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.     

Peptide neuroanatomy of adjuvant-induced arthritic inflammation in rat

The influence of adjuvant-induced arthritis of the rat on central and peripheral peptide neuroanatomy was investigated by immunohistochemistry. The most striking feature of arthritic rats was the differential intensification of neuronal proenkephalin- and prodynorphin-related staining in dorsal horn. Changes were ipsilateral in monoarthritic and bilateral in polyarthritic rats as compared to controls. Opioid responsive neurons were target of substance P (SP) and calcitonin gene-related peptide (CGRP) fibers. Changes of SP and CGRP predominated in peripheral inflamed tissue and consisted of intensified immunostaining and an apparent sprouting of sensory fibers particularly around venules, in the epidermis and in areas infiltrated by immunocompetent cells. Opioid staining was absent from primary afferents but present in some immune cells of inflamed tissue. Endogenous antinociceptive opioids and pro-nociceptive/pro-inflammatory SP and CGRP may be crucial in the concerted response of the neuroimmune system to chronic inflammatory pain.     

Distribution of Met-enkephalyl-Arg-Gly-Leu in rat larynx: partial coexistence with vasoactive intestinal polypeptide, peptide histidine isoleucine and neuropeptide Y

Using light microscopic (LM) enzyme-immunohistochemistry on deparaffinized adjacent sections Met-enkephalyl-Arg-Gly-Leu (ME-RGL) immunoreactivity was found to partially coexist with immunoreactive neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI) in intrinsic laryngeal neurons of the rat. Further ME-RGL-immunoreactive (ir) fibres were found around glands in the subepithelium, in connective tissue of striated muscle and in the perichondrium, as well as around arterial and venous blood vessels. They frequently contacted mast cells and macrophages. The presence of ME-RGL indicates pro-enkephalin-related origin of this novel laryngeal opioid system. From the specific target relations and close interrelations of fibres staining for opioids with those staining for the other peptides--which are known to be more or less characteristic of the sympathetic (NPY), parasympathetic (VIP, PHI) and sensory (calcitonin gene-related peptide; CGRP) subdivisions of the peripheral nervous system--we deduce that opioid/non-opioid interactions might co-control various laryngeal functions, e.g. glandular secretion, blood flow, immune and inflammatory responses and/or might be of relevance in trophic mechanisms.     

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.