Symbiont-supplemented maternal investment underpinning host's ecological adaptation.
Maternal investment for offspring's growth and survival is widespread among diverse organisms. Vertical symbiont transmission via maternal passage is also pivotal for offspring's growth and survival in many organisms. Hence, it is expected that vertical symbiont transmission may coevolve with various organismal traits concerning maternal investment in offspring. Here we report a novel phenotypic syndrome entailing morphological, histological, behavioral, and ecological specializations for maternal investment and vertical symbiont transmission in stinkbugs of the family Urostylididae. Adult females develop huge ovaries exaggerated for polysaccharide excretion, possess novel ovipositor-associated organs for vertical transmission of a bacterial symbiont ("Candidatus Tachikawaea gelatinosa"), and lay eggs covered with voluminous symbiont-supplemented jelly. Newborns hatch in midwinter, feed solely on the jelly, acquire the symbiont, and grow during winter. In spring, the insects start feeding on plant sap, wherein the symbiont localizes to a specialized midgut region and supplies essential amino acids deficient in the host's diet. The reduced symbiont genome and host-symbiont cospeciation indicate their obligate association over evolutionary time. Experimental deprivation of the jelly results in nymphal mortality, whereas restoration of the jelly leads to recovered nymphal growth, confirming that the jelly supports nymphal growth in winter. Chemical analyses demonstrate that the galactan-based jelly contains a sufficient quantity of amino acids to sustain nymphal growth to the third instar. The versatile biological roles of the symbiont-containing egg-covering jelly highlight intricate evolutionary interactions between maternal resource investment and vertical symbiont transmission, which are commonly important for offspring's growth, survival, and ecological adaptation.


Residual risk of transfusion-transmitted infection with human immunodeficiency virus, hepatitis C virus, and hepatitis B virus in Korea from 2000 through 2010.
Despite screening blood donations with advanced technologies and improved donor screening, the risk of transfusion-transmitted infections persists. This risk is mainly due to blood donations collected during the window period. A precise estimate of the transfusion risk of viral infection will help to determine the effect of new and current safety measures and to prioritize and allocate limited resources. Therefore, we estimated the risk of transfusion-transmitted viral infection in blood donations collected in Korea from 2000 to 2010. Blood donations collected at 16 blood centers were tested for HIV, HCV, and HBV to estimate the residual risk of transfusion-transmitted viral infection. The residual risk was calculated in two-year periods using the incidence/window model. The incidence rates for HIV/HCV and the confirmed positive rate for HIV/HCV in first-time and repeat donors were compared. The residual risks for HIV in 2004/2005 and 2009/2010 were 1 in 1,080,244 and 1 in 1,356,547, respectively. The risks for HCV in 2000/2001 and 2009/2010 were 1 in 81,431 and 1 in 2,984,415, and the risks for HBV in 2000/2001 and 2009/2010 were 1 in 45,891 and 1 in 43,666. These estimates indicate that the residual risks for HCV in Korea have declined 36.6-fold, and those for HIV and HBV have not improved significantly, compared to previous estimates. The odds ratios for HCV and HBV positivity in first-time donors compared to repeat donors were 11.8 and 19.6, respectively. The residual risk of HCV declined over the last decade due to improved screening reagents, implementation of the nucleic acid amplification test, and tight application of strict donor selection procedures. Current residual risk estimates for HIV and HCV in Korea are extremely low, but the risk for HBV is still high; therefore, urgent measures should focus on decreasing the residual risk of HBV. Despite the introduction of more sensitive assays in blood screening, several other factors may influence the actual residual risk of transfusion-transmitted infection. A continuous monitoring of residual risk of transfusion-transmitted infection is crucial in managing blood safety.


Acute Pelvic Fractures: I. Causation and Classification.
Acute pelvic fractures are potentially lethal, even with modern techniques of poly-trauma care. The appropriate treatment of such fractures is dependent on a thorough understanding of the anatomic features of the pelvic region and the biomechanical basis of the various types of lesions. Although the anterior structures, the symphysis pubis and the pubic rami, contribute approximately 40% to the stiffness of the pelvis, clinical and biomechanical studies have shown that the posterior sacroiliac complex is more important to pelvic-ring stability. Therefore, the classification of pelvic fractures is based on the stability of the posterior lesion. In type A fractures, the pelvic ring is stable. The partially stable type B lesions, such as "open-book" and "bucket-handle" fractures, are caused by external- and internal-rotation forces, respectively. In type C injuries, there is complete disruption of the posterior sacroiliac complex. These unstable fractures are almost always caused by high-energy severe trauma associated with motor vehicle accidents, falls from a height, or crushing injuries. Type A and type B fractures make up 70% to 80% of all pelvic injuries. Because of the complexity of injuries that most often result in acute pelvic fractures, they should be considered in the context of polytrauma management, rather than in isolation. Any classification system must therefore be seen only as a general guide to treatment. The management of each patient requires careful, individualized decision making.


[Writer's cramp treated with botulinum injections].
To evaluate the first clinical experience with local botulinum toxin A (BTA) injections in patients with writer's cramp. Descriptive. Academic Medical Centre, Amsterdam, the Netherlands. In May 1993-January 1996 ten patients with writer's cramp were treated with BTA (Dysport). Age of the patients varied from 28 to 68 years, the duration of complaints from 1 to 29 years. Muscles for injections were selected by observation, sometimes combined with electromyography. BTA was administered under electromyographic guidance. The amount of BTA administered per treatment session ranged from 15 to 400 IU. In three patients the BTA-induced weakness necessary to reach a beneficial effect on writing was unacceptable. In seven patients the response was satisfactory or good and lasted 2 to 15 months (mean: 3.5 months). The results confirm the efficacy of BTA in writer's cramp.


Processing Human Milk to Increase Nutrient Density for Preterm Infants.
Human milk is the optimal food for newborns. Choices to feed preterm infants in neonatal intensive care units are mother's milk, donor milk, or formula. Preterm infants have better tolerance for human milk, but the lower caloric density of donor milk might not meet preterm infant growth needs. Preterm infants have higher protein and energy requirements with a limited stomach capacity. Therefore, there is a need for human milk with increased nutrient density. To concentrate donor milk to have a higher caloric and protein density while avoiding side effects of high osmolality by precipitating lactose at low temperatures. We investigated the results of volume reduction and lactose removal processes on the lactose, protein, osmolality, and viscosity of human milk. Donor milk was obtained from WakeMed Mothers' Milk Bank. Homogenization and evaporative condensation were applied to samples (N = 36) before they were stored frozen overnight, followed by refrigerated centrifugation for lactose removal at 0 °C. Supernatants were separated and compared to the composition of controls. A significant reduction of lactose (SW = -262, p < .0001) and osmolality (SW = -211.5 p < .01) was achieved in the concentrated milk without a significant protein loss from centrifugation (SW = -44.5, p = .49). A 30%-40% volume reduction is within the American Academy of Pediatrics recommended osmolality for infant feeding. Concentrating human milk in a milk bank setting for feeding preterm infants might be a simple and low-cost process to achieve a product with higher nutrient density and no non-human components.


An event-structural account of passive acquisition in Korean.
Some peculiar properties of children's passives have long been observed in various languages such as an asymmetry between actional passives and nonactional passives. These peculiarities have been accounted for under the hypothesis that children's early passives are adjectival, and as such exhibit properties of adjectival passives in adult grammar. Under this hypothesis, a new prediction follows, namely that children's comprehension of passive predicates will vary depending upon the event structures of predicates. If a predicate has a target/result state in its event structure, it makes a good adjectival passive, and children will comprehend the predicate more easily. By contrast, if a predicate lacks a target/result state, it does not make a good adjectival passive, and children will comprehend the predicate less easily. This paper tested and confirmed this prediction in Korean children's passives. In a picture-aided comprehension task with 67 Korean children ranging from 3;10-8;8, we have found a contrast due to the event structures of predicates. The result shows that children are sensitive to the event structures of passive predicates, and thus provides additional support for the adjectival passive hypothesis.


Influence of hydroxypropyl-Beta-cyclodextrin on the stability of dilute and highly concentrated immunoglobulin g formulations.
Antibody solutions usually require the addition of suitable excipients-such as surfactants and polyols-to overcome stability problems under mechanical or thermal stress. Because cyclodextrins exhibit weak surface activity (similar to surfactants) and a sugar-based structure (like polyols), they can, in principle, stabilize proteins by a double mechanism. Accordingly, the stabilizing potential of increasing concentrations of hydroxypropyl-beta-cyclodextrin (HPβCD) was investigated for two antibodies in dilute (1.8 mg/mL) and highly concentrated (100 mg/mL) solutions and compared with standard polysorbate 80 or sucrose formulations as controls. Formulations were stressed by stirring or elevated temperature, and stability was evaluated by monomer recovery using size-exclusion chromatography, turbidity, and light obscuration measurements. Results show that increasing HPβCD concentrations up to 100 mM lead to a gradual protein stabilization during stirring-irrespective of the protein concentration and unaffected by an increased viscosity. Storage at 50°C induced a decrease of monomer recovery with increasing HPβCD concentrations, which was mirrored in differential scanning calorimetry measurements, where an increasing amount of HPβCD leads to a significant reduction of the protein melting temperature. In the light of previous results on protein stabilization by HPβCD, it is suggested that the stabilizing effects of HPβCD must be tested on a case-by-case basis.


Roles of gastric GATA DNA-binding proteins.
The gastric H+/K(+)-ATPase is a P-type ATPase that is specifically expressed in gastric parietal cells and is responsible for acid secretion into the stomach. We have found one or more gastric mucosal nuclear proteins that recognize a sequence motif in the 5'-upstream regions of the H+/K(+)-ATPase alpha- and beta-subunit genes. This gastric motif, (G/C)PuPu(G/C)NGAT(A/T)PuPy, may be a binding site for a positive transcriptional regulator that functions specifically in parietal cells. We further demonstrated using cDNA cloning and in situ hybridization that novel zinc-finger proteins (GATA-GT1 and GATA-GT2) are present in the gastric parietal cells and bind to this motif. The proteins activate the transcription of the reporter gene with the 5'-upstream region of the H+/K(+)-ATPase beta-subunit gene. These results suggest that gastric GATA DNA-binding proteins have important roles in transcriptional activation of H+/K(+)-ATPase genes in the parietal cells.


Real-space charge-density imaging with sub-ångström resolution by four-dimensional electron microscopy.
The distribution of charge density in materials dictates their chemical bonding, electronic transport, and optical and mechanical properties. Indirectly measuring the charge density of bulk materials is possible through X-ray or electron diffraction techniques by fitting their structure factors1-3, but only if the sample is perfectly homogeneous within the area illuminated by the beam. Meanwhile, scanning tunnelling microscopy and atomic force microscopy enable us to see chemical bonds, but only on the surface4-6. It remains a challenge to resolve charge density in nanostructures and functional materials with imperfect crystalline structures-such as those with defects, interfaces or boundaries at which new physics emerges. Here we describe the development of a real-space imaging technique that can directly map the local charge density of crystalline materials with sub-ångström resolution, using scanning transmission electron microscopy alongside an angle-resolved pixellated fast-electron detector. Using this technique, we image the interfacial charge distribution and ferroelectric polarization in a SrTiO3/BiFeO3 heterojunction in four dimensions, and discover charge accumulation at the interface that is induced by the penetration of the polarization field of BiFeO3. We validate this finding through side-by-side comparison with density functional theory calculations. Our charge-density imaging method advances electron microscopy from detecting atoms to imaging electron distributions, providing a new way of studying local bonding in crystalline solids.


The medical collections at the University of Glasgow.
The medical and other collections in the University of Glasgow have at their core the generous bequest of Dr William Hunter (1718 - 1783), a local man who rose to become an internationally renowned anatomist and obstetrician. The University does not have a Medical Museum as such but an Anatomy Museum, a Zoology Museum, a Pathology Collection, medical displays in the main halls of the Hunterian Museum in the Gilbert Scott Building and a rich collection of antiquarian medical books and archives as well as contemporary libraries. The Hunterian Collection, since its inauguration at the University of Glasgow in 1807, has engendered a spirit of diversity and scholarship that embraces many disciplines across the campus. The Hunterian Museum was the first public museum in Scotland and service to the local, national and international communities and response to their academic needs is very much at heart of its function today.


Anatomy of the subthalamic nucleus, with correlation of deep brain stimulation [RETRACTED].
OBJECT The goal in this study was to examine the cadaveric anatomy of the subthalamic nucleus (STN) and to analyze the implications of the findings for deep brain stimulation (DBS) surgery. METHODS Five formalin-fixed human cerebrums were dissected using the Klingler fiber dissection technique. Digital photographs of the dissections were fused to obtain an anaglyphic image. RESULTS The STN was located posteroinferior to the anterior corticospinal fibers, posterosuperior to the substantia nigra, and anteromedial to the red nucleus, lenticular fasciculus, and thalamic fasciculus. The subthalamic region is ventral to the thalamus, medial to the internal capsule, and lateral and caudal to the hypothalamus. The nuclei found within the subthalamic region include the STN. The relationship between the STN and surrounding structures, which are not delineated sharply, is described. CONCLUSIONS The fiber dissection technique supports the presence of the subthalamic region as an integrative network in humans and offers the potential to aid in understanding the impacts of DBS surgery of the STN in patients with Parkinson disease. Further research is needed to define the exact role of the STN in the integrative process.


Inoperable biliary obstruction treated with percutaneously placed endoprosthesis.
Biliary obstruction was treated with endoprosthetic drainage in 30 patients with pancreatic, 10 with gallbladder and 27 with biliary duct cancer, and 13 of the patients received more than one endoprosthesis. The median survival time in the respective cancer groups was 12, 10 and 9 weeks, including 6, 3 and 4 weeks spent in the patients' own homes. The patients with multiple endoprostheses had 24 weeks median survival with 22 weeks at home. Another patient, with a medically treated malignant endocrine tumour of the pancreas, lived for more than 3 years after biliary tract stenting. Complications associated with insertion of endoprosthesis were few, and clinical cholangitis occurred in seven cases. For individual patients it is difficult to predict the benefit of endoprosthetic drainage, but the procedure seems questionable if the predrainage bilirubin level is very high.


Functional Performance Tests Reveal Promising Results at 6 Months After Shoulder Stabilization Surgery.
Although athletes are mostly allowed to return to play 6 months after shoulder stabilization surgery, there are inadequate data about their functional status during this period. Performance tests would reveal insufficiency in the functional capacity of shoulder 6 months after stabilization surgery. Prospective cohort study. Level 3. A total of 32 male athletes with arthroscopic anterior capsulolabral repair (AACR) were included in the study. Shoulder internal and external rotator (IR-ER) strength was assessed using isokinetic dynamometer at 60°/s and 180°/s angular velocities preoperatively and 6 months postoperatively. Shoulder function was assessed with closed kinetic chain upper extremity stability (CKCUES) test, Y balance test-upper quarter (YBT-UQ), and unilateral seated shot-put test (USSPT) at 6 months postoperation. Western Ontario shoulder instability index (WOSI) and Tampa scale of kinesiophobia (TSK) were used for the self-assessment of the shoulder. Mixed-model ANOVA was used to analyze the changes in the IR-ER strength on both shoulders. Limb symmetry index (LSI) was calculated for the IR-ER strength, YBT-UQ, and USSPT scores. Shoulder IR strength was higher at 6 months postoperatively compared with preoperatively. The LSI was 76.4% and 76.6% for ER strength, and 94.2% and 94% for IR strength at 60°/s and 180°/s angular velocities, respectively, at the postoperative 6 month timepoint. The mean CKCUES test score was 21.8 ± 2.6 touches and the LSI was 94.7% for the YBT-UQ and 102.5% for the USSPT. WOSI (P < 0.001) and TSK (P = 0.001) scores were significantly lower at 6 months postoperatively. Functional status of the patients with shoulder stabilization surgery improved considerably 6 months after surgery, yet they did not fully recover function. Exercise programs focusing on shoulder ER strength and shoulder performance should be emphasized after stabilization surgery.


Epidemiology and risk factors for avascular necrosis in childhood systemic lupus erythematosus in a Taiwanese population.
Childhood-onset systemic lupus erythematosus (SLE) is associated with greater disease activity, more aggressive course, and high rates of organ damage. The prolonged use of corticosteroids in childhood SLE contributes to increased morbidity, including avascular necrosis (AVN). We conducted this retrospective study using claims data from the Taiwan National Health Insurance Research Database, enrolling 1,472 children with newly-diagnosed SLE between 2005 and 2013. The mean age at the diagnosis of SLE was 15.5 ± 3.3 years, and the female to male ratio was 6.2:1. Thirty-nine patients (2.6%) developed symptomatic AVN during a mean follow-up of 4.6 ± 2.5 years. In multivariate analysis, the risk of AVN was higher in the patients with a daily prednisolone dose between 7.5 mg and 30 mg (HR 7.435, 95% CI 2.882-19.178, p < 0.001) and over 30 mg (HR 9.366, 95% CI 2.225-39.418, p = 0.002) than in those with a dose ≤ 7.5 mg/day. In addition, AVN was inversely correlated with the use of hydroxychloroquine > 627 days (HR 0.335, 95% CI 0.162-0.694, p = 0.003). In conclusion, high daily doses of prednisolone were associated with a significant risk of AVN, whereas the use of hydroxychloroquine > 627 days conferred an advantage. We suggest that the judicious use of corticosteroids combined with hydroxychloroquine might be a promising preventive strategy for AVN.


Urinary excretion of hydroxyproline in workers occupationally exposed to vibration.
Urinary hydroxyproline excretion was measured in 130 chain saw operators aged 28-59 and in 31 normal control subjects aged 26-59 with no occupational exposure to vibration. The results measured were expressed as a ratio of hydroxyproline to creatinine. (1) No significant correlation between hydroxyproline/creatinine ratio and age was observed among normal subjects. (2) In chain saw operators grip and pinch strength decreased gradually with an increase of the total chain saw operating time, while the prevalence of pain in the hands or motility disturbance in the elbow joints showed a tendency to become greater as total operating time increased. Hydroxyproline/creatinine ratio in the group with over 9000 hours' experience was significantly higher than that in the group with under 3000 hours (p less than 0.05). By comparison with controls, the ratio in the group with over 3000 hours was significantly higher at the 5% level. (3) Hydroxyproline/creatinine ratio in the group with pain in the hands or with motility disturbance in the elbow joints was significantly higher than that in the group without them (p less than 0.05). (4) Hydroxyproline/creatinine ratio was inversely correlated with grip and pinch strength in operators ranging in age from 40 to 49 (p less than 0.01). (5) All individual ratios for operators with lower grip strength showed a higher increment than the mean values obtained from controls. These results indicate that increased urinary hydroxyproline excretion in chain saw operators may occur in association with damage to the musculoskeletal system caused by the prolonged use of vibrating tools.


Pharmacokinetics of alphaIFN-2b in chronic hepatitis C virus patients undergoing chronic hemodialysis or with normal renal function: clinical implications.
In this prospective controlled study, the pharmacokinetic profiles of alpha-interferon 2b (alphaIFN-2b) were determined by the enzyme-linked immunosorbent assay method in hepatitis C virus-positive (HCV+) dialysis and nonuremic patients, after a single subcutaneous injection of 3 million units. Ten HCV+/RNA+ patients (group A) with a normal renal function (mean serum creatinine: 1.03 +/- 0.26 [SD] mg/dl) and 10 HCV+/RNA+ patients undergoing chronic hemodialysis (group B) were included. The pharmacokinetic profiles of alphaIFN were determined after the very first subcutaneous injection of the drug. Plasma alphaIFN concentrations were determined before the injection and then 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 28, 32, and 36 h after the injection. They were assessed by means of an enzyme-linked immunosorbent assay test. Patients from both groups had a similar body surface area. It was found that in group B: (1) the mean maximum (SD) serum alphaIFN concentration (Cmax) was significantly higher (52 +/- 12 pg/ml) than in group A (39 +/- 12 pg/ml; P = 0.03); (2) the time at which Cmax occurred (Tmax) was significantly higher (10 +/- 3 h) than in group A (7.5 +/- 2 h; P = 0.05); (3) the observed area under the plasma alphaIFN concentration-time curve was about twice as much, i.e., 936 +/- 212 pg x h/ml, as that for group A (485 +/- 184 pg x h/ml; P < 0.0001); and (4) the alphaIFN half-life was significantly longer (9.6 +/- 2.9 h) than in group A (5.3 +/- 1.3 h). As early as 24 h after the alphaIFN injection was given, the drug was no longer detectable in nonuremic patients' sera, whereas it could be detected up to the next injection in all of the dialysis patients' sera. When trough levels of alphaIFN were measured just before the 10th injection, they were always below the threshold level in the 10 patients from group A, i.e., 4.1 pg/ml, whereas in group B they were measurable for four of nine patients (P = 0.05) and ranged between 5.8 and 36.1 pg/ml. Severe neurologic side effects were observed only in group B, i.e., in three patients. Hemoglobin levels did significantly decrease but only in group B patients, and this was significantly correlated with the Cmax (r = 0.67; P = 0.03). This is the first controlled study to demonstrate that the clearance of alphaIFN is about twice as low in dialysis patients as in nonuremic patients. These results might be of relevance when deciding the optimal alphaIFN therapy scheme for HCV+ patients, either with normal renal function or undergoing chronic hemodialysis.


An interactive deep learning-based approach reveals mitochondrial cristae topologies.
The convolution of membranes called cristae is a critical structural and functional feature of mitochondria. Crista structure is highly diverse between different cell types, reflecting their role in metabolic adaptation. However, their precise three-dimensional (3D) arrangement requires volumetric analysis of serial electron microscopy and has therefore been limiting for unbiased quantitative assessment. Here, we developed a novel, publicly available, deep learning (DL)-based image analysis platform called Python-based human-in-the-loop workflow (PHILOW) implemented with a human-in-the-loop (HITL) algorithm. Analysis of dense, large, and isotropic volumes of focused ion beam-scanning electron microscopy (FIB-SEM) using PHILOW reveals the complex 3D nanostructure of both inner and outer mitochondrial membranes and provides deep, quantitative, structural features of cristae in a large number of individual mitochondria. This nanometer-scale analysis in micrometer-scale cellular contexts uncovers fundamental parameters of cristae, such as total surface area, orientation, tubular/lamellar cristae ratio, and crista junction density in individual mitochondria. Unbiased clustering analysis of our structural data unraveled a new function for the dynamin-related GTPase Optic Atrophy 1 (OPA1) in regulating the balance between lamellar versus tubular cristae subdomains.


The polymorphic paraoxonase/arylesterase isozymes of human serum.
There is now considerable evidence that human serum contains an enzyme with both paraoxonase and arylesterase activities. The enzyme probably exists in two common isozymic forms with qualitatively distinctive properties. These isozymes differ particularly in their ratio of paraoxonase /arylesterase activities, one form having a ratio approximately seven times greater than the other. By measuring paraoxonase activity in the presence of 1 M NaCl, and arylesterase activity with phenylacetate under standard conditions, it is possible to classify individuals within one of the three phenotypes determined by a two-allele, single autosomal locus system at the ESA locus. These alleles are designated ESA*A and ESA*B. Pedigree analyses have also shown the anticipated Mendelian segregation of these traits within families. The frequencies of the ESA*A and ESA*B alleles in a sample population of unrelated Caucasian people in the United States were estimated to be 0.685 and 0.315, respectively, for the traits conferring relatively low and high paraoxonase activities. It still remains to be determined whether the distinctive phenotypes affect the degree of sensitivity or resistance to organophosphate agents, such as paraoxon. We do not know what additional functions these polymorphic enzymes may have in the metabolism of other compounds, particularly those of endogenous origin.


Impairment of select forms of spatial memory and neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4.
Aquaporin-4 (AQP4) is the major water channel in the CNS and is primarily expressed in astrocytes. Little is known about the potential for AQP4 to influence synaptic plasticity, although many studies have shown that it regulates the response of the CNS to injury. Therefore, we evaluated long-term potentiation (LTP) and long-term depression (LTD) in AQP4 knock-out (KO) and wild-type mice. KO mice exhibited a selective defect in LTP and LTD without a change in basal transmission or short-term plasticity. Interestingly, the impairment in LTP in KO mice was specific for the type of LTP that depends on the neurotrophin BDNF, which is induced by stimulation at theta rhythm [theta-burst stimulation (TBS)-LTP], but there was no impairment in a form of LTP that is BDNF independent, induced by high-frequency stimulation. LTD was also impaired in KO mice, which was rescued by a scavenger of BDNF or blockade of Trk receptors. TrkB receptors, which mediate effects of BDNF on TBS-LTP, were not altered in KO mice, but p75NTR, the receptor that binds all neurotrophins and has been implicated in some types of LTD, was decreased. The KO mice also exhibited a cognitive defect, which suggests a new role for AQP4 and astrocytes in normal cognitive function. This defect was evident using a test for location-specific object memory but not Morris water maze or contextual fear conditioning. The results suggest that AQP4 channels in astrocytes play an unanticipated role in neurotrophin-dependent plasticity and influence behavior.


Flux Growth of Single-Crystalline Hollandite-Type Potassium Ferrotitanate Microrods From KCl Flux.
Hollandite-type crystals have unique and interesting physical and chemical properties. Here, we report the flux growth of hollandite-type single-crystalline potassium ferrotitanate (KFTO) with faceted surface features from a KCl flux. We varied the flux growth conditions, including the kind of flux, holding temperature, and solute concentration for growing faceted crystallites. KCl was found to be the best flux to grow the single-crystalline KFTO particles, while heating at or above 900°C was needed to yield the KFTO single crystals. The crystal growth was only weakly dependent on the solute concentration. Next, we characterized the grown single crystals and discussed the manner of their growth from the KCl flux. TEM images with clear electron diffraction spots indicated that the KFTO crystals grew along the <001> direction to form microrods ~10 μm in size. DFT calculation results indicated that the surface energy of the (100) face is lower than that of the (001) face. Based on these characterization results, we proposed a possible growth mechanism of the KFTO crystals.


Nature and antigen-specific activities of transfer factor against herpes simplex virus type 1.
Transfer factor specific for herpes simplex virus (HSV) type 1 (TFHSV-1) was prepared from splenic cells of HSV-1 immunized mice. Protection was transferred with TFHSV-1 to nonimmune mouse recipients. The TFHSV-1 injected mice had a higher survival rate after lethal HSV-1 challenge as compared to mice injected with a nonspecific transfer factor (P less than 0.05). 51Cr-labelled leukocyte adherence inhibition (51-Cr-LAI) test was used to demonstrate the specific activity of transfer factor in vitro. Only leukocytes incubated with TFHSV-1 exhibited significant adherence inhibition (P less than 0.01) to HSV-1 antigen, but not to control antigen. Specific activity component of TFHSV-1 (STFc) was separated by affinity adsorption with the antigen. Activity of STFc in 51Cr-LAI test was significantly higher than that of TFHSV-1 (P less than 0.01). Ratio activity of STFc in protective host immunity was 16 times as much as that of TFHSV-1. STFc was analysed by high performance liquid chromatography, thin layer chromatography and isoelectric focusing in the polyacrylamide gel. Results revealed that STFc appeared to be a polypeptide with a molecular weight of about 12,870 dalton.


Acute leukemia in idiopathic sideroblastic anemia: response to combination chemotherapy.
Three patients with idiopathic sideroblastic anemia of variable duration developed acute leukemia. In two the leukemia was morphologically and histochemically myeloblastic, in one lymphoblastic. With combination chemotherapy remission was achieved in all three. The remission inductions were complicated by long periods of bone marrow suppression and the duration of remissions was brief (3, 2 and 3 months). Survival after diagnosis was 13, 10 and 9 mo, respectively. The ring sideroblast abnormality persisted during the leukemic and remission phases and transfusion requirements remained unaltered in the two patients with transfusion dependent anemia throughout their courses.


Antimicrobial susceptibility and plasmid profile of Neisseria gonorrhoeae in India (New Delhi).
To determine the antibiotic susceptibility and plasmid profile of all Neisseria gonorrhoeae strains (PPNG and non-PPNG) isolated from May 1995 to March 1996 in Lok Nayak Hospital, New Delhi, India. The agar plate dilution method was used to determine the minimum inhibitory concentration of five antimicrobials including norfloxacin and ceftriaxone which are most commonly used for treatment of gonorrhoea in Delhi. Isolates were screened for production of penicillinase by paper acidometric method and plasmid analysis of PPNG and non-PPNG was carried out by agarose gel electrophoresis. 50 consecutive isolates of N gonorrhoeae were studied, 8% among them were found to be PPNG while 28% were highly resistant to tetracycline (TRNG). Reduced susceptibility to norfloxacin (MIC > or = 1 microgram/ml) was observed in 12% of all isolates. All PPNG harboured the 4.4 MDa beta lactamase plasmid along with the 25.2 MDa tetracycline resistance plasmid. Norfloxacin resistance (MIC > or = 1 microgram/ml) was present in 28.5% of TRNG but only in 5.5% of the other gonococcal isolates. Results of this study clearly demonstrate that antibiotic resistant gonococcal strains of different clones are frequently found in New Delhi. Continued surveillance of susceptibility to currently prescribed antimicrobials and epidemiological studies are essential to prevent treatment failures leading to further spread of resistant strains.


Lipidated apolipoprotein E4 structure and its receptor binding mechanism determined by a combined cross-linking coupled to mass spectrometry and molecular dynamics approach.
Apolipoprotein E (apoE) is a forefront actor in the transport of lipids and the maintenance of cholesterol homeostasis, and is also strongly implicated in Alzheimer's disease. Upon lipid-binding apoE adopts a conformational state that mediates the receptor-induced internalization of lipoproteins. Due to its inherent structural dynamics and the presence of lipids, the structure of the biologically active apoE remains so far poorly described. To address this issue, we developed an innovative hybrid method combining experimental data with molecular modeling and dynamics to generate comprehensive models of the lipidated apoE4 isoform. Chemical cross-linking combined with mass spectrometry provided distance restraints, characterizing the three-dimensional organization of apoE4 molecules at the surface of lipidic nanoparticles. The ensemble of spatial restraints was then rationalized in an original molecular modeling approach to generate monomeric models of apoE4 that advocated the existence of two alternative conformations. These two models point towards an activation mechanism of apoE4 relying on a regulation of the accessibility of its receptor binding region. Further, molecular dynamics simulations of the dimerized and lipidated apoE4 monomeric conformations revealed an elongation of the apoE N-terminal domain, whereby helix 4 is rearranged, together with Arg172, into a proper orientation essential for lipoprotein receptor association. Overall, our results show how apoE4 adapts its conformation for the recognition of the low density lipoprotein receptor and we propose a novel mechanism of activation for apoE4 that is based on accessibility and remodeling of the receptor binding region.


Protective Effect of Asacol in Combination with Pantoprazole in Ulcerative Colitis Patients Who Defecate Asacol Tablets Intactly: A Clinical Trial Study.
Mesalazine formulations are the drug of choice in the treatment of ulcerative colitis (UC). They are released at alkaline pH in order to deliver 5-aminosalicylic acid to the colon. The colonic pH is significantly lower in UC patients than in normal patients. This study was conducted for the first time to evaluate the clinical efficacy of co-administration of pantoprazole and Asacol in the treatment of ulcerative colitis patients who excrete intact Asacol tablets in the feces. Thirty patients with mild-to-moderate active ulcerative colitis who reported passing intact Asacol tablets in stools received oral Asacol plus pantoprazole for 2 weeks. The demographic characteristics of the patients and the body mass index were collected through interviews. For each patient, the stool frequency, visible blood, and presence of intact Asacol tablets in the stool were compared before and pantoprazole treatment. There was a significant difference in the stool frequency (number of daily stools) before and after pantoprazole treatment (mean ± sd, 6.06 ± 1.04 vs 1.5± 0.5; P<0.001). In addition, pantoprazole administration statistically reduced visible blood in the stool (100%; P<0.001). Co-administration of pantoprazole and Asacol was effective in all age groups and both sexes. None of the patients reported the presence of intact Asacol tablets in their stools. Co-administration of pantoprazole and Asacol would be useful for symptom management UC patients that excrete intact Asacol tablets in their feces through increasing the gastric pH and releasing the maximum concentration of the drug in the proximal gastrointestinal tract.


A longer breast carcinoma screening interval for women age older than 65 years?
The observed increase in sojourn time for preclinical breast carcinoma raises the question of whether women age >/= 65 years can be screened less frequently than younger women. A cost-utility analysis using a computer model that simulates the demography, epidemiology, and natural history of breast carcinoma to estimate expected life-years gained, extra incidence, extra life-years with disease, and costs incurred by different breast carcinoma screening programs in the general population was conducted. The estimated ratio of favorable/unfavorable effects was lower for longer screening intervals compared with shorter screening intervals. The cost-effectiveness ratio was much less favorable in shorter screening intervals. The results of the current analysis showed that although a longer sojourn time for preclinical breast carcinoma should not necessarily be accompanied by a longer screening interval, a shorter screening interval was not very efficient.


Platelet-type von Willebrand's disease: characterization of a new bleeding disorder.
An autosomally transmitted bleeding diathesis sharing some, but not all, features previously described in von Willebrand's disease (vWd) was studied in five patients representing three generations of a single family. Bleeding times in the upper normal range in conjunction with low-normal platelet counts, normal factor VIII coagulant activity and VIII-related antigen, decreased VIII-ristocetin cofactor activity, selective decrease of the higher molecule weight factor VIII/von Willebrand factor (VIII/vWF) multimers, and increased ristocetin-induced platelet agglutination at low ristocetin concentrations were characteristic. Binding of patient VIII/vWF to washed normal platelets was within normal limits, whereas binding of normal VIII/vWF to patient platelets was significantly increased (p less than 0.001 at 0.6 mg/ml ristocetin). This disorder accordingly appears to involve an intrinsic platelet abnormality affecting platelet-VIII/vWF interactions. It is proposed that the concept of vWD be broadened to include patients with this abnormality, which may appropriately be called "Platelet-type von Willebrand's disease."


Hysteroscopic metroplasty for the septate uterus with diode laser: a pilot study.
To evaluate the feasibility and safety of office hysteroscopic metroplasty using a 980nm diode laser. 18 patients were treated for septate uterus between 2013 and 2016. The indications for hysteroscopic metroplasty were recurrent abortion in 11 of the women and primary infertility in the other seven. We used a 5mm-office hysteroscope with a diode laser fibre. After exploration of the cavity, the septum was divided with use of the laser fibre. Operating time was 13,16±1,33min. Intraoperative pain was 3,05±0,72. No intraoperative or postoperative complications were observed. Follow-up performed 2 months after the hysteroscopic metroplasty confirmed the complete removal of the septum and no evidence of intrauterine synechiae. Office hysteroscopic metroplasty with use of a diode laser is safe and feasible; we believe that vaporization of the septum with a diode laser could reduce the formation of adhesions and consequently reduce the occurrence of septum persistence.


Influence of tobacco dependence on caries development in young male adults: A cross-sectional study.
A definite cause and effect relationship between tobacco use and caries are lacking in literature. The aim of this study is to determine the influence of tobacco dependence on caries development in young male adults. Three hundred healthy adult males in the age group of 20-40 years were divided into three groups containing 100 participants each. Group A: participants using smokeless tobacco; Group B: participants who smoke tobacco; and Group C: participants who have never used tobacco. Their dependence on tobacco was assessed using the Fagerstrom test for nicotine dependence. Their dental caries status was assessed using decayed-missing-filled teeth/decayed-missing-filled surfaces (DMFT/DMFS) index adopted by the WHO (1987). Observations were statistically analyzed using Mann-Whitney test, and P < 0.05 was considered statistically significant. Mean DMFT/DMFS was significantly higher for Groups A and B as compared to Group C. Within Group A, mean DMFT/DMFS increased significantly with increased dependence on smokeless tobacco. Within Group B, highest DMFT/DMFS was found in participants with low dependence on smoked tobacco while least mean DMFT/DMFS was found in participants with high dependence. Both forms of tobacco proved to be a significant risk factor for increased caries development. Thus, tobacco use should be an important factor in caries risk assessment of patients.


Neck pain, cervical radiculopathy, and cervical myelopathy: pathophysiology, natural history, and clinical evaluation.
Degenerative cervical disk disease is a ubiquitous condition that is, for the most part, asymptomatic. When symptoms do arise as a result of these degenerative changes, they can be easily grouped into axial pain, radiculopathy and myelopathy. While the pathophysiology of radiculopathy and myelopathy is better understood, the source of neck pain remains somewhat controversial. A discussion of the mechanisms of neck and suboccipital pain, and the chemical and mechanical factors responsible for neurologic symptoms is warranted. Examination of the patient with these symptoms will reveal variations in the clinical presentation. A thorough understanding of the natural history of these conditions will allow appropriate treatment to be carried out. The natural history of these conditions suggests that for the most part patients with axial symptoms are best treated without surgery, while some patients with radiculopathy will continue to be disabled by their pain, and may be candidates for surgery. Myelopathic patients are unlikely to show significant improvement, and in most cases will show stepwise deterioration. Surgical decompression and stabilization should be considered in these patients.


Recurrent pseudomembranous colitis unassociated with prior antibiotic therapy.
Fulminant and recurring pseudomembranous colitis developed in an elderly woman without prior antibiotic administration within the previous year. Stool culture yielded Clostridium difficile, and tissue cultures showed C difficile cytotoxin. Treatment with vancomycin hydrochloride was initially successful, but a serious relapse after its discontinuation necessitated low-dose long-term prophylaxis. Clostridium difficile may be responsible for pseudomembranous colitis unassociated with antibiotic therapy.


Corporeal grafting for severe hypospadias: a single institution experience with 3 techniques.
Correction of severe chordee by corporeal body grafting has been successfully performed using various grafts and biomaterials. We report a single institution comparison of our experience using small intestinal submucosa, tunica vaginalis and dermal grafts at stage 1 hypospadias repair. A retrospective chart review was performed of the records of all patients who underwent staged hypospadias repair from 1985 to 2006 with corporeal body grafting at stage 1 with small intestinal submucosa, tunica vaginalis or dermal grafts. Age at grafting, time between stages, residual chordee at stage 2 repair and the need for additional plication or chordee correction at stage 2 were recorded. A total of 71 patients were identified with a median age of 10 months at stage 1 repair and a median of 7.6 months between stages 1 and 2 repair. Dermal grafts, tunica vaginalis and small intestinal submucosa grafts were used in 29, 21 and 20 patients, respectively. One patient received a combination of small intestinal submucosa and tunica vaginalis. None of the patients receiving tunica vaginalis graft required any further correction of chordee. One patient with a dermal graft and 1 receiving small intestinal submucosa required Nesbit plication at stage 2 repair for minor ventral chordee. One patients receiving small intestinal submucosa showed severe fibrosis at the graft site, requiring excision and repeat grafting with tunica vaginalis. This patient has been previously described. The 2 patients with small intestinal submucosa related complications had 4-ply grafts. We have seen no complications associated with 1-ply small intestinal submucosa. At limited followup we have not seen residual chordee after stage 2 repair. In a large group of children requiring corporeal grafting for severe chordee we observed successful chordee correction with 1-ply small intestinal submucosa, tunica vaginalis or dermal grafts.


Analysis of Real-World Treatment Patterns, Healthcare Resource Utilization, and Costs Between Octreotide and Lanreotide Among Patients With Neuroendocrine Tumors.
The aim of the study was to assess treatment patterns, healthcare resource utilization, and healthcare costs among patients with neuroendocrine tumors (NETs) receiving long-acting octreotide versus lanreotide, overall and in patients with carcinoid syndrome (CS). A provider-based claims database was used to identify NET patients who first initiated long-acting octreotide or lanreotide (index date) from January 2015 to November 2017. Propensity-score matching 1:1 was used. Patients with CS were identified from the previously mentioned matched cohorts. Time-to-treatment discontinuation (TTD) was estimated using Kaplan-Meier analyses. Per-patient-per-month rates of healthcare resource utilization were compared using rate ratios from multivariable Poisson regression models. Multivariable linear regression models were used to compare mean monthly cost differences. The median TTD was similar between the 2 matched cohorts (N = 543 each; long-acting octreotide = 19.2 months, lanreotide = 17.5 months, P = 0.58). Significantly fewer NET-related outpatient visits (rate ratio = 0.95, P = 0.005) and significantly lower total healthcare costs (mean monthly cost difference: all-cause = US -$3701, NET-related = US -$3752, Ps < 0.001) were observed in the long-acting octreotide cohort than lanreotide. Similar results were found in CS patients. Patients on first-line long-acting octreotide and lanreotide had similar TTD. Long-acting octreotide was associated with significantly lower total healthcare costs than lanreotide.


Logistical aspects of large telemedicine networks. 2: Measurement of network activity.
We carried out a retrospective review of the videoconference activity records in a university-run hospital telemedicine studio. Usage records describing videoconferencing activity in the telemedicine studio were compared with the billing records provided by the telecommunications company. During a seven-month period there were 211 entries in the studio log: 108 calls made from the studio and 103 calls made from a far-end location. We found that 103 calls from a total of 195 calls reported by the telecommunications company were recorded in the usage log. The remaining 92 calls were not recorded, probably for one of several reasons, including: failed calls--a large number of unrecorded calls (57%) lasted for less than 2 min (median 1.6 min); origin of videoconference calls--calls may have been recorded incorrectly in the usage diary (i.e. as being initiated from the far end, when actually initiated from the studio); and human error. Our study showed that manual recording of videoconference activity may not accurately reflect the actual activity taking place. Those responsible for recording and analysing videoconference activity, particularly in large telemedicine networks, should do so with care.


Interocular differences of the visual field in normal subjects.
One way of judging if a visual field is abnormal, particularly when a patient has unilateral or asymmetric disease, is to compare the suspicious visual field to that of the normal eye. This assumes that in normal individuals the two visual fields are symmetrical. To determine the extent of normal symmetry, the authors examined the central visual fields of both eyes of 20 normal subjects with program 30-2 of the Humphrey perimeter. The inter-ocular sensitivity difference at single pairs of locations ranged from 0 to 9 decibels with large differences occurring most frequently in the upper field. Confidence intervals constructed from this set of normal data predict that asymmetry exceeding 6 decibels should occur in fewer than 1% of test locations and that asymmetry of overall mean sensitivity exceeding 1.4 decibels should occur in fewer than 1% of normal subjects.


Retrieval processes supporting judgments of recency.
The circumstances under which different retrieval processes can support judgments about how long ago events occurred remain a matter of debate, as do the ways in which retrieved information can be employed in support of such judgments. In order to contribute to an understanding of the nature and number of distinct retrieval processes that support time judgments, event-related potentials (ERPs) were acquired during a continuous verbal memory task, where the lag between presentation and re-presentation of words was varied. Participants made judgments of recency (JORs), indicating the number of words that had intervened between presentation and re-presentation. Two spatially and temporally separable ERP effects predicted JORs, and the two effects bore correspondences with ERP modulations that have been linked to the processes of recollection and familiarity, suggesting that both of these processes contributed to JORs. The two effects predicting recency judgments also did so in the same way, with larger effects uniformly predicting shorter lag judgments. In so far as the sizes of the effects index memory strength, these findings are consistent with theoretical accounts of JORs where strength is employed heuristically: The more information recovered, the more recently the event occurred.


Metapopulation dynamics of rabies and the efficacy of vaccination.
Spatial structure in a host population results in heterogeneity in transmission dynamics. We used a Bayesian framework to evaluate competing metapopulation models of rabies transmission among domestic dog populations in villages in Tanzania. A proximate indicator of disease, medical records of animal-bite injuries, is used to infer the occurrence (presence/absence) of suspected rabid dog cases in one month intervals. State-space models were used to explore the implications of different levels of reporting probability on model parameter estimates. We find evidence for a relatively high rate of infection of these populations from neighbouring districts or from other species distributed throughout the study area, rather than from adjacent wildlife protected areas, suggesting wildlife is unlikely to be implicated in the long-term persistence of rabies. Stochastic simulation of our highest ranked models in vaccinated and hypothetical unvaccinated populations indicated that pulsed vaccination campaigns occurring from 2002 to 2007 reduced rabies occurrence by 57.3 per cent in vaccinated villages in the 1 year following each pulse, and that a similar regional campaign would deliver an 80.9 per cent reduction in occurrence. This work demonstrates how a relatively coarse, proximate sentinel of rabies infection is useful for making inferences about spatial disease dynamics and the efficacy of control measures.


Release of markers of myocardial damage evaluated in the coronary sinus during cardiac surgery.
Myocardial damage is a frequent complication of cardiac surgery by direct mechanical trauma during the surgical procedure and by myocardial ischemia, which occurs during the cardiopulmonary bypass (CBP). Because the concentrations of biomarkers in the blood collected from the coronary sinus are the best witness of the myocardial damages, we measured the levels of specific cardiac troponin I (c-TnI) and nonspecific (adenosine, myoglobin) markers of left ventricular damages in the coronary sinus of patients during cardiac surgery. Thirty patients who underwent aortic valve replacement for aortic stenosis were included. Blood samples were collected in the coronary sinus and in the radial artery at the beginning (T0), at the end of the CBP (T1), and then 24 hours later (T2). At T0 and T1, adenosine, c-TnI, and myoglobin levels were significantly higher in the coronary sinus than in the radial artery (T0: adenosine: mean +27%; c-TnI: +41%; myoglobin: +28%; T1: adenosine: mean +58%; c-TnI: +58%; myoglobin: +25%; p < .001). These parameters were significantly higher in the coronary sinus at T1 compared with T0 (adenosine: +50%; c-TnI: +229%; myoglobin: +94%; p < .01) and in the radial artery (adenosine: +21%; c-TnI: +194%; myoglobin: +98%; p < .01). At T2, c-TnI further increased. Damages to the myocardium during cardiac surgery are minimal in our surgical conditions but are probably underestimated when using markers measured at the peripheral level. However, most of the damages appear several hours after the surgery.


Stage-dependent responses of the developing lung to retinoic acid signaling.
Morphological analysis of vitamin A-deficient rat fetuses and of retinoic acid receptor (RAR and RXR) mutant mice have demonstrated that retinoic acid (RA) is essential for lung development. To gainfurther insight into RA signaling pathways during primary lung budformation and lung branching, we have investigated the effects of RA and of a pan-RAR antagonist in cultures of whole embryos and lung explants. Treatment of E8.0 embryos with the pan-RAR antagonist inhibits the formation of the primitive respiratory system. On the other hand, treatment of E11.75 and E12.5 lung explants with RA inhibits branching morphogenesis, whereas treatment with the pan-RAR antagonist at the same developmental stages stimulates formation of distal buds. The inhibitory effect of RA on branching is strongly decreased in RARbeta null lungs, while enhancement of budding by the pan-RAR antagonist is not affected by an RARgamma null mutation. Additionally, cellular retinol binding protein one (CRBPI) null lungs are more sensitive than wild type lungs to the pan-RAR antagonist-induced stimulation of branching. These data indicate that retinoid signaling is indispensable for the formation of primary lung buds and the oesophagotracheal septum from the primitive foregut. They also suggest that at the pseudoglandular stage, RA signaling through RARbeta, but not RARgamma, inhibits distal bud formation thereby promoting the formation of conducting airways. Moreover, the level of CRBPI in the pseudoglandular lung appears to participate in the control of branching morphogenesis.


Cocaine and food deprivation: effects on food-reinforced fixed-ratio performance in pigeons.
Key pecking by 6 pigeons was maintained by a fixed-ratio 30 schedule of food presentation while body weights were 80% of free-feeding weights. Acute administration of cocaine (0.3 to 13.0 mg/kg, i.m.) dose-dependently decreased response rates. Dose-effect curves were shifted to the right when 3 of the 6 pigeons were maintained at 70% of free-feeding weights and were shifted to the left when the other 3 pigeons were maintained at 90% of free-feeding weights. Then a dose of cocaine that initially decreased response rates by more than 95% of control rates was administered before each daily session. Comparable degrees of tolerance to these rate-decreasing effects developed in the two groups. The rate at which responding recovered was relatively rapid for pigeons in the 70% free-feeding-weight group and was slower for 2 of the 3 pigeons in the 90% free-feeding-weight group. When body weights were then increased from 70% to 80% or were decreased from 90% to 80% of free-feeding weight, performance was disrupted initially only for pigeons whose weight went from 70% to 80% of free feeding. In the present experiment the degree of deprivation may have indirectly influenced the degree of tolerance that developed to cocaine's response rate-decreasing effects because it directly influenced the dose chosen to be administered chronically. The degree of deprivation appeared to have a more direct influence on the rate at which tolerance developed.


Exogenous Interleukin-33 Contributes to Protective Immunity via Cytotoxic T-Cell Priming against Mucosal Influenza Viral Infection.
Influenza is an infectious respiratory illness caused by the influenza virus. Though vaccines against influenza exist, they have limited efficacy. To additionally develop effective treatments, there is a need to study the mechanisms of host defenses from influenza viral infections. To date, the mechanism by which interleukin (IL)-33 modulates the antiviral immune response post-influenza infection is unclear. In this study, we demonstrate that exogenous IL-33 enhanced antiviral protection against influenza virus infection. Exogenous IL-33 induced the recruitment of dendritic cells, increased the secretion of pro-inflammatory cytokine IL-12, and promoted cytotoxic T-cell responses in the local microenvironment. Thus, our findings suggest a role of exogenous IL-33 in the antiviral immune response against influenza infection.


The influence of salt chaotropicity, column hydrophobicity and analytes' molecular properties on the retention of pramipexole and its impurities.
The aim of this study was to examine the interaction of the chaotropic salts of different position in Hofmeister series (CF3COONa, NaClO4, NaPF6) added to the mobile phase with the stationary phases of different hydrophobicity (C8 and C18 XTerra(®) columns), as well as their common influence on the retention behavior of pramipexole and its structurally related impurities. The extended thermodynamic approach enabled the understanding of the underlying separation mechanism. Comparing six different column-salt systems it was observed that general system hydrophobicity presented by salt chaotropicity and column hydrophobicity favors stationary phase ion-pairing over the ion-pair formation in the eluent. Further, an attempt was made to describe the influence of analytes' nature on their retention behavior in such chromatographic systems. An analysis is performed in order to select and elucidate the molecular descriptors (electrostatical, quantum-chemical, geometrical, topological, and constitutional) that best explain the experimental evidence and findings obtained by the thermodynamic approach. The results of this analysis suggest that analytes' charge distribution and its complementarity to the structure of the electric double layer formed on the surface of the stationary phase upon the addition of chaotropic additives can be useful for understanding the differences in retention of structurally related analytes. These findings provide a novel understanding of the interactions between all the components of the chromatographic system containing chaotropic additive and a good basis for further investigations suggesting the development of generally applicable predictors in structure-retention relationship studies in related chromatographic systems.


The management of mechanical hearts.
Mechanical ventricular assist devices are now approved as destination therapy for terminal heart failure. It is the purpose of this review to discuss the physiology of this technology that is considered in outpatient care. The currently available pulsatile devices are solely dependent of preload volume, and when placed in the automatic mode, can maintain physiologic cardiac outputs with exercise. However, because of their dependence on preload volume, there are unique physiologic consequences; device bradycardia represents volume depletion, device tachycardia reflects volume overload. The differential diagnosis of left ventricular assist device dysfunction includes native right ventricular failure, native left ventricular recovery, or other technical considerations. The management of biventricular mechanical support will be discussed, as well as arrhythmia management and the role of echocardiographic assessment in this unique patient population. Expertise in outpatient management of such devices is now a requisite for subspecialists in heart failure. In the future, technical innovations may simplify management for professionals, patients and their families.


Phase stability of Li-Mn-O oxides as cathode materials for Li-ion batteries: insights from ab initio calculations.
In this work, we present a density-functional theory (DFT) investigation of the phase stability, electrochemical stability and phase transformation mechanisms of the layered and over-lithiated Mn oxides. This study includes the thermodynamic stability of Li and oxygen vacancies, to examine the electrochemical activation mechanisms of these cathode materials. The DFT calculations provide phase diagrams of the Li-Mn-O system in both physical and chemical potential spaces, including the crystals containing vacancies as independent phases. The results show the ranges of electrochemical activity for both layered LiMnO2 and over-lithiated Li2MnO3. By using a thermodynamic model analysis, we found that the required temperature for oxygen evolution and Li vacancy formation is too high to be compatible with any practical synthesis temperature. Using solid-state transition calculations, we have identified the key steps in the phase transition mechanism of the layered LiMnO2 into the spinel phase. The calculated effects of pH on the Li-Mn-O phase stability elucidated the mechanism of Mn(2+) formation from the spinel phase under acidic conditions.


[Amino acid metabolism in liver tissue during the consumption of qualitatively different proteins].
To evaluate changes in the liver ability to metabolize amino acids during intake of different proteins, the content of free amino acids was measured in the blood of the portal and liver veins of rats fed krill protein and casein. After 48 h of fasting the animals were given a suspension of krill protein and casein at a rate of 540 mg protein per 100 g bw. After 0.5, 1, 3 and 6 h the content of free amino acids was measured in the blood of the portal and liver veins by ion exchange chromatography with the use of an automatic amino acid analyzer. Administration of krill protein brought about a high enough (63%) absorption of amino acids by the liver during the 6-hour experiment. The degree of casein absorption was 31%. As compared to casein, intake of krill protein led to an earlier saturation of the body with amino acids having branched chains (P less than 0.05). The enzymatic systems of amino acid metabolism responded to the supply of the proteins under study in the same manner, however the rate of adaptation was different, amounting to 0.5 h for krill protein and to 3 h for casein. It is evident that the enzymatic systems involved in amino acid metabolism respond to the intake of krill protein to a larger extent than enzymes involved in metabolism of casein amino acids.


The simultaneous determination of codeine, morphine, hydrocodone, hydromorphone, 6-acetylmorphine, and oxycodone in hair and oral fluid.
Recently, the abuse of prescription opiates as alternatives to heroin has become a national concern. The determination of a six-drug opiate panel, codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, and oxycodone, in hair and oral fluid using solid-phase extraction and capillary gas chromatography-mass spectrometry (GC-MS) is described. Oral fluid was obtained from the donor by insertion of absorptive collectors into the mouth. Hair was collected from the patient and powdered using stainless steel ball bearings in a mini bead-beater apparatus. Opiates present in the samples were extracted from a buffered, aqueous matrix using a solid-phase cartridge. The extracts were concentrated and the methoxime/BSTFA derivatives prepared in order to eliminate interference from the keto-opiates. The extracts were separated by GC-MS in electron impact mode. By utilizing methoxyamine, we were able to produce the methoxime derivatives required for single derivative production and chromatographically separate all six opiates. The routine analysis of these opiates in hair and oral fluid using GC-MS is described for the first time.


Density functional theory for dense nematic liquid crystals with steric interactions.
The celebrated work of Onsager on hard particle systems, based on the truncated second order virial expansion, is valid at relatively low volume fractions for large aspect ratio particles. While it predicts the isotropic-nematic phase transition, it does not provide a realistic equation of state in that the pressure remains finite for arbitrarily high densities. In this work, we derive a mean field density functional form of the Helmholtz free energy for nematics with hard core repulsion. In addition to predicting the isotropic-nematic transition, the model provides a more realistic equation of state. The energy landscape is much richer, and the orientational probability distribution function in the nematic phase possesses a unique feature-it vanishes on a nonzero measure set in orientation space.


Leptin and TNF-alpha levels in patients with chronic obstructive pulmonary disease and their relationship to nutritional parameters.
Leptin is a protein mainly secreted by adipocytes, and the major function of leptin was its role in body weight regulation. In humans, there was a strong correlation between leptin and nutritional parameters, such as body mass index (BMI) and fat mass (FM). Administration of recombinant leptin to OB/OB mice, which have a genetic defect in leptin production, reduces food intake, increases energy expenditure, and decreases body weight. It is suggested that increased levels of circulating leptin levels may contribute to anorexia and weight loss in pathologic conditions including chronic obstructive pulmonary disease (COPD). Recent studies have provided evidence for a link between leptin and proinflammatory cytokines such as TNF-alpha. This study aimed to detect serum leptin and TNF-alpha levels in COPD patients without weight loss during stable disease and acute exacerbation, and to investigate relationships between leptin, TNF-alpha and nutritional parameters at different stages of the disease. 26 stable COPD patients, 16 COPD patients with acute exacerbation and 15 control subjects participated in this study. To eliminate the effects of sex differences, all patients and controls were male. BMI, percent ideal body weight, percent FM, sum of skinfold thickness and serum leptin and TNF-alpha levels were measured in all participants. Leptin and TNF-alpha levels were measured by ELISA. Serum leptin and TNF-alpha levels were significantly higher in the patients experiencing exacerbation than in the stable patients and controls. Although leptin levels were lower and TNF-alpha levels were higher in the stable patient group than in the controls, these differences were not statistically different. Leptin levels were significantly correlated with the nutritional parameters in both control and stable groups. However, in patients with acute exacerbation, a correlation between leptin and nutritional parameters was not found. There was no significant relationship between TNF-alpha and nutritional parameters in the three groups. In addition, while there was no correlation between leptin and TNF-alpha levels in the stable and control groups, a significant positive correlation was observed in patients with exacerbation. In conclusion (1) elevated TNF-alpha levels may be related to increased inflammation in patients, (2) circulating TNF-alpha levels were associated with increased leptin levels and (3) although leptin and nutritional parameters were correlated in the stable COPD patients, the correlation was weaker compared to controls, and during an exacerbation it disappeared completely. Therefore, inappropriately increased levels of leptin and TNF-alpha noted during recurrent acute exacerbations in patients with COPD may lead to changes in nutritional parameters and body weight in the course of the disease.


High-mobility group box 1 protein induces epithelialmesenchymal transition in upper airway epithelial cells.
In the treatment of rhinosinusitis, nasal polyps are a major problem, and the epithelial-to-mesenchymal transition (EMT) process is considered pivotal in their development. Although various studies have addressed the role of high mobility group box 1 (HMGB1) nuclear protein in this setting, its impact on EMT has yet to be evaluated. Our aim was the pathogenic mechanism of HMGB1 in EMT and EMT-induced upper respiratory nasal polyps. We investigated the EMT-related effects of HMGB1 in human nasal epithelial (HNE) cells using western blot analysis, transepithelial-electrical resistance (TEER) testing, wound healing assay, and immunofluorescence. HNE cells were incubated in a low-oxygen environment to evaluate the role of HMGB1 in hypoxia-induced EMT. Further support for our in vitro findings was obtained through murine models. Human nasal polyps and nasal lavage fluid samples were collected for western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). HMGB1 increased mesenchymal markers and decreased epithelial markers in HNE cells. Hypoxia-induced HMGB1 in turn induced EMT, apparently through RAGE signaling. We verified HMGB1-induced EMT in the upper respiratory epithelium of mice by instilling intranasal HMGB1. In testing of human nasal polyps, HMGB1 and mesenchymal markers were heightened, whereas epithelial markers were reduced, compared with tissue controls. HMGB1 secretion in nasal epithelium may be a major pathogenic factor in upper respiratory EMT, contributing to nasal polyps.


Diazepam promotes ATP recovery and prevents cytochrome c release in hippocampal slices after in vitro ischemia.
Benzodiazepines protect hippocampal neurons when administered within the first few hours after transient cerebral ischemia. Here, we examined the ability of diazepam to prevent early signals of cell injury (before cell death) after in vitro ischemia. Ischemia in vitro or in vivo causes a rapid depletion of ATP and the generation of cell death signals, such as the release of cytochrome c from mitochondria. Hippocampal slices from adult rats were subjected to 7 min of oxygen-glucose deprivation (OGD) and assessed histologically 3 h after reoxygenation. At this time, area CA1 neurons appeared viable, although slight abnormalities in structure were evident. Immediately following OGD, ATP levels in hippocampus were decreased by 70%, and they recovered partially over the next 3 h of reoxygenation. When diazepam was included in the reoxygenation buffer, ATP levels recovered completely by 3 h after OGD. The effects of diazepam were blocked by picrotoxin, indicating that the protection was mediated by an influx of Cl(-) through the GABA(A) receptor. It is interesting that the benzodiazepine antagonist flumazenil did not prevent the action of diazepam, as has been shown in other studies using the hippocampus. Two hours after OGD, the partial recovery of ATP levels occurred simultaneously with an increase of cytochrome c (approximately 400%) in the cytosol. When diazepam was included in the reoxygenation buffer, it completely prevented the increase in cytosolic cytochrome c. Thus, complete recovery of ATP and prevention of cytochrome c release from mitochondria can be achieved when diazepam is given after the loss of ATP induced by OGD.


Population cycles emerging through multiple interaction types.
Cyclic dynamics of populations are outstanding and widespread phenomena across many taxa. Previous theoretical studies have mainly focused on the consumer-resource interaction as the driving force for such cycling. However, natural ecosystems comprise diverse types of species interactions, but their roles in population dynamics remains unclear. Here, using a four-species hybrid module with antagonistic, mutualistic and competitive interactions, we analytically showed that the system with major interaction types can drive population cycles. Stronger interactions easily cause cycling, and even when sub-modules with possible combinations of two interactions are stabilized by weak interactions, the system with all interaction types can cause unstable population oscillations. Diversity of interaction types allows to add mutualists to the list of drivers of oscillations in a focal species' population size, when they act in conjunction to other drivers.


The Black diaspora and health inequalities in the US and England: does where you go and how you get there make a difference?
The relatively poor health of Black American people in the US and Black Caribbean people in England is a consistent finding in the health inequalities literature. Indeed, there are many similarities between the health, social, economic and demographic profiles of these two groups. However, there is evidence that Caribbean people in the US are faring considerably better. This paper explores differences in the social and economic position of Black American, Black Caribbean and white people in the US and Black Caribbean and white people in England, how these relate to ethnic inequalities in health, and may be underpinned by differences in patterns and contexts of migration. We use similar surveys from the US and England to explore these questions. The US data were drawn from the National Survey of American Life and the English data were drawn from the Health Survey for England and a follow up study. Findings show the advantaged health position of Caribbean American people in comparison with both Caribbean people in England and Black American people. Multivariate analyses indicate that these differences, and the differences in health between Black and white people in the two countries, are a consequence of social and economic inequalities.


Update in Natural Orifice Translumenal Endoscopic Surgery (NOTES).
The recent developments and clinical applications of natural orifice translumenal endoscopic surgery (NOTES)-procedures and technologies are going to be presented. In experimental as well as clinical settings, NOTES-procedures are predominantly performed in hybrid technique. Current experimental studies focus on the implementation of new surgical approaches as well as on the training of procedures. One emphasis in the clinical application is transrectal and transanal interventions. Transanal total mesorectal excision is equivalent to laparoscopic procedures but with the benefit of an even less invasive access. Transvaginal cholecystectomy can achieve results that are comparable to surgeries that are performed with laparoscopic techniques alone. An analysis of the German NOTES-Register concerning appendectomies as well as the national performance of NOTES-interventions in Switzerland is presented. Apart from intraabdominal approaches, several centers proclaim transoral thyroidectomies and transoral mediastinoscopies. NOTES-procedures are performed in animal experiments as well as in clinical setting although with less frequency. At this time, hybrid techniques using rigid instruments are mainly applied.


PET Imaging of Tissue Factor in Pancreatic Cancer Using 64Cu-Labeled Active Site-Inhibited Factor VII.
Tissue factor (TF) is the main initiator of the extrinsic coagulation cascade. However, TF also plays an important role in cancer. TF expression has been reported in 53%-89% of all pancreatic adenocarcinomas, and the expression level of TF has in clinical studies correlated with advanced stage, increased microvessel density, metastasis, and poor overall survival. Imaging of TF expression is of clinical relevance as a prognostic biomarker and as a companion diagnostic for TF-directed therapies currently under clinical development. Factor VII (FVII) is the natural ligand to TF. The purpose of this study was to investigate the possibility of using active site-inhibited FVII (FVIIai) labeled with (64)Cu for PET imaging of TF expression. FVIIai was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and labeled with (64)Cu ((64)Cu-NOTA-FVIIai). Longitudinal in vivo PET imaging was performed at 1, 4, 15, and 36 h after injection of (64)Cu-NOTA-FVIIai in mice with pancreatic adenocarcinomas (BxPC-3). The specificity of TF imaging with (64)Cu-NOTA-FVIIai was investigated in subcutaneous pancreatic tumor models with different levels of TF expression and in a competition experiment. In addition, imaging of orthotopic pancreatic tumors was performed using (64)Cu-NOTA-FVIIai and PET/MRI. In vivo imaging data were supported by ex vivo biodistribution, flow cytometry, and immunohistochemistry. Longitudinal PET imaging with (64)Cu-NOTA-FVIIai showed a tumor uptake of 2.3 ± 0.2, 3.7 ± 0.3, 3.4 ± 0.3, and 2.4 ± 0.3 percentage injected dose per gram at 1, 4, 15, and 36 h after injection, respectively. An increase in tumor-to-normal-tissue contrast was observed over the imaging time course. Competition with unlabeled FVIIai significantly (P < 0.001) reduced the tumor uptake. The tumor uptake observed in models with different TF expression levels was significantly different from each other (P < 0.001) and was in agreement with the TF level evaluated by TF immunohistochemistry staining. Orthotopic tumors were clearly visible on the PET/MR images, and the uptake of (64)Cu-NOTA-FVIIai was colocalized with viable tumor tissue. (64)Cu-NOTA-FVIIai is well suited for PET imaging of tumor TF expression, and imaging is capable of distinguishing the TF expression level of various pancreatic tumor models.


Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host.
Salmonella enterica subspecies 1 serovar Typhimurium is a principal cause of human enterocolitis. For unknown reasons, in mice serovar Typhimurium does not provoke intestinal inflammation but rather targets the gut-associated lymphatic tissues and causes a systemic typhoid-like infection. The lack of a suitable murine model has limited the analysis of the pathogenetic mechanisms of intestinal salmonellosis. We describe here how streptomycin-pretreated mice provide a mouse model for serovar Typhimurium colitis. Serovar Typhimurium colitis in streptomycin-pretreated mice resembles many aspects of the human infection, including epithelial ulceration, edema, induction of intercellular adhesion molecule 1, and massive infiltration of PMN/CD18(+) cells. This pathology is strongly dependent on protein translocation via the serovar Typhimurium SPI1 type III secretion system. Using a lymphotoxin beta-receptor knockout mouse strain that lacks all lymph nodes and organized gut-associated lymphatic tissues, we demonstrate that Peyer's patches and mesenteric lymph nodes are dispensable for the initiation of murine serovar Typhimurium colitis. Our results demonstrate that streptomycin-pretreated mice offer a unique infection model that allows for the first time to use mutants of both the pathogen and the host to study the molecular mechanisms of enteric salmonellosis.


Identification of N5-methyl-N5-formyl-2,5,6-triamino-4-hydroxypyrimidine as a major adduct in rat liver DNA after treatment with the carcinogens, N,N-dimethylnitrosamine or 1,2-dimethylhydrazine.
A major and previously undetected carcinogen-DNA adduct was found in the livers of rats given N,N-dimethylnitrosamine or 1,2-dimethylhydrazine. This adduct, which accounted for 55% of the total methyl residues in DNA at 72 hours after carcinogen treatment, was chromatographically identical to a synthetic purine ring-opened derivative of 7-methylguanine and could be released from the isolated hepatic DNA by a specific E. coli glycosylase. The synthetic ring-opened adduct was characterized by mass and NMR spectroscopy as N5-methyl-N5-formyl-2,5,6-triamino-4-hydroxypyrimidine and appears to exist in two rotameric forms.


The proximal extent of the ankle capsule and safety for the insertion of percutaneous fine wires.
We have assessed the proximal capsular extension of the ankle joint in 18 patients who had a contrast-enhanced MRI ankle arthrogram in order to delineate the capsular attachments. We noted consistent proximal capsular extensions anterior to the distal tibia and in the tibiofibular recess. The mean capsular extension anterior to the distal tibia was 9.6 mm (4.9 to 27.0) proximal to the anteroinferior tibial margin and 3.8 mm (-2.1 to 9.3) proximal to the dome of the tibial plafond. In the tibiofibular recess, the mean capsular extension was 19.2 mm (12.7 to 38.0) proximal to the anteroinferior tibial margin and 13.4 mm (5.8 to 20.5) proximal to the dome of the tibial plafond. These areas of proximal capsular extensions run the risk of being traversed during the insertion of finewires for the treatment of fractures of the distal tibia. Surgeons using these techniques should be aware of this anatomy in order to minimise the risk of septic arthritis.


Characterization of porcine plasma ficolins that bind Actinobacillus pleuropneumoniae serotype 5B.
Ficolins are collagenous lectins implicated in resistance to infection by some micro-organisms with surfaces containing N-acetylglucosamine residues. Pigs have two known ficolin genes, alpha and beta, but ficolins in pig plasma appear in various electrophoretic forms, the origin and function of which are unclear. In this investigation the forms of ficolin in pig plasma that bind to the pneumonic pathogen Actinobacillus pleuropneumoniae serotype 5b (APP5) were compared with affinity-purified porcine plasma ficolins. APP5-bound ficolins consisted of two distinct multimeric (non-denatured) forms composed of subunits that migrated as multiple 38,40 and 42 kDa forms (apparent MW) with pI range 5.2-6.0. The APPS-binding forms of ficolin were consistent with ficolin alpha and were indistinguishable from affinity-purified plasma ficolins by peptide mass fingerprint analysis. Subunit bands separated by 2D-PAGE were consistent with porcine ficolin alpha. Affinity-purified plasma ficolins had a major subunit mass of 35081 Da by MALDI-TOF MS. Affinity-purified ficolins digested with N-glycosidase F retained APP5-binding activity and migrated faster as a single band of 38 kDa. These studies indicate that ficolin alpha is the major APPS-binding form in porcine plasma and suggest that N-glycosylation contributes to the apparent electrophoretic heterogeneity of porcine ficolins but is not required for APP5-binding activity.


Magnetic resonance imaging in the assessment of pancreatic cancer with quantitative parameter extraction by means of dynamic contrast-enhanced magnetic resonance imaging, diffusion kurtosis imaging and intravoxel incoherent motion diffusion-weighted imaging.
Despite great technical advances in imaging, such as multidetector computed tomography and magnetic resonance imaging (MRI), diagnosing pancreatic solid lesions correctly remains challenging, due to overlapping imaging features with benign lesions. We wanted to evaluate functional MRI to differentiate pancreatic tumors, peritumoral inflammatory tissue, and normal pancreatic parenchyma by means of dynamic contrast-enhanced MRI (DCE-MRI)-, diffusion kurtosis imaging (DKI)-, and intravoxel incoherent motion model (IVIM) diffusion-weighted imaging (DWI)-derived parameters. We retrospectively analyzed 24 patients, each with histopathological diagnosis of pancreatic tumor, and 24 patients without pancreatic lesions. Functional MRI was acquired using a 1.5 MR scanner. Peritumoral inflammatory tissue was assessed by drawing regions of interest on the tumor contours. DCE-MRI, IVIM and DKI parameters were extracted. Nonparametric tests and receiver operating characteristic (ROC) curves were calculated. There were statistically significant differences in median values among the three groups observed by Kruskal-Wallis test for the DKI mean diffusivity (MD), IVIM perfusion fraction (fp) and IVIM tissue pure diffusivity (Dt). MD had the best results to discriminate normal pancreas plus peritumoral inflammatory tissue versus pancreatic tumor, to separate normal pancreatic parenchyma versus pancreatic tumor and to differentiate peritumoral inflammatory tissue versus pancreatic tumor, respectively, with an accuracy of 84%, 78%, 83% and area under ROC curve (AUC) of 0.85, 0.82, 0.89. The findings were statistically significant compared with those of other parameters (p value < 0.05 using McNemar's test). Instead, to discriminate normal pancreas versus peritumoral inflammatory tissue or pancreatic tumor and to differentiate normal pancreatic parenchyma versus peritumoral inflammatory tissue, there were no statistically significant differences between parameters' accuracy (p > 0.05 at McNemar's test). Diffusion parameters, mainly MD by DKI, could be helpful for the differentiation of normal pancreatic parenchyma, perilesional inflammation, and pancreatic tumor.


[Endogenous vasoactive factors in children with nephrotic syndrome].
In accordance with the results of examining 40 children with nephrotic and mixed glomerulonephritis, it has been established that in the pathogenesis of the nephrotic syndrome of paramount importance is imbalance of the output of renal prostanoids, manifesting in the predominance of the vasopressor and proaggregate fraction--thromboxane A2 and in the deficiency of its antagonist prostacyclin that exerts a protective action on glomerular filtration. Sodium and water retention in patients with the nephrotic syndrome favours an increase of the content of antidiuretic hormone and plasma renin activity.


Regulatory factors produced by lymphocytes. I. The occurrence of multiple alpha-lymphotoxins associated with ribonuclease activity.
Supernatant fluids of mitogen-activated human tonsil lymphocytes contain large amounts of a factor toxic to mouse L cells. This substance, with a m.w. of 80,000 +/- 5,000 daltons, is called alpha-lymphotoxin (alpha-LT), to differentiate it from another toxin elaborated by mitogen activated human blood lymphocytes, called beta-lymphotoxin (beta-LT), which differs from alpha-LT in size (45,000 +/- 5,000 daltons), antigenicity, and stability. Further purification of alpha-LT by sequential phosphocellulose and DEAE-cellulose chromatography and polyacrylamide gel electrophoresis (PAGE) identifies a series of cytotoxins differing in ion exchange characteristics and electrophoretic mobilities. The three PAGE fractions (PAGE Ia, Ib and II), recovered in 2, 4.6, and 21% yield from the starting serum-free culture supernatant, represent purifications of 24-, 24- and 1851-fold, respectively. Each cytotoxic fraction has a ribonuclease activity. Comparison of RNase and mouse L cell cytotoxic activities of the three alpha-LT fractions shows that both activities for all three fractions have a similar temperature stability pattern and that both are similarly inhibited by DNA, single strand forms better than double strands, by glycerol in 5 to 20% concentration, and by protein denaturing reagents. These observations suggest, but do not prove, that mouse L cell toxicity and RNase activity are mediated by the same substance, which appears to occur in multiple or isozymic forms.


Precocious Pseudo-Puberty with Testicular Enlargement: Two Cases of Leydig Cell Tumor with Different Histopathological Results.
Leydig cell tumors (LCT) are the most common hormone-secreting testicular tumors; it is a rare cause for precocious pseudo-puberty in boys. The tumors secrete high amounts of testosterone. We present two cases of LCT in prepubertal boys presenting with precocious puberty. Case 1. A 6-year-old boy was referred from the pediatric department with a diagnosis of precocious puberty. The patient had reported enlarged and painless swelling of the left testicle from a year ago. The puberty status of the patient was A1P3G4. Ultrasonography examination had found left testicular mass. Elective radical orchiectomy of the left testicle was performed. Histopathological analysis confirmed the diagnosis of benign LCT. Case 2. A 6-year-old boy presented with an enlarged left testicle for the last three months. Features of puberty were noted on the patient (appearance of pubic and facial hair). The puberty status of the patient was A1P3G3. Left testicle US had found homogenous, hypoechoic mass with calcification. Bone age had found increased bone maturation. Increased androgen hormones were detected through a blood test. Radical orchiectomy of the left testicle was performed. The histopathological examination showed malignant LCT. Leydig cell tumors uncommonly occur in children. Prepubertal-aged boys presented with asymmetrical, firm, painless testicular enlargement with signs of puberty should be evaluated for LCT. Histopathological analysis is the mainstay of diagnosis and radical orchiectomy is the treatment of choice of LCT.


Safety first: Recognizing and managing the risks to child participants in magnetic resonance imaging research.
Specialized and up-to-date knowledge is required to identify and manage the risks associated with advanced biomedical research. Additional complexities need to be considered when the research involves infants or young children. In this article, we focus on recent information about the physical risks of pediatric magnetic resonance imaging research and highlight information gaps. With an eye to assisting institutional review boards and researchers, we consider strategies for the management of these risks and formulate key questions aimed at exposing hidden hazards. Institutional review boards should ask these questions, and researchers should bear them in mind as they develop research protocols.


Ziconotide: neuronal calcium channel blocker for treating severe chronic pain.
Ziconotide (PRIALT) is a neuroactive peptide in the final stages of clinical development as a novel non-opioid treatment for severe chronic pain. It is the synthetic equivalent of omega-MVIIA, a component of the venom of the marine snail, Conus magus. The mechanism of action underlying ziconotide's therapeutic profile derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels (N-VSCCs). Direct blockade of N-VSCCs inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors. This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics. In fact, ziconotide is potently anti-nociceptive in animal models of pain in which morphine exhibits poor anti-nociceptive activity. Moreover, in contrast to opiates, tolerance to ziconotide is not observed. Clinical studies of ziconotide in more than 2,000 patients reveal important correlations to ziconotide's non-clinical pharmacology. For example, ziconotide provides significant pain relief to severe chronic pain sufferers who have failed to obtain relief from opiate therapy and no evidence of tolerance to ziconotide is seen in these patients. Contingent on regulatory approval, ziconotide will be the first in a new class of neurological drugs: the N-type calcium channel blockers, or NCCBs. Its novel mechanism of action as a non-opioid analgesic suggests ziconotide has the potential to play a valuable role in treatment regimens for severe chronic pain. If approved for clinical use, ziconotide will further validate the neuroactive venom peptides as a source of new and useful medicines.


Loss of the RNA helicase SKIV2L2 impairs mitotic progression and replication-dependent histone mRNA turnover in murine cell lines.
RNA surveillance via the nuclear exosome requires cofactors such as the helicase SKIV2L2 to process and degrade certain noncoding RNAs. This research aimed to characterize the phenotype associated with RNAi knockdown of Skiv2l2 in two murine cancer cell lines: Neuro2A and P19. SKIV2L2 depletion in Neuro2A and P19 cells induced changes in gene expression indicative of cell differentiation and reduced cellular proliferation by 30%. Propidium iodide-based cell-cycle analysis of Skiv2l2 knockdown cells revealed defective progression through the G2/M phase and an accumulation of mitotic cells, suggesting SKIV2L2 contributes to mitotic progression. Since SKIV2L2 targets RNAs to the nuclear exosome for processing and degradation, we identified RNA targets elevated in cells depleted of SKIV2L2 that could account for the observed twofold increase in mitotic cells. Skiv2l2 knockdown cells accumulated replication-dependent histone mRNAs, among other RNAs, that could impede mitotic progression and indirectly trigger differentiation.


Prenatal folate deficiency impairs sociability and memory/recognition in mice offspring.
Folate is essential for the normal growth and development of the fetus. Folic acid supplementation during the fetal period affects postnatal brain development and reduces the incidence of mental disorders in animal and human studies. However, the association between folate deficiency (FD) during pregnancy and developmental disorders in children remains poorly understood. In this study, we investigated whether prenatal FD is associated with neurodevelopmental disorders in offspring. ICR mice were fed a control diet (2 mg folic acid/kg diet) or a folate-deficient diet (0.3 mg folic acid/kg diet) from embryonic day 1 until parturition. We evaluated locomotor activity, anxiety, grooming, sociability and learning memory in male offspring at 7-10 weeks of age. No differences were found in locomotor activity or anxiety in the open field test, nor in grooming time in the self-grooming test. However, sociability, spatial memory, and novel object recognition were impaired in the FD mice compared with control offspring. Furthermore, we measured protein expression levels of the NMDA and AMPA receptors, as well as PSD-95 and the GABA-synthesizing enzymes GAD65/67 in the frontal cortex and hippocampus. In FD mice, expression levels of AMPA receptor 1 and PSD-95 in both regions were reduced compared with control mice. Moreover, NMDA receptor subunit 2B and GAD65/67 were significantly downregulated in the frontal cortex of prenatal FD mice compared with the controls. Collectively, these findings suggest that prenatal FD causes behavioral deficits together with a reduction in synaptic protein levels in the frontal cortex and hippocampus.


Use of ultrasound in diagnosing postoperative small-bowel intussusception in pediatric surgical oncology patients: a single-center retrospective review.
Postoperative intussusception can be a complication of abdominal surgery and often poses a diagnostic dilemma. The purpose of this study was to evaluate the utility of ultrasonography in the diagnosis of intussusception in children who had recently undergone resection of a primary solid tumor. We performed a retrospective review of all pediatric surgical oncology patients undergoing laparotomy for excision of an abdominal tumor at our institution from 1995 to 2015. We reviewed those with documented postoperative intussusception. In addition we searched the radiology database for all ultrasound examinations requested to rule out postoperative intussusception during our study interval. We analyzed demographics, primary diagnosis, surgical procedure, presentation, diagnostic investigations and definitive treatment. At our institution 852 laparotomies for abdominal tumor resection were performed during the study period, resulting in 10 postoperative intussusceptions (1.2% of cases), of which half were following neuroblastoma resection and the other half following nephrectomy for Wilms tumor. Postoperative intussusception was suspected if the patient had increasing nasogastric output, abdominal distension or feeding intolerance. Ultrasound was used to diagnose intussusception in 9/10 cases, on postoperative day 6 (standard deviation [SD] 5.6 days) on average, with a sensitivity of 89% (8/9; one false negative; 95% confidence interval [CI] 0.52, 1.00) and a specificity of 100% (no false positives; 95% CI 0.96, 1.00). Ultrasound was highly accurate in diagnosing postoperative intussusception in children who underwent resection of retroperitoneal tumors.