A Scoring Procedure for Malignant Narcissism Based on Personality Inventory for DSM-5 Facets.
The current study focuses on the development and validation of a scoring procedure for malignant narcissism using the Personality Inventory for DSM-5, a self-report measure of Criterion B from the Alternative Model for Personality Disorders. In Study 1, a prototype matching approach was used to aggregate ratings from 15 clinicians specializing in personality disorder treatment and/or assessment. Indices of inter-rater agreement and inter-rater reliability revealed high convergence as to the most important maladaptive facets for malignant narcissism. The scoring procedure, based on additive counts for score computation, included eleven Criterion B facets covering core features of malignant narcissism. Study 2 evaluated the criterion and incremental validity of the scoring procedure in a sample of 288 patients from a personality disorder treatment clinic, as well as in a sample of 1103 participants from the community. In both samples, results from nonparametric mean comparisons, receiver operating characteristic curves, bivariate Pearson correlations, and hierarchical multiple linear regressions showed significant associations between malignant narcissism and broader components of personality functioning, as well as with relevant emotional, relational, and/or behavioral features. This new scoring procedure is a simple and valid method for measuring malignant narcissism, and is suitable for clinical and research settings.


Biochemical characterization of membrane cofactor protein of the complement system.
Membrane cofactor protein (MCP; formerly termed glycoprotein 45-70 to indicate its Mr) of complement is a widely distributed iC3/C3b binding protein with co-factor activity. On human mononuclear cells and cell lines and platelets, MCP is a doublet. The two forms differ in Mr by approximately 5 k and the upper species is predominant in most individuals. To further characterize these two forms, limited proteolytic digestions were performed. Of the four peptides produced, three have identical Mr indicating that the molecules are similar proteins. Both forms also have acidic isoelectric points and shift to a less acidic isoelectric point after treatment with neuraminidase. Glycosidase digestions indicate that both species contain N- and O-linked oligosaccharides but that the quantity of sialic acid is greater on the larger one. Pulse-chase experiments demonstrate approximately equal quantities of two precursor forms with Mr of 41 and 43 k. These two precursors possess N-linked high-mannose type of oligosaccharides and chase into the mature molecules which have complex sugars. The smaller precursor chases at a slower rate, possibly accounting for the reduced quantity of the smaller form of the mature form of MCP. These experiments indicate that the two forms of MCP are structurally similar and are derived from two distinct precursors. They also suggest that variations in the rate of processing of two intracellular precursors may account for the different quantities of the mature forms of this membrane protein.


A program to recruit and educate medical students to practice family medicine in underserved areas.
In an attempt to address the problem of physician maldistribution, Jefferson Medical College initiated the Physician Shortage Area Program (PSAP) in 1974, a special admissions program that preferentially selects applicants who intend to practice family medicine in physician shortage areas in Pennsylvania. Forty-seven students in four classes have been graduated from the program. Evaluation of these students during medical school shows that their academic performance has been similar to their classmates. Follow-up evaluation indicates that PSAP graduates are five times as likely as their peers (non-PSAP) to enter a family medicine residency program during the first postgraduate year (62% v 12%), and almost twice as likely to enter family medicine as a comparable group of non-PSAP students who originally entered Jefferson with plans of becoming a family physician (62% v 33%).


Probing polypeptide GalNAc-transferase isoform substrate specificities by in vitro analysis.
N-acetylgalactosaminyltransferase (GalNAc)-type (mucin-type) O-glycosylation is an abundant and highly diverse modification of proteins. This type of O-glycosylation is initiated in the Golgi by a large family of up to 20 homologous polypeptide GalNAc-T isoenzymes that transfer GalNAc to Ser, Thr and possibly Tyr residues. These GalNAc residues are then further elongated by a large set of glycosyltransferases to build a variety of complex O-glycan structures. What determines O-glycan site occupancy is still poorly understood, although it is clear that the substrate specificities of individual isoenzymes and the repertoire of GalNAc-Ts in cells are key parameters. The GalNAc-T isoenzymes are differentially expressed in cells and tissues in principle allowing cells to produce unique O-glycoproteomes dependent on the specific subset of isoforms present. In vitro analysis of acceptor peptide substrate specificities using recombinant expressed GalNAc-Ts has been the method of choice for probing activities of individual isoforms, but these studies have been hampered by biological validation of actual O-glycosylation sites in proteins and number of substrate testable. Here, we present a systematic analysis of the activity of 10 human GalNAc-T isoenzymes with 195 peptide substrates covering known O-glycosylation sites and provide a comprehensive dataset for evaluating isoform-specific contributions to the O-glycoproteome.


Effects of delayed administration of octreotide in acute experimental pancreatitis.
Multiple therapeutic modalities studied for acute pancreatitis often show a poor correlation between results obtained in experimental studies and results of clinical trials. One of the main reasons for this discrepancy is that in most experimental studies the drugs were administered immediately after induction of pancreatitis, whereas in the clinical setting there is almost always a delay between the onset of the disease and initiation of the treatment. We studied the effects of a delayed treatment with octreotide, the synthetic analogue of the hormone somatostatin, on acute experimental pancreatitis in rats. The disease was induced by intraparenchymal injections of 0.5 ml 5% sodium taurocholate, and octreotide (10 mg/kg/day s.c.) was started either 4 or 12 hr later. Subcutaneous saline injections were used in controls. One-half of the animals of each study group was sacrificed after 36 hr, and the following parameters were examined: pancreatic weight, plasma pH, serum calcium and amylase, and histopathological damage. The same parameters, as well as survival, were assessed after 20 days in the remaining rats. Neither intrapancreatic saline injections, nor octreotide administration without the induction of pancreatitis, caused any biochemical or histological alterations. Hypocalcemia and acidosis in pancreatitis-induced rats were improved by octreotide, but, as expected, it had no effect on amylase levels. Octreotide ameliorated pancreatic edema, intestinal dilatation, and the histopathological injury score 36 hr after induction of pancreatitis. Mortality was 40% in control animals, and only 20% in rats treated with octreotide. Overall, octreotide had beneficial effects in acute experimental pancreatitis, and was more effective when started earlier. These results indicate that octreotide may have a role in the management of acute pancreatitis.


The revival of Amaranth as a third-millennium food.
The article deals with the importance and advantages of the amaranth plant - a genus of herbs of the family Amarantaceae. Amaranth, highly nutritional pseudocereal and traditional american crop has good food potential value. Amaranth grain doesn't contain gluten. The high content of quality protein and unsaturated fatty acids is one of its advantages. It is also a carrier of a very valuable fibre and good source of squalene.


[Analysis of the effect of morphine and promedol on uptake and release of noradrenaline by myocardial tissue].
A study was made of the effect of morphine and promedol on the content, uptake, and release of norepinephrine (NE) on rat myocardium. Promedol proved to decrease the NE level in the myocardium. Morphine failed to influence the release of the NE-14C from the isolated perfused heart, whereas promedol increased it significantly, altering both the "slow" and the "rapid" release of the mediator. Promedol failed to influence the uptake of NE-14C by the perfused heart, whereas morphine decreased it significantly. The competition between morphine and NE was characterized by the effect of incomplete inhibition: morphine and NE produced reciprocal effects on the affinity of one another to the receptor, and their interaction depended on the ratio of the concentrations of these drugs.


Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B.
Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment. In a phase II, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks per cohort. Efficacy was assessed by change in baseline HBsAg (log10 IU/ml) at the primary endpoint (Week 24). Safety assessments included adverse events (AE) and laboratory abnormality monitoring. Pharmacodynamic assessments included peripheral cytokine level quantification and interferon-stimulated gene (ISG) mRNA expression evaluation. The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41-80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex. Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed. In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed. Clinical Trial Number: GS-US-283-1059; NCT 02166047.


Falls in German in-patients and residents over 65 years of age.
The aim of the present study was to describe the first fall rates in hospitals and nursing homes throughout Germany. Relationships between age, gender, care dependency, medical disciplines, bed confinement and falls were investigated. Little is known about fall rates in German hospitals and nursing homes. Prevalence studies were conducted in the year 2002 and 2004. Forty hospitals and 15 nursing homes took part in 2002 (3923 patients and 1252 residents older than 65 years) and in 2004 there was a total of 39 hospitals and 29 nursing homes (4451 patients and 2374 residents older than 65 years). Staff nurses used a standardized instrument to collect data about falls in the last two weeks in their institutions and also about other patient problems. Descriptive and inferential statistics were used as well as logistic regression. The first fall rate in 2002 (2004) in the hospitals was 4.7 (4.2) and in the nursing homes 4.5 (5.1) per 1000 patient/resident days. Most of the hospital patients fell on geriatric wards. The high care dependent patients fell more often than the low care dependent patients. In 2002, mobile nursing home residents were at a higher risk of falling than residents confined to bed, but those results could not be confirmed in 2004. Conclusions. Falls of patients over 65 years of age are as much of a problem in German hospitals as they are in German nursing homes. Fall preventive methods should be implemented both in nursing homes and hospitals. Care dependency is a stable risk factor for falls in hospital patients.


Mutations in the Caenorhabditis elegans orthologs of human genes required for mitochondrial tRNA modification cause similar electron transport chain defects but different nuclear responses.
Several oxidative phosphorylation (OXPHOS) diseases are caused by defects in the post-transcriptional modification of mitochondrial tRNAs (mt-tRNAs). Mutations in MTO1 or GTPBP3 impair the modification of the wobble uridine at position 5 of the pyrimidine ring and cause heart failure. Mutations in TRMU affect modification at position 2 and cause liver disease. Presently, the molecular basis of the diseases and why mutations in the different genes lead to such different clinical symptoms is poorly understood. Here we use Caenorhabditis elegans as a model organism to investigate how defects in the TRMU, GTPBP3 and MTO1 orthologues (designated as mttu-1, mtcu-1, and mtcu-2, respectively) exert their effects. We found that whereas the inactivation of each C. elegans gene is associated with a mild OXPHOS dysfunction, mutations in mtcu-1 or mtcu-2 cause changes in the expression of metabolic and mitochondrial stress response genes that are quite different from those caused by mttu-1 mutations. Our data suggest that retrograde signaling promotes defect-specific metabolic reprogramming, which is able to rescue the OXPHOS dysfunction in the single mutants by stimulating the oxidative tricarboxylic acid cycle flux through complex II. This adaptive response, however, appears to be associated with a biological cost since the single mutant worms exhibit thermosensitivity and decreased fertility and, in the case of mttu-1, longer reproductive cycle. Notably, mttu-1 worms also exhibit increased lifespan. We further show that mtcu-1; mttu-1 and mtcu-2; mttu-1 double mutants display severe growth defects and sterility. The animal models presented here support the idea that the pathological states in humans may initially develop not as a direct consequence of a bioenergetic defect, but from the cell's maladaptive response to the hypomodification status of mt-tRNAs. Our work highlights the important association of the defect-specific metabolic rewiring with the pathological phenotype, which must be taken into consideration in exploring specific therapeutic interventions.


Lectin histochemistry of the boar bulbourethral glands.
The present study describes, for the first time, the glycosidic content of boar bulbourethral glands using lectin histochemistry. Fourteen horseradish peroxidase- or digoxigenin-labelled lectins with different carbohydrate specificities were used in samples obtained from 3 healthy Landrace boars. The results obtained indicate that endpiece and duct cells synthesize and secrete mainly O-glycoproteins with alpha- and beta-D-N-acetylgalactosamine, beta-D-galactose-beta(1-->3)-D-N-acetylgalactosamine, D-N-acetylglucosamine and neuraminic acid residues. Glycoproteins secreted by bulbourethral glands have a role in the protection and lubrication of the urethra. In addition, they may be also involved in the regulation of the sperm metabolic activity and in the maintenance of the structural integrity of acrosomal and plasma membranes.


Modelling thrombosis using dissipative particle dynamics method.
Arterial occlusion is a leading cause of cardiovascular disease. The main mechanism causing vessel occlusion is thrombus formation, which may be initiated by the activation of platelets. The focus of this study is on the mechanical aspects of platelet-mediated thrombosis which includes the motion, collision, adhesion and aggregation of activated platelets in the blood. A review of the existing continuum-based models is given. A mechanical model of platelet accumulation onto the vessel wall is developed using the dissipative particle dynamics (DPD) method in which the blood (i.e. colloidal-composed medium) is treated as a group of mesoscale particles interacting through conservative, dissipative, attractive and random forces. Colloidal fluid components (plasma and platelets) are discretized by mesoscopic (micrometre-size) particles that move according to Newton's law. The size of each mesoscopic particle is small enough to allow tracking of each constituent of the colloidal fluid, but significantly larger than the size of atoms such that, in contrast to the molecular dynamics approach, detailed atomic level analysis is not required. To test this model, we simulated the deposition of platelets onto the wall of an expanded tube and compared our computed results with the experimental data of Karino et al. (Miscrovasc. Res. 17, 238-269, 1977). By matching our simulations to the experimental results, the platelet aggregation/adhesion binding force (characterized by an effective spring constant) was determined and found to be within a physiologically reasonable range. Our results suggest that the DPD method offers a promising new approach to the modelling of platelet-mediated thrombosis. The DPD model includes interaction forces between platelets both when they are in the resting state (non-activated) and when they are activated, and therefore it can be extended to the analysis of kinetics of binding and other phenomena relevant to thrombosis.


12p-amplicon structure analysis in testicular germ cell tumors of adolescents and adults by array CGH.
All invasive testicular germ cell tumors of adolescents and adults (TGCTs), that is, seminomas and nonseminomas, show gain of 12p sequences, mostly as isochromosomes. Although several candidate genes have been suggested, the relevant gene(s) have not been identified yet. About 10% of testicular seminomas, however, show a more restricted amplification of the 12p11.2-p12.1 region, in which the various amplicons show an apparent overlap, allowing for the shortest region of amplification overlap approach, aiming at the identification of pathogenetically relevant sequences residing in this region. Here we report on a high-resolution 12p-amplicon architecture analysis using microarray-based comparative genomic hybridization, the results of which were subsequently confirmed by fluorescent in situ hybridization studies. The 12p-specific microarray contained 63 positionally selected BAC clones, which are more or less evenly distributed over the short arm of chromosome 12 (average spacing: less than 500 Kb), including 20 clones within the region of amplification. Out of a series of 17 seminomas, seven seminomas showed amplification of the whole amplicon region, of which three showed a dip in T/R value in the center of the amplified area. A more complex amplification pattern was found in the other 10 seminomas: three showed predominant amplification at the centromeric border; one mainly at the telomeric border; six showed a balanced amplification of both the centromeric and telomeric regions. The only nonseminoma investigated showed a structure in which the centromeric border was only amplified. These data support a mechanistic model in which at least two 12p genes, situated at the border regions of the amplicon, are positional candidates capable of actively supporting tumor progression in TGCTs.


Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity.
Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to a significant reduction in body weight gain due to enhanced EE thereby reducing fat mass. Specifically thermogenesis in brown adipose tissue (BAT) due to elevated UCP1 is enhanced accompanied by extensive browning of white adipose tissue both in mice and humans. Importantly, selective ablation of Y1R from adipocytes protects against diet-induced obesity. Furthermore, peripheral specific Y1R antagonism also improves glucose homeostasis mainly driven by dynamic changes in Akt activity in BAT. Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity.


Living related liver transplantation for hepatitis B-related liver disease without hepatitis B immune globulin prophylaxis.
Hepatitis B immune globulin (HBIG) is routinely used in liver transplantation for hepatitis B virus (HBV)-related liver disease. With potent oral antivirals, HBIG may not be required. We conducted a prospective trial to evaluate living related liver transplantation (LRLT) without HBIG. Eighty-nine patients with HBV-related liver disease underwent LRLT between January 2005 and January 2012. All donors were vaccinated with the HBV vaccine. All patients were given oral antivirals for HBV before transplantation. Patients with HBV DNA levels ≤ 2000 IU/mL were not given HBIG, and patients with HBV DNA levels > 2000 IU/mL were given HBIG. Recurrence was defined as HBV DNA positivity 6 months after transplantation. Seventy-five of the 89 patients who underwent LRLT for HBV-related liver disease were not given HBIG. Nineteen patients received a combination of lamivudine and adefovir, 42 received entecavir, 12 received tenofovir, and 2 received a combination of entecavir and tenofovir. At the last follow-up (median = 21 months, range = 1-83 months), all patients were HBV DNA-negative. Sixty-six patients cleared hepatitis B surface antigen (HBsAg), and 19 patients formed antibody to hepatitis B surface antigen (anti-HBs). The cumulative probabilities of clearing HBsAg were 90% and 92% at 1 and 2 years after transplantation, respectively. Nine patients were HBsAg-positive with undetectable DNA at the last follow-up. The recurrence rate in our series was 8% (6/75). Five of these 6 patients had stopped taking oral antivirals, and 1 had entecavir resistance. All recurrences were salvaged with changes in the oral antivirals. The actuarial probability of survival in this cohort was 73.7% at 83 months. There was no mortality due to HBV recurrence. In conclusion, HBV prophylaxis with oral antivirals and without HBIG is safe and effective in LRLT. A majority of the patients will clear HBsAg, and some will develop anti-HBs antibodies.


Magnification effects on distance estimation during robotic suturing.
We aimed to understand the impact of magnification on distance estimation during robotic suturing. Twenty subjects estimated the lengths of various sutures externally, in plain sight, to validate their ability to measure distances. They then robotically repaired a 3-cm cystotomy, suturing 10 mm above and below the incision and 10 mm on either side of the incision. The bladder was removed and distances measured. A total of 20 surgeons were analyzed: 7 residents, 8 fellows, and 5 staff. Specialties comprised four urologists, eight general gynecologists, two urogynecologists, three gynecologic oncologists, and three reproductive endocrinologists. The mean estimation for external suture length was not significant at 10 mm: mean = 9.6 (±3.2) mm (p = 0.59). When comparing these data sets, the externally visualized 10-mm suture versus the suture-to-suture and the suture-to-incision distances were both significantly different (p = 0.002 and p < 0.001, respectively). The mean distance between each suture was 6.5 (±1.8) mm, which was significantly different from the 10-mm goal (p < 0.001, 95 % confidence interval (CI) [-4.4,-2.6]). The mean distance from the suture to the incision was 4.1 (±1.0) mm, which was also statistically significantly different from the goal (p < 0.001, 95 % CI [-6.3,-5.4]). Surgical experience was negatively associated with suture-to-incision distance (r s = -0.53, p = 0.016). Inter-suture distance was also negatively associated with experience (r s = -0.30, p = 0.22), though not statistically significant. In vivo distances are significantly underestimated during robotic suture placement. Interestingly, the most experienced surgeons had the worst distance estimation from the incision to the suture.


Inhibitory control and visuo-spatial reversibility in Piaget's seminal number conservation task: a high-density ERP study.
The present high-density event-related potential (ERP) study on 13 adults aimed to determine whether number conservation relies on the ability to inhibit the overlearned length-equals-number strategy and then imagine the shortening of the row that was lengthened. Participants performed the number-conservation task and, after the EEG session, the mental imagery task. In the number-conservation task, first two rows with the same number of tokens and the same length were presented on a computer screen (COV condition) and then, the tokens in one of the two rows were spread apart (INT condition). Participants were instructed to determine whether the two rows had an identical number of tokens. In the mental imagery task, two rows with different lengths but the same number of tokens were presented and participants were instructed to imagine the tokens in the longer row aligning with the tokens in the shorter row. In the number-conservation task, we found that the amplitudes of the centro-parietal N2 and fronto-central P3 were higher in the INT than in the COV conditions. In addition, the differences in response times between the two conditions were correlated with the differences in the amplitudes of the fronto-central P3. In light of previous results reported on the number-conservation task in adults, the present results suggest that inhibition might be necessary to succeed the number-conservation task in adults even when the transformation of the length of one of the row is displayed. Finally, we also reported correlations between the speed at which participants could imagine the shortening of one of the row in the mental imagery task, the speed at which participants could determine that the two rows had the same number of tokens after the tokens in one of the row were spread apart and the latency of the late positive parietal component in the number-conservation task. Therefore, performing the number-conservation task might involve mental transformation processes in adults.


Evidence for siroheme-Fe4S4 interaction in spinach ferredoxin-sulfite reductase.
Spinach ferredoxin-sulfite reductase (SiR) contains one siroheme and one Fe4S4 center per polypeptide subunit. The heme is entirely in the high-spin Fe3+ state in the oxidized enzyme. When SiR is photochemically reduced with ethylenediaminetetraacetate (EDTA)-deazaflavin, the free enzyme and its CN- and CO complexes show changes in absorption spectra associated with the heme even after the heme has been reduced from the Fe3+ to the Fe2+ state. With CO- or CN--SiR, these spectral changes are associated with the appearance of a classical "g = 1.94" type of EPR spectrum characteristic of reduced Fe4S4 centers. The line shapes and exact g values of the g = 1.94 EPR spectra vary with the nature of the ligand bound to the heme Fe. Photoreduction of free SiR results in production of a novel type of EPR signal, with g = 2.48, 2.34, and 2.08 in the fully reduced enzyme; this signal accounts for 0.6 spin per heme. (A small g = 1.94 type EPR signal, representing 0.2 spin per heme, is also found.) These data suggest the presence of a strong magnetic interaction between the siroheme and Fe4S4 centers in spinach SiR, this interaction giving rise to different EPR signals depending on the spin state of the heme Fe in the reduced enzyme.


Assessment of need for coordinated approach in families with victims of head injury.
Forty two men with severe head injury, and 41 with minor head injury, together with their families, were assessed at home after the injury. Despite significant impairment with respect to physical symptoms, personality difficulties, and occupational status in severely injured patients after one year, there was a very poor uptake of hospital rehabilitation facilities. In addition, patients' relatives showed significant psychosocial impairment throughout this period. There is a need for a specialist to coordinate rehabilitation services for patients with head injury and their relatives and, in particular, to integrate physical and psychological aspects of management with a multidisciplinary team approach. Although this task will require specialist hospital teams for future development, at present general practitioners have some specialised knowledge that would enable them to coordinate rehabilitation.


Diverse chiral assemblies of nanoparticles directed by achiral block copolymers via nanochannel confinement.
It is a challenging task to realize large-area manufacture of chiral geometries of nanoparticles in solid-state materials, which exhibit strongly chiroptical responses in the visible and near-infrared ranges. Herein, novel nanocomposites, made from mixtures of achiral block copolymers and nanoparticles in a geometrically confined environment, are conceptually proposed to construct the chiral assemblies of nanoparticles through a joint theoretical-calculation framework and experimental discussion. It is found that the nanochannel-confined block copolymers self-assemble into a family of intrinsically chiral architectures, which serve as structural scaffolds to direct the chiral arrangement of nanoparticles. Through calculations of chiral order parameters and simulations of discrete dipole approximation, it is further demonstrated that certain members of this family of nanoparticle assemblies exhibit intense chiroptical activity, which can be tailored by the nanochannel radius and the nanoparticle loading. These findings highlight the multiple levels of structural control over a class of chiral assemblies of nanoparticles and the functionalities of emerging materials via careful design and selection of nanocomposites.


Radiotherapy patterns of practice: T1N0 glottic cancer in Ontario, Canada.
To describe the variation in the delivery of radiation therapy to patients with T1N0 glottic cancer who were diagnosed in Ontario, Canada, between 1982 and 1995. The patient population consisted of a random sample of 461 patients treated with curative intent from the nine cancer centres that administer radiation therapy in the province. Abstracted variables included prescribed dose (Gy) and fractionation (f), beam energy and arrangement, set-up, field size, beam modifiers, positioning and treatment interruptions. Thirteen prescribed dose-fractionation schemes (> or = four cases each) were identified, including 50.0-53.0 Gy/20 f (54.5%), 55.0-61.0 Gy/25 f (30.3%), and 60.0-66.0 Gy/30-33 f (7.7%). All regimens used one fraction per day, 5 days per week. An isocentric set-up was used (94.3%), with megavoltage (MV) beam energies of Cobalt-60 (87.9%), 6 MV (6.1%) and 4 MV (6.1%). A lateral parallel-opposed pair of beams was the predominant technique (76.4%) versus an anterior oblique pair (17.2%) or angle-down pair (caudally directed fields to achieve shoulder clearance, 5.7%). Wedging (96.3%) and bolus (11.8%) were used as beam-modifying devices. Predominant field-width dimensions were 5.0-6.0 cm (43.4%) and 6.5-7.0 cm (43.1%), and field length dimensions were 5.0-6.0 cm (49.5%) and 6.5-7.0 cm (35.0%). Head, neck or chin immobilisation was used in 86.9% of the cases, with 94.6% of these being custom-made. We found that radiotherapy practice was stable over time, except for a trend of increasing field size and increasing use of immobilisation. In contrast, we found practice variations among the province's cancer centres. On the basis of our findings, we defined a predominant technical practice consisting of Cobalt-60 (reflecting machine availability during the period of the study), an isocentric set-up, a lateral parallel-opposed pair technique with wedging, and supine-head neutral positioning with custom immobilisation. Forty-two per cent of the cases had one or more components of treatment that differed from this definition. Description of practice variation can provoke discussion about unrecognised differences in practice policies, perhaps identifying the need for better evidence, treatment guidelines, or both.


Screening for celiac disease in Down's syndrome patients revealed cases of subtotal villous atrophy without typical for celiac disease HLA-DQ and tissue transglutaminase antibodies.
To investigate the prevalence of celiac disease (CD) as well as CD marker antibodies and susceptibility HLA-DQ haplotypes in 134 karyotyped Down's syndrome (DS) patients. Immunoglobulin A (IgA) and G (IgG) type anti-gliadin antibodies (AGA), IgA type anti-tissue transglutaminase (tTG) antibodies (anti-tTG) with antigen of guinea pig and human source were determined by enzyme-linked immunosorbent assay and endomysium antibodies (EMA) by indirect immunofluorescence test. HLA-DQA1*0501/DQB1*0201 (DQ2) was revealed by polymerase chain reaction. Celiac disease was diagnosed by revised ESPGHAN criteria. 41% of DS patients had AGA, 6.0% IgA anti-tTG with guinea pig antigen, and 3.0% IgA EMA (all positive for anti-tTG with human tTG). Subtotal villous atrophy was found in 5 out of 9 DS patients who had agreed to small bowel biopsy. One of them had DQA1*0501/DQB1*0201 and anti-tTG and EMA i.e. typical for CD markers (this case also fulfilled the ESPGHAN diagnostic criteria),but other four lacked these markers. Three non-biopsied DS patients had also most probably CD because DQA1*0501/DQB1*0201 and IgA anti-tTG (EMA) were detected. Thus, the prevalence of CD among our DS patients population is 3.0% (95 % of confidence interval [CI]: 0.1-5.9%). We confirm the increased frequency of CD among DS patients. In addition, we have revealed a subgroup of patients with subtotal villous atrophy but without characteristic for CD immunological and genetic markers. Whether these cases represent CD (with atypical immunopathogenesis) or some other immune enteropathy, requires further investigations.


Enhanced phagocytic activity of HIV-specific antibodies correlates with natural production of immunoglobulins with skewed affinity for FcγR2a and FcγR2b.
While development of an HIV vaccine that can induce neutralizing antibodies remains a priority, decades of research have proven that this is a daunting task. However, accumulating evidence suggests that antibodies with the capacity to harness innate immunity may provide some protection. While significant research has focused on the cytolytic properties of antibodies in acquisition and control, less is known about the role of additional effector functions. In this study, we investigated antibody-dependent phagocytosis of HIV immune complexes, and we observed significant differences in the ability of antibodies from infected subjects to mediate this critical effector function. We observed both quantitative differences in the capacity of antibodies to drive phagocytosis and qualitative differences in their FcγR usage profile. We demonstrate that antibodies from controllers and untreated progressors exhibit increased phagocytic activity, altered Fc domain glycosylation, and skewed interactions with FcγR2a and FcγR2b in both bulk plasma and HIV-specific IgG. While increased phagocytic activity may directly influence immune activation via clearance of inflammatory immune complexes, it is also plausible that Fc receptor usage patterns may regulate the immune response by modulating downstream signals following phagocytosis--driving passive degradation of internalized virus, release of immune modulating cytokines and chemokines, or priming of a more effective adaptive immune response.


Classical Hodgkin lymphoma.
Classical Hodgkin lymphoma is one of the more frequent lymphomas and is generally considered a highly curable disease with standard first-line chemotherapy and radiotherapy in some cases. Despite these outstanding results, major problems remain unresolved. First, there are still patients who will not be cured with front-line regimens and, second, many patients who are cured of classical Hodgkin lymphoma continue to die prematurely due to the late toxic effects of their therapy. Because the median age of patients with classical Hodgkin lymphoma is in the mid-30s, the disease's impact on the number of years lost from productive life is remarkable. In recent years, the gold standard of chemotherapy (often combined with radiotherapy) has changed, with the approval of immunotherapy mostly in relapse settings.


The AI-discovered aetiology of COVID-19 and rationale of the irinotecan+ etoposide combination therapy for critically ill COVID-19 patients.
We present the AI-discovered aetiology of COVID-19, based on a precise disease model of COVID-19 built under five weeks that best matches the epidemiological characteristics, transmission dynamics, clinical features, and biological properties of COVID-19 and consistently explains the rapidly expanding COVID-19 literature. We present that SARS-CoV-2 implements a unique unbiased survival strategy of balancing viral replication with viral spread by increasing its dependence on (i) ACE2-expressing cells for viral entry and spread, (ii) PI3K signaling in ACE2-expressing cells for viral replication and egress, and (iii) viral- non-structural-and-accessory-protein-dependent immunomodulation to balance viral spread and viral replication. We further propose the combination of irinotecan (an in-market topoisomerase I inhibitor) and etoposide (an in-market topoisomerase II inhibitor) could potentially be an exceptionally effective treatment to protect critically ill patients from death caused by COVID-19-specific cytokine storms triggered by sepsis, ARDS, and other fatal comorbidities.


Use of the internal mammary artery graft in Northern New England. Northern New England Cardiovascular Disease Study Group.
There is evidence that patients who receive an internal mammary artery graft (IMA) during coronary artery bypass surgery have increased long-term survival. However, an IMA is not used in all patients. We studied the use of IMA grafts among 7944 patients undergoing initial, isolated coronary artery bypass surgery in Maine, New Hampshire, and Vermont from 1992 to 1995. Overall, the IMA graft was used in 82% of patients; of these, 97.2% had left IMA grafts. The use of the IMA graft varied considerably by patient and disease factors. Women received an IMA graft significantly less often (76% versus 85% in men, P<.01). Older patients (> or =75 years) were less likely to receive an IMA graft (67% versus 86%, P<.001). Smaller BSA was also associated with lower rates of IMA grafts in both sexes; however, men and women with BSA <1.8 m2 received an IMA graft at about the same rate. In general, more sick and more urgent patients had lower rates of IMA use. Patients with left ventricular ejection fraction <40% received an IMA less often than those with an ejection fraction > or =60% (77% versus 85%, P<.01). Patients with a greater number of diseased coronary vessels received an IMA more often (one, 78%; two, 82%; three, 85%). IMA use varied significantly by priority of surgery, with elective patients receiving an IMA 88% of the time, urgent 83%, and emergent 51% (Ptrend<.01). The use of the IMA graft varied from 42% to 95% among individual surgeons. Surgeons were consistent in their patterns of IMA graft use for specific risk groups. All surgeons had lower rates of IMA use among older patients, lower rates of IMA among women, and lower rates of IMA use among emergent or urgent patients. However, "low-use" surgeons had consistently lower rates of use within these patient groups. The overall rate of IMA graft use increased from 76% in 1992 to 86% in 1995 (Ptrend<.001). IMA graft use increased in all five centers and in all patient subgroups. The largest increases in use were seen among women (from 69% to 83%), among patients older than 75 years (from 55% to 75%), and in emergent patients (from 40% to 72%). This regional prospective study of IMA graft use in initial coronary artery bypass surgery describes substantial variability in patient groups receiving an IMA as well as increasing IMA graft use over time. It also suggests that the practice patterns of surgeons are an important determinant of IMA use. These data indicate that even more patients could benefit from the use of this technique.


The effects of maternal deprivation on the hippocampal structure in adult rats.
To examine the ultrastructural effects of maternal deprivation during developmental periods of limbic-hypothalamo-pituitary-adrenal system on hippocampal dendritic structures in adult rats. The experiments were carried out with male and female Wistar rats in our department. The rats were mated and, after birth, the pups were divided into four groups. The first group (control group) pups remained undisturbed with their dam until postweaning day 22. Maternal deprived groups were separated from their dams for 24 hours at postnatal day 4, 9 and 18. The subjects were provided with food and water ad libitum until 3-months-of-age. At the third month, the rats were transcardially perfused, samples were taken from CA1 and CA3 regions of the hippocampus. Tissues were prepared for electron microscopy. When the data were analyzed, there were no differences between male and female rats in both ultrastructure and semiquantitative analysis of axodendritic synapses. The ultrastructure of Group 1 was seen as normal while in the second Group some neurons nuclear envelope made deep invagination into the nucleus. Additionally, axodendritic synapses were found normal. In Group 3, micrographs and axodendritic synapses were showed normal structure. However, in Group 4 in some neurons invaginations were seen similar to Group 2. Axodendritic synapses were found to be normal. These experiments establish that MD in rats produces slight ultrastructural changes and decreases the number of synapses in CA1 and CA3 subregions of the hippocampus.


Discoid lupus erythematosus as part of a larger disease spectrum. Correlation of clinical features with laboratory findings in lupus erythematosus.
This study compares the immunologic features of a homogeneous group of patients with discoid lupus erythematosus (DLE) strictly limited to the skin (group 1) with those of patients with active discoid skin lesions plus visceral involvement (group 2) and with those of lupus erythematosus (LE) patients with proliferative glomerulonephritis (group 3). Positive antinuclear antibody (ANA) was found in 4% of group 1, 93% of group 2, and 100% of group 3. Low total hemolytic complement (CH50) was found in 4% of group 1, 47% of group 2, and 100% of group 3. Antibodies to native DNA (nDNA) were not found in group 1, were rarely found in group 2, and were present in nearly all patients in group 3. No group 1 patient had subepidermal immunoglobulin deposits in normal skin, 20% of group 2 had this finding, and 100% of group 3 had this finding. The ability to develop chronic discoid skin lesions appears to be associated with a reduced incidence of immunologic parameters of disease activity. The data suggest that patients with active discoid skin lesions rarely have severe renal disease.


[Autoantibodies to light myosin chains as an early marker of damage to the myocardium].
The concentration of autoantibodies to myosin light chains in the blood serum of patients who have undergone operation on heart under conditions of artificial hypothermal circulation was measured after 3, 6, 9, 18, 24, 36 h following the reperfusion of myocardium. According to the postoperative data, the patients were divided into three groups: patients with stable hemodynamics in the postoperative period (group 1); patients with myocardial stunning following reperfusion of myocardium (group 2); and patients with severe heart failure that developed in early postoperative period (group 3). Significant differences in the concentration of autoantibodies to myosin light chains have been found between the groups. A high correlation was established between the duration of cross-clamping of aorta and the concentration of autoantibodies. By means of multivariant regression analysis, factors characterizing the initial severity of disease that can influence the concentration of autoantibodies to myosin light chains in blood have been revealed.