Risk of xerostomia in association with the receipt of radiation therapy in older patients with head and neck cancer.
The purpose of this study was to assess the incidence rate and risk of developing xerostomia in association with the receipt of radiation therapy (RT) among a large population-based cohort of elderly patients diagnosed with head and neck cancer (HNC). The study consisted of 10,387 men and women diagnosed with incident HNC cancer at age 65 years or older from 1991 through 2002, identified from the 16 registries of the Surveillance, Epidemiology and End Results-Medicare linked data. Patients were defined as having xerostomia if there were at least 2 claims (for diagnosis code 527.7) at 30 days apart after the date of HNC diagnosis. Patients receiving RT either with or without chemotherapy had a higher cumulative incidence of developing xerostomia compared with those with neither radiotherapy nor chemotherapy (5.6% and 3.8%, respectively vs. 0.5%) at a median follow-up of 2.4 years. Patients who received RT with concurrent chemotherapy were 9 times more likely to develop xerostomia (hazard ratio = 9.13, 95% confidence interval = 6.68-12.48) compared with patients who received neither RT nor chemotherapy, whereas those who received RT without chemotherapy were over 6 times more likely to develop xerostomia (6.29, 4.72-8.37). The strength of this association was similar when patients were stratified by tumor stage and anatomic tumor site. There was no significant association between the risk of developing xerostomia and ethnicity, marital, and socioeconomic status. Radiation therapy for the treatment of HNC is associated with a significant risk of developing xerostomia regardless of type of surgical treatment rendered, tumor stage, or anatomic tumor site.


[Suprahepatic vein catheterization in 4 cases of severe septic shock].
Splanchnic hypoperfusion, with pathogenic implications for multiple organ failure, can occur during septic shock. We report four patients with septic shock in whom regional hepatosplenic splanchnic perfusion was monitored through suprahepatic vein catheterization and gastric tonometry. Suprahepatic lactate and oxygen saturation showed splanchnic hypoperfusion in all patients. These parameters improved only in the patient that survived. Gastric tonometry was more inconsistent. We conclude that suprahepatic vein catheterization could have a role in the management of septic shock.


Using genomic resources for linkage analysis in Peromyscus with an application for characterizing Dominant Spot.
Peromyscus are the most common mammalian species in North America and are widely used in both laboratory and field studies. The deer mouse, P. maniculatus and the old-field mouse, P. polionotus, are closely related and can generate viable and fertile hybrid offspring. The ability to generate hybrid offspring, coupled with developing genomic resources, enables researchers to conduct linkage analysis studies to identify genomic loci associated with specific traits. We used available genomic data to identify DNA polymorphisms between P. maniculatus and P. polionotus and used the polymorphic data to identify the range of genetic complexity that underlies physiological and behavioral differences between the species, including cholesterol metabolism and genes associated with autism. In addition, we used the polymorphic data to conduct a candidate gene linkage analysis for the Dominant spot trait and determined that Dominant spot is linked to a region of chromosome 20 that contains a strong candidate gene, Sox10. During the linkage analysis, we found that the spot size varied quantitively in affected Peromyscus based on genetic background. The expanding genomic resources for Peromyscus facilitate their use in linkage analysis studies, enabling the identification of loci associated with specific traits. More specifically, we have linked a coat color spotting phenotype, Dominant spot, with Sox10, a member the neural crest gene regulatory network, and that there are likely two genetic modifiers that interact with Dominant spot. These results establish Peromyscus as a model system for identifying new alleles of the neural crest gene regulatory network.


Bodyweight gain and anticonvulsants: a comparative review.
Bodyweight gain is a common and frequent undesirable effect associated with the use of anticonvulsant drugs. This has been observed for many years with valproic acid (sodium valproate) and carbamazepine, and also, more recently, with some of the newer anticonvulsants such as vigabatrin and gabapentin. Very often bodyweight gain in children, adolescents and adults with epilepsy taking such anticonvulsants results in cosmetic adverse effects. On the other hand, bodyweight gain is disturbing to general health, with a possible increase in the risk of diabetes mellitus or heart disease. Other potential adverse effects, such as the association of obesity with polycystic ovaries, have been reported with the use of valproic acid. Potential mechanisms of anticonvulsant-associated bodyweight gain are not yet clear and differ between drugs used. The involvement of lowered blood glucose level, which may stimulate eating through an effect on the hypothalamus, constitutes one of the possible mechanisms. Lowered blood glucose levels may result from a competition between the binding of the drug and long chain fatty acids. An increased availability of the latter stimulates insulin production and lowers the serum glucose levels. Another possible explanation for lowered blood glucose may be a deficiency in carnitine directly caused by the drug, that would result in a reduction of fatty acid metabolism and an increase in glucose consumption. An enhancing effect of gamma-aminobutyric acid-mediated neurotransmission may increase appetite for carbohydrates and reduce energy expenditure. An antidiuretic hormone-like effect or effects on norepinephrine (noradrenaline) or serotonin-mediated neurotransmission are more rarely considered. Many studies on anticonvulsant-associated bodyweight gain illustrate how we could better define the risk factors for the development of anticonvulsant-induced bodyweight gain and uncover the mechanisms behind it.


[Expressions of p-c-jun and cyclinD1 between vascular smooth muscle cells and endothelial cells exposured to cigarette smoke extract].
To investigate the cell viabilities of vascular smooth muscle cells and vascular endothelial cells stimulated by cigarette smoke extract(CSE) . The CSE was prepared by smoke-bubbled phosphate buffered saline(PBS) generation.After culturing cells with different concentrations of CSE, we used the cell counting kit-8 to determine the cell viability.The expression levels of c-jun and cyclinD1 were analyzed through Western blot.The c-jun plasmid was transfected to detect the change of cyclinD1 expression. The smooth muscle cell viability increased when the CSE concentration ranged 0.625%-10%, whereas the endothelial cells viability decreased when exposed to the CSE concentration. After exposure to CSE for 48 hours, there was no difference in c-jun expression between toxin group and PBS group;however, the expression of p-c-jun in the smooth muscle cells significantly increased in the toxin groups than in the PBS group(P<0.05) and the expression of p-c-jun in the vascular endothelial cells significantly decreased(P<0.05) . The level of cyclinD1 significantly increased after exposed to CSE, and its expression level also increased in respond to the c-jun overexpression. CSE can enhance the proliferation of vascular smooth muscle cells and decrease in the activity of endothelial cells proliferation, which may be explained by the phosphorylation of c-jun and the expression of cyclinD1.


Engineered 3D Model of Cancer Stem Cell Enrichment and Chemoresistance.
Intraperitoneal dissemination of ovarian cancers is preceded by the development of chemoresistant tumors with malignant ascites. Despite the high levels of chemoresistance and relapse observed in ovarian cancers, there are no in vitro models to understand the development of chemoresistance in situ. We describe a highly integrated approach to establish an in vitro model of chemoresistance and stemness in ovarian cancer, using the 3D hanging drop spheroid platform. The model was established by serially passaging non-adherent spheroids. At each passage, the effectiveness of the model was evaluated via measures of proliferation, response to treatment with cisplatin and a novel ALDH1A inhibitor. Concomitantly, the expression and tumor initiating capacity of cancer stem-like cells (CSCs) was analyzed. RNA-seq was used to establish gene signatures associated with the evolution of tumorigenicity, and chemoresistance. Lastly, a mathematical model was developed to predict the emergence of CSCs during serial passaging of ovarian cancer spheroids. Our serial passage model demonstrated increased cellular proliferation, enriched CSCs, and emergence of a platinum resistant phenotype. In vivo tumor xenograft assays indicated that later passage spheroids were significantly more tumorigenic with higher CSCs, compared to early passage spheroids. RNA-seq revealed several gene signatures supporting the emergence of CSCs, chemoresistance, and malignant phenotypes, with links to poor clinical prognosis. Our mathematical model predicted the emergence of CSC populations within serially passaged spheroids, concurring with experimentally observed data. Our integrated approach illustrates the utility of the serial passage spheroid model for examining the emergence and development of chemoresistance in ovarian cancer in a controllable and reproducible format.


Evaluation of two milk replacers fed to hand-reared cheetah cubs (Acinonyx jubatus): nutrient composition, apparent total tract digestibility, and comparison to maternal cheetah milk.
Commercially prepared milk replacers are frequently used to provide the sole source of nutrition for hand-reared cheetah cubs (Acinonyx jubatus). The nutrient composition of two commonly used milk replacers was determined. Using titanium dioxide as an indigestible marker, nutrient digestibility was calculated from the analyses of fecal samples collected from each cub (n = 4 on formula 1, and n = 2 on formula 2). Mean apparent total tract digestibility for both formulas was >90% for all nutrients analyzed (crude protein, amino acids, crude fat (CF), and dry matter). However, the total CF content and the concentration of the essential fatty acids, such as α-linolenic, linolenic, and arachidonic acid, of both formulas was lower than reported for maternal cheetah milk. Additionally, one formula contained a comparatively high amount of carbohydrate, at the expense of protein. Although data were lacking for cheetah maternal milk, comparison with domestic cat milk revealed high concentrations of a number of minerals (K, Fe, Zn, and Cu), while vitamin D(3) was not detected in one formula. Both formulas were low in the majority of essential amino acids compared with domestic cat maternal milk. Despite their apparently high digestibility, neither formula was complete or balanced in terms of nutrient concentrations and ratios when maternal cheetah milk and/or the requirements established for growth in domestic cats were used as estimates of ideal. On this basis, although all cubs in this study were healthy and maintained good body conditions for the duration of the trial, the results of dietary analyses indicate that these milk replacers may not provide optimal nutrition for growth in cheetah cubs when used for extended periods.


Apolipoprotein M: bridging HDL and endothelial function.
The review will address the potential roles of apolipoprotein M (apoM) as a carrier protein and modulator of sphingosine-1-phosphate (S1P) bioactivity. Recombinant apoM can bind small lipids such as retinoic acid, oxidized phospholipids, and S1P. Thus, the effects of apoM may be pleiotrophic. The S1P binding ability of apoM has biological impact. ApoM-bound S1P can activate S1P1 receptors on endothelial cells and deficiency of apoM abolishes the presence of S1P in HDL. In mice, the lack of apoM causes dysfunctional endothelial barrier function in the lungs. In humans, sepsis that is characterized by impaired endothelial function is associated with low plasma apoM. Plasma apoM is mainly bound to HDL. The roles of apoM in atherosclerosis and lipoprotein metabolism have been given much attention. New in the field is the discovery of apoM as a chaperone for S1P. S1P is a bioactive lipid with effects on angiogenesis, lymphocyte trafficking, endothelial cell migration, and inflammation. A drug targeting the S1P-system (fingolimod) is now used for treatment of multiple sclerosis. It improves the blood-brain barrier and inhibits migration of lymphocytes into the brain. Further exploration of the apoM/S1P axis may uncover its potential as a biomarker and target for new treatments.


Fine-tuning of substrate preferences of the Src-family kinase Lck revealed through a high-throughput specificity screen.
The specificity of tyrosine kinases is attributed predominantly to localization effects dictated by non-catalytic domains. We developed a method to profile the specificities of tyrosine kinases by combining bacterial surface-display of peptide libraries with next-generation sequencing. Using this, we showed that the tyrosine kinase ZAP-70, which is critical for T cell signaling, discriminates substrates through an electrostatic selection mechanism encoded within its catalytic domain (Shah et al., 2016). Here, we expand this high-throughput platform to analyze the intrinsic specificity of any tyrosine kinase domain against thousands of peptides derived from human tyrosine phosphorylation sites. Using this approach, we find a difference in the electrostatic recognition of substrates between the closely related Src-family kinases Lck and c-Src. This divergence likely reflects the specialization of Lck to act in concert with ZAP-70 in T cell signaling. These results point to the importance of direct recognition at the kinase active site in fine-tuning specificity.


Some effects of breeding season and castration on the prostate and epididymis of the brushtail possum, Trichosurus vulpecula.
In an attempt to understand the mechanism(s) responsible for the reported marked seasonal increase in prostatic, but not epididymal, weight in T. vulpecula, a number of parameters were measured in tissues from mature, entire males sampled within and outside of the breeding season and from castrates. Conditions for the measurement of cytosol androgen receptors were also established. The weight of both the prostate and the epididymis was significantly elevated in the breeding season but the relative increase in prostate weight was considerably greater. The increase in prostatic weight was associated with a decrease in DNA: g tissue and an increase in protein: DNA and RNA: DNA ratios, each indicative of cellular hypertrophy and/or accumulation of secretory product. In the epididymis there were no significant seasonal changes in RNA: DNA, protein: DNA or DNA: g tissue ratios. Low-capacity, high-affinity binding was demonstrated in the epididymal and prostatic cytosols and values for the equilibrium association constants and receptor concentrations were within the range reported for androgen receptors in eutherian species. The temperature sensitivity of the binding, steroid specificity and slow dissociation in the cold indicated that in both tissues cystosol receptor and not androgen-binding or serum-binding protein(s) were being measured. In prostatic, but not epididymal, cytosol a low level of progesterone binding was observed and was masked by triamcinolone acetonide. When expressed in terms of tissue DNA, cytosol androgen receptor level in the prostate only was elevated in the breeding season. Prostatic tissue showed a low level of 5 alpha-reductase in vitro which was not influenced by season. However, both tissues showed a high concentration of 5 alpha-dihydrotestosterone and in the prostate, where seasonal effects were measured, the concentration was higher in the breeding season. This indicates that although 5 alpha-dihydrotestosterone is the likely active androgen in the prostate it may be formed elsewhere. Part of the explanation for the increased growth of the prostate in the breeding season appears to be a change in receptor concentration coupled with elevated tissue androgen level.


High and low density intracellular water.
The proposal that liquid water consists of microdomains of rapidly-exchanging polymorphs of high and low density is examined for its impact upon roles of water in biology. It is assumed that the two polymorphs persist in solution and adjacent to surfaces and that solutes partition asymmetrically between them. It transpires that chaotropes are solutes which partition preferentially into low density water and displace the water equilibrium toward the high density polymorph. Kosmotropes. both ionic and non-polar, partition into high density water and induce low density water. Displacement of the water equilibrium at constant temperature and pressure has a thermodynamic cost which can be high. This appears to be a dominant factor in folding of proteins and DNA, aggregation of biopolymers and insolubility of non-polar kosmotropes. Cells control both the concentration of proteins and the selection of small solutes to produce an intracellular environment most conducive to co-ordinated enzyme function. Intracellular water has similar microdomains to bulk water, but surfaces and solutes redistribute them. Average properties, as measured by NMR are similar, but local properties on a nm scale may differ widely. Enzymes apparently use these local differences to activate cations for transport, induce movement and for synthesis.


[Antibiotic therapy of Lyme borreliosis].
There are still no definite patterns for antibiotic therapy of Lyme borreliosis. Recent studies have shown that ceftriaxone or tetracyclines are superior to the conventional penicillin. Against erythema chronica migrans (stage I) oral therapy, preferably with tetracycline, is sufficient. In cases with stage II symptoms, such as arthritis or neurological affections, high dose parenteral treatment, preferably with ceftriaxone, is recommended, although its effect on the neurologic symptoms is not yet proven. Carditis also calls for high dose parenteral administration of antibiotics, even though there are no published studies on this treatment as yet. Opinion is divided on the cutaneous symptoms such as acrodermatitis chronica atrophicans, morphea, lichen sclerosus et atrophicus (acute inflammatory stage) and lymphadenitis cutis benigna. Even if oral penicillin or tetracycline can cure existing symptoms, in the absence of longterm observations, it remains an open question whether oral treatment can prevent further complications or evolution to chronicity (stage III). For these clinical pictures there is also a tendency to give high dose parenteral antibiotics, and ceftriaxone is likely to win favour. In stage II Lyme borreliosis, autoimmune processes occur which scarcely respond to antibiotics any longer. Nevertheless, parenteral administration of high dose antibiotics remains sensible as a means of eradicating pathogens from the tissues, CSF or synovial fluids, and to avoid further complications. Evaluation of the therapeutic effects of corticosteroids or other immunosuppressive agents would require prospective studies.


Epidemiological characteristics of rabies in Delhi and surrounding areas, 1998.
To describe the epidemiological characteristics of rabies in Delhi in 1998. Analysis of the records of hydrophobia cases admitted to the Infectious Diseases Hospital, Delhi (IDH) in 1998. About 46 percent (99/215) of the hydrophobia cases admitted to the IDH in 1998 belonged to Delhi. The remaining came from the adjoining states, both urban and rural areas. In Delhi residents, overall hospitalization rate was 0.81 per 100,000 population. It was significantly higher in 5-14 year old than in other age groups and in males than in females (p <0.0009). Cases occurred round the year. Almost 96 percent cases (206/215) gave history of animal exposure, 13 days to 10 years (median 60 days) before hospitalization. Majority (195/206) had class III exposure. Animals involved were stray dog (193/206 = 90 percent), pet dog, cat, jackal, mongoose, monkey and fox. Most of cases were never vaccinated (78 percent) or inadequately vaccinated (22 percent); only 1 percent each received appropriate wound treatment, or rabies immunoglobulin. Rabies is a major public health problem in Delhi. Its incidence is significantly higher in 5-14 year old children than in other age groups. The results indicate the need to educate the community and health care workers about the importance of immediate and adequate post-exposure treatment and to start an effective control program for dogs, the principal vector of rabies.


Thymic carcinoma: outcomes after surgical resection.
Thymic carcinoma is a rare malignancy with little information regarding outcomes after therapy with curative intent. We undertook a retrospective analysis of all patients who underwent resection of thymic carcinoma at 2 hospitals. From 1990 to 2011, 16 patients (9 men, 7 women) underwent surgical resection of thymic carcinoma at a mean age of 52 years. Patient demographics, extent of surgical resection, and outcomes were compiled. The distribution of Masaoka stages at presentation was I in 3 (19%), II in 4 (25%), III in 8 (50%), and IV in 1 (6%). Neoadjuvant chemotherapy was administered to 6 patients (38%) whose tumors were deemed to be more locally invasive. Surgical resection included en bloc extrapleural pneumonectomy in 1, lobectomy in 2, and superior vena cava resection and reconstruction in 4. There were no perioperative deaths. Complete resection was achieved in 14 (88%), and of these patients, only 1 experienced local recurrence. At last follow-up, 10 patients were alive and well, 1 patient was alive with disease, and 5 patients had died. Mean survival was 4.2 years. Although considered to have greater malignant potential, long-term survival can be achieved in patients with thymic carcinoma who are amenable to surgical therapy. With increased use of computed tomography imaging, patients with early-stage disease are being identified more frequently, and complete surgical resection appears to have favorable cure rates in these patients. Select patients with locally advanced disease can experience long-term survival with a multimodality approach.


Spatial contingency and the McCollough effect.
On the basis of a conditioning analysis of the orientation-contingent color aftereffect (McCollough effect, ME), orientation stimuli become associated with simultaneously presented chromatic stimuli. This account suggests that decreasing the contingency between the grid orientation and color should decrease the strength of the aftereffect. Results of previous research indicate that decreasing the temporal contingency (by presenting homogeneous chromatic stimuli between presentations of chromatic grids) does not decrease the ME. However, it has been suggested that the appropriate contingency-degradation procedure would involve decreasing spatial (rather than temporal) contingency. That is, the illusion should be attenuated by extending the color beyond the confines of the grid. Contrary to this hypothesis, the results of the present experiments provide no evidence that decreasing the spatial contingency between grid and color decreases the ME; rather, the aftereffect is increased by such a manipulation.


InSight Pressure Data Recalibration, and Its Application to the Study of Long-Term Pressure Changes on Mars.
Observations of the South Polar Residual Cap suggest a possible erosion of the cap, leading to an increase of the global mass of the atmosphere. We test this assumption by making the first comparison between Viking 1 and InSight surface pressure data, which were recorded 40 years apart. Such a comparison also allows us to determine changes in the dynamics of the seasonal ice caps between these two periods. To do so, we first had to recalibrate the InSight pressure data because of their unexpected sensitivity to the sensor temperature. Then, we had to design a procedure to compare distant pressure measurements. We propose two surface pressure interpolation methods at the local and global scale to do the comparison. The comparison of Viking and InSight seasonal surface pressure variations does not show changes larger than ±8 Pa in the CO2 cycle. Such conclusions are supported by an analysis of Mars Science Laboratory (MSL) pressure data. Further comparisons with images of the south seasonal cap taken by the Viking 2 orbiter and MARCI camera do not display significant changes in the dynamics of this cap over a 40 year period. Only a possible larger extension of the North Cap after the global storm of MY 34 is observed, but the physical mechanisms behind this anomaly are not well determined. Finally, the first comparison of MSL and InSight pressure data suggests a pressure deficit at Gale crater during southern summer, possibly resulting from a large presence of dust suspended within the crater.


The case of the forgotten toothbrush.
Although foreign body ingestion is relatively common, toothbrush swallowing is rare. A diagnosis of small-bowel perforation, caused by a sharp or pointed foreign body, is rarely made preoperatively because the clinical symptoms are usually nonspecific and can mimic other surgical conditions, such as appendicitis and diverticulitis. We report a case of a swallowed toothbrush which passed past the pylorus and perforated the terminal ileum. The patient however presented with a fluctuant mass in the left iliac fossa, pyrexia and generalised tenderness mimicking a diverticular abscess. Ingestion of a foreign body is commonly encountered in the clinic among children, adults with intellectual impairment, psychiatric illness or alcoholism, and dental prosthetic-wearing elderly subjects. However, toothbrush swallowing is rare, with only approximately 40 reported cases. Bowel perforation by foreign bodies can mimic acute appendicitis and should be considered in differential diagnoses. Clinically, patients often do not recall ingesting the foreign body, which makes the clinical diagnosis more challenging, and a correct diagnosis is frequently delayed. Several radiological investigations, such as small-bowel series, ultrasonography, and computed tomography scans, may lead to the correct diagnosis, but in most patients, the diagnosis is not confirmed until the surgical intervention has been performed.


Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example.
The nature and incidence of errors in prescribing and giving medicines have previously been estimated by trained observers, or by retrospective analysis of incidents in which patients have come to harm. We have examined prospectively in routine clinical practice the concentrations of intravenous infusions of a drug (acetylcysteine) which is given according to a complicated dosing schedule. We prospectively collected samples before and, where possible, after the infusion of acetylcysteine in 66 anonymous patients requiring treatment for acetaminophen (paracetamol) overdose in four centres in the United Kingdom. We measured the concentration in each infusion bag, and deduced from the weight of the patient the percentage of the anticipated dose that had actually been given. The experimentally determined dose was within 10% of the anticipated dose in 68 of 184 individual bags (37%), and within 20% of the anticipated dose in 112 bags (61%). Doses in 17 bags were more than 50% from the anticipated doses. In three patients, values in all three bags appeared to be systematically wrong by 50% or more; in a further seven cases, individual bags differed by 50% or more from the anticipated value. The median difference between pre- and post-infusion samples was 0% [interquartile range -5.2% to +14.6%], but 9% showed a disparity of greater than +/- 50%. Our data suggest that there is large random variation in administered dosage of intravenous infusions. Systematic calculation errors occur in about 5% [95% confidence interval 2, 8%] of cases, and major errors in drawing up in a further 3% [1, 7%], with inadequate mixing in 9% [4, 14%]. While we have no evidence that patients were adversely affected, and while the regime of administration of the drug studied (acetylcysteine) is complicated, these data suggest that the delivered dose often deviates from the intended dose, and that methods of quality control are needed.


Proton-binding capacity of Staphylococcus aureus wall teichoic acid and its role in controlling autolysin activity.
Wall teichoic acid (WTA) or related polyanionic cell wall glycopolymers are produced by most gram-positive bacterial species and have been implicated in various cellular functions. WTA and the proton gradient across bacterial membranes are known to control the activity of autolysins but the molecular details of these interactions are poorly understood. We demonstrate that WTA contributes substantially to the proton-binding capacity of Staphylococcus aureus cell walls and controls autolysis largely via the major autolysin AtlA whose activity is known to decline at acidic pH values. Compounds that increase or decrease the activity of the respiratory chain, a main source of protons in the cell wall, modulated autolysis rates in WTA-producing cells but did not affect the augmented autolytic activity observed in a WTA-deficient mutant. We propose that WTA represents a cation-exchanger like mesh in the gram-positive cell envelopes that is required for creating a locally acidified milieu to govern the pH-dependent activity of autolysins.


Variation in Listeria monocytogenes dose responses in relation to subtypes encoding a full-length or truncated internalin A.
Internalin A (InlA; encoded by inlA) facilitates the crossing of the intestinal barrier by Listeria monocytogenes. Mutations leading to a premature stop codon (PMSC) in inlA and thus attenuated mammalian virulence have been reported. We recently characterized 502 L. monocytogenes food isolates from a retail survey and 507 human clinical isolates from multiple U.S. states with respect to the presence/absence of inlA mutations. The objective of this study was to investigate the hypothesis that dose responses for human listeriosis vary between L. monocytogenes strains with and those without a PMSC in inlA. Subtype-specific prevalence and concentration distributions in food, along with epidemiologic and consumption data, were input into established dose-response models to generate an r value (probability of a cell causing illness). Under the conservative assumption that L. monocytogenes levels at retail represent levels consumed, mean log(10) r values were -8.1 and -10.7 for L. monocytogenes subtypes with genes encoding a full-length and a truncated InlA, respectively. L. monocytogenes carrying a 5' frameshift mutation in a homopolymeric tract showed a mean log(10) r value of -12.1. Confidence intervals for the r values and their differences varied depending on subtypes. When the increase in concentration of L. monocytogenes subtypes between retail and consumption was considered, mean log(10) r values were reduced to -10.4, -13.8, and -12.8 for the subtypes with genes encoding a full-length InlA, for the subtypes carrying a PMSC in inlA, and for all L. monocytogenes isolates regardless of subtype, respectively. Our study provides further quantitative evidence that L. monocytogenes subtypes vary in abilities and relative likelihoods of causing human disease, which were mechanistically related to defined genetic markers.


Enhanced intercalation dynamics and stability of engineered micro/nano-structured electrode materials: vanadium oxide mesocrystals.
An additive and template free process is developed for the facile synthesis of VO2 (B) mesocrystals via the solvothermal reaction of oxalic acid and vanadium pentoxide. The six-armed star architectures are composed of stacked nanosheets homoepitaxially oriented along the [100] crystallographic register with respect to one another, as confirmed by means of selected area electron diffraction and electron microscopy. It is proposed that the mesocrystal formation mechanism proceeds through classical as well as non-classical crystallization processes, and is possibly facilitated or promoted by the presence of a reducing/chelating agent. The synthesized VO2 (B) mesocrystals are tested as a cathodic electrode material for lithium-ion batteries, and show good capacity at discharge rates ranging from 150-1500 mA g(-1) and a cyclic stability of 195 mA h g(-1) over fifty cycles. The superb electrochemical performance of the VO2 (B) mesocrystals is attributed to the porous and oriented superstructure that ensures large surface area for redox reaction and short diffusion distances. The mesocrystalline structure ensures that all the surfaces are in intimate contact with the electrolyte, and that lithium-ion intercalation occurs uniformly throughout the entire electrode. The exposed (100) facets also lead to fast lithium intercalation, and the homoepitaxial stacking of nanosheets offers a strong inner-sheet binding force that leads to better accommodation of the strain induced during cycling, thus circumventing the capacity fading issues typically associated with VO2 (B) electrodes.


"D.O. or die": identity negotiation among osteopathic medical students.
Doctors of osteopathic medicine (D.O.s) have historically faced an uphill battle to gain professional legitimacy and credibility in a U.S. medical culture dominated by allopathic medicine. Today, struggles surrounding the negotiation of a professional osteopathic identity can be found among osteopathic medical students who actively debate the merits of a potential change in the D.O. designation. This study examines identity construction by analyzing osteopathic medical students' accounts of identity that reveal certain ways they negotiate their emerging professional selves. By merging current literature on identity negotiation from health and organizational communication, we highlight the complex relationship between the discursive construction of professional identity and the embodied and material consequences of becoming a D.O.


Children's eyewitness memory: repeating post-event misinformation reduces the distinctiveness of a witnessed event.
Children may incorporate misinformation into reports of witnessed events, particularly if the misinformation is repeated. One explanation is that the misinformation trace is strengthened by repetition. Alternatively, repeating misinformation may reduce the discriminability between event and misinformation sources, increasing interference between them. We tested trace strength and distinctiveness accounts by showing 5- and 6-year-olds an event and then presenting either the "same" or "varying" items of post-event misinformation across three iterations. Performance was compared to a baseline in which misinformation was presented once. Repeating the same misinformation increased suggestibility when misinformation was erroneously attributed to both event and misinformation sources, supporting a trace strength interpretation. However, suggestibility measured by attributing misinformation solely to the event, was lower when misinformation was presented repeatedly rather than once. In contrast, identification of the correct source of the event was less likely if the misinformation was repeated, whether the same or different across iterations. Thus a reduction in the distinctiveness of sources disrupted memory for the event source. Moreover, there was strong association between memory for the event and a measure of distinctiveness of sources, which takes into account both the number of confusable source and their apparent temporal spacing from the point of retrieval.


Evaluating online filtering algorithms to enhance dynamic multispectral optoacoustic tomography.
Multispectral optoacoustic tomography (MSOT) is an emerging imaging modality, which is able to capture data at high spatiotemporal resolution using rapid tuning of the excitation laser wavelength. However, owing to the necessity of imaging one wavelength at a time to the exclusion of others, forming a complete multispectral image requires multiple excitations over time, which may introduce aliasing due to underlying spectral dynamics or noise in the data. In order to mitigate this limitation, we have applied kinematic α and α β filters to multispectral time series, providing an estimate of the underlying multispectral image at every point in time throughout data acquisition. We demonstrate the efficacy of these methods in suppressing the inter-frame noise present in dynamic multispectral image time courses using a multispectral Shepp-Logan phantom and mice bearing distinct renal cell carcinoma tumors. The gains in signal to noise ratio provided by these filters enable higher-fidelity downstream analysis such as spectral unmixing and improved hypothesis testing in quantifying the onset of signal changes during an oxygen gas challenge.


[Assessment of the quality of response to the 2008 cholera outbreak in Contonou (Benin)].
To assess the quality of the response to the 2008 outbreak of cholera in Cotonou (Benin), this retrospective study focused on the health professionals managing the response, community leaders, cases of cholera found in homes and health service documents. The terms of reference used for the purposes of this assessment included the WHO recommendations and the rules set out in the national plan for the fight against epidemics. The resources and method used in this study complied with the norms specified in the plan, as did the epidemiologic follow-up. Community and family interventions concerned only a limited number of households in comparison with the total number of cases. Of the 402 cases diagnosed between July 28th and October 16th 2008, 384 cases were given treatment complying with the specified protocols, and just one death was recorded (hospital lethality 0.25%). The mean length of hospitalization was 2.43 days ± 1.16. Compliance with standard response procedures resulted in good quality care and very low lethality. The national plan of response to epidemics is therefore validated. An improved management of outbreaks requires national multi-sector coordination. Authorities in the following areas need to be involved: healthcare, environment, education, public administration and local communities.


Sleeping Beauty Screen Identifies RREB1 and Other Genetic Drivers in Human B-cell Lymphoma.
Follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) are the most common non-Hodgkin lymphomas distinguishable by unique mutations, chromosomal rearrangements, and gene expression patterns. Here, it is demonstrated that early B-cell progenitors express 2',3'-cyclic-nucleotide 3' phosphodiesterase (CNP) and that when targeted with Sleeping Beauty (SB) mutagenesis, Trp53R270H mutation or Pten loss gave rise to highly penetrant lymphoid diseases, predominantly follicular lymphoma and DLBCL. In efforts to identify the genetic drivers and signaling pathways that are functionally important in lymphomagenesis, SB transposon insertions were analyzed from splenomegaly specimens of SB-mutagenized mice (n = 23) and SB-mutagenized mice on a Trp53R270H background (n = 7) and identified 48 and 12 sites with statistically recurrent transposon insertion events, respectively. Comparison with human data sets revealed novel and known driver genes for B-cell development, disease, and signaling pathways: PI3K-AKT-mTOR, MAPK, NFκB, and B-cell receptor (BCR). Finally, functional data indicate that modulating Ras-responsive element-binding protein 1 (RREB1) expression in human DLBCL cell lines in vitro alters KRAS expression, signaling, and proliferation; thus, suggesting that this proto-oncogene is a common mechanism of RAS/MAPK hyperactivation in human DLBCL. IMPLICATIONS: A forward genetic screen identified new genetic drivers of human B-cell lymphoma and uncovered a RAS/MAPK-activating mechanism not previously appreciated in human lymphoid disease. Overall, these data support targeting the RAS/MAPK pathway as a viable therapeutic target in a subset of human patients with DLBCL.


The copyright quagmire on the Internet.
The use of the Internet is expanding exponentially. More and more individuals are gaining access to the information structure once limited to universities and military applications. The ease of access and distribution of materials were never envisioned by the authors of the Berne Convention, which outlined original international copyright laws. Along with greater freedom experienced through the Internet and the creative exchange of ideas comes a quagmire of legal issues. This article identifies the issues currently being discussed by world leaders in copyright law and the implications to nursing education as it expands and explores the use of the Internet for educational purposes.


The FHA domain proteins DAWDLE in Arabidopsis and SNIP1 in humans act in small RNA biogenesis.
Proteins containing the forkhead-associated domain (FHA) are known to act in biological processes such as DNA damage repair, protein degradation, and signal transduction. Here we report that DAWDLE (DDL), an FHA domain-containing protein in Arabidopsis, acts in the biogenesis of miRNAs and endogenous siRNAs. Unlike mutants of genes known to participate in the processing of miRNA precursors, such as dcl1, hyponastic leaves1, and serrate, ddl mutants show reduced levels of pri-miRNAs as well as mature miRNAs. Promoter activity of MIR genes, however, is not affected by ddl mutations. DDL is an RNA binding protein and is able to interact with DCL1. In addition, we found that SNIP1, the human homolog of DDL, is involved in miRNA biogenesis and interacts with Drosha. Therefore, we uncovered an evolutionarily conserved factor in miRNA biogenesis. We propose that DDL participates in miRNA biogenesis by facilitating DCL1 to access or recognize pri-miRNAs.


Mathematical modelling of juxtacrine cell signalling.
Juxtacrine signalling is emerging as an important means of cellular communication, in which signalling molecules anchored in the cell membrane bind to and activate receptors on the surface of immediately neighbouring cells. We develop a mathematical model to describe this process, consisting of a coupled system of ordinary differential equations, with one identical set of equations for each cell. We use a generic representation of ligand-receptor binding, and assume that binding exerts a positive feedback on the secretion of new receptors and ligand. By linearising the model equations about a homogeneous equilibrium, we categorize the range and extent of signal patterns as a function of parameters. We show in particular that the signal decay rate depends crucially on the form of the feedback functions, and can be made arbitrarily small by appropriate choice of feedback, for any set of kinetic parameters. As a specific example, we consider the application of our model to juxtacrine signalling by TGF alpha in response to epidermal wounding. We demonstrate that all the predictions of our linear analysis are confirmed in numerical simulations of the non-linear system, and discuss the implications for the healing response.


Characterization of the calcium-activated chloride channel in isolated guinea-pig hepatocytes.
Macroscopic and unitary currents through Ca(2+)-activated Cl- channels were examined in enzymatically isolated guinea-pig hepatocytes using whole-cell, excised outside-out and inside-out configurations of the patch-clamp technique. When K+ conductances were blocked and the intracellular Ca2+ concentration ([Ca2+]i) was set at 1 microM (pCa = 6), membrane currents were observed under whole-cell voltage-clamp conditions. The reversal potential of the current shifted by approximately 60 mV per 10-fold change in the external Cl- concentration. In addition, the current did not appear when Cl- was omitted from the internal and external solutions, indicating that the current was Cl- selective. The current was activated by increasing [Ca2+]i and was inactivated in Ca(2+)-free, 5 mM EGTA internal solution (pCa > 9). The current was inhibited by bath application of 9-anthracenecarboxylic acid (9-AC) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) in a voltage-dependent manner. In single channel recordings from outside-out patches, unitary current activity was observed, whose averaged slope conductance was 7.4 +/- 0.5 pS (n = 18). The single channel activity responded to extracellular Cl- changes as expected for a Cl- channel current. The open time distribution was best described by a single exponential function with mean open lifetime of 97.6 +/- 10.4 ms (n = 11), while at least two exponentials were required to fit the closed time distributions with a time constant for the fast component of 21.5 +/- 2.8 ms (n = 11) and that for the slow component of 411.9 +/- 52.0 ms (n = 11). In excised inside-out patch recordings, channel open probability was sensitive to [Ca2+]i. The relationship between [Ca2+]i and channel activity was fitted by the Hill equation with a Hill coefficient of 3.4 and the half-maximal activation was 0.48 microM. These results suggest that guinea-pig hepatocytes possess Ca(2+)-activated Cl- channels.


The association of extreme body weight with bone mineral density in Saudi children.
The objective to investigate the effect of extreme body weight; obesity and undernutrition, on bone mineral density (BMD). This study is a descriptive cross-sectional study carried between January and June of 2019, and included 224 children and adolescents without any comorbidities or chronic disease. Important data collected included anthropometrics, past medical and surgical history, history of medication intake, level of physical activity and pubertal assessment. Data entry and analysis were conducted using Statistical Package for Social Sciences version 24. Gender distribution showed 48.2% were male and 51.8% were female. The mean age was 9.98 ± 3.5 years. Mean weight was 34.89 ± 18.2 kg. Mean BMD z-score was - 1.64 ± 1.4. Weight was considered to significantly correlate with BMD stature at a P = 0.014. Subjects who were underweight showed a lower mean BMD z-score of <-2 than those who were overweight/obese (mean BMD z-score = -1.60). Both extremes of weight are considered a significant risk factor for the development of low BMD in children. We recommend the early recognition of weight aberrations and consequent aggressive intervention with strict lifestyle modifications to promote the development of maximum peak bone mass.


Hollow fiber flow field-flow fractionation of proteins using a microbore channel.
Protein separation through hollow fiber flow field-flow fractionation (HF FlFFF) at microflow rate regime was successfully achieved by employing a microbore hollow fiber. In most of the flow field-flow fractionation (FlFFF) techniques applied to the separation of proteins, including hollow fiber FlFFF (HF FlFFF), an outflow rate leading to a detector has typically been a few tenths of a milliliter per minute. In this study, it is demonstrated for the first time that 10 microL/min outflow rate in HF FlFFF can be employed for a successful separation of proteins by utilizing a small inner diameter (450 microm) hollow fiber. Initial evaluations of microbore HF FlFFF separation were made to improve separation efficiency by evaluating plate heights, sample recovery, and the limit of detection using protein standards. Microbore HF FlFFF was applied for the separation of low-abundance blood proteins depleted of high-abundance proteins from raw serum using immunoaffinity chromatography.


Mathematical modeling of the Candida albicans yeast to hyphal transition reveals novel control strategies.
Candida albicans, an opportunistic fungal pathogen, is a significant cause of human infections, particularly in immunocompromised individuals. Phenotypic plasticity between two morphological phenotypes, yeast and hyphae, is a key mechanism by which C. albicans can thrive in many microenvironments and cause disease in the host. Understanding the decision points and key driver genes controlling this important transition and how these genes respond to different environmental signals is critical to understanding how C. albicans causes infections in the host. Here we build and analyze a Boolean dynamical model of the C. albicans yeast to hyphal transition, integrating multiple environmental factors and regulatory mechanisms. We validate the model by a systematic comparison to prior experiments, which led to agreement in 17 out of 22 cases. The discrepancies motivate alternative hypotheses that are testable by follow-up experiments. Analysis of this model revealed two time-constrained windows of opportunity that must be met for the complete transition from the yeast to hyphal phenotype, as well as control strategies that can robustly prevent this transition. We experimentally validate two of these control predictions in C. albicans strains lacking the transcription factor UME6 and the histone deacetylase HDA1, respectively. This model will serve as a strong base from which to develop a systems biology understanding of C. albicans morphogenesis.


[A morphogenetic analysis of a callus culture of Nicotiana tabacum L. in chronic irradiation of the plants].
The callus culture of Nicotiana tabacum L. was obtained from the plants chronically irradiated in 10 km zone of Chernobyl Atomic Power Station. The tobacco plants in 10 km zone of Chernobyl during the vegetation period exposed to irradiation with the average dose rate of 0.36 mA/kg (5 mP/h). The total absorbed dose was approximately 0,31 Gy. The morphogenetic analysis of this culture shows a considerable decrease of regeneration index and callus weight.


The inclusion of reports of randomised trials published in languages other than English in systematic reviews.
To assemble a large dataset of language restricted and language inclusive systematic reviews, including both conventional medicinal (CM) and complementary and alternative medicine (CAM) interventions. To then assess the quality of these reports by considering and comparing different types of systematic reviews and their associated RCTs; CM and CAM interventions; the effect of language restrictions compared with language inclusions, and whether these results are influenced by other issues, including statistical heterogeneity and publication bias, in the systematic review process. MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Centralised Information Service for Complementary Medicine. Three types of systematic reviews were included: language restricted; language inclusive/English language (EL) reviews that searched RCTs in languages other than English (LOE) but did not find any and, hence, could not include any, in the quantitative data synthesis; and systematic reviews that searched for RCTs in LOE and included them in the quantitative data synthesis. Fisher's exact test was applied to compare the three different types of systematic reviews with respect to their reporting characteristics and the systematic review quality assessment tool. The odds ratio of LOE trials versus EL trials was computed for each review and this information was pooled across the reviews to examine the influence that language of publication and type of intervention (CM, CAM) have on the estimates of intervention effect. Several sensitivity analyses were performed. The LOE RCTs were predominantly in French and German. Language inclusive/LOE systematic reviews were of the highest quality compared with the other types of reviews. The CAM reviews were of higher quality compared with the CM reviews. There were only minor differences in the quality of reports of EL RCTs compared with the eight other languages considered. However, there are inconsistent differences in the quality of LOE reports depending on the intervention type. The results, and those reported previously, suggest that excluding reports of RCTs in LOE from the analytical part of a systematic review is reasonable. Because the present research and previous efforts have not included every type of CM RCT and the resulting possibility of the uncertainty as to when bias will be present by excluding LOE, it is always prudent to perform a comprehensive search for all evidence. This result only applies to reviews investigating the benefits of CM interventions. This does not imply that systematic reviewers should neglect reports in LOE. We recommend that systematic reviewers search for reports regardless of the language. There may be merit in including them in some aspects of the review process although this decision is likely to depend on several factors, including fiscal and other resources being available. Language restrictions significantly shift the estimates of an intervention's effectiveness when the intervention is CAM. Here, excluding trials reported in LOE, compared with their inclusion, resulted in a reduced intervention effect. The present results do not appear to be influenced by statistical heterogeneity and publication bias. With the exception of CAM systematic reviews, the quality of recently published systematic reviews is less than optimal. Language inclusive/LOE systematic reviews appear to be a marker for a better quality systematic review. Language restrictions do not appear to bias the estimates of a conventional intervention's effectiveness. However, there is substantial bias in the results of a CAM systematic review if LOE reports are excluded from it.


Dissociation of 5-fluorouracil uptake from intracellular pH in Walker 256 carcinosarcoma.
The influence of intracellular pH (pHi) upon 5-fluorouracil (5-FU) uptake has been studied in slices of Walker 256 carcinosarcoma and rat liver. Alteration of pHi was achieved by the addition of either glucose alone or together with oxamic acid to the incubation medium. Results indicated that 5-FU uptake by the tumor slices was not dependent upon pHi, but was enhanced by the presence of glucose. Uptake of 5-FU by liver slices appeared to follow a pattern predictable from the pHi and the pK of the drug.


Acute renal failure: clinical aspects and pathophysiology.
Acute renal failure may be caused by multiple conditions including those which are due to some direct hemodynamic or nephrotoxic insult. In considering the pathophysiology of these entities, it seems appropriate to differentiate between the initiating and the maintenance phase of the disorder. In the former, renal ischemia and/or a direct effect of a given nephrotoxic agent seems to be the basis for the underlying renal damage. In the maintenance phase, renal functional impairment is maintained by a number of factors which include persistent renal vasoconstriction, tubular obstruction, a leakage of filtrate across damaged tubular epithelium, and a reduction in glomerular capillary permeability. The therapy and possible preventive aspects of these entities are discussed.


Characterization of the Adaptive Morphology of Japanese Stream Toad (Bufo torrenticola) Using Geometric Morphometrics.
The order Anura (frogs and toads) is a group of amphibians and contains over 6500 extant species living in a variety of environments. Each frog species evolved body form adaptive for living and breeding in their own habitats. In Japan, four taxa of Bufo are living: Western-Japanese common toad (Bufo japonicus japonicus), Eastern-Japanese common toad (B. japonicus formosus), Miyako toad (B. gargarizans miyakonis) and Japanese stream toad (B. torrenticola). The former three taxa breed in still water as many other species of Bufo do. In contrast, B. torrenticola breeds in running water such as streams in mountainous area. Corresponding to their breeding in a stream environment, both adult and larva of B. torrenticola acquired unique morphological characters. However, few study have explored differences in the body form between B. torrenticola and closely-related Bufo species quantitatively, remaining the details about the morphological adaptation to a stream environment in this toad species poorly understood. In this study, we quantitatively compared the shape of the foot and skull between the adult male of B. torrenticola and its close relative B. j. formosus using landmark-based geometric morphometrics. Our analyses revealed that B. torrenticola has relatively longer toe phalanges with relatively larger foot webs and relatively shorter metatarsals and a narrower and more streamlined skull, compared to closely-related B. j. formosus. These morphological characteristics are considered adaptive for their breeding in mountain torrents.


A distinct configuration of MMPI-2-RF scales RCd and RC9/ACT is associated with suicide attempt risk among suicide ideators in a psychiatric outpatient sample.
Suicide is a major public health problem, claiming the lives of more than 40,000 individuals in the United States each year. Efforts are needed to (a) identify those at heightened risk for suicide, utilizing objective assessment methods and (b) determine factors that may be protective against engaging in suicidal behavior, even in the context of the desire to do so. Scales RCd (demoralization) and RC9 (hypomanic activation) of the Minnesota Multiphasic Personality Inventory (MMPI)-2 Restructured Form (MMPI-2-RF) may be valuable in this regard. Whereas individuals high on both RCd and RC9 are dysphoric and prone to reckless action, individuals high on RCd but low on RC9 are characterized by levels of high lethargy and physical unexcitability that may be protective against making a suicide attempt. The purpose of this study was to determine whether scales RCd and RC9 of the MMPI-2-RF interact to predict suicide attempts among suicide ideators. Participants were 189 psychiatric outpatients between the ages of 18 and 65 years (M = 28.8, SD = 11.8; 68.8% female, 74.5% non-Hispanic White) who reported nonzero levels of suicidal ideation on the Beck Scale for Suicide Ideation. Overall, 46.6% of patients reported a past suicide attempt. Consistent with hypotheses, RCd and RC9 interacted such that elevations on RCd were positively associated with past suicide attempts at high, but not low, levels of RC9. Alternate models demonstrated that this configuration persisted when examining the ACT Specific Problem scale as a surrogate for RC9. This study presents a novel MMPI-2-RF configuration that may enhance the assessment of suicide risk. (PsycINFO Database Record


Drosophila P elements preferentially transpose to replication origins.
The P transposable element recently invaded wild Drosophila melanogaster strains worldwide. A single introduced copy can multiply and spread throughout the fly genome in just a few generations, even though its cut-and-paste transposition mechanism does not inherently increase copy number. P element insertions preferentially target the promoters of a subset of genes, but why these sites are hotspots remains unknown. We show that P elements selectively target sites that in tissue-culture cells bind origin recognition complex proteins and function as replication origins. The association of origin recognition complex-binding sites with selected promoters and their absence near clustered differentiation genes may dictate P element site specificity. Inserting at unfired replication origins during S phase may allow P elements to be both repaired and reduplicated, thereby increasing element copy number. The advantage transposons gain by moving from replicated to unreplicated genomic regions may contribute to the association of heterochromatin with late-replicating genomic regions.


[Intrapleural hemorrhages after the correction of acquired heart defects under hypothermia without perfusion].
The authors conducted a retrospective analysis of the case records of 757 patients who underwent correction of acquired heart valvular disease under conditions of hypothermia without perfusion. Intrapleural hemorrhage occurred in the postoperative period in 43 (5.7%) patients, in 35 of them rethoracotomy had to be performed to arrest the bleeding. In patients with aortal valvular diseases a relation was revealed between the postoperative blood loss and the patient's age, the volume of operative blood loss (reverse correlation), and total dose of protamine sulfate (direct correlation), in patients with mitral valvular diseases the postoperative blood loss was related to the volume of diuresis in the first postoperative day (direct correlation). It is concluded that defective surgical hemostasis is the main cause of intrapleural hemorrhages after correction of acquired valvular diseases of the heart under conditions of hypothermia without perfusion.


Comparison of brief group behavioural parent training with individual parent training for preschool children with attention deficit hyperactivity disorder: A randomized feasibility study.
Behaviour parent training (BPT) is first-line treatment for preschool attention deficit hyperactivity disorder (ADHD). BPT in a group format can be a cost- and time-effective alternative in low and middle-income countries (LMIC) settings with limited resources. We conducted a randomized controlled trial to compare the feasibility and efficacy of group BPT with individual BPT in improving ADHD severity in the preschool age group over 12 weeks. After approval by the ethical committee, the study was conducted in the child guidance clinic, JIPMER. Fifty-six children aged 2.5 to 6 years diagnosed with ADHD according to DSM5 were recruited. Children with autism spectrum disorder and a social quotient less than 50 were excluded. Block randomization parallel design was done. Group interventions were delivered with 4-8 parents per group, focusing on psychoeducation, structuring of routine, attention enhancing tasks, behavioural parenting techniques, and TAU. ADHD severity was assessed using Conner's abbreviated behaviour rating scale at baseline, 4, 8, and 12 weeks. Parental stress was estimated by FISC-MR adapted for ADHD. Statistical analysis included repeated measures ANOVA. Significant improvement was noticed for both groups (F = 20.261, p < .001, ES (η2 ) = 0.539). Group intervention was not inferior to individual BPT in reducing ADHD severity (F = 0.860, p = .468, ES (η2 ) = 0.047). There was a statistically significant difference from baseline to 12 weeks of intervention in the reduction of parental stress (F = 20.80, p < .001, ES (η2 ) = 0.278) and enhancement of the coping strategies (F = 64.4, (p < .001), ES (η2 ) = 0.78). The intervention had high attendance and fidelity rates. Group BPT was promising in treating ADHD in low-resource settings.


Telephone Crisis Support Workers' Intentions to Use Recommended Skills While Experiencing Functional Impairment.
Empathic engagement with distressed others can lead to elevated symptoms of psychological distress and functional impairment, which preclude helping professionals' delivery of optimal patient care. Whether telephone crisis support workers are impacted in a similar way is not currently reported in the literature. This study examined the relationship between functional impairment and intentions to use recommended support skills in a representative national sample of 210 telephone crisis support workers. Participants completed an online survey including measures of functional impairment and intentions to use recommended telephone crisis support skills with callers reporting suicidal ideation, symptoms of depression, and anxiety. As a group, participants who experienced greater functional impairment during the past month reported significantly lower intentions to use recommended support skills with callers than those who reported lower functional impairment. Future research is needed to clarify the extent to which results generalize to telephone crisis support workers from other organizations. Results warrant further research to (a) identify determinants of telephone crisis support workers' functional impairment, and (b) for the deliberate management of telephone crisis support workers' functional impairment through developing and/or modifying existing service strategies to optimize workers' psychological well-being and delivery of support to callers.


Feasibility and Morbidity of Magnetic Resonance Imaging-Guided Stereotactic Laser Ablation of Deep Cerebral Cavernous Malformations: A Report of 4 Cases.
Magnetic resonance imaging (MRI)-guided laser interstitial thermal therapy (MRgLITT) has been used successfully to treat epileptogenic cortical cerebral cavernous malformations (CCM). It is unclear whether MRgLITT would be as feasible or safe for deep CCMs. To describe our experience with MRgLITT for symptomatic deep CCMs. Patients' records were reviewed retrospectively. MRgLITT was carried out using a commercially available system in an interventional MRI suite with efforts to protect adjacent brain structures. Immediate postoperative imaging was used to judge ablation adequacy. Delayed postoperative MRI was used to measure lesion volume changes during follow-up. Four patients with CCM in the thalamus, putamen, midbrain, or subthalamus presented with persistent and disabling neurological symptoms. A total of 2 patients presented with disabling headaches and sensory disturbances and 2 with recurrent symptomatic hemorrhages, of which 1 had familial CCM. Patients were considered by vascular neurosurgeons to be poor candidates for open surgery or had refused it. Multiple trajectories were used in most cases. Adverse events included device malfunction with leakage of saline causing transient mass effect in one patient, and asymptomatic tract hemorrhage in another. One patient suffered an expected mild but persistent exacerbation of baseline deficits. All patients showed improvement from a previously aggressive clinical course with lesion volume decreased by 20% to 73% in follow-up. MRgLITT is feasible in the treatment of symptomatic deep CCM but may carry a high risk of complications without the benefit of definitive resection. We recommend cautious patient selection, low laser power settings, and conservative temperature monitoring in surrounding brain parenchyma.


MXene-based Membranes for Drinking Water Production.
The soaring development of industry exacerbates the shortage of fresh water, making drinking water production an urgent demand. Membrane techniques feature the merits of high efficiency, low energy consumption, and easy operation, deemed as the most potential technology to purify water. Recently, a new type of two-dimensional materials, MXenes as the transition metal carbides or nitrides in the shape of nanosheets, have attracted enormous interest in water purification due to their extraordinary properties such as adjustable hydrophilicity, easy processibility, antifouling resistance, mechanical strength, and light-to-heat transformation capability. In pioneering studies, MXene-based membranes have been evaluated in the past decade for drinking water production including the separation of bacteria, dyes, salts, and heavy metals. This review focuses on the recent advancement of MXene-based membranes for drinking water production. A brief introduction of MXenes is given first, followed by descriptions of their unique properties. Then, the preparation methods of MXene membranes are summarized. The various applications of MXene membranes in water treatment and the corresponding separation mechanisms are discussed in detail. Finally, the challenges and prospects of MXene membranes are presented with the hope to provide insightful guidance on the future design and fabrication of high-performance MXene membranes.


[Quetiapine in the treatment of the Gilles de la Tourette syndrome. A case study].
In this article we describe the clinical response of an 8-year-old boy with the Gilles de la Tourette syndrome (GTS) when treated with quetiapine. Upon admission for observation he received a trial course of quetiapine, to which he responded favourably. We searched the Medline and Psycinfo databases for information about the recommended dose of quetiapine for children with GTS. From the 12 case-studies and one open-label trial that we found, we conclude that the maximum dose of quetiapine for children with GTS is 200 mg. Data concerning the safety of quetiapine when administered to children are limited and contradictory.


Determinants of Quality of Life and the Need for Support for the Elderly with Good Physical and Mental Functioning.
BACKGROUND The ageing of population is the reason that there are various strategies developed to help seniors acquire greater independence and a better quality of life. The aim of this study was to explore the relationship between the elderly peope's need for assistance and assessed quality of life. MATERIAL AND METHODS The study included 100 participants who were members of a Seniors Club in Poznań, Poland. The cross-sectional study utilized the following instruments: Abbreviated Mental Test Score (AMTS), Instrumental Activities of Daily Living (IADL), EASY-Care Standard 2010 questionnaire, (WHO Quality of Life-BREF (WHOQOL-BREF) questionnaire. RESULTS Members of the Seniors' Club showed good functional condition. In the AMTS test, they scored near maximum values (average 9.39±0.77 points), somewhat poorer results were found in the IADL scale (average 20.92±3.96 points). In the EASY-Care questionnaire, the study participants usually required partial support in the following areas: Mental health and well-being (59%), Staying healthy (29%), Getting around (22%), and Seeing, hearing and communicating (22%). The average score on Independence was 13.13±18.51, The risk of breakdown in care scale was 4.39±3.21. The risk of falls affected 21 participants (21%). Quality of life study using WHOQOL-BREF questionnaire found that the highest scores were achieved in Psychological and Environment domains, and the lowest score in the Physical health domain. CONCLUSIONS Quality of life as well as level of independence, risk of falls, and need for 24-hour care were significantly affected by the following factors: urinary incontinence, difficulties in mobility outside the home, despondency, and forgetfulness.


Rheological properties and gelation of aqueous cellulose-NaOH solutions.
The shear rheology of a microcrystalline cellulose dissolved in a 9% NaOH aqueous solution was studied in the steady and oscillatory modes. The cellulose-(9% NaOH-H(2)O) mixtures show not to be true solutions. In the dilute regime, with cellulose concentration below 1%, the rheological behavior is typical of the one of suspensions. The formation of cellulose aggregates is favored when temperature is increased. In the semidilute regime, an irreversible aggregate-based gelation occurs, being faster with increasing temperature.


The effects of three modalities on delayed onset muscle soreness.
Delayed onset muscle soreness is a common problem that can interfere with rehabilitation as well as activities of daily living. The purpose of this study was to test the impact of therapeutic massage, upper body ergometry, or microcurrent electrical stimulation on muscle soreness and force deficits evident following a high-intensity eccentric exercise bout. Forty untrained, volunteer female subjects were randomly assigned to one of three treatment groups or to a control group. Exercise consisted of high-intensity eccentric contractions of the elbow flexors. Resistance was reduced as subjects fatigued, until they reached exhaustion. Soreness rating was determined using a visual analog scale. Force deficits were determined by measures of maximal voluntary isometric contraction at 90 degrees of elbow flexion and peak torque for elbow flexion at 60 degrees/sec on a Cybex II isokinetic dynamometer. Maximal voluntary isometric contraction and peak torque were determined at the 0 hour (before exercise) and again at 24 and 48 hours postexercise. Treatments were applied immediately following exercise and again at 24 hours after exercise. The control group subjects rested following their exercise bout. Statistical analysis showed significant increases in soreness rating and significant decreases in force generated when the 0 hour was compared with 24- and 48-hour measures. Further analysis indicated no statistically significant differences between massage, microcurrent electrical stimulation, upper body ergometry, and control groups.


[Schooling, living conditions and study motivation of students partaking in the traditional or reformed course of instruction at the Charité (Hospital)].
There are two different tracks in undergraduate medical education at the Charité, a traditional (TT) one and a reformed one (RT) which was implemented in 1999. We report a survey reflecting on possible differences between students joining the two tracks. During the winter term 2001/02 a questionnaire was sent to all 223 newly enrolled medical students. Three groups were distinguished: those following either the traditional or the reformed course (TT or RT), or those who followed the TT, although they had applied for it, because there were not enough vacancies in the RT. 150 (63% female; average age: 21.5 years) of 223 first year medical students. Applicants for the RT did not differ significantly from those of the other groups with respect to school-leaving grades, their choice of main courses at school an their motivation to study medicine. But they differed in the demands that they placed on their instruction. The wish for a good practical medical training, advancing their individual potential and the ability to select for themselves any instructional priorities were of greater importance for those choosing the RT than those who preferred the TT. More students of the RT than the TT would again have chosen to study medicine and less often stated that they had considered giving up their medical course. Students have different expectations concerning medical curricula. The possibility to choose between different ways of studying may help to meet different expectations.


Changes in emergency department use in British Columbia, Canada, during the first 3 years of the COVID-19 pandemic.
Previous studies have shown reductions in the volume of emergency department visits early in the COVID-19 pandemic, but few have evaluated the pandemic's impact over time or stratified analyses by reason for visits. We aimed to quantify such changes in British Columbia, Canada, cumulatively and during prominent nadirs, and by reason for visit, age and acuity. We included data from the National Ambulatory Care Reporting System for 30 emergency departments across BC from January 2016 to December 2022. We fitted generalized additive models, accounting for seasonal and annual trends, to the monthly number of visits to estimate changes throughout the pandemic, compared with the expected number of visits in the absence of the pandemic. We determined absolute and relative differences at various times during the study period, and cumulatively since the start of the pandemic until the overall volume of emergency department visits returned to expected levels. Over the first 16 months of the pandemic, the volume of emergency department visits was reduced by about 322 300 visits, or 15% (95% confidence interval 12%-18%), compared with the expected volume. A sharp drop in pediatric visits accounted for nearly one-third of the reduction. The timing of the return to baseline volume of visits differed by subgroup. The largest and most sustained decreases were in respiratory-related emergency department visits, visits among children, visits among oldest adults and non-urgent visits. Later in the pandemic, we observed increased volumes of highest-urgency visits, visits among children and visits related to ear, nose and throat. We have extended evidence that the impact of the COVID-19 pandemic and associated mitigation strategies on emergency department visits in Canada was substantial. Both our findings and methods are relevant in public health surveillance and capacity planning for emergency departments in pandemic and nonpandemic times.


Self-Expanding Valve System for Treatment of Native Aortic Regurgitation by Transcatheter Aortic Valve Implantation (from the STS/ACC TVT Registry).
Transcatheter aortic valve implantation (TAVI) is approved for treatment of symptomatic aortic stenosis in patients at increased risk for surgical valve replacement, but outcomes data in patients with severe native aortic regurgitation (AR) treated with TAVI remain limited. The objective of this analysis was to evaluate outcomes among patients identified in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry who underwent TAVI for native AR with a commercially available self-expanding valve system. From January 2014 to December 2017, 230 patients in the TVT Registry underwent TAVI for primary severe native AR using a commercially available self-expanding valve (n = 81, CoreValve; n = 149, Evolut R). For inclusion, AR was either pure or mixed with predominantly moderate/severe AR and mean aortic valve gradient ≤20 mm Hg. Thirty-day outcomes were evaluated using time-to-event methods. Device success was reported in 81.7% of patients (CoreValve, 72.2%; Evolut R, 86.9%; p = 0.0.01). Thirty-day all-cause mortality was 13.3%. All patients presented with moderate/severe AR at baseline; at 30 days, 9.1% of implanted patients with data continued to have moderate and 1.4% severe AR. There was a significant reduction in residual moderate/severe AR from the CoreValve to Evolut R device (19.1% vs 6.3%, p = 0.02). Multivariable analysis revealed factors associated with 30-day all-cause mortality include number of valves used (hazard ratio [HR] 2.361, 1.643 to 3.391, p <0.001), albumin < 3.3 mg/dL (HR 3.358, 1.551 to 7.273, p=0.002), and left ventricular ejection fraction (HR 0.978, 0.957 to 1.000, p = 0.047). Despite higher 30-day all-cause mortality, self-expanding TAVI may be an option in selected patients with AR who have no surgical options.


Coarse-grained and all-atom modeling of structural states and transitions in hemoglobin.
Hemoglobin (Hb), an oxygen-binding protein composed of four subunits (α1, α2, β1, and β2), is a well-known example of allosteric proteins that are capable of cooperative ligand binding. Despite decades of studies, the structural basis of its cooperativity remains controversial. In this study, we have integrated coarse-grained (CG) modeling, all-atom simulation, and structural data from X-ray crystallography and wide-angle X-ray scattering (WAXS), aiming to probe dynamic properties of the two structural states of Hb (T and R state) and the transitions between them. First, by analyzing the WAXS data of unliganded and liganded Hb, we have found that the structural ensemble of T or R state is dominated by one crystal structure of Hb with small contributions from other crystal structures of Hb. Second, we have used normal mode analysis to identify two distinct quaternary rotations between the α1β1 and α2β2 dimer, which drive the transitions between T and R state. We have also identified the hot-spot residues whose mutations are predicted to greatly change these quaternary motions. Third, we have generated a CG transition pathway between T and R state, which predicts a clear order of quaternary and tertiary changes involving α and β subunits in Hb. Fourth, we have used the accelerated molecular dynamics to perform an all-atom simulation starting from the T state of Hb, and we have observed a transition toward the R state of Hb. Further analysis of crystal structural data and the all-atom simulation trajectory has corroborated the order of quaternary and tertiary changes predicted by CG modeling.


Mutual antagonism of estrogen receptors alpha and beta and their preferred interactions with steroid receptor coactivators in human osteoblastic cell lines.
Estrogen is a major sex steroid that affects the growth, maintenance, and homeostasis of the skeleton. Two isoforms of the estrogen receptor (ERalpha and ERbeta) mediate the transcriptional effects of estrogen. Although both isoforms of ER are present and functional in some human osteoblast (OB) cell lines, there is minimal information on the differential regulation of transcription by ERalpha and ERbeta homo- or heterodimers. This report demonstrates that ERalpha and ERbeta coexpression decreases the transcriptional capacity (relative to each ER isoform alone) on an estrogen response element-dependent reporter gene in OBs but not in other non-osteoblastic cell lines. These data suggest that ERalpha and ERbeta coexpression can differentially influence the degree of transcriptional activation in certain cell types. Interestingly, the overexpression of the steroid hormone receptor coactivator-1 (SRC1) resulted in preferential transcriptional enhancement by ERbeta as well as coexpressed ERalpha and ERbeta, whereas SRC2 overexpression appeared to preferentially enhance ERalpha transactivation. SRC3 overexpression failed to enhance estrogen-dependent transcription of any ER combination in OBs. Similar overexpression experiments in COS7 cells exhibited preferential enhancement of ERalpha function with all SRCs, including SRC3. Our data also demonstrated that SRC3 mRNA is reduced in osteoblastic cells, suggesting that SRC3 may have only a minor role in these cells. These data suggest that the transactivation capacity of various ER isoforms is both SRC species and cell type dependent.


NADPH oxidase activation increases the sensitivity of intracellular Ca2+ stores to inositol 1,4,5-trisphosphate in human endothelial cells.
Many stimuli that activate the vascular NADPH oxidase generate reactive oxygen species and increase intracellular Ca(2+), but whether NADPH oxidase activation directly affects Ca(2+) signaling is unknown. NADPH stimulated the production of superoxide anion and H(2)O(2) in human aortic endothelial cells that was inhibited by the NADPH oxidase inhibitor diphenyleneiodonium and was significantly attenuated in cells transiently expressing a dominant negative allele of the small GTP-binding protein Rac1, which is required for oxidase activity. In permeabilized Mag-indo 1-loaded cells, NADPH and H(2)O(2) each decreased the threshold concentration of inositol 1,4,5-trisphosphate (InsP(3)) required to release intracellularly stored Ca(2+) and shifted the InsP(3)-Ca(2+) release dose-response curve to the left. Concentrations of H(2)O(2) as low as 3 microm increased the sensitivity of intracellular Ca(2+) stores to InsP(3) and decreased the InsP(3) EC(50) from 423.2 +/- 54.9 to 276.9 +/- 14. 4 nm. The effect of NADPH on InsP(3)-stimulated Ca(2+) release was blocked by catalase and by diphenyleneiodonium and was not observed in cells lacking functional Rac1 protein. Thus, NADPH oxidase-derived H(2)O(2) increases the sensitivity of intracellular Ca(2+) stores to InsP(3) in human endothelial cells. Since Ca(2+)-dependent signaling pathways are critical to normal endothelial function, this effect may be of great importance in endothelial signal transduction.


Vitamin E for antipsychotic-induced tardive dyskinesia.
Antipsychotic (neuroleptic) medication is used extensively to treat people with chronic mental illnesses. Its use, however, is associated with adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. Vitamin E has been proposed as a treatment to prevent or decrease TD. The primary objective was to determine the clinical effects of vitamin E in people with schizophrenia or other chronic mental illness who had developed antipsychotic-induced TD.The secondary objectives were:1. to examine whether the effect of vitamin E was maintained as duration of follow-up increased;2. to test the hypothesis that the use of vitamin E is most effective for those with early onset TD (less than five years) SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information. We included reports if they were controlled trials dealing with people with antipsychotic-induced TD and schizophrenia who remained on their antipsychotic medication and had been randomly allocated to either vitamin E or to a placebo, no intervention, or any other intervention. We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assumed that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE. The review now includes 13 poorly reported randomised trials (total 478 people), all participants were adults with chronic psychiatric disorders, mostly schizophrenia, and antipsychotic-induced TD. There was no clear difference between vitamin E and placebo for the outcome of TD: not improved to a clinically important extent (6 RCTs, N = 264, RR 0.95, 95% CI 0.89 to 1.01, low-quality evidence). However, people allocated to placebo may show more deterioration of their symptoms compared with those given vitamin E (5 RCTs, N = 85, RR 0.23, 95% CI 0.07 to 0.76, low-quality evidence). There was no evidence of a difference in the incidence of any adverse effects (9 RCTs, N = 205, RR 1.21, 95% CI 0.35 to 4.15, very low-quality evidence), extrapyramidal adverse effects (1 RCT, N = 104, MD 1.10, 95% CI -1.02 to 3.22, very low-quality evidence), or acceptability of treatment (measured by participants leaving the study early) (medium term, 8 RCTs, N = 232, RR 1.07, 95% CI 0.64 to 1.80, very low-quality evidence). No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, outcomes designated important to patients. There is no trial-based information regarding the effect of vitamin E for those with early onset of TD. Small trials of limited quality suggest that vitamin E may protect against deterioration of TD. There is no evidence that vitamin E improves symptoms of this problematic and disfiguring condition once established. New and better trials are indicated in this under-researched area, and, of the many adjunctive treatments that have been given for TD, vitamin E would be a good choice for further evaluation.


The spatial pattern of aggregation centres in the cellular slime mould.
The spatial pattern of aggregation centres of the slime mould Dictyostelium discoideum was analysed by using nearest-neighbour distributions. Both undisturbed cultures, and cultures that were initiated from cells dissociated from cultures that had already aggregated, formed non-randomly spaced patterns. However, the minimal distance between aggregates in undisturbed cultures was approximately ten times that observed in dissociated cultures. In undisturbed cultures the aggregate size is regulated as a function of cell density (Bonner + Hoffman, 1963): as cell density increases aggregate density decreases and the aggregate size consequently increases. At the same cell density more and smaller aggregates were formed by dissociated cultures than by undisturbed cultures. Nevertheless, the same cell-density-dependent regulation of aggregate density existed in the dissociated cultures. Here a model is developed to account for both the non-random spacing and the cell-density-dependent regulation of aggregate density. In this model, distance-dependent competition occurs between points in a random prepattern to generate patterns very similar to those observed in experiments. The cell-density-dependent regulation of the aggregate density can be explained by assuming that a constant fraction of the cell population has the capacity to initiate centres at the time of pattern determination regardless of the cell density. As the cell density is increased the fraction of potential centres that survive distance-dependent competition decreases and hence the aggregate size increases. These results suggest that distance-dependent competition may be a mechanism that evolved to control aggregate size at high cell densities. Results obtained with this model indicate that the decrease in aggregate size in dissociated cultures is due primarily to an increase in the fraction of the cell population capable of initiating centres. This implies that as morphogenesis progresses a greater fraction of the cell population acquire a capacity which they will not normally express. Although this increase may have a function in later stages of morphogenesis, it may also provide a way to ensure aggregation in small populations of amoebae and at low cell densities.


Crystal imperfections in ice Ih.
In this paper, we present an overview of crystal imperfections in ice Ih. Due to its molecular nature, the fundamental asymmetry of the hydrogen bond, and proton disorder, crystal defects in this condensed form of water reveal a complexity not usually seen in atomic crystalline solids. The discussion is organized in terms of the spatial extent of the defects. We start with zero-dimensional imperfections such as the molecular vacancy and interstitial, Bjerrum, and ionic defects, as well as possible defect complexes that can be formed from them. Subsequently, we turn to the properties of dislocations, which are the one-dimensional disturbances that carry plastic deformation in crystalline solids. Finally, we discuss two-dimensional defects such as stacking faults and grain boundaries and discuss to what extent the latter are similar to other interfaces in ice Ih such as the free surface. We conclude with an outlook at the road ahead, discussing future challenges toward understanding the role of crystal defects in the macroscopic behavior of ice Ih.


Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy.
Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear. We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses. PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I-II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34-0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22-0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14-0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17-0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission. This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.


Myths and truths of growth hormone and testosterone therapy in heart failure.
Heart failure is a chronic clinical syndrome with very poor prognosis. Despite being on optimal medical therapy, many patients still experience debilitating symptoms and poor quality of life. In recent years, there has been a great interest in anabolic hormone replacement therapy - namely, growth hormone and testosterone - as an adjunctive therapy in patients with advanced heart failure. It has been observed that low levels of growth hormone and testosterone have been associated with increased mortality and morbidity in patients with heart failure. Animal studies and clinical trials have shown promising clinical improvement with hormonal supplementation. Growth hormone has been shown to increase ventricular wall mass, decrease wall stress, increase cardiac contractility, and reduce peripheral vascular resistance, all of which might help to enhance cardiac function, resulting in improvement in clinical symptoms. Likewise, testosterone has been shown to improve hemodynamic parameters via reduction in peripheral vascular resistance and increased coronary blood flow through vasodilation, thereby improving functional and symptomatic status. To date, growth hormone and testosterone therapy have shown some positive benefits, albeit with some concerns over adverse effects. However, large randomized controlled trials are still needed to assess the long-term safety and efficacy.


Research Progress on the Pathogenesis of Aortic Aneurysm and Dissection in Metabolism.
Aortic aneurysm and dissection are complicated diseases having both high prevalence and mortality. It is usually diagnosed at advanced stages and posing diagnostic and therapeutic challenges due to the limitations of current detecting methods for aortic dissection used in clinics. Metabonomics demonstrated its great potential capability in the early diagnosis and personalized treatment of several diseases. Emerging evidence suggests that metabolic disorders including amino acid metabolism, glycometabolism, and lipid metabolism disturbance are involved in the pathogenesis of aortic aneurysm and dissection by affecting multiple functional aortic cells. The purpose of this review is to provide new insights into the metabolism alterations and their related regulatory mechanisms with a focus on recent advances and findings and provide a theoretical basis for the diagnosis, prevention, and drug development for aortic aneurysm and dissection.


The effect of a ketamine constant rate infusion on cardiovascular variables in sheep anesthetized at the minimum alveolar concentration of sevoflurane that blunts adrenergic responses.
To evaluate the effect of a constant rate infusion of ketamine on cardiac index (CI) in sheep, as estimated using noninvasive cardiac output (NICO) monitoring by partial carbon dioxide rebreathing, when anesthetized with sevoflurane at the previously determined minimum alveolar concentration that blunts adrenergic responses (MACBAR). 12 healthy Dorset-crossbred adult sheep. Sheep were anesthetized 2 times in a balanced placebo-controlled crossover design. Anesthesia was induced with sevoflurane delivered via a tight-fitting face mask and maintained at MACBAR. Following induction, sheep received either ketamine (1.5 mg/kg IV, followed by a constant rate infusion of 1.5 mg/kg/h) or an equivalent volume of saline (0.9% NaCl) solution (placebo). After an 8-day washout period, each sheep received the alternate treatment. NICO measurements were performed in triplicate 20 minutes after treatment administration and were converted to CI. Blood samples were collected prior to the start of NICO measurements for analysis of ketamine plasma concentrations. The paired t test was used to compare CI values between groups and the ketamine plasma concentrations with those achieved during the previous study. Mean ± SD CI of the ketamine and placebo treatments were 2.69 ± 0.65 and 2.57 ± 0.53 L/min/m2, respectively. No significant difference was found between the 2 treatments. Mean ketamine plasma concentration achieved prior to the NICO measurement was 1.37 ± 0.58 µg/mL, with no significant difference observed between the current and prior study. Ketamine, at the dose administered, did not significantly increase the CI in sheep when determined by partial carbon dioxide rebreathing.