Temperature-controlled power modulation compensates for heterogeneous nanoparticle distributions: a computational optimization analysis for magnetic hyperthermia

Purpose: To study, with computational models, the utility of power modulation to reduce tissue temperature heterogeneity for variable nanoparticle distributions in magnetic nanoparticle hyperthermia.

Methods: Tumour and surrounding tissue were modeled by elliptical two- and three-dimensional computational phantoms having six different nanoparticle distributions. Nanoparticles were modeled as point heat sources having amplitude-dependent loss power. The total number of nanoparticles was fixed, and their spatial distribution and heat output were varied. Heat transfer was computed by solving the Pennes’ bioheat equation using finite element methods (FEM) with temperature-dependent blood perfusion. Local temperature was regulated using a proportional-integral-derivative (PID) controller. Tissue temperature, thermal dose and tissue damage were calculated. The required minimum thermal dose delivered to the tumor was kept constant, and heating power was adjusted for comparison of both the heating methods.

Results: Modulated power heating produced lower and more homogeneous temperature distributions than did constant power heating for all studied nanoparticle distributions. For a concentrated nanoparticle distribution, located off-center within the tumor, the maximum temperatures inside the tumor were 16% lower for modulated power heating when compared to constant power heating. This resulted in less damage to surrounding normal tissue. Modulated power heating reached target thermal doses up to nine-fold more rapidly when compared to constant power heating.

Conclusions: Controlling the temperature at the tumor-healthy tissue boundary by modulating the heating power of magnetic nanoparticles demonstrably compensates for a variable nanoparticle distribution to deliver effective treatment.     

Linkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample

Several prior reports have suggested that chromosomal region 13q32 may harbor a schizophrenia susceptibility gene. In an attempt to replicate this finding, we assessed linkage between chromosome 13 markers and schizophrenia in 166 families, each with two or more affected members. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Studies Program, included 392 sampled affected subjects and 216 affected sib pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizoaffective disorder, depressed. The families had mixed ethnic backgrounds. The majority were northern European-American families (n = 62, 37%), but a substantial proportion were African-American kindreds (n = 60, 36%). Chromosome 13 markers, spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the 13q32 region were genotyped and the data analyzed using semi-parametric affected only linkage analysis. For the combined sample (with race broadly defined and schizophrenia narrowly defined) the maximum LOD score was 1.43 (Z-score of 2.57; P = 0.01) at 79.0 cM between markers D13S1241 (76.3 cM) and D13S159 (79.5 cM). Both ethnic groups showed a peak in this region. The peak is within 3 cM of the peak reported by Brzustowicz et al. [1999: Am J Hum Genet 65:1096-1103].     

In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens

Cytotoxic T lymphocytes (CTL) respond to antigenic peptides presented on MHC class I molecules. On most cells, these peptides are exclusively of endogenous, cytosolic origin. Bone marrow-derived antigen-presenting cells, however, harbor a unique pathway for MHC I presentation of exogenous antigens. This mechanism permits cross-presentation of pathogen-infected cells and the priming of CTL responses against intracellular microbial infections. Here, we report a novel diphtheria toxin-based system that allows the inducible, short-term ablation of dendritic cells (DC) in vivo. We show that in vivo DC are required to cross-prime CTL precursors. Our results thus define a unique in vivo role of DC, i.e., the sensitization of the immune system for cell-associated antigens. DC-depleted mice fail to mount CTL responses to infection with the intracellular bacterium Listeria monocytogenes and the rodent malaria parasite Plasmodium yoelii.     

RTS,S/AS01E malaria vaccine induces IgA responses against CSP and vaccine-unrelated antigens in African children in the phase 3 trial

BackgroundThe evaluation of immune responses to RTS,S/AS01 has traditionally focused on immunoglobulin (Ig) G antibodies that are only moderately associated with protection. The role of other antibody isotypes that could also contribute to vaccine efficacy remains unclear. Here we investigated whether RTS,S/AS01_E elicits antigen-specific serum IgA antibodies to the vaccine and other malaria antigens, and we explored their association with protection.MethodsNinety-five children (age 5–17 months old at first vaccination) from the RTS,S/AS01_E phase 3 clinical trial who received 3 doses of RTS,S/AS01_E or a comparator vaccine were selected for IgA quantification 1 month post primary immunization. Two sites with different malaria transmission intensities (MTI) and clinical malaria cases and controls, were included. Measurements of IgA against different constructs of the circumsporozoite protein (CSP) vaccine antigen and 16 vaccine-unrelated Plasmodium falciparum antigens were performed using a quantitative suspension array assay.ResultsRTS,S vaccination induced a 1.2 to 2-fold increase in levels of serum/plasma IgA antibodies to all CSP constructs, which was not observed upon immunization with a comparator vaccine. The IgA response against 13 out of 16 vaccine-unrelated P. falciparum antigens also increased after vaccination, and levels were higher in recipients of RTS,S than in comparators. IgA levels to malaria antigens before vaccination were more elevated in the high MTI than the low MTI site. No statistically significant association of IgA with protection was found in exploratory analyses.ConclusionsRTS,S/AS01_E induces IgA responses in peripheral blood against CSP vaccine antigens and other P. falciparum vaccine-unrelated antigens, similar to what we previously showed for IgG responses. Collectively, data warrant further investigation of the potential contribution of vaccine-induced IgA responses to efficacy and any possible interplay, either synergistic or antagonistic, with protective IgG, as identifying mediators of protection by RTS,S/AS01_E immunization is necessary for the design of improved second-generation vaccines.Clinical trial registration: ClinicalTrials.gov: NCT008666191.     

The effects of feeding an Asian or Western diet on sperm numbers, sperm quality and serum hormone levels in cynomolgus monkeys (Macaca fascicularis) injected with testosterone enanthate (TE) plus depot medroxyprogesterone acetate (DMPA)

The aim of this study was to elucidate the effects of an Asian diet compared to a Western diet on sperm numbers and quality, and serum hormones in cynomolgus monkeys (Macaca fascicularis) injected with testosterone enanthate (TE) plus depot medroxyprogesterone acetate (DMPA). Thirty male monkeys were divided into three groups of ten animals each. The first group (control) was fed with standard diet 'monkey chow' (9% fat, 13% protein, 78% carbohydrate); the second group was fed an 'asian' diet (15% fat, 15% protein, 70% carbohydrate); the third group was fed a 'Western' diet (35% fat, 25% protein, 40% carbohydrate). These diets were administered from the beginning (adaptation) until the experiment was terminated. Three months after the adaptation period, all groups were injected with 20 mg TE (once per week) and 25 mg DMPA (once every 6 weeks) for 18 weeks, while TE injections were continued for another 6 weeks. There were no differences in sperm numbers and quality, or in hormone levels between the first and second groups. In both of these groups azoospermia was achieved in 100% of animals, while in the third group only 70% achieved azoospermia. In all 3 groups, spermatozoa were once again detectable by week 33. However, by the end of the study at week 39, sperm numbers in the first and second groups reached only severe oligozoospermia (two animals remained azoospermic in the first group) while in the third group, numbers had returned to normozoospermia. The quality of spermatozoa during and after the treatment in the third group was better than in the first and second groups. Hormone concentrations decreased more rapidly in both the first and second groups, compared to the third group, while the recovery period was slower in the first and second groups, compared to the third group. It is concluded that different formula diets result in differential decreases in sperm numbers and quality, and in hormone concentrations in M. fascicularis injected with TE in combination with DMPA. Animals fed with either monkey chow or an Asian diet exhibited more severe and prolonged decreases in these parameters than did animals fed with a Western diet.     

Hepatoprotective effect of Pandanus odoratissimus seed extracts on paracetamol-induced rats

ContextPandanus odoratissimus Linn. (Pandanaceae) seed extract is known to have antioxidant activities. However, the potential hepatoprotective effect is still unclear.ObjectiveTo investigate the hepatoprotection aspect of P. odoratissimus methanol extract towards paracetamol-induced rats.Materials and methodsThirty male Sprague–Dawley rats were randomly divided into six equal groups: one group served as the healthy control and five groups with hepatotoxicity (hepatotoxic control and 4 treatment groups). The oral treatment of paracetamol-induced hepatotoxicity of 3 g/kg using three different concentrations of P. odoratissimus (300, 600 and 900 mg/kg), and silymarin (200 mg/kg) groups were administered once a day for 14 days. Enzyme activities and protein levels in serum were determined in rats at the end of the treatments. The histopathology of rat livers was observed under an electron microscope with 10× magnification.ResultsPandanus odoratissimus significantly decreased the serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT) activities in induced-paracetamol rat serum (p < 0.05). Moreover, P. odoratissimus significantly decreased total bilirubin and direct bilirubin levels (p < 0.05). It significantly blocked the decline of serum albumin and protein levels (p < 0.05). Histopathological changes amplified paracetamol-induced liver damage and the hepatoprotective effect of P. odoratissimus in the liver.Discussion and conclusionsPandanus odoratissimus improved the hepatoprotective effect in a concentration-dependent manner by reducing related hepatic enzyme and protein markers, suggesting as a useful agent in hepatotoxicity treatment, and it can be generalized to a broader study population in different hepatotoxic animal models.     

Malignant melanoma representing with testicular metastasis: a case report and review of the literature

We present the case of a 52-year-old man, with a history of malignant melanoma, who presented with a testicular lump. Radical orchidectomy confirmed a metastatic malignant melanoma. We discuss salient features of this disease in the light of the published literature.     

Alcohol-related acute-on-chronic liver failure—Comparison of various prognostic scores in predicting outcome

Background and Aims

Various prognostic scores are available for predicting outcome in acute-on-chronic liver failure (ACLF). We compared the available prognostic models as predictors of outcome in alcohol-related ACLF patients.

Methods

All consecutive patients with alcohol-related ACLF were included. At admission, prognostic indices-acute physiology and chronic health evaluation score (APACHE II), model for end-stage liver disease (MELD), MELD-Na, Maddrey’s discriminant function (DF), age-bilirubin-INR-creatinine (ABIC), and Chronic Liver Failure Consortium (CLIF-C) ACLF score (CLIF-C ACLF) score were calculated. Receiver operator characteristic (ROC) curves were plotted for all prognostic scores with in-hospital, 90-day, and 1-year mortality as outcome.

Results

Of the 171 patients, 170 were males, and grade 1 ACLF in 20 (11.7%), grade 2 in 52 (30.4%), and grade 3 in 99 (57.9%) patients. One hundred and nineteen (69.6%) died in-hospital. The median (IQR) Maddrey’s score, MELD, MELD-Na, ABIC, APACHE II, and CLIF-C ACLF were 87.8 (66.5–123.0), 33.1 (27.6–40.0), 34.4 (29.5–40.0), 8.5 (7.3–9.6), 15 (12–21), and 51.1 (44.1–56.4), respectively. On multivariate Cox regression analysis, independent predictors of in-hospital outcome were presence of hepatic encephalopathy (early HR, 2.078; 95%CI, 1.173–3.682, p?=?0.012 and advanced, HR, 2.330; 95% CI, 1.270–4.276, p?=?0.006), elevated serum creatinine (HR, 1.140; 95% CI, 1.023–1.270, p?=?0.018), and infection at admission (HR, 1.874; 95% CI, 1.160–23.029, p?=?0.010). On comparison of ROC curves, APACHE II and CLIF-C ACLF AUROC were significantly higher than MELD, MELD-Na, DF, and ABIC (p?<?0.05) for predicting in-hospital, 90-day, and 1-year mortality. The AUROC was highest for APACHE II followed by CLIF-C ACLF (Hanley and McNeil, p?=?0.660).

Conclusions

Alcohol-related ACLF has high in-hospital mortality. Among the available prognostic scores, CLIF-C ACLF and APACHE II perform best.