Certolizumab treatment during late pregnancy in patients with rheumatic diseases: Low drug levels in cord blood but possible risk for maternal infections. A case series of 13 patients

OBJECTIVE Due to reduction of immune-suppressive drugs, patients with rheumatic diseases can experience an increase in disease activity during pregnancy. In such cases, TNF-inhibitors may be prescribed. However, monoclonal antibodies with the Fc moiety are actively transported across the placenta, resulting in therapeutic drug levels in the newborn. As certolizumab (CZP) lacks the Fc moiety, it may bear a lower risk for the child. METHOD We report a case series of thirteen patients (5 with rheumatoid arthritis and 8 with spondyloarthritis) treated with CZP during late pregnancy to control disease activity. RESULT CZP measured in cord blood of eleven infants ranged between undetectable levels and 1μg/mL whereas the median CZP level of maternal plasma was 32.97μg/mL. Three women developed an infection during the third trimester, of whom one had a severe infection and one had an infection that resulted in a pre-term delivery. During the postpartum period, 6 patients remained on CZP while breastfeeding. CZP levels in the breast milk of two breastfeeding patients were undetectable. CONCLUSION The lack of the active transplacental transfer of CZP gives the possibility to treat inflammatory arthritis during late gestation without potential harm to the newborn. However, in pregnant women treated with TNF-inhibitors and prednisone, attention should be given to the increased susceptibility to infections, which might cause prematurity. CZP treatment can be continued while breastfeeding.

An interferon-inducible protein, p202, in cancer gene therapy

Interferons (IFNs) have been shown to exert antiviral, cell growth regulatory, and immunomodulatory effects on target cells. Both type I (α and β) and type II (γ) IFNs regulate cellular activities by specifically inducing the expression or activation of endogenous proteins that perform distinct biological functions. p202 is a 52 kDa nuclear phosphoprotein known to be induced by IFNs. p202 interacts with a variety of cellular transcription and growth regulatory factors and affects their functions. ^ In this report, we showed that the expression of p202 was associated with an anti-proliferative effect on human prostate cancer cells. Cells that expressed p202 showed reduced ability to grow in soft-agar, indicating a loss of transformation phenotype. More importantly, p202 expression reduced the tumorigenicity of human prostate cancer cells. p202-expressing cells exhibit an elevated level of hypophosphorylated form of pRb, and reduced level of cyclin B1 and p55CDC. ^ Our data suggest that p202 is a growth inhibitor gene in prostate cancer cells and its expression may also suppress transformation phenotype and tumorigenicity of prostate cancer cells. ^ In addition to inhibiting in vitro cell growth, suppressing the tumorigenicity of breast cancer cells in vivo, p202 expression could sensitize breast cancer cells to apoptosis induced by TNF-α treatment. One possible mechanism contributing to this sensitization is the inactivation of NF-κB by its interaction with p202. These results provide a scientific basis for a novel therapeutic strategy that combines p202 and TNF-α treatment against breast cancer. ^ It has been reported that NF-κB is constitutively active in human pancreatic cancer cells. Since p202 interacts with NF-κB and inhibits its activity, we examined a potential p202-mediated anti-tumor activity in pancreatic cancer. We used both ectopic and orthotopic xenograft models and demonstrated that p202 expression is associated with multiple anti-tumor activities that include inhibition of tumor growth, reduced tumorigenicity, prolonged survival, and remarkably, suppression of metastasis and angiogenesis. In vitro invasion assay also showed that p202-expressing pancreatic cancer cells are less invasive than those without p202 expression. That observation was supported by the findings that p202-expressing tumors showed reduced expression of angiogenic factors such as IL-8, and VEGF by inhibiting their transcription, and p202-expressing pancreatic cancer cells have reduced level of MAP-2 activity, a secreted protease activity important for metastasis. Together, our results strongly suggest that p202 expression mediates multiple anti-tumor activities against pancreatic cancer, and that may provide a scientific basis for developing a p202-based gene therapy in pancreatic cancer treatment. ^ Importantly, we demonstrated a treatment efficacy by using p202/SN2 liposome complex in a nude mice orthotopic breast cancer, and an ectopic pancreatic cancer xenograft model, through systemic and intra-tumor injection respectively. These results suggest a feasibility of using p202/SN2 liposome in future pre-clinical gene therapy experiments. ^

14-3-3 zeta overexpression in early stage breast disease and tumor progression

Recent progress in diagnostic tools allows many breast cancers to be detected at an early pre-invasive stage. Thus, a better understanding of the molecular basis of early breast cancer progression is essential. 14-3-3 is a family of highly conserved and ubiquitously expressed proteins that are expressed in all eukaryotic organisms. In mammals there are seven isoforms, which bind to phosphor-serine/threonine residues regulating essential cellular processes such as signal transduction, cell cycle progression, and apoptosis. Our laboratory has discovered that a particular 14-3-3 family member, Zeta, is overexpressed in over 40% of breast tumor tissues. Furthermore, I examined the stage of breast disease in which 14-3-3ζ overexpression occurs and found that increased expression of 14-3-3ζ begins at the stage of atypical ductal hyperplasia, a very early stage of breast disease that confers increased risk for progress toward breast cancer. To determine whether 14-3-3ζ overexpression is a decisive early event in breast cancer, I overexpressed 14-3-3ζ in MCF10A cells, a non-transformed mammary epithelial cell (MEC) line and examined its impact on acini formation in a three dimensional (3D) culture model which simulates a basic unit of structure in the mammary gland. I discovered that 14-3-3ζ overexpression severely disrupted the acini architecture resulting in the disruption of polarity and luminal filling. Both are critical morphological events in the pre-neoplastic breast disease. This thesis focuses on the molecular mechanism of luminal filling. Proper lumen formation is a result of anoikis, a specific type apoptosis of cells not attached to the basement membrane. I found that 14-3-3ζ overexpression conferred a resistance to anoikis. Additionally, 14-3-3ζ overexpression in MCF10A cells and in MECs from 14-3-3ζ transgenic mice reduced expression of p53, which is known to mediate anoikis. Mechanistically, 14-3-3ζ induced hyperactivation of the PI3K/Akt pathway which led to phosphorylation and translocation of the MDM2 to the nucleus resulting in increased p53 degradation. Ectopic expression of p53 restored luminal apoptosis in 14-3-3ζ overexpressing MCF10A acini in 3D cultures. These data suggest that 14-3-3ζ overexpression is a critical event in early breast disease and down-regulation of p53 is one of the mechanisms by which 14-3-3ζ alters MEC acini structure and may increase the risk of progression to breast cancer. ^

Effect of parental weight status on the food packed in preschool children's lunches

Problem. Recent statistics show that over a fifth of children aged 2-5 years in 2006-2008 were overweight, with 7% above the 97 th percentile of the BMI-for-age growth charts (extreme obesity). Because poor diet is an important environmental determinant of obesity and the preschool years are crucial developmentally, examination of factors related to diet in the pre-school years is important for obesity prevention efforts. ^ Objective. The goals of this study were to determine the association between BMI of the parents and the number of servings of fruits, vegetables, and whole grains (FVWG) packed; the nutrient content of preschool children’s lunches; and norms and expectations about FVWG intake.^ Methods. This study was a cross sectional analysis of parents enrolled in the Lunch is in the Bag program at baseline. The independent measure was weight status of the parents/caregivers, which was determined using body mass index (BMI) calculated from self-reported height and weight. BMI was classified as healthy weight (BMI <25) or overweight/obese (BMI ≥25). Outcomes for the study included the number of servings of fruits, vegetables and whole grains (FVWG) in sack lunches, as well as the nutrient content of the lunches, and psychosocial constructs related to FVWG consumption. Linear regression analysis was conducted and adjusted for confounders to examine the associations of these outcomes with parental weight status, the main predictor. ^ Results. A total of 132 parent/child dyads were enrolled in the study; 59.09% (n=78) of the parents/caregivers were healthy weight and 39.01% (n=54) of the parents/caregivers were overweight/obese. Parents/caregivers in the study were predominantly white (68%, n=87) and had at least some college education (98%, n=128). No significant associations were found between the weight status of the parents and the servings of fruits, vegetables and whole grain packed in preschool children’s lunchboxes. The results were similar for the association of parental weight status and the nutrient contents of the packed lunches. Both healthy weight and overweight/obese parents packed less than the recommended amounts of vegetables (mean servings = 0.49 and 0.534, respectively) and whole grains (mean servings = 0.58 and 0.511, respectively). However, the intentions of the obese/overweight parents were higher compare to the healthy for vegetables and whole grains.^ Conclusion. Results from this study indicate that there are few differences in the servings of fruits, vegetables and whole grains packed by healthy weight parents/caregivers compared to overweight/obese parents/caregivers in a high income, well-educated population, although neither group met the recommended number of servings of vegetables or whole grains. Thus, results indicate the need for behaviorally-based health promotion programs for parents, regardless of their weight status; however, this study should be replicated with larger and more diverse populations to determine if these results are similar with less homogenous populations.^

BLOOD PRESSURE CHANGES IN RELATION TO DEMOGRAPHIC, ANTHROPOMETRIC, AND SEXUAL MATURATION VARIABLES IN U.S. HEALTH EXAMINATION SURVEY OF CHILDREN AND YOUTHS (UNITED STATES)

The determinants of change in blood pressure during childhood and adolescence were studied in a cohort of U.S. national probability sample of 2146 children examined on two occasions during the Health Examination Survey. Significant negative correlations between the initial level and the subsequent changes in blood pressure were observed. The multiple regression analyses showed that the major determinants of systolic blood pressure (SBP) change were change in weight, baseline SBP, and baseline upper arm girth. Race, time interval between examinations, baseline age, and height change were also significant determinants in SBP change. For the change in diastolic blood pressure (DBP), baseline DBP, baseline weight, and weight change were the major determinants. Baseline SBP, time interval and race were also significant determinants. Sexual maturation variables were also considered in the subgroup analysis for girls. Weight change was the most important predictor of the change in SBP for the group of girls who were still in the pre-menarchal or pre-breast maturation status at the time of the follow-up examination, and who had started to menstruate or to develop breast maturation at sometime between the two examinations. Baseline triceps skinfold thickness or initial SBP were more important variables than weight change for the group of girls who had already experienced menarche or breast maturation at the time of the initial survey. For the total group, pubic hair maturation was found to be a significant predictor of SBP change at the 5% significance level. The importance of weight change and baseline weight for the changes in blood pressure warrants further study. ^

A Pre-Clinical Assessment of Minocycline for Treatment of Chronic Neuropathic Pain after Spinal Cord Injury

Patients living with a spinal cord injury (SCI) often develop chronic neuropathic pain (CNP). Unfortunately, the clinically approved, current standard of treatment, gabapentin, only provides temporary pain relief. This treatment can cause numerous adverse side effects that negatively affect the daily lives of SCI patients. There is a great need for alternative, effective treatments for SCI-dependent CNP. Minocycline, an FDA-approved antibiotic, has been widely prescribed for the treatment of acne for several decades. However, recent studies demonstrate that minocycline has neuroprotective properties in several pre-clinical rodent models of CNS trauma and disease. Pre-clinical studies also show that short-term minocycline treatment can prevent the onset of CNP when delivered during the acute stage of SCI and can also transiently attenuate established CNP when delivered briefly during the chronic stage of SCI. However, the potential to abolish or attenuate CNP via long-term administration of minocycline after SCI is unknown. The purpose of this study was to investigate the potential efficacy and safety of long-term administration of minocycline to abolish or attenuate CNP following SCI. A severe spinal contusion injury was administered on adult, male, Sprague-Dawley rats. At day 29 post-injury, I initiated a three-week treatment regimen of daily administration with minocycline (50 mg/kg), gabapentin (50 mg/kg) or saline. The minocycline treatment group demonstrated a significant reduction in below-level mechanical allodynia and above- level hyperalgesia while on their treatment regimen. After a ten-day washout period of minocycline, the animals continued to demonstrate a significant reduction in below-level mechanical allodynia and above-level hyperalgesia. However, minocycline-treated animals exhibited abnormal weight gain and hepatotoxicity compared to gapabentin-treated or vehicle-treated subjects.The results support previous findings that minocycline can attenuate CNP after SCI and suggested that minocycline can also attenuate CNP via long-term delivery of minocycline after SCI (36). The data also suggested that minocycline had a lasting effect at reducing pain symptoms. However, the adverse side effects of long-term use of minocycline should not be ignored in the rodent model. Gabapentin treatment caused a significant decrease in below-level mechanical allodynia and below-level hyperalgesia during the treatment regimen. Because gabapentin treatment has an analgesic effect at the concentration I administered, the results were expected. However, I also found that gabapentin-treated animals demonstrated a sustained reduction in pain ten days after treatment withdrawal. This result was unexpected because gabapentin has a short half-life of 1.7 hours in rodents and previous studies have demonstrated that pre-drug pain levels return shortly after withdrawal of treatment. Additionally, the gabapentin-treated animals demonstrated a significant and sustained increase in rearing events compared with all other treatment groups which suggested that gabapentin treatment was not only capable of reducing pain long-term but may also significantly improve trunk stability or improve motor function recovery.

Implementation of active surveillance cultures and associated infection control practices for the reduction of methicillin resistant Staphylococcus aureus in the healthcare setting: An interrupted time series analysis

OBJECTIVE. To determine the effectiveness of active surveillance cultures and associated infection control practices on the incidence of methicillin resistant Staphylococcus aureus (MRSA) in the acute care setting. DESIGN. A historical analysis of existing clinical data utilizing an interrupted time series design. ^ SETTING AND PARTICIPANTS. Patients admitted to a 260-bed tertiary care facility in Houston, TX between January 2005 through December 2010. ^ INTERVENTION. Infection control practices, including enhanced barrier precautions, compulsive hand hygiene, disinfection and environmental cleaning, and executive ownership and education, were simultaneously introduced during a 5-month intervention implementation period culminating with the implementation of active surveillance screening. Beginning June 2007, all high risk patients were cultured for MRSA nasal carriage within 48 hours of admission. Segmented Poisson regression was used to test the significance of the difference in incidence of healthcare-associated MRSA during the 29-month pre-intervention period compared to the 43-month post-intervention period. ^ RESULTS. A total of 9,957 of 11,095 high-risk patients (89.7%) were screened for MRSA carriage during the intervention period. Active surveillance cultures identified 1,330 MRSA-positive patients (13.4%) contributing to an admission prevalence of 17.5% in high-risk patients. The mean rate of healthcare-associated MRSA infection and colonization decreased from 1.1 per 1,000 patient-days in the pre-intervention period to 0.36 per 1,000 patient-days in the post-intervention period (P<0.001). The effect of the intervention in association with the percentage of S. aureus isolates susceptible to oxicillin were shown to be statistically significantly associated with the incidence of MRSA infection and colonization (IRR = 0.50, 95% CI = 0.31-0.80 and IRR = 0.004, 95% CI = 0.00003-0.40, respectively). ^ CONCLUSIONS. It can be concluded that aggressively targeting patients at high risk for colonization of MRSA with active surveillance cultures and associated infection control practices as part of a multifaceted, hospital-wide intervention is effective in reducing the incidence of healthcare-associated MRSA.^

Composición corporal y mineral óseo en gimnastas femeninas pre- y peripuberales

La actividad física puede modificar la composición corporal y la mineralización ósea. Se compararon ambas variables en gimnastas femeninas de competición y controles apareados por edad y sexo que realizaban gimnasia recreativa (n = 12 en cada grupo; edades 9 a 14 años). La composición corporal se evaluó por métodos antropométricos y densitometría de rayos X (DXA). El contenido mineral y la densidad mineral óseas se midieron por DXA en cuerpo entero y columna lumbar. La ingesta de calcio se estimó por encuesta.

Microthermometry and Raman analysis of fluid inclusions in different generations of quartz veins of the Athabasca Basin

The Athabasca Basin (Canada) contains the highest grade unconformity-type uranium deposits in the world. Underlying the Athabasca Group sedimentary rocks of the Dufferin Lake zone are variably graphitic pelitic schists (VGPS), altered to chlorite and hematite (Red/Green Zone: RGZ), and locally bleached near the unconformity during paleoweathering and/or later fluid interaction, leading to a loss of graphite near the unconformity. Fluid inclusions were examined in different generations of quartz veins, using microthermometry and Raman analysis, to characterize and compare the different fluids that interacted with the RGZ and the VGPS. In the VGPS, CH4-, N2- and CO2-rich fluids circulated. CH4- and N2-rich fluids could be the result of the breakdown of graphite to CH4/CO2, whereas N2-rich fluid is interpreted to be the result of breakdown of feldspars/micas to NH4+/N2. In the RGZ, highly saline fluids interpreted to be basinally derived have been recorded. The circulation of the two types of fluids (carbonic and brines) occurred at two different distinct events: 1) during the retrograde metamorphism of the basement rocks before the deposition of the Athabasca Basin for the carbonic fluids, and 2) after the deposition of the Athabasca Basin for the brines. Thus, in addition to possibly be related to graphite depletion in the RGZ, the brines can be linked to uranium mineralization.

Neogene and Paleocene-Maestrichtian calcareous nannofossils in sediments of the upper continental rise off New Jersey

Maestrichtian to Holocene calcareous nannofossils from two closely spaced sites on the upper continental rise some 100 miles (161 km) southeast of Atlantic City, New Jersey, were zoned in order to help date a major canyon-cutting event in the late Miocene and to delineate and correlate other hiatuses with seismic stratigraphy. Mid-middle Eocene through middle Miocene sediments (Zones CP14 to CN6) were not recovered in these holes, but nearly all other zones are accounted for. The Eocene section is described in a companion chapter (Applegate and Wise, 1987, doi:10.2973/dsdp.proc.93.118.1987). Nannofossils are generally sparse and moderately preserved in the clastic sediments of Site 604. Sedimentation rates are extremely high for the upper Pleistocene (201 m/m.y. minimum) above a hiatus calculated to span 0.44 to 1.1 Ma. The associated disconformity is correlated with local seismic reflection Horizon Pr . Sedimentation rates continue to be high (93 m/m.y.) down to a second hiatus in the upper Pliocene dated from about 2.4 to 2.9 (or possibly 3.3) Ma. The disconformity associated with this hiatus is correlated with local seismic reflection Horizon P2 and regional Reflector Blue, which can be interpreted to mark either the onset of Northern Hemisphere continental glaciation or circulation changes associated with the closure of the Central American Seaway. Sedimentation rates in the pre-glacial lower Pliocene are only about a third those in the glacial upper Pliocene. A prominent disconformity in the upper Miocene marks a major lithologic boundary that separates Messinian(?) glauconitic claystones above from lower Tortonian conglomeratic debris flows and turbidites below. The debris flows recovered are assigned to nannofossil Zones CN8a and CN7, but drilling difficulties prevented penetration of the bottom of this sequence some 100 m below the terminal depth of the hole. Correlation of the lower bounding seismic reflector (M2/Merlin?) to a drift sequence drilled on the lower rise at DSDP Site 603, however, predicts that the debris flows began close to the beginning of the late Miocene (upper Zone CN6 time) at about 10.5 Ma. The debris flows represent a major canyon-cutting event that we correlate with the beginning of the particularly severe late Miocene glaciations believed to be associated with the formation of the West Antarctic Ice Sheet. The existence of these spectacular debris flows strongly suggest that the late Miocene glacio-eustatic low stand occurred during Vail Cycle TM3.1 (lower Tortonian) rather than during Vail Cycle TM3.2 (Messinian) as originally published. Beneath a set of coalesced regional disconformities centered upon seismic reflection Horizon Au, coccoliths are abundant and in general are moderately preserved at Site 605 in a 619-m carbonate section extending from the middle Eocene Zone CP13b to the upper Maestrichtian Lithraphidites quadratus Zone. Sedimentation rates are 37 m/m.y. in the Eocene down to a condensed interval near the base (Zone CP9). A disconformity is suspected near the Eocene/Paleocene boundary. Sedimentation rates for the upper Paleocene Zone CP8 are similar to those of the Eocene, but Zones CP7 and CP6 lie within another condensed interval. The highest Paleocene rates are 67 m/m.y. down through Zones CP5 and CP4 to a major disconformity that separates the upper Paleocene from the Danian. This hiatus spans about 2.6 m.y. (upper Zone CP3 to lower Zone CP2) and corresponds to the major sea-level drop at the base of Vail Cycle TE2.1. As the most prominent break in this Paleogene section, it may correspond to seismic reflection Horizon A* of the North American Basin. Sedimentation rates from this point to the Cretaceous/Tertiary boundary drop to 11 m/m.y., still high for a Paleocene DSDP section. No major break in deposition could be detected at the Cretaceous/Tertiary boundary.

Neodymium isotopes in benthic foraminifera from the South Atlantic

Records of the past neodymium (Nd) isotope composition of the deep ocean can resolve ambiguities in the interpretation of other tracers. We present the first Nd isotope data for sedimentary benthic foraminifera. Comparison of the epsilon-Nd of core-top foraminifera from a depth transect on the Cape Basin side of the Walvis Ridge to published seawater data, and to the modern dissolved SiO2- epsilon-Nd trend of the deep Atlantic, suggests that benthic foraminifera represent a reliable archive of the deep water Nd isotope composition. Neodymium isotope values of benthic foraminifera from ODP Site 1264A (Angola Basin side of the Walvis Ridge) from the last 8 Ma agree with Fe-Mn oxide coatings from the same samples and are also broadly consistent with existing fish teeth data for the deep South Atlantic, yielding confidence in the preservation of the marine Nd isotope signal in all these archives. The marine origin of the Nd in the coatings is confirmed by their marine Sr isotope values. These important results allow application of the technique to down-core samples. The new epsilon-Nd datasets, along with ancillary Cd/Ca and Nd/Ca ratios from the same foraminiferal samples, are interpreted in the context of debates on the Neogene history of North Atlantic Deep Water (NADW) export to the South Atlantic. In general, the epsilon-Nd and delta13C records are closely correlated over the past 4.5 Ma. The Nd isotope data suggest strong NADW export from 8 to 5 Ma, consistent with one interpretation of published delta13C gradients. Where the epsilon-Nd record differs from the nutrient-based records, changes in the pre-formed delta13C or Cd/Ca of southern-derived deep water might account for the difference. Maximum NADW-export for the entire record is suggested by all proxies at 3.5-4 Ma. Chemical conditions from 3 to 1 Ma are totally different, showing, on average, the lowest NADW export of the record. Modern-day values again imply NADW export that is about as strong as at any stage over the past 8 Ma.

Empirical Evidence Reveals Seasonally Dependent Reduction in Nitrification in Coastal Sediments Subjected to Near Future Ocean Acidification

Research so far has provided little evidence that benthic biogeochemical cycling is affected by ocean acidification under realistic climate change scenarios. We measured nutrient exchange and sediment community oxygen consumption (SCOC) rates to estimate nitrification in natural coastal permeable and fine sandy sediments under pre-phytoplankton bloom and bloom conditions. Ocean acidification, as mimicked in the laboratory by a realistic pH decrease of 0.3, significantly reduced SCOC on average by 60% and benthic nitrification rates on average by 94% in both sediment types in February (pre-bloom period), but not in April (bloom period). No changes in macrofauna functional community (density, structural and functional diversity) were observed between ambient and acidified conditions, suggesting that changes in benthic biogeochemical cycling were predominantly mediated by changes in the activity of the microbial community during the short-term incubations (14 days), rather than by changes in engineering effects of bioturbating and bio-irrigating macrofauna. As benthic nitrification makes up the gross of ocean nitrification, a slowdown of this nitrogen cycling pathway in both permeable and fine sediments in winter, could therefore have global impacts on coupled nitrification-denitrification and hence eventually on pelagic nutrient availability.