Miracle-dz/UniFAR-FTUs huggingface dataset:
Diarrhea Associated with Propranolol Treatment for Hemangioma of Infancy (HOI)

To the Editor: We read with interest the study from Lawley et al (1) raising the issue of safety of systemic beta-blockers for hemangiomas of infancy (HOI). Oral propranolol, recently suggested to improve HOI (2), is now being used enthusiastically, for both complicated and simple HOI, before any systematic studies of efficacy or safety have been published. We report three infants with periocular HOI who developed diarrhea on propranolol 1 mg ⁄kg bid (Table 1). In two, the diarrhea resolved immediately on stopping or halving the dose and recurring on challenge in one. In the third, mild diarrhea resolved spontaneously. The patients were on no concurrent medication. Infants could be more susceptible to diarrhea from propranolol, which has occasionally been reported in adults (3). Alternatively, diarrhea might be induced osmotically by maltitol (hydrogenated glucose syrup) present in the oral propranolol suspension we used (Syprol 5 mg ⁄5 mL; Rosemont Pharmaceuticals Ltd., Leeds, UK). The manufacturer disclosed two other reports of diarrhea, both in children. The adverse effects of propranolol are well characterized in adults, but experience in infants is limited. They may be at increased risk, because hepatic first-pass metabolism is immature and bioavailability therefore greater. Bradycardia, hypotension, hypoglycaemia, bronchospasm, sweats, and cold extremities have now been reported with propranolol in HOI (4). Liquid formulations contain variously maltitol, propylene glycol, sorbitol, ethanol, and benzyl alcohol, each of which can have adverse effects, and for which the safe dose in neonates is unknown (5). There was enthusiasm for interferon-alfa treatment in HOI before the risk of spastic diplegia was revealed. Propranolol is a promising treatment for HOI, but controlled studies to establish its efficacy and safety are urgently needed. We welcome the cautionary advice offered by Lawley et al (1) and would add that, diarrhea is a side effect of oral propranolol treatment.
Outcomes After Multiple Lines of Chemotherapy for Platinum-Resistant Epithelial Cancers of the Ovary, Peritoneum, and Fallopian Tube

Background: Platinum-resistant and refractory cancers of the ovary, fallopian tube, and peritoneum have a poor prognosis, yet in some cases, they can respond to multiple lines of chemotherapy. Uncertainty remains over optimal drug choice and when therapeutic focus should be switched from active therapy to supportive care. Methods: A retrospective case note review was performed on 274 women treated for platinum-resistant/refractory ovarian, fallopian tube, or peritoneal carcinoma at the Christie Hospital between 2004 and 2008. Baseline data at onset of platinum resistance and outcomes from subsequent lines of therapy were recorded. Results: A total of 689 lines of therapy were administered with a median overall survival from initiation of first-line therapy for platinum-resistant disease of 61 weeks. Twenty-eight percent of women commenced cytotoxic therapy in the last 3 months of life. Treatment efficacy declined rapidly with successive lines of therapy particularly if disease progression occurred during first-line therapy. Factors independently associated with worse overall survival at recognition of platinum resistance were performance status, presence of stage IV disease, elevated cancer antigen 125, and platinum-refractory disease. Conclusions: A significant proportion of women who were treated received therapy within the last few months of life with little clinical benefit. Disease progression on 2 consecutive lines of therapy should be used as a guide to discontinue cytotoxic treatment. A subset of patients with poor prognosis at the onset of platinum resistance, who may have little gain from anticancer treatment, can be identified.
Next‐generation sequencing of urine specimens: A novel platform for genomic analysis in patients with non–muscle‐invasive urothelial carcinoma treated with bacille Calmette‐Guérin

Biopsies from patients with high‐risk (HR) non–muscle‐invasive urothelial carcinoma (NMIUC), especially flat urothelial carcinoma in situ, frequently contain scant diagnostic material or denuded mucosa only, and this precludes further extensive genomic analysis. This study evaluated the use of next‐generation sequencing (NGS) analysis of urine cytology material from patients with HR NMIUC in an attempt to identify genetic alterations that might correlate with clinical features and responses to bacille Calmette‐Guérin (BCG) treatment.
Topical Propranolol Therapy for Infantile Hemangiomas

Abstract: The nonselective beta‐adrenergic receptor antagonist propranolol is an effective therapy for infantile hemangiomas. Systemic propranolol therapy shows a rapid therapeutic effect with good drug tolerability. We report on the efficacy of local application of propranolol ointment in superficial hemangiomas of the skin. In our outpatient department, 45 children with 65 hemangiomas were treated with 1% propranolol in a hydrophilic ointment topically applied twice a day. Before start of treatment and at each visit, clinical photographs were taken. If ultrasound did not confirm occult deeper components, children were included in the study. Treatment in the proliferative phase within the first 6 months of life (including seven preterm infants) induced regression in 59% and cessation of growth in 26% of the hemangiomas. No response or proliferation of subcutaneous components was observed in 15%. Clinically, no side effects caused by the beta‐receptor blocker were noticed. Treatment of two ulcerated hemangiomas of the perineal region twice using a flash lamp pulsed‐dye laser and propranolol ointment in the surrounding lesion led to healing of the ulcers in 3 and 6 weeks, respectively. In six patients, topical therapy was started between the ages of 7 and 33 months. Even in these hemangiomas, improvement was obvious after 2 or 3 months. Propranolol administered topically in 1% ointment could have a beneficial effect on superficial hemangiomas of the skin. The treatment was well tolerated without side effects even in preterm infants and in children with numerous or large lesions.
Early involvement of synapsin III in neural progenitor cell development in the adult hippocampus

Synapsin III is a synaptic vesicle‐associated protein that is expressed in cells of the subgranular layer of the hippocampal dentate gyrus, a brain region known to sustain substantial levels of neurogenesis into adulthood. Here we tested the hypothesis that synapsin III plays a role in adult neurogenesis with synapsin III knockout and wild‐type mice. Immunocytochemistry of the adult hippocampal dentate gyrus revealed that synapsin III colocalizes with markers of neural progenitor cell development (nestin, PSA‐NCAM, NeuN, and Tuj1) but did not colocalize with markers of mitosis (Ki67 and PCNA). Because neurogenesis consists of a number of stages, the proliferation, survival, and differentiation of neural progenitor cells were systematically quantitated in the hippocampal dentate gyrus of adult synapsin III knockout and wild‐type mice. We found a 30% decrease in proliferation and a 55% increase in survival of neural progenitor cells in synapsin III knockout mice. We also observed a 6% increase in the number of neural progenitor cells that differentiated into neurons. No difference in the volume of the dentate gyrus was observed between synapsin III knockout and wild‐type mice. Collectively, our results demonstrate a novel role for synapsin III in regulating the proliferation of neural progenitor cells in the adult hippocampal dentate gyrus. These findings suggest a distinct function for this synaptic vesicle protein, in addition to its role in neurotransmission. J. Comp. Neurol. 507:1860–1870, 2008. © 2008 Wiley‐Liss, Inc.
Neuronal assemblies of the Drosophila mushroom body

The mushroom body (MB) of the insect brain has important roles in odor learning and memory and in diverse other brain functions. To elucidate the anatomical basis underlying its function, we studied how the MB of Drosophila is organized by its intrinsic and extrinsic neurons. We screened for the GAL4 enhancer‐trap strains that label specific subsets of these neurons and identified seven subtypes of Kenyon cells and three other intrinsic neuron types. Laminar organization of the Kenyon cell axons divides the pedunculus into at least five concentric strata. The α′, β′, α, and β lobes are each divided into three strata, whereas the γ lobe appears more homogeneous. The outermost stratum of the α/β lobes is specifically connected with a small, protruded subregion of the calyx, the accessory calyx, which does not receive direct olfactory input. As for the MB extrinsic neurons (MBENs), we found three types of antennal lobe projection neurons, among which two are novel. In addition, we resolved 17 other types of MBENs that arborize in the calyx, lobes, and pedunculus. Lobe‐associated MBENs arborize in only specific areas of the lobes, being restricted along their longitudinal axes, forming two to five segmented zones in each lobe. The laminar arrangement of the Kenyon cell axons and segmented organization of the MBENs together divide the lobes into smaller synaptic units, possibly facilitating characteristic interaction between intrinsic and extrinsic neurons in each unit for different functional activities along the longitudinal lobe axes and between lobes. Structural differences between lobes are also discussed. J. Comp. Neurol. 508:711–755, 2008. © 2008 Wiley‐Liss, Inc.
Afferent connections of septal nuclei of the domestic chick (Gallus domesticus): A retrograde pathway tracing study

The afferents to the septum of the domestic chicken were studied using retrograde tracers, rhodamine conjugated latex bead or Fast Blue, placed in different septal subregions. The results were verified by anterograde tracer injections deposited to selected areas. The main telencephalic afferents to the septum arise ipsilaterally from the hippocampal formation, dorsolateral corticoid area, piriform cortex, amygdaloid pallium, and the ventral pallidum. Contralateral afferents originate from the lateral septum and the amygdaloid pallium. A massive bilateral projection arises from the lateral hypothalamus. Other hypothalamic afferents arise from the periventricular, paraventricular and anterior medial nuclei, and the premammillary and mammillary areas. The dorsal thalamic nuclei (dorsal medial anterior and posterior) and the reticular dorsal nuclei also contribute septal afferents. Brainstem afferents arise bilaterally from the ventral tegmental area, substantia nigra, central gray, A8, locus coeruleus, ventral subcoeruleus nucleus, and raphe nuclei. The main terminal fields for septal afferents lie in the lateral septal nucleus and the belt of medial septal nucleus. The core of the latter is invaded mainly by fibers from the brainstem, presumably belonging to the ascending activating system. The septal afferents of the chicken are largely similar to those of other avian and nonavian species. The most prominent differences with previous pigeon data were found in the subregional selectivity of the hippocampal formation, dorsolateral corticoid area, mammillary nuclei, some dorsal thalamic nuclei, substantia nigra, and subcoeruleus nuclei in their projections to defined septal nuclei. J. Comp. Neurol. 511:109–150, 2008. © 2008 Wiley‐Liss, Inc.
Molecular Therapeutics for Heritable Skin Diseases

Over the past two decades, there has been tremendous progress in molecular genetics of heritable skin diseases, and as many as 500 distinct human genes are now known to harbor mutations in these diseases (Feramisco et al., 2009). The clinical implications of this progress are evident in the diagnosis and management of these diseases. For example, (a) identification of the specific mutations can be used for confirmation of diagnosis with prognostic implications; (b) identification of mutations has facilitated assessment of the precise mode of inheritance, particularly in cases with no previous family history of the disease; and (c) identification of candidate genes and mutations has formed the basis for DNA-based prenatal testing and preimplantation genetic diagnosis in families at risk for recurrence (Uitto, 2009). However, in spite of significant progress in identification of the molecular bases of heritable skin diseases, there has been relatively little progress until very recently in developing effective and specific treatments. This synopsis will highlight some of the milestones in progress towards treatment and cure of heritable skin diseases, primarily focusing on epidermolysis bullosa (EB) as a paradigm of such conditions, with emphasis on development of gene-, protein-, and cell-based molecular strategies just entering the clinical arena (Uitto et al., 2012).
RECOMMENDATIONS FOR STANDARDS IN TRANSTHORACIC TWO-DIMENSIONAL ECHOCARDIOGRAPHY IN THE DOG AND CAT*

Recommendations are presented for standardized imaging planes and display conventions for two-dimensional echocardiography in the dog and cat. Three transducer locations (“windows”) provide access to consistent imaging planes: the right parasternal location, the left caudal (apical) parasternal location, and the left cranial parasternal location. Recommendations for image display orientations are very similar to those for comparable human cardiac images, with the heart base or cranial aspect of the heart displayed to the examiner's right on the video display. From the right parasternal location, standard views include a long-axis four-chamber view and a long-axis left ventricular outflow view, and short-axis views at the levels of the left ventricular apex, papillary muscles, chordae tendineae, mitral valve, aortic valve, and pulmonary arteries. From the left caudal (apical) location, standard views include long-axis two-chamber and four-chamber views. From the left cranial parasternal location, standard views include a long-axis view of the left ventricular outflow tract and ascending aorta (with variations to image the right atrium and tricuspid valve, and the pulmonary valve and pulmonary artery), and a short-axis view of the aortic root encircled by the right heart. These images are presented by means of idealized line drawings. Adoption of these standards should facilitate consistent performance, recording, teaching, and communicating results of studies obtained by two-dimensional echocardiography.
Retinal ganglion cells in the eastern newt Notophthalmus viridescens: Topography, morphology, and diversity

The topography and morphology of retinal ganglion cells (RGCs) in the eastern newt were studied. Cells were retrogradely labeled with tetramethylrhodamine‐conjugated dextran amines or horseradish peroxidase and examined in retinal wholemounts. Their total number was 18,025 ± 3,602 (mean ± SEM). The spatial density of RGCs varied from 2,100 cells/mm2 in the retinal periphery to 4,500 cells/mm2 in the dorsotemporal retina. No prominent retinal specializations were found. The spatial resolution estimated from the spatial density of RGCs varied from 1.4 cycles per degree in the periphery to 1.95 cycles per degree in the region of the peak RGC density. A sample of 68 cells was camera lucida drawn and subjected to quantitative analysis. A total of 21 parameters related to RGC morphology and stratification in the retina were estimated. Partitionings obtained by using different clustering algorithms combined with automatic variable weighting and dimensionality reduction techniques were compared, and an effective solution was found by using silhouette analysis. A total of seven clusters were identified and associated with potential cell types. Kruskal‐Wallis ANOVA‐on‐Ranks with post hoc Mann‐Whitney U tests showed significant pairwise between‐cluster differences in one or more of the clustering variables. The average silhouette values of the clusters were reasonably high, ranging from 0.52 to 0.79. Cells assigned to the same cluster displayed similar morphology and stratification in the retina. The advantages and limitations of the methodology adopted are discussed. The present classification is compared with known morphological and physiological RGC classifications in other salamanders. J. Comp. Neurol. 516:533–552, 2009. © 2009 Wiley‐Liss, Inc.
SynCAM1 expression correlates with restoration of central synapses on spinal motoneurons after two different models of peripheral nerve injury

SynCAM1 and neuroligins (NLGs) are adhesion molecules that govern synapse formation in vitro. In vivo, the molecules are expressed during synaptogenesis, and altered NLG function is linked to synapse dysfunction in autism. Less is known about SynCAM1 and NLGs in adult synapse remodeling. CNS synapse elimination occurs after peripheral nerve injury, which causes a transient decrease in synapse number on spinal motoneurons. Here we have studied the expression of SynCAM1 and NLGs in relation to changes in synaptic covering on spinal motoneurons. We performed sciatic nerve transection (SNT) or crush (SNC), axotomy models that result in poor or good conditions for axon regeneration, respectively. The two lesions resulted in similar synapse elimination and in poor (SNT) and good (SNC) return of synapses after 70 days. Functional recovery was good after SNC but absent after SNT. SynCAM1 mRNA decreased after 14 days in both models and was restored 70 days after SNC, but not after SNT. NLG2 and ‐3 mRNAs decreased to a smaller degree after SNC than after SNT. Synaptophysin immunoreactivity correlated with SynCAM1 mRNA 70 days after SNT and NLG2 mRNA 70 days after SNC. Surprisingly, an inverse correlation was seen between NLG3 mRNA and Vglut2, a marker for excitatory synapses, 70 days after SNT. We conclude that 1) SynCAM1 mRNA levels seem to reflect the loss and restoration of synapses on motoneurons, 2) down‐regulation of NLGs is not a prerequisite for synapse elimination, and 3) expression of SynCAM1 and NLGs is regulated by different mechanisms during regeneration. J. Comp. Neurol. 517:670–682, 2009. © 2009 Wiley‐Liss, Inc.
Localization of relaxin‐3 in brain of Macaca fascicularis: Identification of a nucleus incertus in primate

Relaxin‐3 (RLN3) is a highly conserved, ancestral member of the insulin/relaxin peptide family. RLN3 mRNA is highly expressed in rat, mouse, and human brain and molecular genetic and pharmacological studies suggest that RLN3 is the cognate ligand for the relaxin family peptide‐3 receptor (RXFP3). The distribution of RLN3/RXFP3 networks has been determined in rat and mouse brain, but not in higher species. In this study we describe the distribution of RLN3 neurons in the brain of macaque (Macaca fascicularis) using in situ hybridization histochemistry and immunohistochemistry. RLN3 mRNA and high levels of RLN3‐like immunoreactivity (‐LI) were observed in neurons within a ventromedial region of the central gray of the pons and medulla that appears to represent the primate analog of the nucleus incertus (NI) described in lower species. Nerve fibers and terminals containing RLN3‐LI were observed throughout brain regions identical to those known to receive afferents from the NI in the rat, including the septum, hippocampus, entorhinal cortex, lateral, dorsomedial and ventromedial hypothalamus, supramammillary and interpeduncular nuclei, anterodorsal, paraventricular and reuniens thalamic nuclei, lateral habenula, central gray, and dorsal raphe, solitary tract, and ambiguus nuclei. Experimental studies in the rat strongly implicate a role of this neuropeptide‐receptor system in arousal, feeding, and metabolism, learning and memory, and central responses to psychological stressors. These new anatomical findings support the proposition that the RLN3 system is similarly involved in the integration and modulation of behavioral activation and arousal and responses to stress in nonhuman primates and humans. J. Comp. Neurol. 517:856–872, 2009. © 2009 Wiley‐Liss, Inc.
Structural alterations of spiny stellate cells in the somatosensory cortex in ephrin‐A5‐deficient mice

Previous studies demonstrated that in ephrin‐A5‐deficient mice corticothalamic arbors are reduced by more than 50% in layer 4 of the somatosensory cortex (S1), where ephrin‐A5 is normally expressed. Here we examined possible consequences of the reduced thalamic input on spiny stellate cells, the target neurons of thalamocortical afferents. Using ballistic delivery of particles coated with lipophilic dyes in fixed slices and confocal laser‐microscopy, we could quantitatively analyze the morphology of these neurons. Cells were examined in S1 at postnatal day 8 (P8), when thalamic afferents establish synaptic contacts and the dendrites of their target cells are covered with filopodia, and at P23, after synapse formation and replacement of filopodia by spines. Our results indicate that at P8 the dendrites of cells in mutant animals exhibit more filopodia and are more branched than dendrites of wildtype cells. In contrast, there is no difference in the extent of the dendritic tree between knockout and control animals. At P23, dendrites of neurons in ephrin‐A5‐deficient mice are still more branched, but possess fewer spines than wildtype cells. Thus, at early stages layer 4 neurons appear to compensate the reduced thalamic input by increasing dendritic branching and the density of filopodia. However, while at later stages the dendrites of layer 4 neurons in mutants are still more branched, their spine density is now lower than in wildtype cells. Taken together, these data demonstrate that the structure of spiny stellate cells is shaped by thalamic input and Eph receptor signaling. J. Comp. Neurol. 517:645–654, 2009. © 2009 Wiley‐Liss, Inc.
Altered balance of γ‐aminobutyric acidergic and glutamatergic afferent inputs in rostral ventrolateral medulla‐projecting neurons in the paraventricular nucleus of the hypothalamus of renovascular hypertensive rats

An imbalance of excitatory and inhibitory functions has been shown to contribute to numerous pathological disorders. Accumulating evidence supports the idea that a change in hypothalamic γ‐aminobutyric acid (GABA)‐ergic inhibitory and glutamatergic excitatory synaptic functions contributes to exacerbated neurohumoral drive in prevalent cardiovascular disorders, including hypertension. However, the precise underlying mechanisms and neuronal substrates are still not fully elucidated. In the present study, we combined quantitative immunohistochemistry with neuronal tract tracing to determine whether plastic remodeling of afferent GABAergic and glutamatergic inputs into identified RVLM‐projecting neurons of the hypothalamic paraventricular nucleus (PVN‐RVLM) contributes to an imbalanced excitatory/inhibitory function in renovascular hypertensive rats (RVH). Our results indicate that both GABAergic and glutamatergic innervation densities increased in oxytocin‐positive, PVN‐RVLM (OT‐PVN‐RVLM) neurons in RVH rats. Despite this concomitant increase, time‐dependent and compartment‐specific differences in the reorganization of these inputs resulted in an altered balance of excitatory/inhibitory inputs in somatic and dendritic compartments. A net predominance of excitatory over inhibitory inputs was found in OT‐PVN‐RVLM proximal dendrites. Our results indicate that, along with previously described changes in neurotransmitter release probability and postsynaptic receptor function, remodeling of GABAergic and glutamatergic afferent inputs contributes as an underlying mechanism to the altered excitatory/inhibitory balance in the PVN of hypertensive rats. J. Comp. Neurol. 518:567–585, 2010. © 2009 Wiley‐Liss, Inc.