Clinical efficacy of high dose monotherapy of oral dihydroartemisinin in uncomplicated falciparum malaria in viet nam

The clinical efficacy of the monotherapy involving the administration of a high dose of dihydroartemisinin (DHA 900 mg) for 5 days was compared with that of the combination regimen (DHA 600 mg + mefloquine [MQ] 750 mg) in an open randomized study in 90 patients with uncomplicated falciparum malaria in the southern part of Viet Nam. Patients were randomly treated with the DHA-5 day monotherapy regimen (300, 300, 100, 100, and 100 mg given at 0, 24, 48, 72, and 96 h) or the DHA-MQ combination regimen (300 mg DHA at 0 h, then 300 mg DHA plus 750 mg MQ at 24 h). The end points for comparison were the parasite and fever clearance times (PCT and FCT) and recrudescence rates (by day 28 for DHA-5 days and day 42 for DHA-MQ). Eighty-nine patients completed the trial per protocol, including 45 cases receiving DHA-5 day and 44 receiving DHA-MQ. There was no difference in clinical manifestations, parasitemia density or other laboratory tests between the two patient groups. The PCTs were 35.3 +/- 17.4 h (mean +/- SD; range, 12-96) and 37.8 +/- 19.2 h (range, 12-96), respectively for the DHA-5 day and DHA-MQ regimens (P > 0.05). Twelve patients receiving the DHA-5 day regimen relapsed with falciparum malaria by day 28 (26.7%) and 5 patients receiving the DHA-MQ regimen relapsed by day 42 (11.4%) (P=0.07). Survival analysis showed that the DHA-5 day regimen had a radical cure rate significantly lower than that of the DHA-MQ regimen (P=0.003). The high dose of DHA in the monotherapy regimen did not increase the efficacy of the treatment of patients with uncomplicated Plasmodium falciparum malaria. The DHA combination regimens are suggested to be the better regimens for DHA.     

Modulation of metallothionein isoforms is associated with collagen deposition in proliferating keloid fibroblasts in vitro

Please cite this paper as: Modulation of metallothionein isoforms is associated with collagen deposition in proliferating keloid fibroblasts in vitro. Experimental Dermatology 2010; 19 : 987–993. Abstract: The keloid fibroblast (KF) is known to have higher proliferative capacity than normal dermal fibroblast (NF). Metallothionein (MT), a metal‐binding protein, has been reported to promote cell proliferation. In this study, we evaluated the expression of MT isoforms at the mRNA level in fetal bovine serum (FBS)‐stimulated proliferating KF. Although the morphological appearance of NF and KF was similar when viewed under light, confocal and transmission electron microscopy, there was surprisingly a generally lower expression of MT isoforms in KF when compared with NF and also reduced MT staining in dermal fibroblasts of keloids as opposed to normal skin. Primary cultures of KF grown in 5% FBS or 10% FBS compared to without FBS demonstrated significantly higher proliferative activity and more abundant deposition of collagen. Contrary to expectation, MT‐1A, ‐1F, ‐1G, ‐1X and ‐2A isoforms were significantly down‐regulated in proliferating KF. Moreover, stimulating KF with TGF β1, which is known to promote collagen synthesis and keloid formation, increased expression of Collagen 1A and 3A genes accompanied by reduction in MT‐2A gene expression. Furthermore, down‐regulation of the MT‐2A gene in proliferating KF by siRNA‐mediated silencing enhanced cell proliferation with concomitant up‐regulation of the NF‐κB gene and 10 of 13 other NF‐κB pathway–related genes analysed but no alteration of the Collagen 1 and Collagen 3 gene expression. It would appear that down‐regulation of MT isoforms in proliferating KF, in particular MT‐2A, enhances keloidogenesis with the possible involvement of the NF‐κB signalling pathway.     

The Neural Processes Interlinking Social Isolation,Social Support,and Problem Alcohol Use

BackgroundSubjective feeling of social isolation, as can be measured by perceived burdensomeness (PB), is a major risk factor for alcohol misuse. Heightened PB is associated with elevated stress response and diminished cognitive control, both of which contribute to problem drinking. Here, we sought to identify the neural substrates underlying the relationship between PB and alcohol misuse.MethodsWe employed resting-state functional magnetic resonance imaging data collected from 61 problem drinkers to characterize the functional connectivity of the hypothalamus and ventral striatum (VS) in relation to PB. We specifically examined whether the connectivities of the hypothalamus and VS were differentially influenced by PB to produce contrasting effects on alcohol use. Finally, we evaluated how individual differences in social support modulate the inter-relationships of social isolation, neural connectivity, and the severity of problem drinking.ResultsWhole-brain multiple regressions show a positive relationship between PB and hypothalamic connectivity with the hippocampus and an inverse pattern for VS connectivity with the middle frontal gyrus. Difference in strength between the 2 connectivities predicted the severity of problem drinking, suggesting an imbalance involving elevated hypothalamic and diminished prefrontal cortical modulation in socially isolated problem drinkers. A path analysis further revealed that the lack of social support was associated with a bias toward low prefrontal connectivity, which in turn increased PB and facilitated problem drinking.ConclusionsAltered hypothalamus and VS connectivity may underlie problem drinking induced by social isolation. The current findings also highlight the important role of social support as a potential protective factor against alcohol misuse.     

In vivo augmentation of rat lung natural killer cell activity and inhibition of experimental metastases by double-stranded polynucleotides

The in vivo effect on natural killer cell activity of the compound rln X r(C12 X U)m, a mismatched nontoxic analogue of polyinosinic-polycytidylic acid [rln X rCn], was tested in inbred Wistar AG rats by measuring the natural killer cell activity of lymphocytes freshly isolated from lung capillaries. Lysis was measured in a 4-h chromium release assay using YAC-1 or syngeneic P77 lung tumor cells as target. Treatment of an animal with rln X r(C12 X U)n substantially enhanced natural killer cell activity to an extent comparable to the increase produced by rln X rCn. This boosting of natural killer activity was correlated closely with a decrease in the incidence of experimental pulmonary metastasis. However, the beneficial effect lasted for only a short period after stimulation, due to the transient nature of double stranded polynucleotide enhancement and to the concomitantly rapid extravasation of tumor cells into the lung parenchyma. It is concluded that natural killer cells are important in host defense against circulating tumor cells and can be boosted by nontoxic mismatched double stranded polynucleotides.     

Management options for rectal variceal bleeding in the setting of hepatic encephalopathy

Bleeding related to rectal varices associated with portal hypertension is rare but life‐threatening, and requires prompt treatment. We reviewed the literature for patients with this complex presentation and current recommendations, and commented on a case at our institution of a 68‐year‐old man with Child‐Pugh B alcoholic liver cirrhosis and hepatic encephalopathy who presented with profuse life‐threatening rectal variceal bleeding. Treatment options for rectal varices in patients with hepatic encephalopathy were reviewed and a management algorithm was devised from current knowledge in the literature. We suggest endoscopic management, and if unsuccessful then to proceed to angioembolization and/or balloon‐occluded retrograde transvenous obliteration, which may be used in conjunction with surgical management. The chosen therapeutic option may depend on the clinical condition of the patient, the cause of portal hypertension and clinical expertise or facilities available. Given that transjugular intra‐hepatic portosystemic shunting is contraindicated in patients with hepatic encephalopathy, management of life‐threatening rectal variceal bleeding should be multimodal.     

Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis

Purpose

Grade 3 NENs are aggressive tumours with poor prognosis. PRRT+/? radiosensitising chemotherapy is a potential treatment for disease with high somatostatin receptor (SSTR) expression without spatially discordant FDG-avid disease. We retrospectively evaluated the efficacy of PRRT in G3 NEN.

Methods

Kaplan–Meier estimation was used to determine progression-free survival (PFS) and overall survival (OS) defined from start of PRRT. Subgroup analysis was performed for patients with Ki-67 ≤ 55% and >55%. Anatomical response (RECIST 1.1) and toxicity 3 months after PRRT was determined. Disease control rate (DCR) was defined as complete response (CR), partial response (PR) and stable disease (SD) of those with prior progression.

Results

28 patients (M = 17; age 16–78 years; Ki-67 ≤ 55% = 22) were reviewed. 17 patients had pancreatic, 5 small bowel, 3 large bowel, 2 bronchial and 1 unknown primary disease. 25/28 had significant FDG-avid disease prior to treatment. Most had ¹⁷⁷Lu-DOTA-octreotate (median cumulative activity 24.4 GBq, median 4 cycles). Twenty patients had radiosensitising chemotherapy. 89% were treated for disease progression; 79% after prior chemotherapy. Median follow-up was 29 months. The median PFS was 9 months for all patients. 16 patients died (Ki-67 ≤ 55% = 11; Ki-67 > 55% = 5) with median OS of 19 months. For Ki-67 ≤ 55% (N = 22), the median PFS was 12 months and median OS 46 months. For Ki-67 > 55% (N = 6), the median PFS was 4 months and median OS 7 months. On CT imaging, DCR at 3 months post-PRRT was 74%, 35% (8/23) PR and 39% (9/23) SD. Eleven patients received further PRRT due to recrudescent disease after response. Five patients developed progression of discordant FDG-avid disease and were referred for targeted therapy/chemotherapy. Grade 3 and 4 lymphopenia and thrombocytopenia occurred in five and five patients, respectively. No renal or liver toxicity related to treatment was seen.

Conclusions

PRRT achieves clinically relevant disease control with acceptable toxicity in G3 NENs.

     

Pediatric brain MRI,Part 2: Advanced techniques

Pediatric neuroimaging is a complex and specialized field that uses magnetic resonance (MR) imaging as the workhorse for diagnosis. MR protocols should be tailored to the specific indication and reviewed by the supervising radiologist in real time. Targeted advanced imaging sequences can be added to provide information regarding tissue microstructure, perfusion, metabolism and function. In part 2 of this review, we highlight the utility of advanced imaging techniques for superior evaluation of pediatric neurologic disease. We focus on the following techniques, with clinical examples: phase-contrast imaging, perfusion-weighted imaging, vessel wall imaging, diffusion tensor imaging, task-based functional MRI and MR spectroscopy.     

Effect of endogenous and exogenous interferons on the differentiation of human monocyte cell line U937

The effect of interferons (IFNs) on the differentiation of hematopoietic cells was examined with the human monocyte cell line U937. The differentiation of U937 was induced by hydroxyvitamin D3 and was evaluated through the study of specific markers. The induction of the U937 differentiation was associated with a production of IFN and with a marked increase in (2'5') oligoadenylate synthetase. Addition of anti-IFN-alpha/beta antibodies inhibited the enhancement of (2'5') oligoadenylate synthetase and reduced the inhibitory effect of hydroxyvitamin D3 on cell growth. Nevertheless, neutralization of endogenous IFN excreted during U937 cell maturation did not modify the expression of the differentiation markers examined. Exogenous natural IFN-alpha, IFN-beta, or recombinant (r) IFN-gamma, when added to the culture medium, did not promote a "global" U937 differentiation. Most of the differentiation markers, except for reduction of nitroblue-tetrazolium, were not induced by IFN-alpha or -beta. However, rIFN-gamma was able to induce the appearance of several monocytic membrane markers at an extent comparable or slightly inferior to that elicited by hydroxyvitamin D3. Different effects on the expression of HLA antigens were obtained with these IFNs: IFN-alpha or -beta enhanced mainly class I HLA antigen expression, whereas rIFN-gamma increased selectively the expression of class II HLA DC1 but not HLA DR antigens. In contrast, phytohemagglutinin-leukocyte conditioned medium elicited a marked and selective enhancement of the expression of HLA-DR antigens. This induction of HLA DC1 antigens by rIFN-gamma was not observed in two other leukemic cell lines (HL60 and HEL). The present study shows that IFN-alpha or -beta may participate in the antiproliferative effect occurring during cellular differentiation, while IFN-gamma may be involved in the induction of the expression of specific monocytic markers involved in cellular immunoregulation.