Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans

Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We investigated the ability of human recombinant IL-1Ra to block the effects of low-dose endotoxin. Fourteen healthy male volunteers between 18 and 30 years old were injected intravenously with 3 ng/kg Escherichia coli endotoxin. Concurrent with the injections, nine volunteers received a 3-hour continuous intravenous infusion of IL-1Ra. The other five subjects were given a 3-hour infusion of saline. Volunteers injected with endotoxin experienced a threefold increase in circulating neutrophils over baseline. This neutrophilia was significantly reduced by 48% in subjects administered endotoxin plus IL-1Ra (P = .0253). Ex vivo mitogen-induced peripheral blood mononuclear cell proliferation decreased by greater than 60% at 3 and 6 hours after endotoxin injection (P = .0053). This endotoxin-induced reduction in mitogen response was reversed in subjects coinjected with IL-1Ra (P = .0253). Endotoxin-induced symptoms, fever, and tachycardia were unaffected by IL-1Ra. IL-1 appears to be an important mediator in endotoxemia because some of its hematologic and immunomodulatory effects can be blocked by IL-1Ra.     

Etoposide causes illegitimate V(D)J recombination in human lymphoid leukemic cells

Etoposide is one of the most widely used antineoplastics. Unfortunately, the same treatment schedules associated with impressive efficacy are associated with an increased risk of secondary acute myeloid leukemia (AML), which has prompted its withdrawal from some treatment regimens, thereby potentially compromising efficacy against the original tumor. Because etoposide-associated AML is characterized by site-specific illegitimate DNA recombination, we studied whether etoposide could directly cause site-specific deletions of exons 2 and 3 in the hprt gene. Human lymphoid CCRF-CEM cells were treated with etoposide for 4 hours, and DNA was isolated after subculturing. The deletion of exons 2 and 3 from hprt was assayed by a quantitative polymerase chain reaction (PCR) method. In the absence of etoposide treatment, the frequency of deletions of exons 2 and 3 was very low (5.05 x 10(-8)). After exposure to 10 mumol/ L etoposide, the frequency of the exon 2 + 3 deletion was increased immediately after and at 24 hours after etoposide treatment (65 to 89 x 10(-8)) and increased to higher levels (128 to 173 x 10(-8)) after 2 and 6 days of subculture (P < .001 overall). The frequency of the exon 2 + 3 deletion assessed at 6 days of subculture after 4 hours of 0, 0.25, 1, 2.5, 5, and 10 mumol/L etoposide treatment increased with etoposide concentration, ie, 5.05 x 10(-8), 89.2 x 10(-8), 108 x 10(-8), 142 x 10(-8), 163 x 10(-8), and 173 x 10(-8), respectively (P < .0001). Sequencing of a subset of amplified products confirmed the presence of DNA sequences at the breakpoints consistent with V(D)J recombination. By contrast, exon 2 + 3 deletions after etoposide treatment in the myeloid cell lines KG-1A and K562 showed no evidence of V(D)J recombinase in their genesis. We conclude that etoposide can induce the illegitimate site-specific action of V(D)J recombinase on an unnatural DNA substrate after a single treatment in human lymphoid cells.     

Omega-3 Fatty Acid Intake during Pregnancy and Child Neuropsychological Development: A Multi-Centre Population-Based Birth Cohort Study in Spain

Background: There are few studies that look at the intake of all types of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during the different stages of pregnancy along with a long-term neuropsychological follow-up of the child. This study aims to explore the association between maternal n-3 PUFA intake during two periods of pregnancy and the child’s neuropsychological scores at different ages. Methods: Prospective data were obtained for 2644 pregnant women recruited between 2004 and 2008 in population-based birth cohorts in Spain. Maternal n-3 PUFA intake during the first and third trimester of pregnancy was estimated using validated food frequency questionnaires. Child neuropsychological functions were assessed using Bayley Scales of Infant Development version one (BSID) at 1 year old, the McCarthy Scale of Children’s Abilities (MSCA) at 4 years old, and the Attention Network Test (ANT) at 7 years old. Data were analysed using multivariate linear regression models and adjusted for potential covariates, such as maternal social class, education, cohort location, alcohol consumption, smoking, breastfeeding duration, and energy intake. Results: Compared to participants in the lowest quartile (<1.262 g/day) of n-3 PUFA consumption during the first trimester, those in the highest quartile (>1.657 g/day) had a 2.26 points (95% confidence interval (CI): 0.41, 4.11) higher MSCA general cognitive score, a 2.48 points (95% CI: 0.53, 4.43) higher MSCA verbal score, and a 2.06 points (95% CI: 0.166, 3.95) higher MSCA executive function score, and a 11.52 milliseconds (95% CI: −22.95, −0.09) lower ANT hit reaction time standard error. In the third pregnancy trimester, the associations were weaker. Conclusions: Positive associations between n-3 PUFA intake during early pregnancy and child neuropsychological functions at 4 and 7 years of age were found, and further clinical research is needed to confirm these findings.     

Effect of different doses of iron supplementation during pregnancy on maternal and infant health

Currently, there is no consensus regarding the optimum iron supplementation during pregnancy. The aim of this study is to evaluate the effect of different iron supplementation doses (including no supplementation) during pregnancy on the iron status of the mother and on the health of the neonate. A longitudinal study was conducted involving 358 pregnant women and their newborns. Mothers were classified as non-supplemented, low iron supplemented (<60 mg/day), moderate iron supplemented (between 60 and 100 mg/day) or high iron supplemented (>100 mg/day). General clinical and obstetric histories, haemoglobin (Hb), serum ferritin (SF) and transferrin saturation were evaluated in the first, second, third trimesters, and at partum. SF and Hb decreased less sharply in the iron-supplemented groups compared to the non-supplemented group. The higher the doses of iron supplementation, the lower the percentages of iron depletion at partum (p?<?0.001), iron deficiency anaemia (p?<?0.001) and preterm deliveries (p?=?0.009) as well as a higher birth weight of the newborn. However, the group with high supplementation had a greater percentage (27.6 %) of women at risk of haemoconcentration at partum. Our Mediterranean women began gestation with iron stores close to deficit (SF, 28.1 μg/L; 95 % CI 27.9–28.4). With these iron stores, supplementation with iron at daily doses of between 60 and 100 mg appears to be the most beneficial for the health of mother and child. These findings need to be confirmed in further randomised clinical trials.     

Intriguing issues of EGFR targeting in head and neck cancer

We have read the recent comprehensive review by Cruz et al.[1] regarding the targeting of receptor tyrosine kinases andtheir therapeutic perspectives in head and neck squamous cellcarcinomas (HNSCC). The major focus of this report was epidermalgrowth factor receptor (EGFR) biology and targeting. However,we feel     

Myelin thickenings in val 102/fs null mutation of MPZ gene

Painful sensory neuropathies consist of a wide range of neuropathies that can involve large as well as small nerve fibres. Even if most cases remain of unknown cause, some of them may be associated with an underlying disorder such as diabetes, HIV, infections, amyloidosis, and Sjogren's syndrome. Since in some cases an autoimmune mechanism has been postulated, we investigated a panel of circulating autoantibodies including anti‐gliadin (AGA), anti‐endomysium (EmA), anti‐transglutaminase (tTGA) and anti‐nuclear (ANA) antibodies in the sera of patients with unexplained painful sensory neuropathies in order to identify other potentially treatable disorders. We tested the sera of 10 patients (4M; 6F) previously investigated for other causes of neuropathies, including anti‐nerve, onconeural, anti‐extractable nuclear, anti‐neutrophil cytoplasmic, anti‐thyroglobulin (TgA) and anti‐peroxidase (TPOA) antibodies. We found the presence of AGA positivity in 4 patients (40%), ANA in 7 (70%) and AGA + ANA in 4 (40%), two of whom were negative for celiac disease by gastrointestinal biopsy. None of the patients had EmA positivity. Three (30%) had TgA and TPOA and none had anti‐nerve or onconeural antibodies. Whether the presence of circulating autoantibodies in patients with unexplained painful neuropathy reflects an autoimmune involvement which may be amenable to immune therapy and not only to symptomatic treatment remains to be established.     

Small bowel obstruction due to metastatic lobular carcinoma of the breast

Although breast cancer most frequently metastasizes to the bone, lung, pleura, liver, adrenal glands and brain, it can also affect other organs such as the small bowel and ovaries, especially if the type of cancer is infiltrating and lobular. We present a case of metastases to the small bowel and ovaries from pleomorphic type infiltrating lobular breast carcinoma presenting as intestinal obstruction. Barium transit study revealed a stenosis in the jejunum and another in the terminal ileum at the ileocecal valve area. A flat formation in the area of the ileocecal valve was observed on endoscopy but the results of biopsy were negative, a fairly frequent finding due to the absence of infiltration of the intestinal mucosa. Pathological and immunohistochemical study of the intestinal and ovarian surgical specimens confirmed the diagnosis of metastases from lobular carcinoma of the breast, which was corroborated by breast biopsy.