Cytoplasmic peptidoglycan intermediate levels in Staphylococcus aureus.
Intracellular cytoplasmic peptidoglycan (PG) intermediate levels were determined in Staphylococcus aureus during log-phase growth in enriched media. Levels of UDP-linked intermediates were quantitatively determined using ion pairing LC-MS/MS in negative mode, and amine intermediates were quantitatively determined stereospecifically as their Marfey's reagent derivatives in positive mode. Levels of UDP-linked intermediates in S. aureus varied from 1.4 μM for UDP-GlcNAc-Enolpyruvyate to 1200 μM for UDP-MurNAc. Levels of amine intermediates (L-Ala, D-Ala, D-Ala-D-Ala, L-Glu, D-Glu, and L-Lys) varied over a range of from 860 μM for D-Ala-D-Ala to 30-260 mM for the others. Total PG was determined from the D-Glu content of isolated PG, and used to estimate the rate of PG synthesis (in terms of cytoplasmic metabolite flux) as 690 μM/min. The total UDP-linked intermediates pool (2490 μM) is therefore sufficient to sustain growth for 3.6 min. Comparison of UDP-linked metabolite levels with published pathway enzyme characteristics demonstrates that enzymes on the UDP-branch range from >80% saturation for MurA, Z, and C, to <5% saturation for MurB. Metabolite levels were compared with literature values for Escherichia coli, with the major difference in UDP-intermediates being the level of UDP-MurNAc, which was high in S. aureus (1200 μM) and low in E. coli (45 μM).


Placental and blood-CSF transfer of intramuscularly administered atropine in the same person.
Both placental and blood-CSF transfer of atropine (0.01 mg/kg intramuscularly) was measured (by RIA) in 11 parturients undergoing Caesarean section under spinal analgesia. In the foeto-placental unit a significant penetration into amniotic fluid was found, whereas in CSF there was a measurable level of the drug (greater than 1.5 ng/ml) in only one mother. Our results show that there is a fundamental difference in the penetrability of tertiary ammonium alkaloids like atropine through these two biological membranes. However, our results concern penetration into human lumbar CSF and do not necessarily reflect potential penetration into the ventricular CSF, choroid plexus or brain ventricular ependyma.


Photoredox-Catalyzed Synthesis of Remote Fluoroalkylated Azaarene Derivatives and the α-Deuterated Analogues via 1,n-Hydrogen-Atom-Transfer-Involving Radical Reactions.
A modular strategy to access the remote fluoroalkylated azaarene derivatives and the α-deuterated analogues, which are the isosteres of many pharmaceutically important compounds, is reported. Transformations under the sustainable photoredox catalysis platform could efficiently experience cascade radical addition, 1,n-hydrogen atom transfer (HAT), and single-electron reduction to offer the crucial anions α to azaarenes. Through reacting with H2O or the inexpensive D2O, two series of valuable products were obtained in high yields with substantial deuterium incorporation. The work demonstrates that the HAT of the α-sp3 C-H of the electron-withdrawing azaarenes with alkyl radicals is viable.


Micropipette system for sampling and injecting small volumes.
We have developed a micropipette system that allows sampling of preset volumes of liquids and injection of preset small amounts of liquids, using thermal expansion of an oil phase in a micropipette, achieved by increasing or decreasing the current applied to heat the shaft of the micropipette. The system has been tested to inject or collect volumes of about 20 nl, but smaller and larger volumes are possible. The amount injected or collected for a given temperature step of the micropipette is largely independent of the physical properties, e.g. of viscosity, into which the sample is injected or from which it is collected. The pipette tip is not measurably heated when heating the shaft for injection or collection, thus avoiding damage of the biological material into which the injection occurs or from which it is sampled.


Copper and selenium deficiency in cattle: an evaluation of methods of oral therapy and an observation of a copper-selenium interaction.
The efficacies of oxidised copper particles, selenium bullets and soluble glass bullets in raising the copper and/or selenium reserves of young cattle marginally deficient in both trace elements were examined. Selenium bullets were associated with a reduced copper uptake when selenium bullets and oxidised copper particles were given together. Responses in liveweight gains to trace-element supplementation and relationships between copper or selenium in blood components and liver are presented.


Diabetes mellitus: a risk factor for ischemic stroke in a large biracial population.
We previously reported increased incidence of ischemic stroke among both blacks and whites with diabetes mellitus, especially in those aged <55 years. With rising prevalence of diabetes mellitus in the past decade, we revisit the impact of diabetes mellitus on stroke incidence in the same population (≈1.3 million) 5 and 10 years later. This is a population-based study. First ischemic strokes among black and white residents of the 5-county Greater Cincinnati/Northern Kentucky region, aged ≥ 20 years, for periods 7/1993 to 6/1994, 1999, and 2005, were included in this analysis. Incidence rates were adjusted for sex, race, and age, as appropriate, to the 2000 US population. History of diabetes mellitus among first ischemic strokes was reported for 493/1709 (28%) in 1993/1994, 522/1778 (29%) in 1999, and 544/1680 (33%) in 2005. Risk ratios (95% confidence interval) for rates of stroke in those with versus without diabetes mellitus for blacks reduced significantly from 5.6 in 1993/1994 to 3.2 in 2005; for whites the risk ratio remained stable at 3.8 in 1993/1994 and 2005. However, risk ratios varied with age, with an overall 5- to 14-fold increased risk observed in those aged 20 to 65 years. Those with diabetes mellitus remain at greatly increased risk for stroke at all ages, especially <65 years, regardless of race. The rates and risk ratios for 1999 and 2005, although similar to those previously reported for the mid-1990s, take on increased significance, given the epidemic of diabetes mellitus and metabolic syndrome throughout the US and the world.


Autofluorescence of NADH is a new biomarker for sorting and characterizing cancer stem cells in human glioma.
The existing cell surface markers used for sorting glioma stem cells (GSCs) have obvious limitations, such as vulnerability to the enzymatic digestion and time-consuming labeling procedure. Reduced nicotinamide adenine dinucleotide (NADH) as a cellular metabolite with property of autofluorescence has the potential to be used as a new biomarker for sorting GSCs. A method for sorting GSCs was established according to the properties of the autofluorescence of NADH. Then, the NADHhigh and NADHlow subpopulations were sorted. The stem-like properties of the subpopulations were evaluated by qRT-PCR, western blot analyses, limiting dilution assay, cell viability assay, bioluminescence imaging, and immunofluorescence analysis in vitro and in vivo. The relationship between CD133+/CD15+ cells and NADHhigh subpopulation was also assessed. NADHhigh cells expressed higher stem-related genes, formed more tumor spheres, and harbored stronger pluripotency in vitro and higher tumorigenicity in vivo, compared to NADHlow subpopulation. NADHhigh glioma cells had the similar stemness with CD133+ or CD15+ GSCs, but the three subpopulations less overlaid each other. Also, NADHhigh glioma cells were more invasive and more resistant to chemotherapeutic drug temozolomide (TMZ) than NADHlow cells. In addition, the autofluorescence of NADH might be an appropriate marker to sort cancer stem cells (CSCs) in other cancer types, such as breast and colon cancer. Our findings demonstrate that intracellular autofluorescence of NADH is a non-labeling, sensitive maker for isolating GSCs, even for other CSCs.


Investigation on bile acid receptor regulators. Discovery of cholanoic acid derivatives with dual G-protein coupled bile acid receptor 1 (GPBAR1) antagonistic and farnesoid X receptor (FXR) modulatory activity.
Bile acids, the end products of cholesterol metabolism, activate multiple mechanisms through the interaction with membrane G-protein coupled receptors including the bile acid receptor GPBAR1 and nuclear receptors such as the bile acid sensor, farnesoid X receptor (FXR). Even if dual FXR/GPBAR1 agonists are largely considered a novel opportunity in the treatment of several liver and metabolic diseases, selective targeting of one of these receptors represents an attractive therapeutic approach for a wide range of disorders in which dual modulation is associated to severe side effects. In the present study we have investigated around the structure of LCA generating a small library of cholane derivatives, endowed with dual FXR agonism/GPBAR1 antagonism. To the best of our knowledge, this is the first report of bile acid derivatives able to antagonize GPBAR1.


[Diagnosis of vascular impotence: comparison of Doppler sonography and arteriography].
The use of Doppler ultrasonography to examine penile arteries represents an important step in the multidisciplinary evaluation of erectile dysfunction. This noninvasive method for demonstrating the presence of arterial lesions was found to have a sensitivity of 92.6% and an accuracy of 90% when compared with selective arteriography. The necessity of performing selective arteriography can be markedly reduced in cases of erectile dysfunction by investigations using Doppler ultrasonography.


Association of 4-basepair G-to-A transition in the 5'-untranslated region of ANKH gene with selected patients of primary knee osteoarthritis: A cross sectional study.
A cohort study was carried out for a year to evaluate the presence of G-to-A transition in 5'-untranslated region of ankylosis human (ANKH) gene in Indian Khatri patients (closely resembling Europeans of primary knee osteoarthritis (OA), residing in Lucknow, India. In the total participants, 25 were Khatri primary knee OA patients (cases) residing in Lucknow and 101 were random blood donors' samples (controls) collected from a blood bank. All were studied for the abovementioned mutation using real-time polymerase chain reaction (RT-PCR). GG genotype was present in 72.3% of controls and 76% of Khatri knee OA patients. The studied G-to-A mutation was found to be positive in 24.8% of controls and 16% of cases, odds ratio (95% confidence interval) being 0.6 (0.19-1.98, P = 0.42). The frequency of AA (D) genotype found around 3% (cases) and 8% (controls) with P value of 0.70. The combined frequency of both homozygous and heterozygous mutation (GA and AA) in the studied population was 28 (27.7%) in controls and 6 (24%) in cases with the odds ratio (OD) ratio of 0.82 (0.29-2.27, P = 0.70). No significant differences were observed at both genotype and allelic level in the distribution of ANKH-4 G-to-A gene polymorphism in studied subjects. This study did not show any significant G to A mutation in the studied subjects.


Fluoroscopy of spontaneous breathing is more sensitive than phrenic nerve stimulation for detection of right phrenic nerve injury during cryoballoon ablation of atrial fibrillation.
Right phrenic nerve palsy (PNP) is a typical complication of cryoballoon ablation of the right-sided pulmonary veins (PVs). Phrenic nerve function can be monitored by palpating the abdomen during phrenic nerve pacing from the superior vena cava (SVC pacing) or by fluoroscopy of spontaneous breathing. We sought to compare the sensitivity of these 2 techniques during cryoballoon ablation for detection of PNP. A total of 133 patients undergoing cryoballoon ablation were monitored with both SVC pacing and fluoroscopy of spontaneous breathing during ablation of the right superior PV. PNP occurred in 27/133 patients (20.0%). Most patients (89%) had spontaneous recovery of phrenic nerve function at the end of the procedure or on the following day. Three patients were discharged with persistent PNP. All PNP were detected first by fluoroscopic observation of diaphragm movement during spontaneous breathing, while diaphragm could still be stimulated by SVC pacing. In patients with no recovery until discharge, PNP occurred at a significantly earlier time (86 ± 34 seconds vs. 296 ± 159 seconds, P < 0.001). No recovery occurred in 2/4 patients who were ablated with a 23 mm cryoballoon as opposed to 1/23 patients with a 28 mm cryoballoon (P = 0.049). Fluoroscopic assessment of diaphragm movement during spontaneous breathing is more sensitive for detection PNP as compared to SVC pacing. PNP as assessed by fluoroscopy is frequent (20.0%) and carries a high rate of recovery (89%) until discharge. Early onset of PNP and use of 23 mm cryoballoon are associated with PNP persisting beyond hospital discharge.


Dose effects of aspirin on gastric prostaglandins and stomach mucosal injury.
To determine if a dose of aspirin exists that might inhibit thromboxane-dependent platelet function without causing gastric mucosal injury, we studied the effects of a wide range of doses of aspirin (3 mg/d to 2600 mg/d) on gastric juice prostaglandins (PGE2 and PGF2 alpha), on serum thromboxane B2, and on stomach mucosal injury as reflected by gastric juice hemoglobin and DNA concentrations. A randomized, placebo-controlled study. Research laboratory at a Veterans Affairs medical center. 16 healthy volunteers (5 men and 11 women). In the first part of the study, volunteers received placebo; aspirin, 324 mg/d; 1300 mg/d; or 2600 mg/d for 2 days. In the second part, volunteers received placebo; aspirin, 3 mg/d; 10 mg/d; 30 mg/d; or 81 mg/d for 8 days. Gastric juice PGE2 and PGF2 alpha, hemoglobin and DNA concentrations; gastric juice volume and acidity; and serum salicylate and thromboxane B2 concentrations. In the first part, significant and similar (approximately 50%) inhibition of gastric juice prostaglandin output was observed with daily aspirin doses of 324 to 2600 mg. However, a significant increase in gastric juice hemoglobin output occurred only with 2600 mg/d. In the second part, significant inhibition (approximately 50%) of gastric PGE2 output was noted at a daily aspirin dose of 30 mg. Lower aspirin doses did not reduce PGE2 output significantly, although these doses did significantly reduce serum thromboxane B2 in a dose-related manner. Aspirin can significantly reduce serum thromboxane B2 at doses of 3 mg/d or 10 mg/d, which are significantly below the threshold dose for significant gastric prostaglandin inhibition and acute stomach mucosal injury.


Wear analysis of the first-generation cross-linked polyethylene at minimum 10 years follow-up after THA: no significant effect of sports participation.
The impact of sports on long-term wear of highly cross-linked polyethylene (XLPE) after total hip arthroplasty (THA) is not fully understood. We investigated (1) the wear performance of the first-generation XLPE, and (2) whether sports participation influences the steady wear rate of XLPE. The femoral head penetration into the cup was measured digitally on radiographs of hips undergoing THA with XLPE. We retrospectively reviewed data that included age, gender, body mass index, follow-up period, preoperative diagnosis, types of XLPE, ball diameter, head material, inclination of the cup, physical function score, and sports participation. Statistical analyses were applied to determine whether sports affect the wear of XLPE and which factors were associated with the steady wear rate. Creep and steady wear rate were found to be 0.18 mm and 0.005 mm/year, respectively. Sports participation, regardless of impact, provided no significant difference in the steady wear rate. Multiple regression analysis demonstrated that sports did not increase the steady wear rate. Our findings showed excellent wear performance of the first-generation XLPE at a minimum of ten years after THA, without significant effect of sports participation on the liner wear.


Emotion and attention interactions in social cognition: brain regions involved in processing anger prosody.
Multiple levels of processing are thought to be involved in the appraisal of emotionally relevant events, with some processes being engaged relatively independently of attention, whereas other processes may depend on attention and current task goals or context. We conducted an event-related fMRI experiment to examine how processing angry voice prosody, an affectively and socially salient signal, is modulated by voluntary attention. To manipulate attention orthogonally to emotional prosody, we used a dichotic listening paradigm in which meaningless utterances, pronounced with either angry or neutral prosody, were presented simultaneously to both ears on each trial. In two successive blocks, participants selectively attended to either the left or right ear and performed a gender-decision on the voice heard on the target side. Our results revealed a functional dissociation between different brain areas. Whereas the right amygdala and bilateral superior temporal sulcus responded to anger prosody irrespective of whether it was heard from a to-be-attended or to-be-ignored voice, the orbitofrontal cortex and the cuneus in medial occipital cortex showed greater activation to the same emotional stimuli when the angry voice was to-be-attended rather than to-be-ignored. Furthermore, regression analyses revealed a strong correlation between orbitofrontal regions and sensitivity on a behavioral inhibition scale measuring proneness to anxiety reactions. Our results underscore the importance of emotion and attention interactions in social cognition by demonstrating that multiple levels of processing are involved in the appraisal of emotionally relevant cues in voices, and by showing a modulation of some emotional responses by both the current task-demands and individual differences.


[Sacrococcygeal chordoma: about a case].
Sacrococcygeal chordoma is a rare disease. It has been described in less than 3% of cases. We here report the case of a female patient with locally advanced sacrococcygeal chordoma treated at the Oujda Regional Oncology Center in Morocco. The treatment was based on exclusive radiotherapy; surgical resection couldn't be performed. At 2-year follow-up the tumor is clinically and radiologically stable and general condition of the patient is good.


Identification and characterization of dynamically regulated hepatitis-related genes in a concanavalin A-induced liver injury model.
Concanavalin A (ConA)-induced liver damage of mice is a well-established murine model mimicking the human autoimmune hepatitis (AIH). However, the pathogenic genes of the liver injury remain to be revealed. Using time-series liver transcriptome, top dynamic genes were inferred from a set of segmented regression models, and cross-checked by weighted correlation network analysis (WGCNA). AIH murine models created by ConA were used to verify the in vivo effect of these genes. We identified 115 top dynamic genes, of which most were overlapped with the hub genes determined by WGCNA. The expression of several top dynamic genes including Cd63, Saa3, Slc10a1, Nrxn1, Ugt2a3, were verified in vivo. Further, Cluster determinant 63 (Cd63) knockdown in mice treated with ConA showed significantly less liver pathology and inflammation as well as higher survival rates than the corresponding controls. We have identified the top dynamic genes related to the process of acute liver injury, and highlighted a targeted strategy for Cd63 might have utility for the protection of hepatocellular damage.


Anatomy of the thenar branch of the median nerve.
The gross and interfascicular anatomy of the terminal portion of the thenar (or recurrent median) nerve was defined by a microdissection of 20 fresh-frozen cadaveric hands. The traditionally described pattern of one main thenar trunk with three terminal branches, one each to the abductor pollicis brevis, opponens pollicis, and flexor pollicis brevis muscles, was observed in nine specimens (45%). One main trunk with two terminal branches (one branch to the abductor and one to the opponens, but no branch to the flexor) was seen in six specimens (30%). The remaining five specimens (25%) exhibited four other terminal patterns with either two, three, or four branches off the main trunk. In 15 specimens (75%), a previously undescribed "accessory thenar nerve" (ATN) arose from either the first common digital nerve (25%) or the radial proper digital nerve to the thumb (50%). The ATN innervated the flexor pollicis brevis.


Virulence factors that modulate the cell biology of Listeria infection and the host response.
The Gram-positive bacterial pathogen Listeria monocytogenes has become one of the best studied models in infection biology. This review will update our knowledge of Listeria virulence factors and highlight their role during the Listeria infection process.


Prophylactic Cranial Irradiation Versus Surveillance: Physician Bias and Patient-centered Decision-making.
An original work in this month's issue of Clinical Lung Cancer highlights the role of physician bias in the decision to recommend prophylactic cranial irradiation (PCI) to patients with small-cell lung cancer, and presents a patient decision aid to facilitate discussion. After decades of clinical trials, we've learned that PCI can significantly decrease the risk of brain metastases and possibly improve survival. However, PCI is also associated with negative impacts on cognition and quality of life. At present, there is no consensus on how to balance these risks and benefits. Understanding and exploring these issues in a structured fashion offers an opportunity to return decision-making to patients, incorporating their values and priorities.


Treatment of wastewater containing Cl2 residue by packed cage rotating biological contactor (RBC) system.
A packed cage rotating biological contactor (RBC) system was applied to treat wastewater containing Cl2 residue with concentration even up to 20 mg/L. However, Cl2 exhibited a negative effect on the efficiency of the system as evidenced by the decrease in the growth of bio-film. It could be concluded that the removal efficiency of the system decreased with the increase of Cl2 concentration or Cl2 loading. Due to inhibition of bio-film growth by the effects of Cl2 residue, the effluent suspended solids (SS) of the system was decreased. The bio-film was easily detached from the media under high growth rate conditions resulting in an increase of effluent SS. The COD and BOD5 removal efficiencies of the system under the highest organic and Cl2 loadings of 4.07 g BOD5/m2 d and 203.6 mg Cl2/m2 d, respectively, were 58.0+/-3.2% and 60.7+/-3.9%, respectively, while they were up to 83.3+/-1.8% and 85.8+/-2.0%, respectively, under the lowest organic and Cl2 loading of 2.04 g BOD5/m2 d and 25.5 mg Cl2/m2 d. However, the effluent SS of the system under above operating conditions was lower than 20 mg/L.


Establishment of Namalva cell lines which grow continuously in glutamine-free medium.
Glutamine has been shown to be a preferred energy source for some established cell lines and cancer cells in culture (Kovacevic, 1971; Kovacevic, 1972; Lavietes, 1974). Empirically, glutamine is the most abundant amino acid in most of the culture media developed. The major end product of glutamine metabolism is ammonia. Ammonia build up is one of the limiting factors in the proliferation of mammalian cells in higher density culture and is directly related to the initial glutamine concentration. The susceptibility of glutamine to thermodecomposition prevents the heat sterilization of glutamine-enriched media and this significantly increases the cost of medium preparation at the industrial scale. In an attempt to overcome these drawbacks, a population of Namalva cells capable of growing in glutamine-free media was established. The adapted cells were found to contain a higher level of glutamine synthetase activity which enable them to synthesize sufficient amounts of glutamine for their growth.


Oddity performance in preschool children at risk for mental retardation: transfer and maintenance.
The oddity performance of five preschool children at risk for mental retardation was facilitated by increasing the number of nonodd elements in a visual array. A combination intrasubject reversal and multiple baseline across subjects design indicated the internal validity of interventions designed to enhance the perceptual salience and consequent stimulus control of the odd stimulus. Results demonstrate that transfer and maintenance of oddity learning can be obtained even with individuals for whom correct oddity responding is uncommon. The typically poor performance of young and developmentally delayed children as compared to nondelayed children on tasks such as the oddity task may be attributable to a lower sensitivity to relational information.


Brain dysfunction primarily related to previous overt hepatic encephalopathy compared with minimal hepatic encephalopathy: resting-state functional MR imaging demonstration.
To investigate whether resting-state brain functional connectivity (FC) differed among cirrhotic patients without overt hepatic encephalopathy (HE) (OHE), those who currently had minimal HE (MHE), or those who had recovered from previous OHE and to investigate whether previous bouts of OHE rather than current MHE predominantly contributed to brain dysfunction in patients without current OHE. This study was approved by the institutional ethics committee, and informed consent was obtained. Resting-state functional magnetic resonance (MR) data were compared between healthy controls and the following groups of cirrhotic patients: (a) patients without MHE and without previous OHE, (b) patients with current MHE and without previous OHE, and (c) patients with previous OHE. Independent component analysis was applied to identify the best-fit component for the default-mode network (DMN). One-way analysis of variance was performed to detect different FC among groups. Pearson correlation analyses were conducted to determine the relationships between FC and neurocognitive performance. Two important regions within the DMN, including the precuneus and posterior cingulate cortex and left medial frontal gyrus, showed significantly different FC among the four groups. A trend of gradually reduced FC in two regions was observed from controls, to patients without HE, and to patients with current MHE, while patients with previous OHE showed remarkably reduced FC in these two regions. Significant correlations were found between FC and neurocognitive performance in cirrhotic patients. The reduced resting-state FC within DMN was associated with neurocognitive impairments in MHE and after clinical resolution of OHE. Previous OHE rather than current MHE might be primarily related to brain dysfunction in patients with latent OHE. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120026/-/DC1.


Measuring antenatal counseling skill with a milestone-based assessment tool: a validation study.
Antenatal counseling for parents in the setting of expected preterm delivery is an important component of pediatric training. However, healthcare professionals receive a variable amount and quality of formal training. This study evaluated and discussed validity of a practical tool to assess antenatal counseling skills and provide evaluative feedback: the Antenatal Counseling Milestones Scale (ACoMS). Experts in antenatal counseling developed an anchored milestone-based tool to evaluate observable skills. Study participants with a range of antenatal counseling skills were recruited to participate in simulation of counseling sessions in person or via video with standardized patient actors presenting with preterm labor at 23 weeks' gestation. Two faculty observers scored each session independently using the ACoMS. Participants completed an ACoMS self-assessment, demographic, and feedback survey. Validity was measured with weighted kappas for inter-rater agreement, Kruskal-Wallis and Dunn's tests for milestone levels between degrees of expertise in counseling, and cronbach's alpha for item consistency. Forty-two participants completed observed counseling sessions. Of the 17 items included in the tool, 15 items were statistically significant with scores scaling with level of training. A majority of elements had fair-moderate agreement between raters, and there was high internal consistency amongst all items. This study demonstrates that the internal structure of the ACoMS rubric has greater than fair inter-rater reliability and high internal consistency amongst items. Content validity is supported by the scale's ability to discern level of training. Application of the ACoMS to clinical encounters is needed to determine utility in clinical practice.


Serum Dickkopf-1 levels and poststroke depression in ischemic stroke patients.
Serum Dickkopf-1 (Dkk-1) levels are associated with poor ischemic stroke prognosis, although their impact on poststroke depression (PSD) remains unclear. This study aimed to examine the association between serum Dkk-1 levels and PSD. Serum Dkk-1 levels were measured in 564 patients with ischemic stroke who participated in the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The patients' depression status at 3 months after stroke was assessed using the Hamilton Rating Scale for Depression (HRSD-24). The HRSD score cutoff point for the diagnosis of depression was ≥8. A total of 224 (39.72%) patients were categorized as having PSD 3 months after ischemic stroke. After adjusting for potential confounders, including age, sex, and other important covariates, elevated Dkk-1 levels were associated with an increased risk of PSD (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.14-3.22; Ptrend = 0.037). Similarly, each standard deviation (SD) increase in log-transformed Dkk-1 levels was associated with a 24% increased risk of PSD (OR, 1.24; 95% CI, 1.03-1.49; P = 0.025). Subgroup analyses further confirmed the significant associations between Dkk-1 levels and PSD. Higher serum Dkk-1 levels at baseline are independently associated with an increased risk of PSD at 3 months after stroke, suggesting that Dkk-1 levels may be a promising prognostic biomarker for PSD. This study measured serum Dkk-1 levels only in the acute phase of stroke not in different phases; therefore, the relationship between dynamic changes in Dkk-1 levels and PSD could not be evaluated.


Bilateral ocular panadnexal mass as initial presentation of systemic blastoid variant of mantle-cell lymphoma.
A 66-year-old man developed a slowly enlarging, bilateral, painless, periorbital, and orbital swelling with ptosis, nonaxial proptosis, chemosis, exposure keratopathy, and decreased vision in both eyes. He had fever, night sweats, and weight loss (B-symptoms), along with lymphadenopathy and elevated serum lactate dehydrogenase, with no prior history of lymphoma. A transpalpebral incisional biopsy revealed a rare case of mantle-cell lymphoma of blastoid variant, stage IVB. The main immunophenotype characteristics were cyclin D1+, CD5+, CD10-, CD23-, Bcl-6-/+, and a high (up to 80%) Ki-67 proliferation index. Following an excellent response to the immune-chemotherapy treatment plan, all ocular adnexal lymphoma manifestations disappeared completely; however, 13 months after the initial presentation, there was a recurrence of the disease with rapid worsening and death. The blastoid variant of mantle cell lymphoma, a rare subtype of mantle-cell lymphoma, is a highly aggressive neoplasm, ultimately having a fatal outcome. As the initial manifestation of the disease, ocular adnexal region blastoid variant of mantle-cell lymphoma is an exceptional event, with only one previous case reported.


[Training in emergency procedures and care and management of elderly people].
Since the introduction of skills-based training reference frameworks for the training of nursing assistants and student nurses, certification in training in emergency procedures and care is an integral part of the initial training of future healthcare professionals. The elderly person is a great example for learning rightgestures.


Multislice CT angiography of interrupted aortic arch.
Interrupted aortic arch (IAA) is defined as complete luminal and anatomic discontinuity between the ascending and descending aorta. Because almost all patients with IAA become critically ill during the neonatal period, they should undergo urgent corrective surgery. This clinical urgency necessitates a fast and accurate noninvasive diagnostic method. Although echocardiography remains the primary imaging tool for this purpose, it is not always sufficient for planning surgical correction of IAA, principally due to a limited acoustic window and the inexperience of imagers. In this context, multislice CT angiography is regarded as an appropriate imaging technique complementary to echocardiography because it is fast, accurate, and objective for the diagnosis of IAA. In this article we describe what cardiac radiologists should know about IAA in their clinical practice, including clinicopathological features, CT features with contemporary surgical methods and postoperative complications, and differentiation from coarctation of the aorta and aortic arch atresia.


Cadmium-induced apoptosis of Leydig cells is mediated by excessive mitochondrial fission and inhibition of mitophagy.
Cadmium is one of the environmental and occupational pollutants and its potential adverse effects on human health have given rise to substantial concern. Cadmium causes damage to the male reproductive system via induction of germ-cell apoptosis; however, the underlying mechanism of cadmium-induced reproductive toxicity in Leydig cells remains unclear. In this study, twenty mice were divided randomly into four groups and exposed to CdCl2 at concentrations of 0, 0.5, 1.0 and 2.0 mg/kg/day for four consecutive weeks. Testicular injury, abnormal spermatogenesis and apoptosis of Leydig cells were observed in mice. In order to investigate the mechanism of cadmium-induced apoptosis of Leydig cells, a model of mouse Leydig cell line (i.e. TM3 cells) was subjected to treatment with various concentrations of CdCl2. It was found that mitochondrial function was disrupted by cadmium, which also caused a significant elevation in levels of mitochondrial superoxide and cellular ROS. Furthermore, while cadmium increased the expression of mitochondrial fission proteins (DRP1 and FIS1), it reduced the expression of mitochondrial fusion proteins (OPA1 and MFN1). This led to excessive mitochondrial fission, the release of cytochrome c and apoptosis. Conversely, cadmium-induced accumulation of mitochondrial superoxide was decreased by the inhibition of mitochondrial fission through the use of Mdivi-1 (an inhibitor of DRP1). Mdivi-1 also partially prevented the release of cytochrome c from mitochondria to cytosol and attenuated cell apoptosis. Finally, given the accumulation of LC3II and SQSTM1/p62 and the obstruction of Parkin recruitment into damaged mitochondria in TM3 cells, the autophagosome-lysosome fusion was probably inhibited by cadmium. Overall, these findings suggest that cadmium induces apoptosis of mouse Leydig cells via the induction of excessive mitochondrial fission and inhibition of mitophagy.


Identification of polymorphic variants associated with erlotinib-related skin toxicity in advanced non-small cell lung cancer patients by DMET microarray analysis.
Erlotinib is a targeted agent commonly used in advanced non-small cell lung cancer (aNSCLC). However, drug-related skin toxicity often may affect the quality of life of cancer patients and lead to treatment discontinuation. Genetic polymorphisms in drug transporters and metabolizing enzymes play a major role in the interindividual variability in terms of efficacy and toxicity of erlotinib treatment. The aim of our study was to identify genetic determinants in adsorption, distribution, metabolism, and excretion genes influencing skin rash (SR) by the novel drug-metabolizing enzyme and transporter (DMET) microarray Affymetrix platform in aNSCLC patients. In a retrospective study, 34 erlotinib-treated aNSCLC patients were genotyped by DMET Plus chip: 23 patients experienced SR (cases), while 11 patients did not (controls). Peripheral blood DNA was genotyped. Genotype association was analyzed by Fisher's exact test, and the toxicity-associated gene sets underwent Ingenuity Pathway Analysis (IPA). Seven SNPs in six genes (CYP27B1, MAT1A1, CHST1, CYP4B1, ADH6, and SLC22A1) were associated with the occurrence of SR or with a protective effect. Specifically, the rs8176345 in CYP27B1 gene was significantly correlated with SR (p = 0.0003, OR 55.55, 95% CI 2.7036-1141.1707). The IPA on SR-related genes highlighted the role of a variety of canonical pathways including 1,25-dihydroxyvitamin D3 biosynthesis, S-adenosyl-L-methionine biosynthesis, and methionine degradation I (to homocysteine) in SR development. Although exploratory, this study indicates rs8176345 in CYP27B1 gene as significantly correlated with erlotinib-induced SR in aNSCLC patients probably through a mechanism mediated by vitamin D3 and inflammation at skin level.


Ameliorative effect of Koflet formulations against pyridine-induced pharyngitis in rats.
In present study two formulations of Koflet (syrup and lozenges) were evaluated against pyridine-induced pharyngitis in rats. Topical application of 10% pyridine showed extravasation of Evans blue stain as a characteristic feature of on-going inflammation. In addition, the levels of TNF-α (p < 0.01) and IL-6 (p < 0.01) were significantly increased compared to control. Further, histopathology of the pharyngeal tissue showed submucosal gland hypertrophy, severe mucosal inflammation characterized by presence of mononuclear cells and neutrophils along with haemorrhages and congestion; however, saline applied animals (normal control) showed normal cytoarchitecture of the pharynx. Interestingly, pre-treatment with dexamethasone (1 mg/kg, p.o.), Koflet lozenges (KL) (500 and 1000 mg/kg, p.o.) and Koflet syrup (KS) (2 and 4 ml/kg, p.o.) for 7 days showed significant and dose dependent protection by decreasing the EB dye extravasation, and serum levels of TNF-α and IL-6. In addition, histopathological findings have further supported the protective effect of Koflet formulations. These findings suggest that, both Koflet syrup and Koflet lozenges are highly effective in treating non-infectious type of pharyngitis. Among the two formulations KS was found to be more potent than KL, and possible mechanism of action thought to be mediating through inhibition of TNF-α and/or phospholipids-arachidonic acid pathway.


Neuronally mediated non-cholinergic contraction of guinea-pig bronchial smooth muscle is inhibited by a substance P antagonist.
The isolated main bronchi of the guinea-pig respond to electrical field stimulation with a twitch followed by a slow contraction. Atropine blocked the slow contraction. The substance P antagonist, (D-Pro2, D- Trp7 ,9)-SP, greatly reduced the atropine-resistant contraction. The results suggest the involvement of substance P in non-cholinergic neurotransmission in the guinea-pig airways.


Understanding the return on health, safety and environmental investments.
Traditionally, health safety and environmental (HS & E) investments have been viewed as expensive but necessary. HS & E professionals had a difficult task of providing data showing that these investments can also contribute to business success. An ORC task force developed a way for traditional financial analysis methods to be applied to HS & E investments and decisions. The result of the task force effort is the software called the ORC Return on Health, Safety and Environmental Investments (ROHSEI), a supporting tool to provide a comprehensive look at health, safety or environmental investment projects and their potential financial impacts. Since its development, more than 200 companies, government agencies, and educational institutions have been trained in the ROHSEI process and software. HS & E professionals who are able to evaluate and communicate the business value of health, safety and environmental efforts will improve understanding of the impacts HS & E projects and contribute to better decision making by their organizations.


Antioxidant lignoids from leaves of Ribes nigrum.
Phytochemical investigation of the leaves of Ribes nigrum resulted in the isolation of fourteen compounds, including four 7,7'-epoxylignans, three tetrahydrofuran-type sesquilignans, and a spirocyclic dilignan. Their structures were elucidated by extensive spectroscopic analyses and by chemical transformations. The isolated compounds were evaluated for their antioxidant activities using superoxide anion scavenging assay and DPPH free radical scavenging assay. Ribesin D and ribesin G showed the most potent superoxide anion scavenging activity with EC50 values of 1.24 and 1.12 μM, respectively, and the structure-activity relationship was discussed.


Post-operative pain treatment in Denmark from 2000 to 2009: a nationwide sequential survey on organizational aspects.
In Denmark, the first acute pain service (APS) was introduced in 1993. An important objective became to facilitate implementation of accelerated post-operative rehabilitation programmes (ACC) in selected procedures in abdominal, gynaecological and orthopaedic surgery. Therefore, it is of considerable interest to study the association between the developments of post-operative pain management and the ACC by sequential analyses from 2000 to 2009. In 2000, 2003, 2006 and 2009, a questionnaire was mailed to all Danish anaesthesiology departments. The headings of the questionnaire were demographics of responder departments, resources allocated to pain management methods, quality assessment methods, research activities and implementation of ACC. The responder rates varied between 80% and 94% (mean 88%) representing a mean number of anaesthetics of 340.000 per year. The number of APSs in the study period varied in university hospitals between 52% and 71% (P = 0.01), regional hospitals between 8% and 40% (P < 0.01), and local hospitals between 0% and 47% (P < 0.01). The prevalences of departments actively engaged in ACC were 40% in 2000, 54% in 2003, 73% in 2006 and 80% in 2009 (P < 0.01). The study, spanning nearly a decade, illustrates that following an increase in number of APSs from 2000 to 2006, followed by a significant decline, a steadily increasing number of departments implemented ACC.


Molecular Interactions Governing Autoantigen Presentation in Type 1 Diabetes.
Type 1 diabetes is a chronic autoimmune disease resulting from T cell-mediated destruction of insulin-producing beta cells within pancreatic islets. Disease incidence has increased significantly in the last two decades, especially in young children. Type 1 diabetes is now predictable in humans with the measurement of serum islet autoantibodies directed against insulin and beta cell proteins. Knowledge regarding the presentation of insulin and islet antigens to T cells has increased dramatically over the last several years. Here, we review the trimolecular complex in diabetes, which consists of a major histocompatibility molecule,self-peptide, and T cell receptor, with a focus on insulin peptide presentation to T cells. With this increased understanding of how antigens are presented to T cells comes the hope for improved therapies for type 1 diabetes prevention.


Pericardiocentesis under two-dimensional echocardiographic guidance in loculated pericardial effusion.
Pericardiocentesis to relieve tamponade from a loculated pericardial effusion in patients following cardiac surgery is greatly aided by two-dimensional echocardiographic imaging guidance. This technique delineates the fluid distribution and the site of adhesions, defines the path for introduction of an aspiration needle, alerts to the possibility of myocardial contact, and helps in positioning the drainage catheter. Two-dimensional echocardiographic imaging can be performed at the patient's bedside, and the images are easy to interpret. This technique simplifies pericardiocentesis and helps to avoid complications.


Biogenic amine levels in the mid-term human fetus.
Spectrophotofluorometric assays were used to measure concentrations of DA, NA, 5-HT and 5-HIAA present in extracts of brain tissue and CSF taken from midterm gestational fetuses of both sexes. The presence of biogenic amines was demonstrated in fetuses as early as 10.5 weeks gestation. In the hypothalamus, the concentrations (expressed in ng/100 mg tissue) ranged from 10.2 to 62.2 for NA, 11.6 to 258.8 for DA, 7.6 to 38.6 for 5-HT and 56.6 to 114.1 for 5-HIAA. Concentrations of DA and 5-HT were found to be significantly (P less than 0.05) higher in the hypothalamus than in the cortex, but those of NA and 5-HIAA were similar in both areas. No sex difference was observed. The concentrations of biogenic amines in the CSF (expressed in ng/ml) were 63.1-286.7 for NA, 43.2-108.1 for DA, 30.9-87.5 for 5-HT and 8.0-42.8 for 5-HIAA.


The effect of graded inclusion of baked beans (Phaseolus vulgaris) on plasma and liver lipids in hypercholesterolaemic pigs given a Western-type diet.
The aim of the present study was to measure the effect of graded inclusion of baked beans (Phaseolus vulgaris) on plasma and liver lipids in hypercholesterolaemic pigs fed on a Western-type diet. Twenty-four Large White x Landrace pigs of about 30 kg body weight were made hypercholesterolaemic by feeding a semi-purified diet, high in saturated fat and supplemented with 10 g cholesterol/kg, for 14 d. After that, six pigs were randomly assigned to one of the four experimental groups. They received their respective diets, containing 0, 100, 200 or 300 g baked beans/kg, on a dry-matter basis, for a further 28 d. Fasting blood samples were taken and analysed for total plasma cholesterol, lipoproteins and triacylglycerols. After the pigs were slaughtered at the end of the study, livers were analysed for their cholesterol content. Consumption of baked beans at 100, 200 and 300 g/kg reduced plasma total cholesterol by 5.3, 20.2 and 35.6% respectively. However, only the diet with 300 g baked beans/kg showed a significant reduction (P < 0.05) compared with the control (without baked beans). The level of low-density-lipoprotein-cholesterol was also significantly (P < 0.05) reduced by 48% at 300 g baked beans/kg. Plasma very-low-density-lipoprotein-cholesterol, high-density-lipoprotein-cholesterol and triacylglycerol contents were not affected by bean consumption. The supplements of 200 and 300 g baked beans/kg promoted a significant (P < 0.05) reduction of about 50% in cholesterol deposition in the liver, compared with the control.


[Nickel, chromium and cobalt release from a metal prosthesis in metal-sensitive patients].
Six rejected stainless steel hip prostheses that had been removed from 15 metal sensitive patient were immersed in different solutions in various containers and maintained at 37 degrees C in complete darkness. Two months later by means of atomic absorption spectrophotometric studies we were able to determine the amount of nickel, chrome and cobalt released in a saline solution. When the chromium oxide passivation coat of the metal prostheses is damaged by orthopaedic surgical implantation procedures the prostheses may rust, releasing metallic ions.


Calibration of magnification in two-dimensional low-dose full-body imaging for preoperative planning of total hip arthroplasty.
Preoperative planning of total hip arthroplasty (THA) using two-dimensional low-dose (2DLD) full-body imaging has gained popularity in recent years. The low-dose imaging system is said to produce a calibrated image with constant 1:1 magnification. However, the planning software used in conjunction with those images may introduce variations in the degree of magnification in 2DLD imaging, and this has not yet been investigated. The purpose of the present study was to quantify any variation in 2DLD image to assess the need for image calibration when using conventional planning software. Postoperative 2DLD images from 137 patients were retrospectively evaluated. Only patients who underwent THA for primary osteoarthritis were included in the study cohort. The femoral head diameter was measured by two independent observers using both Orthoview™ and TraumaCad™ planning software programs. Actual sizes of the femoral head implants were extracted from surgical reports to calculate image magnification. Magnification measurement reliability was calculated with the intra-class correlation coefficient (ICC) index. Image magnification varied among cases (mean 133%, range 129-135%). There was no statistical difference in mean image magnification among the various implant sizes (p = 0.8). Mean observer and inter-observer reliability was rated excellent. THA planning with 2DLD imaging is subject to variation in magnification as analyzed with conventional planning software in this series. This finding is of paramount importance for surgeons using 2DLD imaging in preparation for THA since errors in magnification could affect the accuracy of preoperative planning and ultimately the clinical outcome.


Two-photon exchange in (muonic) deuterium at N3LO in pionless effective field theory.
We present a study of the two-photon-exchange (2 γ -exchange) corrections to the S-levels in muonic ( μ D) and ordinary (D) deuterium within the pionless effective field theory (EFT). Our calculation proceeds up to next-to-next-to-next-to-leading order (N3LO) in the EFT expansion. The only unknown low-energy constant entering the calculation at this order corresponds to the coupling of a longitudinal photon to the nucleon-nucleon system. To minimise its correlation with the deuteron charge radius, it is extracted using the information about the hydrogen-deuterium isotope shift. We find the elastic 2 γ -exchange contribution in μ D larger by several standard deviations than obtained in other recent calculations. This discrepancy ameliorates the mismatch between theory and experiment on the size of 2 γ -exchange effects, and is attributed to the properties of the deuteron elastic charge form factor parametrisation used to evaluate the elastic contribution. We identify a correlation between the deuteron charge and Friar radii, which can help one to judge how well a form factor parametrisation describes the low-virtuality properties of the deuteron. We also evaluate the higher-order 2 γ -exchange contributions in μ D, generated by the single-nucleon structure and expected to be the most important terms beyond N3LO. The uncertainty of the theoretical result is dominated by the truncation of the EFT series and is quantified using a Bayesian approach. The resulting extractions of the deuteron charge radius from the μ D Lamb shift, the 2 S - 1 S transition in D, and the 2 S - 1 S hydrogen-deuterium isotope shift, with the respective 2 γ -exchange effects evaluated in a unified EFT approach, are in perfect agreement.


The effect of chemical modification of Saccharomyces cerevisiae on electrophoretic mobility, cell-wall structure and amphotericin B uptake.
Saccharomyces cerevisiae NCYC 239 suspended in solutions of NaCl showed two distinct plateaus in plots of electrophoretic mobility vs. pH, corresponding to pKa values of approx. 2 and 5. This is in contrast to cells suspended in buffer where only a single pKa (4) can be determined. Modification of cells with KI/I2 or nitrous acid led to altered electrophoretic mobility, indicating the presence of sulphydryl and amino groups, respectively, in the yeast cell surface, whereas uranyl nitrate modification had little effect, suggesting phosphate groups to be absent. Electron micrographs showed visible effects of KI/I2 and nitrous acid modification on cell membrane structure, and in these modified cells amphotericin B uptake was rapid. It is suggested that diffusion through the cell wall is the rate-limiting step for amphotericin B uptake. An activation energy of 20 kJ X mol-1 was determined for uptake of amphotericin B by unmodified cells.


Petrification and Revitalization: The Role of Somatic Narration in Working Through A War Trauma.
The author investigates bodily aspects of the defense organization in the treatment of a soldier suffering from a war traumatization. The patient reports two situations-a bomb attack and the subsequent confrontation with wounded comrades-that had a traumatizing impact. In the treatment process, a phase of stagnation is described before the shared attention is focused on the bodily perception of the patient. His petrified body feeling ("my body feels like concrete") was systematically examined in the therapeutic process then slowly transformed through shared perception, leading to a process of vitalizing reorganization. This method is called somatic narration. It reverses the defense processes of the encapsulated body engram. This capsule results from the threatening impact of a traumatic event, disorganizing the patient's body-self. This disorganization then is encapsulated through a process of petrification and avoidance of awareness. The therapeutic process is described in detail. The structure of the bodily unconscious is revealed. The process of reorganization of perception and memory is outlined.


Safety and efficacy of addition of hyaluronidase to a mixture of lidocaine and bupivacaine in scalp nerves block in elective craniotomy operations; comparative study.
Patients undergoing craniotomy operations are prone to various noxious stimuli, many strategies are commenced to provide state of analgesia, for better control of the stress response and to overcome its undesired effects on the haemodynamics and post-operative pain. Scalp nerves block are considered one of these strategies. This study was conceived to evaluate the effect of addition of hyaluronidase to the local anaesthetic mixture used in the scalp nerves block in patients undergoing elective craniotomy operations. 64 patients undergoing elective craniotomy operations were enrolled in this prospective randomized, double-blind comparative study. Patients were randomly assigned to two groups. Group LA, patients subjected to scalp nerves block with 15 ml bupivacaine 0.5%, 15 ml lidocaine 2%, in 1:400000 epinephrine. Group H as Group LA with15 IU /ml Hyaluronidase. Patients in the H group showed lower VAS values for 8 h postoperative, compared to the LA group. The haemodynamic response showed lower values in the H group, compared to the LA group. Those effects were shown in the intraoperative period and for 6 h post-operative. No difference was detected regarding the incidence of complications nor the safety profile. Our data supports the idea that addition of hyaluronidase to the local anesthetic mixture improves the success rates of the scalp nerves block and its efficacy especially during stressful intraoperative periods and in the early postoperative period. No evident undesirable effects in relation to the addition of hyaluronidase. Clinical Trial registry on ClinicalTrials.gov , NCT 03411330 , 25-1-2018.


Phosphine-free cross-coupling reaction of arylboronic acids with carboxylic anhydrides or acyl chlorides in aqueous media.
The palladium acetate-catalyzed coupling reaction of aryl boronic acid with carboxylic anhydride or acyl chloride was carried out smoothly in water in the presence of poly(ethylene glycol) (PEG) or 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]) to give high yields of ketones without the use of phosphine ligands. The Pd(OAc)2-H2O-[bmim][PF6] catalytic system can be recovered and reused eight times with high efficiency for both carboxylic anhydride and acyl chloride.


Why do outpatients fail to keep their clinic appointments? Results from a survey and recommended remedial actions.
We undertook a survey of 2555 outpatients (both new and review) to look at the reasons for high non-attendance (DNA) rates. Completed questionnaires (n = 983, 38.5% response) indicated the main reasons: forgetting or not receiving the appointment because of illness, and less often because of feeling better; transport problems; and short notice. Our remedial actions included improving the clerical system, announcing DNA rates on a regular basis in GP surgeries and in the outpatient department, introducing a tear-off slip with the appointment letter for patients to return, installing a free answerphone, active GP/consultant involvement in DNA-related problems and local publicity campaigns. A new scheme in our trust--outpatient telephone follow-up--may also help in reducing DNA rates.


In vitro alpha-amylase inhibition and in vivo antioxidant potential of Amaranthus spinosus in alloxan-induced oxidative stress in diabetic rats.
Amaranthus spinosus Linn. (Amaranthaceae), commonly known as "Mulluharivesoppu" in Kannada, is used in the Indian traditional system of medicine for the treatment of diabetes. The present study deals with the scientific evaluation of alpha amylase and the antioxidant potential of methanol extract of A. spinosus (MEAS). The aim of this study was to investigate in vitro alpha-amylase enzyme inhibition by CNPG3 (2-chloro-4-nitrophenol α-d-maltotrioside) and in vivo antioxidant potential of malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and total thiols (TT) in alloxan-induced diabetic rats of a methanolic extract of A. spinosus. Blood sugar was also determined in MEAS-treated alloxan-induced diabetic rats. MEAS showed significant inhibition of alpha-amylase activity and IC50 46.02 μg/ml. Oral administration of MEAS (200 and 400 mg/kg) for 15 days showed significant reduction in the elevated blood glucose, MDA and restores GSH, CAT and TT levels as compared with a diabetic control. The present study provides evidence that the methanolic extract of A. spinosus has potent alpha amylase, anti-diabetic and antioxidant activities.


Comparison between the outcomes of fluorescein angiography-guided and indocyanine green angiography-guided half-time photodynamic therapy for central serous chorioretinopathy.
This study aimed to compare the efficacy of fluorescein angiography (FA)-guided and indocyanine green angiography (ICGA)-guided half-time photodynamic therapy (PDT) for central serous chorioretinopathy (CSC). Medical records of 61 eyes of 61 CSC patients who underwent half-time PDT were retrospectively reviewed. The irradiation area was determined using information from FA or ICGA with physicians' discretion. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), subfoveal choroidal thickness (SCT), and resolution of subretinal fluid (SRF) were evaluated at baseline and 1, 3, 6, and 12 months after PDT. A total of 29 and 32 eyes received FA-guided PDT (irradiation area, 2898.3 ± 705.7 μm) and ICGA-guided PDT (irradiation area, 4993.8 ± 333.1 μm), respectively. A significant improvement in the mean BCVA was found at 1 month in the FA-guided group (P = 0.02), but not in the ICGA-guided group (P = 0.88). BCVA was significantly improved in both groups at 3, 6, and 12 months with no significant intergroup difference at any time points. CRT and SCT were significantly reduced in both groups at all time points with no significant intergroup differences. No significant intergroup differences were observed in the rate of recurrence and persistent SRF. However, there was a significant difference between groups in the rate of recurrence and/or persistent SRF (P = 0.04). Multivariate analysis revealed that choice of FA-guided was significantly associated with recurrence and/or persistent SRF (P = 0.04). Half-time PDT with ICGA-guided irradiation spot might be more effective than that with FA-guided in treating CSC patients in complete resolution of SRF.


Cardiac nuclear medicine: positron emission tomography in clinical medicine.
Positron-emission tomography (PET) and radioactively labelled substrates permit metabolic studies to be carried out in vivo and in situ with few if any limitations regarding the choice of substrates as long as they can be tagged with positron-emitting radionuclides, especially those like 11C and 13N. With respect to cardiology, 13N-ammonia and 82Rb are helpful in the examination of myocardial perfusion. The evaluation of myocardial glucose and fatty acid metabolism with 18F-deoxyglucose (FDG) and 11C-palmitate has proved to be clinically useful. Thus, myocardial ischemia and hypoxia, infarct size, the transmural extent of the infarction and tissue viability after it can all be examined as can pathological biochemistry in patients with primary or secondary cardiomyopathies. Single-photon-emitting labelled substances such as 123I-labelled fatty acid analogues also provide information equivalent to that which can be gathered by PET for clinical use. Thus, one major task of PET is the validation of methods and the transformation of these methods to single-photon-emitting radiotracers for broad clinical application, in situations where the expense of PET cannot at present be justified.


PIFA-mediated selenylative spirocyclization of indolyl ynones: facile access to selenated spiro[cyclopentenone-1,3'-indoles].
A fast selenylative spirocyclization of indolyl ynones mediated by PIFA has been developed. This transformation was enabled by the reactive RSeOCOCF3 species generated in situ from diselenides with PIFA, involving an electrophilic dearomative cascade cyclization. This protocol provides a facile and efficient method for the synthesis of selenated spiro[cyclopentenone-1,3'-indoles] and tolerates broad functional groups.


Low doses of tizanidine synergize the anti-nociceptive and anti-inflammatory effects of ketorolac or naproxen while reducing of side effects.
The aim of the present study was to determine whether tizanidine, an alpha2-adrenoceptor agonist, is able to increase the anti-inflammatory and anti-nociceptive effects of naproxen and ketorolac with a low incidence of gastric injury and spontaneous activity in rats. The anti-inflammatory effect was assayed in a carrageenan test, and oral administration of tizanidine (ED40 =0.94±0.2mg/kg), naproxen (ED40=3.18±0.4mg/kg), and ketorolac (ED40=16.4±1.9mg/kg) showed a dose-dependent effect on inflammation. The anti-nociceptive effect was assayed in the formalin test, and administration of tizanidine (ED40=0.39±0.06mg/kg, p.o.), naproxen (ED40=33.9±3.9mg/kg, p.o.) or ketorolac (ED40=6.49±1mg/kg, p.o.) each showed a dose-dependent anti-nociceptive effect. The effects of combinations of tizanidine/naproxen and tizanidine/ketorolac were determined considering their ED40 at a rate of 1:1. Additionally, the tizanidine/naproxen and tizanidine/ketorolac combinations showed anti-inflammatory and anti-nociceptive effects. The tizanidine/ketorolac combination was more potent than tizanidine/naproxen, in both inflammatory (interaction index=0.03 tizanidine/ketorolac and 0.07 tizanidine/naproxen) and nociceptive (interaction index=0.005 tizanidine/ketorolac and 0.01 tizanidine/naproxen) processes. In both cases, tizanidine improved naproxen and ketorolac gastrointestinal tolerability by 50%. Furthermore, co-administration of tizanidine with naproxen or ketorolac did not modify the spontaneous activity in the same way as individual tizanidine administration. Considering that tizanidine increases the anti-inflammatory and anti-nociceptive effects of naproxen or ketorolac, with an increase in gastric tolerability, tizanidine could provide therapeutic advantages in the clinical treatment of inflammation and pain.


[From "wet caries" to controllable complication. History of post-traumatic and postoperative osteitis].
In former times treatment of osteomyelitis was based on very few surgical principles such as incision of the infected region, debridement with sequestrectomy, and continuous drainage to prevent superficial closing of the wound. There were no rules for asepsis, anesthesia, and microbiology in the treatment of bone infection. Therapy improved dramatically when J. Lister introduced and performed antisepsis. With the beginning of the twentieth century it became much more standardized and differentiated. In the 4th decade of the twentieth century, the development of antibiotics changed the regime of osteomyelitis therapy again. Especially systemic intravenous antibiotic therapy was very successful in the treatment of the hematogeneous osteomyelitis. Treatment failed in post-traumatic and postoperative osteitis. Local antibiotic therapy on a delivery system was the breakthrough for these cases. The application of PMMA cement as an antibiotic delivery system led to this new possibility for treating bone infections and is still in use nowadays.


Effect of X-rays on expression of caspase-3 and p53 in EL-4 cells and its biological implications.
To investigate the effect of X-rays on expression of caspase-3 and p53 protein in EL-4 cells and its implications in induction of apoptosis and polyploid cells. Mouse lymphoma cell line (EL-4 cells) was used. Fluorescent staining and flow cytometry analysis were employed for measurement of protein expression, apoptosis, cell cycle, and polyploid cells. The expression of caspase-3 protein increased significantly at 8 h and 12 h, compared with that of sham-irradiated control (P<0.05, respectively) and the expression of p53 protein increased significantly at 2, 4, 8, 12, and 24 h, compared with that of sham-irradiated control (P<0.05-P<0.01) in EL-4 cells after 4.0 Gy X-irradiation. Apoptosis of EL-4 cells was increased significantly at 2, 4, 8, 12, 24, 48, and 72 h after 4.0 Gy exposure, compared with that of sham-irradiated control (P<0.05-P<0.001). G2 phase cells were increased significantly at 4, 8, 12, 24, 48, and 72 h (P<0.05-P<0.001). However, no marked change in the number of 8 C polyploid cells was found from 2 to 48 h after 4.0 Gy exposure. The expressions of caspase-3 and p53 protein in EL-4 cells are induced by X-rays, which might play an important role in the induction of apoptosis, and the molecular pathway for polyploid formation might be p53-independent.


Less contribution of the nicotinic cholinergic and alpha2-adrenergic action of high acetaldehyde concentration on the inhibition of intestinal ethanol absorption.
In the present study, we investigated the effects of hexamethonium, a ganglionic nicotinic receptor blocking agents and yohimbine, an alpha2-adrenergic antagonist, on reduction of ethanol absorption in presence of high acetaldehyde concentration. Hexamethonium had no effect, whereas yohimbine by itself reduced ethanol absorption, but no additional effects were observed with presence of high acetaldehyde. Propionaldehyde had an inhibitory action on intestinal 1-propanol absorption. As both yohimbine and propionaldehyde are associated with vagus nerve activation, these results indirectly support the hypothesis that a cholinergic mechanism through vagus nerve activation is responsible for the inhibition of intestinal ethanol absorption by acetaldehyde.


Chloroquine resistance of Plasmodium falciparum in semi-immune children in Zaria, northern Nigeria.
Fifty-nine children with Plasmodium falciparum malaria were subjected to the World Health Organization (WHO) extended field test to assess the in vivo sensitivity of the parasite to chloroquine in Zaria urban area, Nigeria. The parasites in 53 children (90%) were positive but those in 6 (10%) were resistant at the RI-RII level. 36 isolates from the patients were successfully cultured in vitro for the WHO standard microtest. 13 (37%) of the isolates underwent schizogony at chloroquine concentrations of 1.6 microM/litre and above. Probit analysis showed that the chloroquine concentrations producing 50% (EC50), 90% (EC90) and 99% (EC99) schizont inhibition were 0.4, 1.6 and 4.9 microM/litre, respectively. The results indicate a rapid decline in the sensitivity of P. falciparum to chloroquine in the study area during the past 3 years.


Evidence in practice.
A clinical scenario is used to illustrate how the principles outlined in the previous articles in the series could be applied to help improve patient care. A practical demonstration of the art of formulating answerable clinical questions, finding evidence, critically appraising evidence, and putting evidence into practice is provided. The importance of integrating evidence with patient's preferences, and taking account of issues such as availability of interventions, costs, and so on is discussed. Finally, some of the issues involved in the development of evidence based policies within clinical teams are outlined.


Stereotactic body radiation therapy for liver metastases: Clinical outcomes and literature review.
The role of stereotactic body radiation therapy (SBRT) in the management of liver metastasis is increasing, using ablative doses with the goal of local control and ultimately improving survival. The aim of this study is to evaluate our initial results regarding local control, overall survival and toxicity in patients with liver metastases treated with this technique, due to the lack of evidence reported in Latin America. We performed a retrospective chart review from November 2012 to June 2018 of 24 patients with 32 liver metastases. Kaplan-Meier curves were constructed for local control and overall survival. Clinical and prognostic factors were further analyzed by independent analysis. Median follow-up period was 22 months (range, 1-65 months). Median age was 62 years (range, 40-84 years). Colorectal carcinoma was the most common primary cancer. Overall 1-year and 2-years local control rates were 82% (95% Confidence Interval [CI], 70-98%) and 76.2% (95% CI, 45-90%), respectively. Median overall survival rate was 35 months (95%, CI 20.5-48 months). Overall 1-year and 2-year survival rates were 85.83% (95% CI, 64-99%) and 68% (95% CI, 45-84%), respectively. No acute or late grade 3 or 4 toxicity was observed during the follow-up period. SBRT achieves excellent local control and overall survival rates with low toxicity in patients with liver metastases. Based on our literature review, our results are consistent with larger reports. Further randomized trials are required to compare with other local therapies.


Diffuse melanosis after chemotherapy-induced tumor lysis syndrome in a patient with metastatic melanoma.
Diffuse melanosis is a rare event associated with advanced metastatic malignant melanoma. A 35-year-old woman with stage IV melanoma is presented, who developed slate bluish-gray to brown discoloration of her skin after chemotherapy-induced tumor lysis syndrome. A number of studies were performed to re-evaluate possible mechanisms of melanosis. Skin tissue was examined on routine hematoxylin-and-eosin-stained sections, Fontana stains, immunohistochemical studies with antibodies for Melan-A, gp100, tyrosinase, FXIIIa, and CD68, and by electron microscopy. The main cell types found to contain melanin pigment were histiocytes and dendritic cells. In the dermis, they were distributed mainly around venules. In the subcutaneous fat, they were scattered throughout the fat lobule. Melanin pigment was not only seen within cells but also extracellularly. No melanoma cells were seen in the skin. No increase in melanin pigment or number of melanocytes was seen in the epidermis. A bone marrow biopsy contained melanophages but no melanoma cells. Ultrastructural examination of the patient's serum revealed the presence of melanosomes. Sequence analysis of the tumor's cDNA failed to identify any mutations in the tyrosinase gene, and no tyrosinase protein was detected in non-melanocytic cells, indicating that it was unlikely that a mutation had resulted in a secretory form of the protein. These findings document that diffuse melanosis may result from tumor lysis, with release of melanosomes into the bloodstream.


Reviving a successful blunt chest wall injury protocol.
This article describes a quality improvement project that assessed nurses' knowledge and practices for patients admitted with a blunt chest wall injury and utilized interactive learning to revive the use of the protocol.


Enhancement of corneal permeation of riboflavin-5'-phosphate through vitamin E TPGS: a promising approach in corneal trans-epithelial cross linking treatment.
Corneal accumulation of riboflavin-5'-phosphate (riboflavin) is an essential step in the so called corneal cross-linking (CXL), an elective therapy for the treatment of progressive keratoconus, corneal ectasia and irregular astigmatism. CXL is usually performed after surgical debridement of corneal epithelium, since it impedes the stromal penetration of riboflavin in a relatively short time. d-Alpha-tocopheryl poly(ethylene glycol) 1000 succinate (VE-TPGS) is an effective permeation enhancer used to increase adsorption of drugs trough different biological barriers. Moreover, belonging to the group of tocopherol pro-drugs, VE-TPGS exerts a protective effect on biological membrane against free-radical damage. The aim of this work is the evaluation of VE-TPGS effects on riboflavin corneal permeability, and the assessment of its protective effect against free-radicals generated during CXL procedures. Different solutions containing riboflavin (0.125% w/w), dextran (20.0% w/w) and increasing concentration of VE-TPGS were tested. Corneal permeation was evaluated in vitro by the use of modified Franz-cell type diffusion cells and freshly excised porcine corneas as barrier. The effect of VE-TPGS on riboflavin corneal penetration was compared with a standard commercial solution of riboflavin in dextran at different times. Accumulation experiments were conducted both on epithelized and non-epithelized corneas. Moreover, epithelized porcine corneas, treated with the tested solutions, were subjected to an in vitro CXL procedure versus non-epithelized corneas, treated with a commercial solution of riboflavin. Differences were measured by means of corneal rigidity using Young's modulus. The photo-protective effect of tested solutions on corneal epithelium was, finally, evaluated. CXL treatment was applied, in vitro, on human explanted corneas and resulting morphology of corneal epithelium was investigated by scanning electron microscopy.


Incidence of Deep Vein Thrombosis and Its Effect on Health-Related Quality of Life Among Nurses of Greek Public Hospitals: A Multicenter Study.
Vein thrombosis (VTE) is a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE). The aim of this study was to investigate the impact of DVT and its association with health-related quality of life among Greek nurses. This is a multicenter descriptive correlation study. The sample of the study was nursing staff working in Greek public hospitals. The diagnosis of DVT was set by Hicks's clinical criteria. The study included 6304 nurses with a mean age of 47.4 ± 4.9 years. Diagnosed by a physician, DVT had 544 (8.6%) participants. The mean score of the overall dimension of physical health-related quality of life was 68.1 ± 21.9 and the overall score of mental health scale was 53.3 ± 10.4. The odds of DVT occurrence increased dramatically for female gender (CI: 27.76, 95% CI: 8.12-94.89, p = 0.001). Increased odds were found also for advanced age (CI: 1.21, 95% CI: 1.09-1.33, p = 0.001), advanced BMI (CI: 1.06, 95% CI: 1.02-1.10, p = 0.001), and smoking (CI: 2.72, 95% CI: 1.51-4.90, p = 0.001). Moreover, previous pregnancy (CI: 1.66, 95% CI: 1.21-2.29, p = 0.002), work experience (CI: 1.13, 95% CI: 1.03-1.23, p = 0.008), and Rhesus (CI: 2.55, 95% CI: 1.11-5.84, p = 0.027) were found to be risk factors for DVT. Nurses are potentially a professional group for developing deep vein thrombosis, and given the high incidence found in this study, as well as the lower proportion of nurses who were undiagnosed while meeting the clinical criteria of Hick, it is essential for nurses to check their lower extremities for DVT annually.


Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy.
The natural history of biochemical recurrence after radical prostatectomy can be long but variable. Better risk assessment models are needed to identify men who are at high risk for prostate cancer death early and who may benefit from aggressive salvage treatment and to identify men who are at low risk for prostate cancer death and can be safely observed. To define risk factors for prostate cancer death following radical prostatectomy and to develop tables to risk stratify for prostate cancer-specific survival. Retrospective cohort study of 379 men who had undergone radical prostatectomy at an urban tertiary care hospital between 1982 and 2000 and who had a biochemical recurrence and after biochemical failure had at least 2 prostate-specific antigen (PSA) values at least 3 months apart in order to calculate PSA doubling time (PSADT). The mean (SD) follow-up after surgery was 10.3 (4.7) years and median follow-up was 10 years (range, 1-20 years). Prostate cancer-specific mortality. Median survival had not been reached after 16 years of follow-up after biochemical recurrence. Prostate-specific doubling time (<3.0 vs 3.0-8.9 vs 9.0-14.9 vs > or =15.0 months), pathological Gleason score (< or =7 vs 8-10), and time from surgery to biochemical recurrence (< or =3 vs >3 years) were all significant risk factors for time to prostate-specific mortality. Using these 3 variables, tables were constructed to estimate the risk of prostate cancer-specific survival at year 15 after biochemical recurrence. Clinical parameters (PSADT, pathological Gleason score, and time from surgery to biochemical recurrence) can help risk stratify patients for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. These preliminary findings may serve as useful guides to patients and their physicians to identify patients at high risk for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy to enroll them in early aggressive treatment trials. In addition, these preliminary findings highlight that survival in low-risk patients can be quite prolonged.


Differential transcriptional regulation of hypoxia-inducible factor-1α by arsenite under normoxia and hypoxia: involvement of Nrf2.
Arsenite (As(III)) is widely distributed in nature and can be found in water, food, and air. There is significant evidence that exposure to As(III) is associated with human cancers originated from liver, lung, skin, bladder, kidney, and prostate. Hypoxia plays a role in tumor growth and aggressiveness; adaptation to it is, at least to a large extent, mediated by hypoxia-inducible factor-1α (HIF-1α). In the current study, we investigated As(III) effects on HIF-1α under normoxia and hypoxia in the hepatoma cell line HepG2. We found that As(III) increased HIF-1α protein levels under normoxia while the hypoxia-mediated induction of HIF1α was reduced. Thereby, the As(III) effects on HIF-1α were dependent on both, transcriptional regulation via the transcription factor Nrf2 mediated by NOX4, PI3K/Akt, and ERK1/2 as well as by modulation of HIF-1α protein stability. In line, the different effects of As(III) via participation of HIF-1α and Nrf2 were also seen in tube formation assays with endothelial cells where knockdown of Nrf2 and HIF-1α abolished As(III) effects. Overall, the present study shows that As(III) is a potent inducer of HIF-1α under normoxia but not under hypoxia which may explain, in part, its carcinogenic as well as anti-carcinogenic actions. As(III) increased HIF-1α under normoxia but reduced its hypoxia-dependent induction. The As(III) effects on HIF-1α were dependent on ROS, NOX4, PI3K/Akt, and ERK1/2. The As(III) effects under normoxia involved transcriptional regulation via Nrf2. Knockdown of Nrf2 and HIF-1α abolished As(III) effects in tube formation assays. The data may partially explain As(III)'s carcinogenic and anti-carcinogenic actions.


Practical treatment guide for dose individualisation in cancer chemotherapy.
Dosages of anticancer drugs are usually calculated on the basis of a uniform standard, the body surface area (BSA). Although many physiological functions are proportionate to BSA, overall drug clearance is only partially related to this parameter. Consequently, following administration of equivalent drug dosages based on BSA, a wide variability in plasma drug concentrations can be found between patients, as a result of which some patients experience little toxicity while others may show severe toxic symptoms. A clear pharmacokinetic/pharmacodynamic correlation has been demonstrated for some anticancer drugs, and this relationship provides a background against which rational dose optimisation can be implemented for individual patients. The 3 strategies that can be employed for optimising dosage regimens, none based on BSA, are described and criticised. A priori adaptive dosage determination is based on the relative contribution of identifiable characteristics of patient, drug therapy and disease state that influence plasma drug concentrations; the dosage regimen is based on each patient's profile with regard to these characteristics. Although this approach is most successful with drugs whose clearance is closely tied to renal function, patient characteristics such age, obesity, serum albumin or hepatic function may be useful. The anticancer drug most closely identified with this approach is carboplatin, although dosage reduction strategies for etoposide, taxanes, anthracyclines, topotecan, oxazaphosphorines, vinca alkaloids or melphalan are advocated for patients with renal or hepatic dysfunction. The importance of pharmacogenetics for fluorouracil and mercaptopurine is also briefly discussed. The second approach consists of adaptive dosage adjustments during repetitive or continuous administration of a drug. It has been used for several years to administer methotrexate therapy and, more recently, it has been developed more fully and applied to continuous infusion of fluorouracil or etoposide. It was based, after determination of a target plasma concentration or area under the plasma drug concentration-time curve (AUC), on modification of the drug dosage during the cycle of chemotherapy or for the next cycle. Finally, the third approach of adaptive dosage adjustment with feedback control, based on population pharmacokinetics, with limited sampling strategy, may allow a feedback revision of the dosage following measurement of plasma drug concentration and comparison with the population previously studied. This approach is a theoretical strategy which has not, until now, been used prospectively in clinical oncology. For drugs such as anticancer agents with a very narrow therapeutic index, every effort should be made to minimise interpatient variability in drug exposure in order to maximise the benefit while keeping the risk of serious adverse effects at an acceptable level. This is particularly important when treatment is being given with curative intent.


Serodiagnosis of Mycobacterium abscessus complex infection in cystic fibrosis.
Early signs of pulmonary disease with Mycobacterium abscessus complex (MABSC) can be missed in patients with cystic fibrosis (CF). A serological method could help stratify patients according to risk. The objective of this study was to test the diagnostic accuracy of a novel method for investigating IgG activity against MABSC.A prospective study of all patients attending the Copenhagen CF Centre was conducted by culturing for MABSC during a 22-month period and then screening patients with an anti-MABSC IgG ELISA. Culture-positive patients had stored serum examined for antibody kinetics before and after culture conversion.307 patients had 3480 respiratory samples cultured and were then tested with the anti-MABSC IgG ELISA. Patients with MABSC pulmonary disease had median anti-MABSC IgG levels six-fold higher than patients with no history of infection (434 versus 64 ELISA units; p<0.001). The test sensitivity was 95% (95% CI 74-99%) and the specificity was 73% (95% CI 67-78%). A diagnostic algorithm was constructed to stratify patients according to risk.The test accurately identified patients with pulmonary disease caused by MABSC and was suited to be used as a complement to mycobacterial culture.


Acid-suppressive efficacy of a reduced dosage of rabeprazole: comparison of 10 mg twice daily rabeprazole with 20 mg twice daily rabeprazole, 30 mg twice daily lansoprazole, and 20 mg twice daily omeprazole by 24-hr intragastric pH-metry.
Rabeprazole achieves more potent acid suppression than other proton pump inhibitors. Therefore it is administered at reduced as well as high dosages in eradication therapy for Helicobacter pylori; however, there is incomplete assessment of the efficacy of a reduced dosage of rabeprazole as might be employed in therapy. In this study, we evaluated acid-suppressive efficacy of a reduced dosage of rabeprazole on day 7 by 24-hr pH-metry in 10 healthy male cytochrome P-450 2C19 extensive metabolizers without Helicobacterpylori infection and compared the results with those of high dosages of rabeprazole, lansoprazole, and omeprazole. Median intragastric pH value, pH >3 holding time ratio (pH>3HT), pH>4HT, pH>5HT, pH>6HT, and pH>7HT for 24 hr with rabeprazole, 10 mg twice daily, were not significantly different from those of rabeprazole, 20 mg twice daily, lansoprazole, 30 mg twice daily, and omeprazole, 20 mg twice daily. In conclusion, for acid-suppressive efficacy, a reduced dosage of rabeprazole is comparable to high dosages of rabeprazole, lansoprazole, and omeprazole.


The involvement of the pentose shunt in thyroid metabolism after stimulation with TSH or with immunoglobulins from patients with thyroid disease. 1. The generation of NADPH in relation to stimulation of thyroid growth.
It has been shown previously that both thyrotrophin (TSH), and also immunoglobulins (Ig) derived from patients with goitrous Graves' disease, stimulate DNA-synthesis in guinea-pig thyroid tissue maintained in vitro. Here we describe the use of the same in vitro system and methods of quantitative cytochemistry to test the effect of these substances on the generation of NADPH, which is another indicator of the potential for growth. As could be predicted by its trophic action, TSH stimulated the generation of NADPH by glucose 6-phosphate dehydrogenase. The Ig-fraction from normal subjects depressed this activity. The Ig-fraction from Graves' disease patients with goitres stimulated the generation of NADPH, whereas the Ig from patients with Graves' disease but with minimal enlargement of the thyroid gland behaved like normal Ig. A similar lack of stimulation was found with Ig from patients with Pendred's syndrome, other dyshormonogenetic goitres, and autonomous single adenomas. In all specimens tested, there was good correlation between the amount of DNA-synthesis, measured by Feulgen cytophotometry, and the activity of glucose 6-phosphate dehydrogenase activity that generated NADPH. These results support the concept that there is a distinct type of autoantibody that influences thyroid growth.


Revising ventricular septal defect residual shunts without aortic re-cross-clamping: a safe and effective surgical procedure.
The conventional approach to revising a residual shunt following ventricular septal defect (VSD) closure is to re-occlude the aorta and repair the residual shunt under cardioplegic arrest. The present study evaluated the safety and effectiveness of a new approach for revising residual shunts following VSD repair without re-occluding the aorta. This approach is known as on beating heart surgery. This retrospective study included 80 pediatric patients who underwent surgical closure of a simple VSD. Residual shunts larger than 2 mm were intraoperatively detected by transesophageal echocardiography (TEE) and these patients received immediate reintervention. Of the patients, 37 received on beating heart surgery without aortic cross-clamping (Group A) and 43 patients were operated on with aortic cross-clamping and cardioplegia (Group B). Residual VSD closures were successfully performed in all patients. Group A had significantly shorter aortic cross-clamp times (P<0.0001), significantly shorter CPB times (P<0.01), a lower incidence of prolonged ventilation (>6 hours) (P=0.04), a lower incidence of prolonged intensive care unit (ICU) stay (ICU stay >1 day) (P=0.02), and reduced in-hospital expenses (P<0.0001) compared with Group B. There was no significant difference in the incidence of recurrent residual shunts (P=0.96), prolonged postoperative hospital stay (>5 days) (P=0.24), or the incidence of perioperative complications (P=0.81) between the groups. On beating heart surgery is a safe and effective approach for the closure of residual VSDs and is significantly associated with a lower incidence of prolonged ventilation, a lower incidence of prolonged ICU stay, and reduced in-hospital expenses.


Evaluation of the impact of transgenic maize BT799 on growth, development and reproductive function of Sprague-Dawley rats in three generations.
BT799 was Bacillus thuringiensis-genetic modified (GM) maize, and Sprague-Dawley (SD) rats were treated with different diet formulations containing BT799 maize grain (33% and 66%) or its non-transgenic Zhengdan 958 (ZD958, 33% and 66%). The feeding lasted for 10 (P)/14 (F1 and F2) weeks. The reproductive capacity and pathological responses were detected in each generation of rats fed with BT799 and ZD958. During the growth and development of parental rats, each group showed the same trend in body weight gain and food intake, with a few fluctuations at individual time points. No statistically significant difference was observed in reproductive data (copulation index, fertility index, and live birth rate) of rats fed with transgenic maize compared with non-transgenic maize. We observed some apparent changes in reproductive data (sperm numbers and motility) and pathological responses (organ relative weights, hematological parameters, serum chemistry parameters, and sex hormone levels) among rats fed with BT799 maize grain. However, these differences were within the laboratory's historical normal range of control SD rats and not maize grain dose-dependent. These changes were not considered to be adverse or toxic. No significant difference in macroscopic or histological adverse effects was observed between rats consuming transgenic BT799 diet and non-transgenic diet. In conclusion, the long-term intake of BT799 maize was as safe as the corresponding non-transgenic maize for three-generation SD rats.


Reliability of 2D video analysis assessing running kinematic variables in patients with exercise-related leg pain in a primary care practice.
Suboptimal lower limb and trunk positionings is known to influence exercise-related leg pain (ERLP). It is unknown whether simple 2D video analysis is useful for recording and interpreting running variables in a primary care practice. Is 2D video analysis a reliable instrument to assess running variables in patients with ERLP in a primary care practice? Participants undergoing an evaluation for ERLP in two primary care practices were studied. In this reliability study, analysis of running variables was performed by 4 blinded raters on one-stride videos captured with non-high speed cameras (30 fps). Intraclass correlation coefficients (two-way random; ICC 2,1) were calculated to determine the inter-rater reliability. The intra-rater reliability was presented by ICC type two-way mixed (3,1). Footstrike pattern was analyzed by calculating the Fleiss' kappa for inter-rater agreement and Cohen's kappa for intra-rater agreement. Sample size calculation indicated that 16 participants would be required for answering the research question. Data of all 16 participants (9 males, age 31 ± 10 yr) were of sufficient quality for analysis. The 2D video analysis demonstrated excellent inter-rater reliability with an overall ICC value of 0.999 (95 % CI = 0.998-0.999). The ICC value of the eversion was 0.384 (95 % CI = 0.148-0.66) and after correction of the systematic error, 0.817 (95 % CI = 0.664-0.922). The agreement on footstrike was substantial with a Fleiss kappa of 0.737. The overall intra-rater reliability was excellent with an ICC value of 0.997 (95 % CI = 0.996-0.997). The intra-rater agreement of the footstrike was excellent with a Cohen's kappa of 0.868. 2D video analysis provides a highly reliable, relative inexpensive, feasible and suitable measuring instrument for determining running variables in patients ERLP in a primary care setting. This simple technique may identify possible running variables associated with different types of ERLP and may serve as an instrument for tailor-made gait retraining programs.


A factorial study of salt restriction and a low-fat/high-fibre diet in hypertensive subjects.
To compare the independent and additive effects of sodium restriction and a low-fat, high polyunsaturated: saturated fatty acids (P:S) ratio, high-fibre diet upon blood pressure. A randomized, parallet, double-blind, placebo-controlled (for sodium) 2 x 2 factorial trial. Clinical. Ninety-five hypertensive subjects (mean blood pressure, 137/83 mmHg), mean age 53.5 years, consuming less than 30 ml ethanol/day were selected from community volunteers. Seventy-nine treated and twelve untreated hypertensives completed the trial. Subjects followed either a low-sodium, low-fat/high-fibre diet (less than 60 mmol sodium/day; 30% fat energy; P:S ratio = 1; 30-50 g fibre/day) or a low-sodium, normal-fat/normal-fibre diet (less than 60 mmol sodium/day; 40% fat energy; P:S ratio = 0.3; 15 g fibre/day) for 8 weeks. Half of each group received 100 mmol/day NaCl and the remainder received placebo. Blood pressure and blood lipids. Sodium restriction significantly reduced standing and supine systolic blood pressure, with no effect upon diastolic blood pressure. The low-fat/high-fibre diet had no effect upon blood pressure, but significantly reduced total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Sodium restriction reduced blood pressure and did not raise low-density lipoprotein cholesterol. A low-fat/high-fibre diet did not reduce blood pressure but lowered cholesterol levels. A combination of the two regimes has the greater potential for reducing cardiovascular risk in hypertensives.


Two tagging single-nucleotide polymorphisms to capture HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02 haplotype associated with asparaginase hypersensitivity.
Asparaginase (ASP) hypersensitivity is a well-known challenge in the treatment of lymphoblastic malignancies. In terms of cost considerations, the cheap native Escherichia coli ASP, the most immunogenic form of this medication, is used in the first line in middle-income countries. Previously, the role of the HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02 haplotype had been established to associate with E. coli ASP hypersensitivity. We investigated a possible cost-effective genetic testing method to identify patients harbouring the risk HLA haplotype in order to pave the way for safer ASP treatment. In 241 patients with previously determined HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02 haplotype and known ASP hypersensitivity status, 4 candidate HLA-tagging single-nucleotide polymorphisms (SNP)s were measured, and the performance of the different sets of these tag SNPs was evaluated. We identified a combination of 2 SNPs - rs28383172 and rs7775228 - as a tag for HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02 haplotype with sensitivity and specificity values >95%. In line with previous findings, we found complete concordance between HLA-DRB1*07:01 and rs28383172. With bioinformatics methods, the results were also confirmed in the 1000 Genomes dataset in different ethnic groups. Rs28383172 and rs7775228 are suitable for identifying HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02 carriers. Compared to the rest of the population, patients with hypersensitivity-prone genotype would benefit more from the administration of less immunogenic PEGylated ASP before the hypersensitivity evolves, incurring minimal extra cost.


Modified Needleman-Wunsch algorithm for clinical pathway clustering.
Clinical pathways are used to guide clinicians to provide a standardised delivery of care. Because of their standardisation, the aim of clinical pathways is to reduce variation in both care process and patient outcomes. When learning clinical pathways from data through data mining, it is common practice to represent each patient pathway as a string corresponding to their movements through activities. Clustering techniques are popular methods for pathway mining, and therefore this paper focuses on distance metrics applied to string data for k-medoids clustering. The two main aims are to firstly, develop a technique that seamlessly integrates expert information with data and secondly, to develop a string distance metric for the purpose of process data. The overall goal was to allow for more meaningful clustering results to be found by adding context into the string similarity calculation. Eight common distance metrics and their applicability are discussed. These distance metrics prove to give an arbitrary distance, without consideration for context, and each produce different results. As a result, this paper describes the development of a new distance metric, the modified Needleman-Wunsch algorithm, that allows for expert interaction with the calculation by assigning groupings and rankings to activities, which provide context to the strings. This algorithm has been developed in partnership with UK's National Health Service (NHS) with the focus on a lung cancer pathway, however the handling of the data and algorithm allows for application to any disease type. This method is contained within Sim.Pro.Flow, a publicly available decision support tool.