Ketamine as an Anesthetic for Patients with Acute Brain Injury: A Systematic Review

Neurocritical Care - For years, the use of ketamine as an anesthetic to patients suffering from acute brain injury has been debated because of its possible deleterious effects on the cerebral...     

HLA-A24 and survivin: possibilities in therapeutic vaccination against cancer

Recently, it was described that an HLA-A24 restricted peptide derived from the survivin splice variant survivin-2B can be recognized by CD8(+) cytotoxic T-cells. The identification of an HLA-A24 epitope is critical for survivin-based immunotherapy as HLA-24 is the most frequent HLA allele in Asia. Consequently, this survivin-2B epitope is already a target in a clinical study in patients with advanced or recurrent colorectal cancer expressing survivin. However, the splice variant survivin-2B has been described to be pro-apoptotic, and is only expressed at low levels in most malignant tissues. Furthermore, survivin-2B expression are significantly decreased in later tumor stages and inversely correlated with tumor differentiation and invasion. Consequently, survivin is a more general vaccination candidate than the splice variant survivin-2B. Here, we on the basis of spontaneous immune responses in HLA-A24+ cancer patients describes that a HLA-A24-restricted survivin epitopes does indeed exist. Consequently, this epitope is an attractive target for the ongoing survivin-based peptide immunotherapy against cancer.     

Neural classifier construction using regularization, pruning and test error estimation

In this paper we propose a method for construction of feed-forward neural classifiers based on regularization and adaptive architectures. Using a penalized maximum likelihood scheme, we derive a modified form of the entropic error measure and an algebraic estimate of the test error. In conjunction with optimal brain damage pruning, a test error estimate is used to select the network architecture. The scheme is evaluated on four classification problems.     

Mode of delivery and risk of allergic rhinitis and asthma

BACKGROUND: It has been hypothesized that cesarean section might increase the risk of developing allergic disease by depriving the fetus and newborn of exposure to maternal microflora. Furthermore, it has been suggested that complicated modes of delivery might be associated with an increased risk of asthma. OBJECTIVE: The purpose of this investigation was to study whether cesarean section and other complicated modes of delivery are associated with an increased risk of allergic rhinitis or asthma. METHODS: Information on self-reported allergic rhinitis, asthma ever, current asthma, and occupation was obtained from 9722 singleton women born in Denmark during the period 1973-1977 who participated in a national cohort study during the period 1997-2001. For these women, information was available on mode of delivery (spontaneous delivery, cesarean section, vacuum extraction, or other complicated mode of delivery, such as rotation/traction or use of forceps), gestational age, birth weight, and length at birth from the Danish Medical Birth Register. Information on parity and maternal age was obtained from the Danish Civil Registration System. RESULTS: The odds ratios (ORs) of allergic rhinitis were 1.16 (95% CI, 0.90-1.49) for cesarean section and 1.06 (95% CI, 0.85-1.32) for other complicated modes of delivery in comparison with spontaneous delivery. The corresponding ORs of asthma ever were 1.33 (95% CI, 1.02-1.74) and 1.18 (95% CI, 0.94-1.49) for cesarean section and other complicated modes of delivery, respectively, and the ORs of current asthma were 1.22 (95% CI, 0.87-1.73) and 1.26 (95% CI, 0.94-1.68), respectively, in comparison with spontaneous delivery. CONCLUSIONS: Our findings do not support the hypothesis that cesarean section or other complicated modes of delivery are associated with the development of allergic rhinitis. However, there might be a positive association with development of asthma--in particular, for cesarean section--that was not explained by gestational age, birth weight, ponderal index, smallness for gestational age, parity, maternal age, or occupation.     

Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms

Whereas the stress-inducible heat-shock protein 70 (Hsp70) has gained plenty of attention as a putative target for tumor therapy, little is known about the role of other Hsp70 proteins in cancer. Here we present the first thorough analysis of the expression and function of the cytosolic Hsp70 proteins in human cancer cells and identify Hsp70-2, a protein essential for spermatogenesis, as an important regulator of cancer cell growth. Targeted knock-down of the individual family members by RNA interference revealed that both Hsp70 and Hsp70-2 were required for cancer cell growth, whereas the survival of tumorigenic as well as nontumorigenic cells depended on Hsc70. Cancer cells depleted for Hsp70 and Hsp70-2 displayed strikingly different morphologies (detached and round vs. flat senescent-like), cell cycle distributions (G2/M vs. G1 arrest) and gene expression profiles. Only Hsp70-2 depletion induced the expression of macrophage inhibitory cytokine-1 that was identified as a target of P53 tumor-suppressor protein and a mediator of the G1 arrest and the senescent phenotype. Importantly, concomitant depletion of Hsp70 and Hsp70-2 had a synergistic antiproliferative effect on cancer cells. Thus, highly homologous Hsp70 proteins bring about nonoverlapping functions essential for cell growth and survival.     

Comparison of two urinary antigen tests for establishment of pneumococcal etiology of adult community-acquired pneumonia

The Binax NOW immunochromatographic test (ICT) detecting the pneumococcal C polysaccharide and a serotype-specific latex agglutination (LA) test detecting 23 pneumococcal capsular antigens were evaluated for establishing pneumococcal etiology in community-acquired pneumonia (CAP) by use of nonconcentrated urine. ICT was considered to be strongly positive for result lines at least as intense as the control line and weakly positive for less intense result lines. When 215 adult CAP patients were tested, strong ICT, weak ICT, and LA positivity were found in 28, 24, and 16 patients, respectively; of these patients, 13 (46%), 6 (25%), and 13 (81%), respectively, had pneumococcal bacteremia and 27 (96%), 17 (71%), and 15 (94%), respectively, had Streptococcus pneumoniae isolated from blood, sputum, and/or nasopharynx. Among 108 controls tested, 2 (1.9%) were weakly ICT positive. When weak positivity was considered negative, the sensitivity of ICT decreased from 79% (19 of 24) to 54% (13 of 24), while the specificity increased from 83% (158 of 191) to 92% (176 of 191); no controls were false positive. The sensitivity and specificity of LA were 54% (13 of 24) and 98% (188 of 191), respectively. Eight of nine LA serotypes corresponded to culture serotypes. In conclusion, using nonconcentrated urine and dividing ICT-positive results into strongly and weakly positive results is a suitable way of performing ICT. While weak ICT positivity should be interpreted with caution, strong ICT positivity and LA positivity should be considered supportive of pneumococcal etiology in adult CAP. As such, these assays might have implications for antibiotic use in CAP. LA has promising potential for pneumococcal serotyping, although further evaluation is required.     

The selectivity of isoprinosine, NPT 15392, avridine and cyclophosphamide on multiple immune responses in rats

Multiple concomitant immune responses were assessed in individual rats following treatment with the immunoenhancing drugs, isoprinosine (5 or 50 mg/kg), NPT 15392 (0.1 or 1.0 mg/kg) and avridine (1 or 25 mg/kg), or the immunosuppressant, cyclophosphamide (75 mg/kg). Immune responses assessed in each rat were specific antibody synthesis, delayed-type hypersensitivity (DTH), natural killer cell (NKC) cytotoxicity and production of three immunoregulatory cytokines, interleukin 1 (IL1), interleukin 2 (IL2) and prostaglandin E2 (PGE2). Spleen and thymus weights and numbers of splenocytes and resident peritoneal cells were also recorded. Rats treated with isoprinosine had dose-related, significant increases in spleen weights and DTH reactions. Rats treated with NPT 15392 had significantly enhanced DTH reactions at the 0.1 mg/kg dose. Rats treated with the 25 mg/kg dose of avridine had significantly increased spleen weights, DTH reactions and NKC cytotoxicity. The effect of avridine treatment on DTH reactions and IL1 and IL2 production was inverse to the dose administered, while the NKC response was directly related to the dose. Thymus weights, antibody production and PGE2 synthesis were not significantly altered in rats treated with isoprinosine, NPT 15392 or avridine. Cyclophosphamide-treated rats had significantly reduced spleen and thymus weights, antibody synthesis, DTH reactions, NKC cytotoxicity and IL2 production, but IL1 and PGE2 synthesis were significantly elevated. It can be concluded that isoprinosine, NPT 15392 and avridine act as general immunostimulants in the rat, with avridine having the greatest effect under these experimental conditions. It also appears that these drugs are differentially immunoselective in the rat and this effect is at least partially related to the dose administered. These results could be of significance in the selective therapeutic manipulation of different arms of the immune system. Also, enhanced production of PGE2 following cyclophosphamide treatment may contribute to the immunosuppressive effects of this drug.     

Lifestyle Intervention in Pregnant Women With Obesity Impacts Cord Blood DNA Methylation,Which Associates With Body Composition in the Offspring

Maternal obesity may lead to epigenetic alterations in the offspring and might thereby contribute to disease later in life. We investigated whether a lifestyle intervention in pregnant women with obesity is associated with epigenetic variation in cord blood and body composition in the offspring. Genome-wide DNA methylation was analyzed in cord blood from 208 offspring from the Treatment of Obese Pregnant women (TOP)-study, which includes pregnant women with obesity randomized to lifestyle interventions comprised of physical activity with or without dietary advice versus control subjects (standard of care). DNA methylation was altered at 379 sites, annotated to 370 genes, in cord blood from offspring of mothers following a lifestyle intervention versus control subjects (false discovery rate [FDR] <5%) when using the Houseman reference-free method to correct for cell composition, and three of these sites were significant based on Bonferroni correction. These 370 genes are overrepresented in gene ontology terms, including response to fatty acids and adipose tissue development. Offspring of mothers included in a lifestyle intervention were born with more lean mass compared with control subjects. Methylation at 17 sites, annotated to, for example, DISC1, GBX2, HERC2, and HUWE1, partially mediates the effect of the lifestyle intervention on lean mass in the offspring (FDR <5%). Moreover, 22 methylation sites were associated with offspring BMI z scores during the first 3 years of life (P < 0.05). Overall, lifestyle interventions in pregnant women with obesity are associated with epigenetic changes in offspring, potentially influencing the offspring’s lean mass and early growth.