factor synthesis. The metabolite accumulation in the condition medium increases both the level of the aldehyde factor and that of luciferase. It is assumed that some precursors of the aldehyde factor are involved in the regulation of the luminescence development.


Synthetic Cannabinoid-Associated Multiple Organ Failure: Case Series and Literature Review.
We describe a multicenter descriptive case series of six patients admitted with synthetic cannabinoid (SC) intoxication displaying similar symptoms and sequelae, all resulting in multiple organ failure. Patients were included in this report if they presented with known SC use and experienced multiple organ failure between March 1, 2016, and July 19, 2016, to the intensive care units of three hospitals in Maryland. Patients were followed to either discharge or death, and complications related to SC were documented. All six patients presented with altered mental status and severe rhabdomyolysis, with a peak creatine phosphokinase ranging from 4000 to >320,000 units/L. The majority of patients (five of six) presented with acute kidney injury, with most (four of six) requiring continuous renal replacement therapy. Most patients experienced fever (five of six) and myocardial injury, as evidenced by a troponin elevation (three of six). Seizures occurred in half of patients (three of six patients). Two patients required emergent fasciotomies of the bilateral lower extremities for acute compartment syndrome. Two patients developed fulminant hepatic failure that necessitated liver transplant evaluation, one requiring Molecular Adsorbent Recirculating System (MARS) therapy as a bridge to successful transplant, while the patient without it did not survive. Delirium, severe rhabdomyolysis, acute kidney injury, and fever are common in patients with synthetic cannabinoid intoxication. Given the growing abuse of these substances, clinicians should consider their use in the differential of such patient presentations. To our knowledge, only a few published case reports discuss multiple organ failure associated with SC toxicity, and only two have described an associated acute liver failure. Our report describes the first case of SC-associated acute liver failure requiring organ transplantation. Clinicians should be aware of life-threatening complications and consider SC ingestion in the differential diagnosis of patients presenting with multiple organ failure.


Magnetite carboxymethylcellulose as biological macromolecule-based absorbent for cationic dyes removal from environmental samples.
In this study, magnetite carboxymethylcellulose (CMC@Fe3O4) composite as magnetic biological molecules were synthetized for the use as adsorbent to remove four types of cationic dyes, namely Methylene Blue, Rhodamine B, Malachite Green, and Methyl Violet from aqueous solution. The characteristic of the adsorbent was achieved by Fourier Transform Infrared Spectroscopy, Field Emission Scanning Electron Microscope (FESEM), X-ray Diffraction, Vibrating Sample Magnetometer and Thermal Gravimetric Analysis techniques. Besides, essential influencing parameters of dye adsorption; the solution pH, solution temperature, contact time, adsorbent concentration and initial dye dosage were studied. FESEM analysis showed the magnetic Fe3O4-TB, Fe3O4@SiO2, Fe3O4@SiO2-NH2 and CMC@Fe3O4 composites were in spherical shape, with average size of 43.0 nm, 92.5 nm, 134.0 nm and 207.5 nm, respectively. On the saturation magnetization (Ms), the results obtained were 55.931 emu/g, 34.557 emu/g, 33.236 emu/g and 11.884 emu/g. From the sorption modelling of Isotherms, Kinetics, and Thermodynamics, the adsorption capacity of dyes is (MB = 103.33 mg/g), (RB = 109.60 mg/g), (MG = 100.08 mg/g) and (MV = 107.78 mg/g). With all the adsorption processes exhibited as exothermic reactions. The regeneration and reusability of the synthetized biological molecules-based adsorbent was also assessed.