Corticosteroid-induced kidney dysmorphogenesis is associated with deregulated expression of known cystogenic molecules, as well as Indian hedgehog.

An intact genome is essential for kidney growth and differentiation, but less is known about whether, and how, an altered fetal milieu modifies these processes. Maternal low-protein diets perturb growth of the metanephros, the precursor of the mature kidney. Fetal corticosteroid overexposure may, in part, mediate this, because such diets downregulate placental 11beta-hydroxysteroid dehydrogenase-2, which degrades maternal corticosteroids. We report that glucocorticoid and mineralocorticoid receptors are expressed in mouse metanephric epithelia. Metanephroi maintained in organ culture with hydrocortisone (1.4 or 14 microM) underwent a dose-dependant deceleration of overall growth accompanied by cyst formation. Dexamethasone, a glucocorticoid, reproduced these outcomes, but aldosterone, a mineralocorticoid, did not. Hydrocortisone upregulated transcripts levels of cadherin-11 and downregulated prospero-related homeobox-1, hence mimicking reported effects of maternal low-protein diet. Hydrocortisone also upregulated transcripts encoding Na(+)-K(+)-ATPase subunits and ligands for the epidermal growth factor receptor, all previously implicated in renal cyst growth. The most upregulated transcript, however, was indian hedgehog, and the encoded protein was immunodetected in metanephric cysts. Furthermore, in the presence of hydrocortisone, cystogenesis, but not whole organ growth, was significantly reduced by cyclopamine, a drug downregulating hedgehog signaling. Finally, both glucocorticoid receptor and indian hedgehog proteins were detected by immunohistochemistry in cystic tubules within human dysplastic kidneys, consistent with the hypothesis that these molecules modify the severity of this congenital malformation. Collectively, our observations raise the possibility that enhanced hedgehog signaling is an important stimulus for renal cyst formation. Furthermore, pharmacological inhibition of this pathway should be explored as a potential therapy for renal cystic diseases, starting with relevant animal models.

When t-tests or Wilcoxon-Mann-Whitney tests won't do.

t-Tests are widely used by researchers to compare the average values of a numeric outcome between two groups. If there are doubts about the suitability of the data for the requirements of a t-test, most notably the distribution being non-normal, the Wilcoxon-Mann-Whitney test may be used instead. However, although often applied, both tests may be invalid when discrete and/or extremely skew data are analyzed. In medicine, extremely skewed data having an excess of zeroes are often observed, representing a numeric outcome that does not occur for a large percentage of cases (so is often zero) but which also sometimes takes relatively large values. For data such as this, application of the t-test or Wilcoxon-Mann-Whitney test could lead researchers to draw incorrect conclusions. A valid alternative is regression modeling to quantify the characteristics of the data. The increased availability of software has simplified the application of these more complex statistical analyses and hence facilitates researchers to use them. In this article, we illustrate the methodology applied to a comparison of cyst counts taken from control and steroid-treated fetal mouse kidneys.

Seizures in 204 comatose children: incidence and outcome.

PURPOSE: Seizures are common in comatose children, but may be clinically subtle or only manifest on continuous electroencephalographic monitoring (cEEG); any association with outcome remains uncertain. METHODS: cEEG (one to three channels) was performed for a median 42 h (range 2-630 h) in 204 unventilated and ventilated children aged ≤15 years (18 neonates, 61 infants) in coma with different aetiologies. Outcome at 1 month was independently determined and dichotomized for survivors into favourable (normal or moderate neurological handicap) and unfavourable (severe handicap or vegetative state). RESULTS: Of the 204 patients, 110 had clinical seizures (CS) before cEEG commenced. During cEEG, 74 patients (36%, 95% confidence interval, 95% CI, 32-41%) had electroencephalographic seizures (ES), the majority without clinical accompaniment (non-convulsive seizures, NCS). CS occurred before NCS in 69 of the 204 patients; 5 ventilated with NCS had no CS observed. Death (93/204; 46%) was independently predicted by admission Paediatric Index of Mortality (PIM; adjusted odds ratio, aOR, 1.027, 95% CI 1.012-1.042; p < 0.0005), Adelaide coma score (aOR 0.813, 95% CI 0.700-0.943; p = 0.006), and EEG grade on admission (excess slow with >3% fast, aOR 5.43, 95% CI 1.90-15.6; excess slow with <3% fast, aOR 8.71, 95% CI 2.58-29.4; low amplitude, 10th centile <9 µV, aOR 3.78, 95% CI 1.23-11.7; and burst suppression, aOR 10.68, 95% CI 2.31-49.4) compared with normal cEEG, as well as absence of CS at any time (aOR 2.38, 95% CI 1.18-4.81). Unfavourable outcome (29/111 survivors; 26%) was independently predicted by the presence of ES (aOR 15.4, 95% CI 4.7-49.7) and PIM (aOR 1.036, 95% CI 1.013-1.059). CONCLUSION: Seizures are common in comatose children, and are associated with an unfavourable outcome in survivors. cEEG allows the detection of subtle CS and NCS and is a prognostic tool.

A communication-based intervention for nonverbal children with autism: what changes? Who benefits?

OBJECTIVE: This article examines the form and function of spontaneous communication and outcome predictors in nonverbal children with autism following classroom-based intervention (Picture Exchange Communication System [PECS] training). METHOD: 84 children from 15 schools participated in a randomized controlled trial (RCT) of PECS (P. Howlin, R. K. Gordon, G. Pasco, A. Wade, & T. Charman, 2007). They were aged 4-10 years (73 boys). Primary outcome measure was naturalistic observation of communication in the classroom. Multilevel Poisson regression was used to test for intervention effects and outcome predictors. RESULTS: Spontaneous communication using picture cards, speech, or both increased significantly following training (rate ratio [RR] =1.90, 95% CI [1.46, 2.48], p < .001; RR = 1.77, 95% CI [1.35, 2.32], p < .001; RR = 3.74, 95% CI [2.19, 6.37], p < .001, respectively). Spontaneous communication to request objects significantly increased (RR = 2.17, 95% CI [1.75, 2.68], p < .001), but spontaneous requesting for social purposes did not (RR = 1.34, 95% CI [0.83, 2.18], p = .237). Only the effect on spontaneous speech persisted by follow-up (9 months later). Less severe baseline autism symptomatology (lower Autism Diagnosis Observation Schedule [ADOS] score; C. Lord et al., 2000) was associated with greater increase in spontaneous speech (RR = 0.90, 95% CI [0.83, 0.98], p = .011) and less severe baseline expressive language impairment (lower ADOS item A1 score), with larger increases in spontaneous use of speech and pictures together (RR = 0.62, 95% CI [0.44, 0.88], p = .008). CONCLUSION: Overall, PECS appeared to enhance children's spontaneous communication for instrumental requesting using pictures, speech, or a combination of both. Some effects of training were moderated by baseline factors. For example, PECS appears to have increased spontaneous speech in children who could talk a little at baseline.