A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.

Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.

Magneto-optical diagnosis of symptomatic malaria in Papua New Guinea.

Improved methods for malaria diagnosis are urgently needed. Here, we evaluate a novel method named rotating-crystal magneto-optical detection (RMOD) in 956 suspected malaria patients in Papua New Guinea. RMOD tests can be conducted within minutes and at low cost. We systematically evaluate the capability of RMOD to detect infections by directly comparing it with expert light microscopy, rapid diagnostic tests and polymerase chain reaction on capillary blood samples. We show that compared to light microscopy, RMOD exhibits 82% sensitivity and 84% specificity to detect any malaria infection and 87% sensitivity and 88% specificity to detect Plasmodium vivax. This indicates that RMOD could be useful in P. vivax dominated elimination settings. Parasite density correlates well with the quantitative magneto-optical signal. Importantly, residual hemozoin present in malaria-negative patients is also detectable by RMOD, indicating its ability to detect previous infections. This could be exploited to reveal transmission hotspots in low-transmission settings.

Optical Shielding of Destructive Chemical Reactions between Ultracold Ground-State NaRb Molecules.

We propose a method to suppress the chemical reactions between ultracold bosonic ground-state ^{23}Na^{87}Rb molecules based on optical shielding. By applying a laser with a frequency blue-detuned from the transition between the lowest rovibrational level of the electronic ground state X^{1}Σ^{+}(v_{X}=0,j_{X}=0), and the long-lived excited level b^{3}Π_{0}(v_{b}=0,j_{b}=1), the long-range dipole-dipole interaction between the colliding molecules can be engineered, leading to a dramatic suppression of reactive and photoinduced inelastic collisions, for both linear and circular laser polarizations. We demonstrate that the spontaneous emission from b^{3}Π_{0}(v_{b}=0,j_{b}=1) does not deteriorate the shielding process. This opens the possibility for a strong increase of the lifetime of cold molecule traps and for an efficient evaporative cooling. We also anticipate that the proposed mechanism is valid for alkali-metal diatomics with sufficiently large dipole-dipole interactions.

Application of computed tomography to assess the effect of egg yolk ratio on body composition in chickens of different genotype and gender at hatch and during the rearing period.

1. Computed tomography was used for the in vivo determination of yolk ratio in 7000 domestic hen eggs, originated from two markedly different genotypes, in order to examine the effect of egg yolk ratio, gender and genotype on the development of hatched chicks. 2. Eggs with extremely low, average and extremely high yolk ratio were chosen for further investigation (n = 350 in each group in both genotypes). After incubating the selected eggs, hatched birds were reared and slaughtered at 11 weeks of age. 3. The yolk ratio of eggs significantly affected the body composition of the chickens at hatching and during rearing to 8-9 weeks of age. 4. Chickens of a genotype selected partly for weight gain had significantly higher live weight from hatching to the end of the rearing period and had better slaughter characteristics than those of the dual purpose TETRA-H genotype. 5. At hatching, only the dry matter content of the body was affected by the gender of the birds. The effect of gender on the live weight and body composition of chickens was evident from the 5th week of age to the time of slaughter. 6. It was concluded that eggs with a low yolk ratio were most beneficial for broiler production, because chickens hatched from these eggs had the highest slaughter weight and muscle index and the lowest fat index for their body mass.

Malaria pigment crystals as magnetic micro-rotors: key for high-sensitivity diagnosis.

The need to develop new methods for the high-sensitivity diagnosis of malaria has initiated a global activity in medical and interdisciplinary sciences. Most of the diverse variety of emerging techniques are based on research-grade instruments, sophisticated reagent-based assays or rely on expertise. Here, we suggest an alternative optical methodology with an easy-to-use and cost-effective instrumentation based on unique properties of malaria pigment reported previously and determined quantitatively in the present study. Malaria pigment, also called hemozoin, is an insoluble microcrystalline form of heme. These crystallites show remarkable magnetic and optical anisotropy distinctly from any other components of blood. As a consequence, they can simultaneously act as magnetically driven micro-rotors and spinning polarizers in suspensions. These properties can gain importance not only in malaria diagnosis and therapies, where hemozoin is considered as drug target or immune modulator, but also in the magnetic manipulation of cells and tissues on the microscopic scale.

The double electrostatic ion ring experiment: a unique cryogenic electrostatic storage ring for merged ion-beams studies.

We describe the design of a novel type of storage device currently under construction at Stockholm University, Sweden, using purely electrostatic focussing and deflection elements, in which ion beams of opposite charges are confined under extreme high vacuum cryogenic conditions in separate "rings" and merged over a common straight section. The construction of this double electrostatic ion ring experiment uniquely allows for studies of interactions between cations and anions at low and well-defined internal temperatures and centre-of-mass collision energies down to about 10 K and 10 meV, respectively. Position sensitive multi-hit detector systems have been extensively tested and proven to work in cryogenic environments and these will be used to measure correlations between reaction products in, for example, electron-transfer processes. The technical advantages of using purely electrostatic ion storage devices over magnetic ones are many, but the most relevant are: electrostatic elements which are more compact and easier to construct; remanent fields, hysteresis, and eddy-currents, which are of concern in magnetic devices, are no longer relevant; and electrical fields required to control the orbit of the ions are not only much easier to create and control than the corresponding magnetic fields, they also set no upper mass limit on the ions that can be stored. These technical differences are a boon to new areas of fundamental experimental research, not only in atomic and molecular physics but also in the boundaries of these fields with chemistry and biology. For examples, studies of interactions with internally cold molecular ions will be particular useful for applications in astrophysics, while studies of solvated ionic clusters will be of relevance to aeronomy and biology.

Precision lifetime measurements of He(-) in a cryogenic electrostatic ion-beam trap.

We have developed a small purely electrostatic ion-beam trap which may be operated in thermal equilibrium at precisely controlled temperatures down to 10 K. Thus, we avoid magnetic field induced mixing of quantum states and may effectively eliminate any influence from absorption of photons from blackbody radiation. We report the first correction-free measurement of the lifetime of the 1s2s2p {4}P{5/2}{0} level of 4He(-) yielding the high-precision result 359.0 +/- 0.7 micros. This result is an essential proof-of-principle for cryogenic electrostatic storage rings and traps for atomic and molecular physics.

Clinical outcome of long-term home parenteral nutrition in non-oncological patients: a report from two specialised centres.

OBJECTIVE AND METHODS: Forty-one (20 m, 21 f) non-oncological home parenteral nutrition (HPN) patients (52.0+/-16.6 years, BMI 20.2+/-4.0 kg/m(2)), enrolled from 1995 to 2005, underwent a clinical and biochemical follow-up at 3 months, 1 and 3 years. RESULTS: At admittance the Karnofsky Index ranged between 40 and 50 in 13 (31.7%) and 60 and 80 in 28 (68.3%) patients; the most frequent underlying disease was mesenteric infarction (11 patients, 27%). All had a central venous access. Mean catheterization days were 864+/-992, while mean HPN days were 630+/-668. At the 3-month follow-up, all patients were on HPN, at 1 year 24 (58.5%) and at 3 years 11 (27%). At 3 months, 1 and 3 years there was a significant increase in BMI (p=0.001), body weight (p=0.001) and Karnofsky Index (p=0.001), as well as an improvement of several biochemical parameters. Survival rate of HPN patients was 90.2% at 1 year, 87.8% at 3 years and 82.9% at 5 years. As to HPN-related complications, there was a central venous catheter (CVC) obstruction in 8 patients (19.5%) and 47 CVC infections in 24 (58.5%) patients. The infection rate was 1.32/(00) days of catheterization (1.8/(00) from 1995 to 1998 and 1.0/(00) from 1999 to 2005). Hospitalisation was necessary in over 50% of patients, and death occurred in 8, always as a consequence of the primary disease. CONCLUSIONS: The experience of the nutritional team and careful patient and caregiver training reduce CVC infection rate and the overall risk of complications possibly due to HPN.

Central venous catheter complications in 447 patients on home parenteral nutrition: an analysis of over 100.000 catheter days.

RATIONALE: The purpose of this study is to report the frequency of central venous catheter (CVC) complications and to analyze the potential risk factors for complications requiring CVC removal in home parenteral nutrition (HPN) patients. METHODS: A questionnaire developed by the ESPEN HAN WORKING GROUP was distributed to 12 European centers to investigate the complications occurring during the period between January 1995 and December 2000 when HPN patients used their first CVC. The questionnaire collected informations related to the Home Parenteral Nutrition technique and the underlying disease. Factors affecting the time of CVC removal were jointly investigated using Cox's multivariable regression models. RESULTS: The study was performed on 447 patients for a total of 110869 CVC-days. Complications occurred in about 1/4 of patients, approximately half were infections and about half required Central Venous Catheter removal. The Cox analysis showed that using the CVC 7 times/week and implanted ports were associated with a hazard ratio of 3 and 2.8, respectively. A reduced risk of removal (of about 40%) was associated with using CVC also for non-nutritional purposes (P = 0.0016). CONCLUSIONS: Within the limits of this retrospective investigation, the type of CVC, the type of administration of HPN and the type of training are important factors associated with occurrence of complications or with CVC removal. However, in our opinion, proper care of the CVC, of preparation and administration of the nutritive admixture seem to be paramount for a safe management of HPN.

Effect of plasticizer on the dynamic surface tension and the free volume of Eudragit systems.

The purpose of the present study was to determine the changes of dynamic surface tension of aqueous Eudragit dispersions quantitatively and compare these data with the free volume of the free films formed from several dispersions of different dibutyl sebacate (DBS) concentrations. Eudragit L 30D and Eudragit RL 30D aqueous colloidal polymer dispersions and their cast free films were examined. The concentration of DBS varied in the dispersions from 0 to 20%. The dynamic surface tension of the dispersions were measured by the Du Nouy ring method while the free volume of cast films were determined by positron annihilation spectroscopy. The obtained results show that dynamic surface tension measurements indicate the white point (WP) of Eudragit dispersions by a significant standard deviation increase. This may suggest the applicability of dynamic surface tension measurements for the determination of the WP of polymeric dispersions. A decrease in the WP temperature of Eudragit dispersions with an increasing plasticizer concentration was observed up to the DBS concentration of 10% w/w. Above this concentration neither the WP of the polymer dispersion nor the free volume of the free films of the polymer were changed remarkably.

Evidence for Fermi-shuttle ionization in intermediate velocity C+ + Xe collisions.

Experimental evidence has been found for consecutive projectile-target-projectile (triple) and projectile-target-projectile-target (quadruple) "ping-pong" scattering of ionized target electrons in single C+ +Xe collisions at 150 and 233 keV/u impact energies. Distinct signatures of the multiple electron scattering contributions to the high-energy part (300-3400 eV) of the double differential electron spectra have been separated and identified with the help of reference measurements using He+ projectile ions and different calculations.

Predictors of survival in terminal-cancer patients with irreversible bowel obstruction receiving home parenteral nutrition.

Clinical, anthropometric, hematologic, and biochemical variables, evaluated immediately before starting nutritional treatment, were related to survival in 76 terminal-cancer patients with irreversible bowel obstruction receiving home parenteral nutrition. At baseline, abnormally low values were observed in the following percentages of patients: 40.8% for body mass index, 59.2% for serum albumin, 84.2% for hemoglobin, 48.7% for lymphocyte count, and 60% for serum cholesterol. Survival on home parenteral nutrition ranged between 6 and 301 d, with a median of 74 d. Hemoglobin, serum albumin and serum cholesterol were lower in patients with a survival of less than 3 mo. With regard to Karnofsky performance status, median survival times were 63 d for a score below or equal to 50 and 128 d for a score between 60 and 70. Albumin and a Karnofsky score above 50 (but not age, weight, body mass index, lymphocyte count, or cholesterol) emerged (with a positive sign) as predictors of survival. In conclusion, terminal-cancer patients with irreversible bowel obstruction are often malnourished, showing a high prevalence of anemia and hypoalbuminemia. Survival differs widely and can be predicted only to a limited extent from initial values of serum albumin and Karnofsky performance status.

Inhibition of food intake in response to intestinal lipid is mediated by cholecystokinin in humans.

Intraduodenal fat inhibits gastric emptying and exerts early satiation in animals and humans, but it is not clear whether the effects are mediated by cholecystokinin (CCK) in humans. Here, we tested whether CCK-A receptors mediate the inhibition of fat on food intake. Two sequential, double-blind, crossover studies were performed in 24 male subjects. First, subjects received either intraduodenal fat or saline together with a preload of either water or banana shake. Second, 12 subjects received either intraduodenal fat or saline perfusion plus a concomitant infusion of saline or loxiglumide, a specific CCK-A receptor antagonist, together with a preload of banana shake. In both studies, subjects were free to eat and drink as much as they wished. Fat induced a reduction in calorie intake (P < 0.05) compared with controls. Furthermore, a decrease in hunger feelings was observed. Infusion of loxiglumide abolished the effects of fat. Duodenal fat interacts with an appetizer to modulate energy intake in humans. This effect is mediated by CCK-A receptors.

A study of vibrato: assessment by panel of judges compared to spectral voice analysis.

Experts in voice singing and voice training were asked to judge the vibrato of 30 singers (4 samples per singer: a sung [a] held without vibrato; a sung a[ held with vibrato; a self-selected passage and an imposed passage. In the first part, they ticked the type of oscillations (vibrato, straight tone, tremolo, quivering...). In the second part, they appraised various criteria. Intra-judge and inter-judge consistencies were determined. The subjective parameters were thereafter correlated with the measurements of six parameters of the MDVP (MultiDimentional Voice Program). The measurements were carried out on each task. Intra-judge consistency was good for only one judge (67-87% consistency). Since judge 2 and 3 were hardly reproducible (45-73%; 28-57%) measurement of the inter-judge consistency was pointless. The results of judge 1 were correlated with the Fundamental Tremor Frequency Index, the jitter and the shimmer.

Outcome of cancer patients receiving home parenteral nutrition. Italian Society of Parenteral and Enteral Nutrition (S.I.N.P.E.).

BACKGROUND: Indication for home parenteral nutrition (HPN) in cancer patients is controversial because intestinal failure and malnutrition are often only two of the many problems found in such patients that may deserve priority of treatment. METHODS: This was a retrospective study of 75 cancer patients from nine institutions included in the Italian HPN Registry. The patients had a mean weight loss of 12.5%, serum albumin of 3.1 g/dL, lymphocyte count of 1150/mm3, and serum total iron-binding capacity of 190 micrograms/dL. The main indication for HPN was intestinal obstruction (66%); 72% of the patients had metastatic disease. A series of demographic, oncologic, and nutritional characteristics were analyzed in an attempt to predict a possible benefit of HPN. RESULTS: A total of 9897 days of HPN were delivered to 75 cancer patients, for a median of 4 months (range 1 to 15 months) per patient. Sixty-nine patients died while receiving HPN, five had a remission of their intestinal failure, and one chose to stop the treatment. Complications related to parenteral nutrition were as follows: 19 cases of sepsis, 6 catheter occlusions, 4 catheter dislocations, and 2 metabolic imbalances. HPN preserved nutritional status and slightly improved weight, lymphocyte count, serum albumin, and Karnofsky performance status in patients who survived > 3 months. Quality of life during HPN was judged by the clinicians to have improved in only 9% of those who survived < 3 months, but in 68% of the patients who survived for > 3 months. Karnofsky performance status > 50 at the start of HPN was correlated with longer survival (p = .02). CONCLUSIONS: Our study demonstrated a positive effect of HPN on nutritional status and quality of life in patients who survived > 3 months and suggests that HPN should be avoided when Karnofsky performance status is < 50.

Tubular basement membrane thickening in diabetes mellitus.

Authors measured the thickness of the basement membranes of the proximal and distal tubuli in the renal cortex in 20 patients with verified diabetes mellitus. The test group consisted of 20 patients with small abnormalities of glomeruli (or in the range of variable norm), of the same sex and comparable age. Measurements were performed in locations without tubulo-interstitial changes. The average thickness of TBM in patients with diabetes mellitus was 1540 +/- 616 nm, and in the test group 360 +/- 86 nm, which is a statistically significant difference (p < 0.000000). In spite of the small number of cases and possible error in the manual measurement of electron microscopic pictures, a significant thickening of TBM in diabetes mellitus has been found. We consider this to be of diagnostic value.

[Blind insertion of a peritoneal catheter in continuous peritoneal dialysis therapy]. / Zavádzanie peritoneálneho katétra metódou na slepo v liecbe kontinuálnou peritoneálnou dialýzou (CAPD).

Insertion of the peritoneal catheter is most important for peritoneal continual dialysis. Various techniques described in the literature do not indicate an unequivocal preference of methods and the blind method used by the authors makes it possible to perform the procedure safely by a team of experienced well trained nephrologists and specialists in internal medicine.