Femoral Head Growth Plate Dysplasia and Fracture in Juvenile Rabbits Induced by Off-target Antiangiogenic Treatment.

Epiphyseal growth plate dysplasia (chondrodysplasia) might be considered as the pathognomonic feature of antiangiogenic treatment in preclinical species as it is reliably and dose-responsively induced in rodents and monkeys with vascular endothelial growth factor receptor (VEGFR) inhibitors, fibroblast growth factor (FGF) receptor inhibitors, matrix metalloproteinase inhibitors, and vascular targeting agents. Here we report epiphyseal growth plate dysplasia in juvenile rabbits treated with an oral spleen tyrosine kinase inhibitor induced by off-target antiangiogenic inhibition of VEGF and FGF family kinase receptors. Epiphyseal growth plate dysplasia resulted in weakening and fracturing of the femoral head physis in 6 of 10 male and 1 of 10 female animals as well as microfracturing and dysplasia of the distal femoral articular cartilage in 1 male animal. Fracture lines ran through the zone of hypertrophic cartilage (as well as adjacent zones), were orientated parallel to the physeal plane, and often involved displacement of the femoral head. We would suggest that the high prevalence of growth plate fracture in the rabbit may represent a potential additional adverse risk to those already established for children treated with antiangiogenic therapy.

Effect of combined exogenous progesterone with luteotrophic support via equine chorionic gonadotrophin (eCG) on corpus luteum development, circulating progesterone concentrations and embryo development in cattle.

The aim was to examine the effect of a single intramuscular (i.m.) injection of equine chorionic gonadotrophin (eCG) on Day 3 after oestrus on corpus luteum (CL) development, circulating progesterone and conceptus development in cross-bred beef heifers. In Experiment 1, heifers received: (1) saline, or a single i.m. injection of eCG on Day 3 at (2) 250IU (3) 500IU (4) 750IU or (5) 1000IU. Administration of eCG resulted in increased luteal tissue area and progesterone and oestradiol concentrations compared with controls. In Experiment 2, heifers received (1) a progesterone-releasing intravaginal device (PRID Delta) from Day 3 to 5 or (2) a PRID Delta from Day 3 to 5 plus a single injection of 750IU eCG on Day 3. In vitro-produced blastocysts (n=10 per recipient) were transferred on Day 7 and heifers were slaughtered on Day 14 to assess conceptus development. Administration of eCG reduced the number of short cycles (6.3% vs 31.3%) and increased mean luteal tissue weight (P=0.02). Insertion of a PRID Delta on Day 3 resulted in an elevation (P<0.05) in serum progesterone until removal on Day 5. Administration of eCG at the time of PRID Delta insertion resulted in higher progesterone levels (P<0.05) from Day 10 onwards. Conceptus dimensions were not affected. In conclusion, a single injection of eCG on Day 3 increased CL size and progesterone concentrations and, when given in conjunction with a progesterone-releasing device, appeared to reduce the number of short cycles, presumably due to its luteotrophic nature. The implications of the elevated oestradiol concentrations for embryo quality require further study.

Key Factors Affecting Reproductive Success of Thoroughbred Mares and Stallions on a Commercial Stud Farm.

To evaluate factors contributing to fertility of thoroughbred mares, data from 3743 oestrous periods of 2385 mares were collected on a large thoroughbred farm in Ireland. Fourteen stallions (mean age 8.3 years; range 4-15 years) had bred 2385 mares (mean age 9.4 years; range 3-24 years). Maiden mares accounted for 12%, mares with a foal at foot for 64%, and barren, slipped or rested mares for 24% of the total. The mean pregnancy rate per cycle was 67.8% (68.6% in year 1 and 66.9% in year 2). Backward stepwise multivariable logistic regression analysis was utilized to develop two models to evaluate mare factors, including mare age, reproductive status, month of foaling, dystocia, month of cover, foal heat, cycle number, treatments, walk-in status and stallion factors including stallion identity, stallion age, shuttle status, time elapsed between covers and high stallion usage on the per cycle pregnancy rate and pregnancy loss. Old age (p < 0.001) and cover within 20 days post-partum (p < 0.003) were associated with lowered pregnancy rates. High mare age (p < 0.05) and barren, slipped or rested reproductive status (p = 0.05) increased the likelihood of pregnancy loss. Uterine inflammation or infection, if appropriately treated, did not affect fertility. Only high usage of stallions (used more than 21 times in previous week) was associated with lowered (p = 0.009) pregnancy rates. However, shuttle stallions were more likely to have increased (p = 0.035) pregnancy survival, perhaps reflecting a bias in stallion selection. In conclusion, mare age exerted the greatest influence on fertility; nonetheless, thoroughbreds can be effectively managed to achieve high reproductive performance in a commercial setting.

The relationship between activity clusters detected by an automatic activity monitor and endocrine changes during the periestrous period in lactating dairy cows.

The aim of this study was to determine the relationship between observed estrous-related behavior, activity clusters (AC; detected by automatic activity monitor), endocrine profiles, and ovulation time. Twenty-one cows in estrus (after 2 cloprostenol treatments, 11 d apart) and 12 nonsynchronized cows, to establish Heatime (SCR Engineers Ltd., Netanya, Israel) herd baseline activity, were enrolled. Cows had Heatime monitors applied 3 wk before the trial to establish their own baseline activity level. Cows in standing estrus had ultrasonography and phlebotomy carried out every 4 h to determine dominant follicle size, endocrine profiles, and ovulation time. After ovulation, these procedures were repeated once on d 3 to 6. Heatime alerted estrus in 90% of cows, and incorrectly alerted 17% of AC. The mean±SEM duration for standing estrus was 9±1 and 13±1 h for estrous-related behavior. Estrous-related behavior began after the start of the proestrous estradiol-17ß (E2) increase (59±6.5 h). Cows with longer durations of raised proestrous E2 had longer intervals from its onset to the start of standing estrus and AC. The AC duration increased with longer durations of estrous-related behavior. Higher peak E2 occurred with longer standing estrus and estrous-related behavior. As E2 concentration decreased after the peak, 90% of cows still had estrous-related behavior. Duration of estrous-related behavior increased with higher average E2 concentration during the last 8 h before the start of the LH surge. During this surge 90% of cows had all of their standing estrus. As yields increased, so did the magnitude of the preovulatory FSH surges. Higher surges occurred with shorter standing estrus and estrous-related behavior. Cows with shorter LH surges had longer standing estrus. Peak LH preceded the AC peak (6.6±0.8 h). Duration of overlap between the AC start and the LH surge end ranged between 0 and 14 h; 1 cow had none. No association was found between the AC characteristics with the E2, LH, or FSH profiles. In conclusion, the relationship between the timing of the E2 increase and estrous activity may be mediated by other factors (GnRH surge). Estrous-related behavior, but not endocrine profiles, was related to AC duration. Timing of standing estrus during the LH surge ensures that mating allows sperm maturation before ovulation. Based on the interval from the start of an AC to ovulation (27±1 h), the optimum time to artificial insemination is, on average, between 9 and 15 h after the AC start.

Primary bladder exstrophy closure in neonates: challenging the traditions.

PURPOSE: We describe a novel approach to neonatal bladder exstrophy closure that challenges the role of postoperative immobilization and pelvic osteotomy. MATERIALS AND METHODS: We reviewed the primary management of bladder exstrophy at our institutions between 2007 and 2011. In particular we compared postoperative management in the surgical ward using epidural analgesia to muscle paralysis and ventilation in the intensive care unit. Clinical outcome measures were time to full feed, length of stay, postoperative complications and redo closure. Cost-effectiveness was also evaluated using hospital financial data. Data are expressed as median (range). Significance was explored by Fisher exact test and unpaired t-test. RESULTS: A total of 74 patients underwent primary closure without osteotomy. Successful closure was achieved in 70 patients (95%). A total of 48 cases (65%) were managed on the ward (group A) and 26 (35%) were transferred to the intensive care unit (group B). The 2 groups were homogeneous for gestational age (median 39 weeks, range 27 to 41) and age at closure (3 days, 1 to 152). Complications requiring surgical treatment were noted in 4 patients (8.3%) in group A and 3 (11.5%) in group B (p = 0.609). Length of stay was significantly shorter for the group managed on the ward (11 vs 18 days, p <0.0001). Median costs were $42,732 for patients admitted to the intensive care unit and $16,214 for those admitted directly to the surgical ward (p <0.0001). CONCLUSIONS: Primary closure of bladder exstrophy without lower limb immobilization and osteotomy is feasible. Postoperative care on the surgical ward using epidural analgesia results in shorter hospitalization.

Effect of hCG administration during corpus luteum establishment on subsequent corpus luteum development and circulating progesterone concentrations in beef heifers.

This study examined the effect of a single administration of human chorionic gonadotrophin (hCG) on Day 1 to 4 after oestrus on corpus luteum (CL) development and circulating progesterone (P4). Oestrus-synchronized heifers (n=43) were administered a single intramuscular injection of saline on Day 1 (control) or 3000IU hCG on Day 1, 2, 3 or 4 after oestrus. Administration of hCG on Day 1 had no effect on CL area, on Day 2 increased CL area from Day 6 to 12 (P<0.05), on Day 3 increased CL area from Day 9 to 11, while on Day 4 increased CL size on Days 9 and 10 (P<0.05). Administration of hCG on Day 4 induced the formation of an accessory CL in 89% of heifers, resulting in a significant increase in total luteal tissue area on the ovaries compared with all other groups. Consistent with the effects on the CL, hCG on Day 1 did not affect P4 concentrations, on Day 2 significantly increased P4 compared with the control from Day 6 to 11 (P<0.05), on Day 3 resulted in a non-significant increase in P4 while hCG on Day 4 increased P4 from Day 8 to 13 compared with the control (P<0.05). In conclusion, administration of hCG as early as Day 2 after oestrus results in increased P4 in circulation from Day 6, which should have beneficial downstream effects in terms of uterine receptivity and conceptus elongation.

Added value of abdominal cross-sectional imaging (CT or MRI) in staging of Wilms' tumours.

AIM: To assess the added information gained from computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen over abdominal ultrasound in children undergoing staging of Wilms' tumours. MATERIALS AND METHOD: Fifty-two consecutive patients with histologically proven Wilms' tumours were identified. Each had an initial staging abdominal ultrasound followed by either a CT or MRI examination of the abdomen. Details including tumour size, site, and characteristics, presence of lymph nodes, local invasion, evidence of nephroblastomatosis, and any other relevant finding were gathered from the report of each ultrasound and CT or MRI. Each CT/MRI was then re-reviewed by a consultant paediatric radiologist and a paediatric radiology fellow. The difference in findings between the ultrasound and cross-sectional imaging were noted. RESULTS: Twelve patients were excluded from the study because the CT/MRI was performed before the ultrasound, or imaging was incomplete. Twenty-six patients were female, 14 male. The ages ranged from 9 months to 10.8 years (mean 3.75 years). Twenty-one patients out of the remaining 40 had additional findings detected on the CT or MRI examination that had not been reported on the ultrasound. The most important additional findings included three patients with nephroblastomatosis and two with contralateral tumours. Other findings included two patients with tumour haemorrhage, four with abdominal lymph node enlargement, three with inferior vena cava (IVC)/renal vein thrombus, four with adjacent organ invasion, one patient where the origin of the abdominal tumour was confirmed as renal, and one patient where possible liver invasion was excluded. CONCLUSION: In over half the patients, CT or MRI added additional information in the local staging of Wilms' tumours. Sole reliance on ultrasound for Wilms' staging risks missing significant abnormalities.

The effect of lactation on post-partum uterine involution in Holstein dairy cows.

The objective was to examine the effect of lactation on uterine involution in post-partum dairy cows. Holstein primiparous cows were used (n = 19, mean age: 3.9 ± 0.1 years). At calving, cows were randomly assigned to one of two treatment groups, lactating (n = 11) or non-lactating (i.e. dried off at calving, n = 8). Examination of the reproductive tract was carried out by ultrasonography twice weekly until week 7 post-partum. Blood samples were collected twice weekly for the analysis of progesterone to indicate the resumption of cyclicity and metabolites indicative of energy status. Uterine involution was assessed in terms of size of the uterine horns, uterine body diameter and uterine fluid volume as assessed by the amount of non-echogenic material measured by ultrasound and position of the uterus. Vaginal mucous score was taken on day 28 post-partum for the assessment of uterine inflammation. Resumption of cyclicity (serum progesterone > 1 ng/ml) had occurred in both groups on average by day 21 post-partum. Concentrations of non-esterified fatty acids and beta-hydroxybutyrate were higher, whereas concentrations of glucose, insulin and IGF-1 were lower (p < 0.05) in lactating compared to non-lactating cows. Lactating cows had a smaller mean uterine body diameter (p < 0.05) than non-lactating cows from days 28 to 42 post-partum (day 28: 20.2 ± 1.3 vs 24.9 ± 1.5 mm, respectively) and had a lower mean uterine fluid volume up to day 49 (p < 0.05). By day 49, there was no difference in uterine diameter (15.2 ± 1.8 vs 15.2 ± 1.6 mm) or uterine fluid volume (0.11 ± 0.38 vs 0.18 ± 0.46) between lactating and non-lactating cows, respectively. Vaginal mucous score revealed no evidence of uterine inflammation in either group. In conclusion, while lactation induced significant alterations in metabolic status, it did not have a major effect on the rate of uterine involution as defined in this study.

Effect of follicular aspiration just before ovulation on corpus luteum characteristics, circulating progesterone concentrations and uterine receptivity in single-ovulating and superstimulated heifers.

The aim of this study was to investigate, in unstimulated and superstimulated heifers, the effect of follicle aspiration just before ovulation on corpus luteum (CL) development, circulating progesterone (P(4)) concentrations and the ability of the uterus to support embryo development. Following follicle aspiration or ovulation timed from GNRH administration, CL development was assessed by daily ultrasonography, and CL function was assessed in terms of the capacity to produce P(4) and the expression of genes involved in steroidogenesis in luteal tissue. The capacity of the uterine environment to support conceptus development was assessed following transfer and recovery of in vitro-produced embryos. Follicular aspiration just before the expected time of ovulation leads to a significant reduction in CL diameter, CL area and area of luteal tissue. This was associated with a decrease in circulating P(4) in both unstimulated and superstimulated heifers. Follicle aspiration leads to a reduction in conceptus length and area on day 14 in unstimulated heifers only. Follicle aspiration leads to a reduction in the expression of LHCGR in luteal tissue from unstimulated heifers compared with those in which the CL formed after ovulation. Superstimulation significantly reduced the expression of STAR in luteal tissue in both ovulated and follicle-aspirated heifers. In conclusion, in stimulated and unstimulated heifers, aspiration of the preovulatory dominant follicle(s) just before expected ovulation interferes with the subsequent formation and function of the CL, in terms of size and P(4) output and this, in turn, is associated with a reduced capacity of the uterus to support conceptus elongation in unstimulated heifers.

Effects of human chorionic gonadotrophin administration on day 5 after oestrus on corpus luteum characteristics, circulating progesterone and conceptus elongation in cattle.

The aim of the present study was to test the hypothesis that elevated concentrations of progesterone (P4) resulting from the induction of an accessory corpus luteum (CL) by human chorionic gonadotrophin (hCG) administration on day 5 after oestrus would lead to advanced conceptus elongation on day 14 following embryo transfer on day 7. The oestrous cycles of cross-bred beef heifers were synchronised and animals were randomly assigned to receive either of two treatments: (1) intramuscular injection of 3000 IU hCG on day 5 after oestrus (n=14); or (2) intramuscular injection of saline on day 5 after oestrus (n=13). Ovaries were scanned daily by transrectal ultrasonography to assess CL development. Serum concentrations of P4 were determined from daily blood samples collected from the jugular vein. In vitro-produced bovine blastocysts were transferred to synchronised recipients on day 7 after oestrus (n=15 blastocysts per recipient). Heifers were killed on day 14 after oestrus and the uterus was flushed to recover the embryos. Injection of hCG on day 5 induced ovulation of the dominant follicle in all treated heifers and increased the total area of luteal tissue on the ovary, which was associated with a significant increase (P<0.001) in serum concentrations of P4 from day 7 to day 14. Positive associations were detected between circulating P4 with CL area (within-day correlations ranging from r=0.45 to r=0.67) and total area of luteal tissue (within-day correlations ranging from r=0.65 to r=0.86) Administration of hCG did not affect the proportion of day 14 conceptuses recovered. However, compared with the control group, hCG-treated heifers had increased conceptus length (3.91±1.23 vs. 5.57±1.02 mm, respectively; P=0.06), width (1.00±0.06 vs. 1.45±0.05 mm, respectively; P=0.002) and area (5.71±0.97 vs. 8.31±0.83, respectively; P=0.02). Although numerically greater, mean interferon-τ (IFNT) production in vitro did not differ significantly (P=0.54) between embryos recovered from hCG-treated and control heifers. In contrast, there was a strong positive correlation between individual embryo length (r=0.76; P<0.001) and individual embryo area (r=0.72; P<0.001) and IFNT production. In conclusion, administration of hCG on day 5 after oestrus resulted in the formation of an accessory CL and hypertrophy of the original CL, the result of which was an increase in P4 concentrations from day 7 onwards. These elevated P4 concentrations were associated with an increased conceptus area. Furthermore, conceptus size was highly correlated with IFNT secretion in vitro.

Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment.

Intermittent preventive treatment in pregnancy (IPTp) is used to prevent Plasmodium falciparum malaria. However, parasites resistant to the IPTp drug sulfadoxine-pyrimethamine (SP) have emerged worldwide, and infections with mixed resistant and susceptible parasites are exacerbated by pyrimethamine in mice. In a prospective delivery cohort in Muheza, Tanzania, we examined the effects of SP IPTp on parasite resistance alleles, parasite diversity, level of parasitemia, and inflammation in the placenta. IPTp use was associated with an increased fraction of parasites carrying the resistance allele at DHPS codon 581, an increase in the level of parasitemia, and more intense placental inflammation. The lowest mean level of parasite diversity and highest mean level of parasitemia occurred in women after recent IPTp use. These findings support a model of parasite release and facilitation, whereby the most highly resistant parasites out-compete less fit parasite populations and overgrow under drug pressure. Use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance.

Changes in the endometrial transcriptome during the bovine estrous cycle: effect of low circulating progesterone and consequences for conceptus elongation.

In cattle, elevated concentrations of circulating progesterone (P4) in the immediate postconception period are associated with advanced conceptus development, while low P4 is implicated as a causative factor in low pregnancy rates observed in dairy cows. This study aimed to: 1) describe the transcriptional changes that occur in the bovine endometrium during the estrous cycle, 2) determine how elevated P4 affects these changes, 3) identify if low P4 alters the expression of these genes, and 4) assess the impact that low P4 has on conceptus development. Relatively few differences occurred in endometrial gene expression during the early luteal phase of the estrous cycle (Day 5 vs. 7), but comparison of endometria from more distant stages of the luteal phase (Day 7 vs. 13) revealed large transcriptional changes, which were significantly altered by exogenous supplementation of P4. Induction of low circulating P4 altered the normal temporal changes in gene expression, and these changes were coordinate with a delay in the down-regulation of the PGR from the LE and GE. Altered endometrial gene expression induced by low P4 was associated with a reduced capacity of the uterus to support conceptus development after embryo transfer on Day 7. In conclusion, the present study provides clear evidence that the temporal changes in the transcriptome of the endometrium of cyclic heifers are sensitive to circulating P4 concentrations in the first few days after estrus. Under low P4 conditions, a suboptimal uterine environment with reduced ability to support conceptus elongation is observed.

Impact of geoengineering schemes on the global hydrological cycle.

The rapidly rising CO(2) level in the atmosphere has led to proposals of climate stabilization by "geoengineering" schemes that would mitigate climate change by intentionally reducing solar radiation incident on Earth's surface. In this article we address the impact of these climate stabilization schemes on the global hydrological cycle. By using equilibrium climate simulations, we show that insolation reductions sufficient to offset global-scale temperature increases lead to a decrease in global mean precipitation. This occurs because solar forcing is more effective in driving changes in global mean evaporation than is CO(2) forcing of a similar magnitude. In the model used here, the hydrological sensitivity, defined as the percentage change in global mean precipitation per degree warming, is 2.4% K(-1) for solar forcing, but only 1.5% K(-1) for CO(2) forcing. Although other models and the climate system itself may differ quantitatively from this result, the conclusion can be understood based on simple considerations of the surface energy budget and thus is likely to be robust. For the same surface temperature change, insolation changes result in relatively larger changes in net radiative fluxes at the surface; these are compensated by larger changes in the sum of latent and sensible heat fluxes. Hence, the hydrological cycle is more sensitive to temperature adjustment by changes in insolation than by changes in greenhouse gases. This implies that an alteration in solar forcing might offset temperature changes or hydrological changes from greenhouse warming, but could not cancel both at once.

Pgs28 belongs to a family of epidermal growth factor-like antigens that are targets of malaria transmission-blocking antibodies.

Although Pgs28, a 28-kD surface protein of Plasmodium gallinaceum oökinetes, was previously thought not to be a target of transmission-blocking antibodies, we found that polyclonal antisera to Pgs28 completely blocked parasite infectivity to Aedes aegypti mosquitoes. Antisera raised against reduced Pgs28 were less effective in blocking transmission than were antisera to nonreduced Pgs28; thus, the target epitope(s) of transmission-blocking antibodies appears to be conformation dependent. In stage-specific assays, polyclonal antisera impaired the in vitro transformation of zygotes to mature oökinetes, as well as the in vivo development of mature oökinetes to oöcysts. Using microsequence of immunoaffinity-purified Pgs28, we cloned the 666-bp open reading frame of the Pgs28 gene. The deduced amino acid sequence of Pgs28 is strikingly similar to that of a P. gallinaceum zygote surface protein, Pgs25, and its P. falciparum analogue, Pfs25. Pgs28, like Pgs25 and Pfs25, has a presumptive secretory signal sequence, followed by four epidermal growth factor-like domains, and a terminal hydrophobic region.

ACETYLCHOLINESTERASE IN FROG SYMPATHETIC AND DORSAL ROOT GANGLIA : A Study by Electron Microscope Cytochemistry and Microgasometric Analysis with the Magnetic Diver.

The localization and chemical determination of acetylcholin esterase in the frog sympathetic and dorsal root ganglia were studied by a combination of the methods of electron microscopy, histochemistry, and microgasometric analysis with the magnetic diver. The Koelle-Friedenwald copper thiocholine histochemical method was modified by eliminating the sulfide conversion and by treatment of the tissue with potassium permanganate. In fixed tissue, enzymatic activity was demonstrated on the inner surface of the endoplasmic reticulum, nuclear envelope, subsurface cisternae, and agranular reticulum of the perikaryon and axon. In briefly fixed tissue, end product appeared also at the axon-sheath and the sheath-sheath interface. Activity at the synaptic junction was most readily obtained in unfixed tissue. Isolated neurons recovered from the diver following chemical analysis were studied with the electron microscope. Cells having a high enzyme activity showed a badly ruptured or absent neural plasmalemma and sheath. In this case the measured activity was apparently due to the enzyme present in the endoplasmic reticulum. Neurons having low activity exhibited an intact plasmalemma and sheath. This may reflect the effectiveness of the neural plasmalemma and sheath as a penetration barrier. The effects of fixation on enzyme activity are discussed. Electron microscopic examination of cells following microgasometric analysis is shown to be essential for the interpretation of the biochemical data.

Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta.

Women are particularly susceptible to malaria during first and second pregnancies, even though they may have developed immunity over years of residence in endemic areas. Plasmodium falciparum-infected red blood cells (IRBCs) were obtained from human placentas. These IRBCs bound to purified chondroitin sulfate A (CSA) but not to other extracellular matrix proteins or to other known IRBC receptors. IRBCs from nonpregnant donors did not bind to CSA. Placental IRBCs adhered to sections of fresh-frozen human placenta with an anatomic distribution similar to that of naturally infected placentas, and this adhesion was competitively inhibited by purified CSA. Thus, adhesion to CSA appears to select for a subpopulation of parasites that causes maternal malaria.

Interplanetary Magnetic Field Polarity and the Size of Low-Pressure Troughs Near 180{degrees}W Longitude.

When the interplanetary magnetic field is directed away from the sun, the area of wintertime low-pressure (300-millibar) troughs near 180 degrees W longitude is significantly larger than when the field is toward the sun. This relation persists during most of the winters of 1951 to 1973.

Antigens for pre-erythrocytic malaria vaccines: building on success.

Immunization with attenuated pre-erythrocytic malaria parasites can confer sterile protection against malaria in humans and rodents, and a single pre-erythrocytic antigen incorporated in a subunit vaccine has substantially reduced clinical Plasmodium falciparum malaria episodes in African infants during phase 2 trials. Building upon this success has been hindered by technical obstacles that limit research on pre-erythrocytic parasites, especially the liver stage (LS) parasites, and by an incomplete understanding of the immune mechanisms that confer protection in humans. Recent improvements in growing and isolating LS parasites have allowed progress in defining the transcriptome and proteome of the LS parasite, although more work remains to be done particularly for the early LS parasite of P. falciparum. Next generation pre-erythrocytic antigens can be assessed and prioritized based on immunization studies in animals, and on models of immunity such as attenuated parasite vaccines that confer sterile protection or naturally acquired LS-specific immune responses that correlate with protection in endemic areas. Although mechanisms of protection in humans remain poorly understood, the availability of a human malaria challenge model for early clinical testing of candidate vaccines is a valuable tool to confirm which immunogens should move forward to larger field trials.

Is it safe to use aluminum in the treatment of pediatric hemorrhagic cystitis? A case discussion of aluminum intoxication and review of the literature.

In pediatric oncology patients, hemorrhagic cystitis can be a life-threatening complication of bone marrow transplantation, chemotherapy, and radiation therapy. The treatment of this condition is often challenging and includes intravesical irrigation with aluminum, embolization, endoscopic laser coagulation, hydrostatic pressure, use of hyperbaric oxygen, instillation of formalin, prostaglandins, and oral sodium pentosan polysulfate. Although the efficacy of aluminum irrigation is well documented for the management of hemorrhagic cystitis in adults, there are limited reports describing its use in children. The potential multisystem toxic effects of aluminum are well described and the range and progression of aluminum toxicity can be devastating. We report a case of a 9-year-old girl suffering from acute lymphocytic leukemia with hemorrhagic cystitis. Although the symptoms resolved after intravesical aluminum treatment, she developed significant aluminum toxicity. We have reviewed the literature relating to aluminum toxicity in the pediatric age group and present our recommendations for the effective and safe use of aluminum in this cohort of patients.

Rapid and sensitive detection of Avibacterium paragallinarum in the presence of other bacteria using a 5' Taq nuclease assay: a new tool for diagnosing infectious coryza.

A 5' Taq nuclease assay specific for Avibacterium paragallinarum was designed and optimized for use in diagnosing infectious coryza. The region chosen for assay design was one of known specificity for Av. paragallinarum. The assay detected Av. paragallinarum reference strains representing the three Page and the eight Kume serovars, and field isolates from diverse geographical locations. No cross-reactions were observed with other Avibacterium species, with other bacteria taxonomically related to Av. paragallinarum nor with bacteria and viruses likely to be present in swabs collected from suspected infectious coryza cases. The detection limit for the assay was 6 to 60 colony-forming units per reaction. Twenty-two out of 53 swabs collected from sick birds reacted in the 5' Taq nuclease assay, whereas Av. paragallinarum was not isolated from any of the swabs. All of the 22 swabs yielded other bacteria in culture. The presence of Av. paragallinarum in the swabs was also demonstrated by sequencing, thereby confirming the ability of the assay to detect Av. paragallinarum in the presence of other bacteria. The ability to quantify bacterial load in the swabs using the 5' Taq nuclease assay was demonstrated.