No abstract

Epidemiological and animal studies strongly indicate that the environment experienced in utero determines, in part, an individual's likelihood of developing cardiovascular disease in later life. This risk has been further linked to impaired kidney function, as a result of compromised development during fetal life. The present study therefore examined the influence of maternal nutrient restriction (NR), targeted at specific periods of kidney development during early to mid gestation, on the mRNA abundance of receptors for glucocorticoid (GCR), growth hormone (GHR) and insulin-like growth factors-I (IGF-IR) and -II (IGF-IIR), and the IGF-I and -II ligands. This was undertaken in both singleton and twin fetuses. At conception ewes were randomly allocated to either an adequately fed control group or one of four nutrient-restricted groups that were fed half the control amount from 0 to 30, 31 to 65, 66 to110 or 0 to110 days gestation. At 110 days gestation all ewes were humanely euthanased and fetal kidneys and surrounding adipose tissue sampled. There was no effect of NR or fetal number on kidney weight, shape or nephron number, but the surrounding fat mass was increased in singleton fetuses exposed to NR for 110 days. An increase in kidney mRNA abundance with NR only occurred in singleton fetuses where IGF-IR mRNA was enhanced with NR from 66 -110 days gestation. In twin fetuses, NR had no effect on mRNA abundance. However, for all genes examined mRNA expression was lower in the kidneys of twin compared with singleton fetuses following NR, and the magnitude of the effect was dependent on the timing of NR. In conclusion, the abundance of mRNA for receptors which regulate fetal kidney development are lower in twin animals compared with singletons following periods of nutrient deficiency. This may impact on later kidney development and function.

Studies have shown that the risk of hypertension in adulthood can be affected by the in utero environment. It is established that hypertension is linked to compromised kidney function and that factors affecting organogenesis can increase the risk of later disease. Prostaglandins (PG) and growth factors are known to play an important role in regulating kidney function and renal organogenesis. The extent, however, to which global energy restriction (where all nutrients are reduced) of the mother can programme later blood pressure control or renal PG and growth factor status is unknown. A study is described that aimed to examine the long-term effects of maternal nutrient restriction (NR) and elucidate their relationship with compromised kidney development. First, it was necessary to establish animal models. A sheep model of 50% NR during specific stages of gestation was used to investigate fetal renal development, whilst a rat model of 50% NR throughout pregnancy was used to investigate postnatal kidney development and adult functioning. Molecular analysis has shown that expression of the growth hormone-insulin-like growth factor (GH-IGF) axis is affected by NR in the fetal sheep kidneys, and that changes are dependent on the timing of NR and whether the fetus is a singleton or a twin. Analysis of the kidneys from the rat model has shown nutritional differences in the expression of PG receptors and the enzymes responsible for PG synthesis and degradation that persist into adulthood. In conclusion, NR does affect the GH-IGF and PG axes, and these changes may be important in the nutritional programming of renal functioning and adult blood pressure control.

The mechanisms whereby maternal nutritional manipulation through pregnancy result in altered blood pressure in the offspring may include changes in fetal and newborn and adult renal prostaglandin (PG) synthesis, metabolism, and receptor expression. Since the postnatal effects of nutrient restriction on the renal PG synthesis and receptor system during nephrogenesis in conjunction with nephron numbers and blood pressure have not been evaluated in the rat, the present study examined the effect of reducing maternal food intake by 50% of ad libitum through pregnancy on young male rats. Six control-fed mothers and eight nutrient-restricted pregnant rats with single litter mates were used at each sampling time point, most of which occurred during nephrogenesis. Offspring of nutrient-restricted dams were lighter from birth to 3 days. This was accompanied by reduced PGE2, with smaller kidneys up to 14 days. Nutrient restriction also decreased mRNA expression of the PG synthesis enzyme, had little effect on the PG receptors, and increased mRNA expression of the degradation enzyme during nephrogenesis and the glucocorticoid receptor in the adult kidney. These mRNA changes were normally accompanied by similar changes in protein. Nephron number was also reduced from 7 days up to adulthood when blood pressure (measured by telemetry) did not increase as much as in control offspring during the dark, active period. In conclusion, maternal nutrient restriction suppressed renal PG concentrations in the offspring, and this was associated with suppressed kidney growth and development and decreased blood pressure.kidney; nutrient restriction; offspring; prostaglandins MATERNAL NUTRIENT RESTRICTION during pregnancy has been previously shown to affect the renal development of the offspring. In the sheep, nutrient restriction targeted to the period of early kidney development subsequently increases organ size as well as affecting kidney shape and promotes glucocorticoid receptor (GCR) mRNA abundance (32). Global nutrient restriction (9) and protein restriction in particular can both reduce the total number of nephrons formed in developing rat kidneys, but this does not necessarily result in raised blood pressure in the offspring (11). The mechanisms by which maternal nutritional manipulation acts to compromise fetal development and ultimately adult health remain uncertain. It has been proposed that this is dependent in part on increased maternal corticosterone concentrations acting directly on the fetus (16). This proposal is supported by the finding that maternal administration of dexamethasone, which crosses the placenta to the fetus during pregnancy, can cause similar cardiovascular outcomes as observed with maternal food deprivation (40); indeed, dexamethasone administration also results in reduced maternal food consumption, suggesting a behavioural effect on appetite (37, 40). Recently, it has been shown that a transient increase in maternal corticosterone on days 14 and 15 of pregnancy in rats can impair development of the intra-...

Adult brain tumors establish an immunosuppressive tumor microenvironment as a modality of immune escape, with several immunotherapies designed to overcome this barrier. However, the relationship between tumor cells and immune cells in pediatric brain tumor patients is not as well-defined. In this study, we sought to determine whether the model of immune escape observed in adult brain tumors is reflected in patients with pediatric brain tumors by evaluating NKG2D ligand expression on tissue microarrays created from patients with a variety of childhood brain tumor diagnoses, and infiltration of Natural Killer and myeloid cells. We noted a disparity between mRNA and protein expression for the 8 known NKG2D ligands. Surprisingly, high-grade gliomas did not have increased NKG2D ligand expression compared to normal adjacent brain tissue, nor did they have significant myeloid or NK cell infiltration. These data suggest that pediatric brain tumors have reduced NK cell-mediated immune surveillance, and a less immunosuppressive tumor microenvironment as compared to their adult counterparts. These data indicate that therapies aimed to improve NK cell trafficking and functions in pediatric brain tumors may have a greater impact on anti-tumor immune responses and patient survival, with fewer obstacles to overcome.

1 VDZ has demonstrated statistically significant differences in clinical remission from placebo in patients (patients) with moderately to severely active Crohn's disease (CD), 2 but endoscopic healing was not previously assessed. The present study evaluated the effect of VDZ on endoscopic remission and healing in patients with CD. Methods: Patients with moderately to severely active CD (≥3 months; CD Activity Index [CDAI] 220-450; Simple Endoscopic Score for CD [SES-CD] ≥7; ≥1 mucosal ulceration on centrally read endoscopy) who had previously experienced treatment failure with corticosteroids, immunomodulators, and/or at least one tumour necrosis factor-alpha (TNF) antagonist were enrolled. Patients received VDZ 300 mg intravenously at weeks 0, 2, 6, and then every 8 weeks for 26 weeks, followed by a 26-week treatment extension period. The primary endpoint was endoscopic remission (SES-CD ≤4) at week 26, assessed by centrally read ileocolonoscopy. Key secondary endpoints included endoscopic response (SES-CD ≥50% reduction from baseline) and complete endoscopic healing (absence of ulcerations) at week 26. Subgroup analyses stratified by TNF antagonist exposure status were performed for all endpoints and by disease severity for endoscopic remission only. Results: Of the 101 patients enrolled, 55% had previously failed at least one TNF antagonist (TNF-F), and 46% were categorised as having severe endoscopic activity at entry (SES-CD score of >15). Endoscopic remission rates at week 26 were 12% overall, 20% in TNF antagonist naïve (TNF-N), and 6% in TNF-F patients, respectively (Table 1). Endoscopic remission at week 26 was achieved in 17% of patients with moderate endoscopic activity (SES-CD score of 7-15) compared with 7% of patients with severe disease. Endoscopic response and complete endoscopic healing rates at week 26 are shown in Table 1.

No abstract

We present the case of a 29-year-old south Asian man born of consanguineous marriage, presenting with ataxia, peripheral neuropathy and cognitive impairment. An initial diagnosis of coeliac disease was thought to explain the pertinent clinical features; however, further investigation led to an additional diagnosis of the rare yet treatable autosomal recessive condition, cerebrotendinous xanthomatosis. With both conditions employing highly diverse and overlapping clinical phenotypes, this contributed to a delay in diagnosis. Our report highlights the importance of paying close attention to both the clinical phenotype and family history.