On the Importance of Countergradients for the Development of Retinotopy: Insights from a Generalised Gierer Model

During the development of the topographic map from vertebrate retina to superior colliculus (SC), EphA receptors are expressed in a gradient along the nasotemporal retinal axis. Their ligands, ephrin-As, are expressed in a gradient along the rostrocaudal axis of the SC. Countergradients of ephrin-As in the retina and EphAs in the SC are also expressed. Disruption of any of these gradients leads to mapping errors. Gierer's (1981) model, which uses well-matched pairs of gradients and countergradients to establish the mapping, can account for the formation of wild type maps, but not the double maps found in EphA knock-in experiments. I show that these maps can be explained by models, such as Gierer's (1983), which have gradients and no countergradients, together with a powerful compensatory mechanism that helps to distribute connections evenly over the target region. However, this type of model cannot explain mapping errors found when the countergradients are knocked out partially. I examine the relative importance of countergradients as against compensatory mechanisms by generalising Gierer's (1983) model so that the strength of compensation is adjustable. Either matching gradients and countergradients alone or poorly matching gradients and countergradients together with a strong compensatory mechanism are sufficient to establish an ordered mapping. With a weaker compensatory mechanism, gradients without countergradients lead to a poorer map, but the addition of countergradients improves the mapping. This model produces the double maps in simulated EphA knock-in experiments and a map consistent with the Math5 knock-out phenotype. Simulations of a set of phenotypes from the literature substantiate the finding that countergradients and compensation can be traded off against each other to give similar maps. I conclude that a successful model of retinotopy should contain countergradients and some form of compensation mechanism, but not in the strong form put forward by Gierer

Ventilatory drive and the apnea-hypopnea index in six-to-twelve year old children

BACKGROUND: We tested the hypothesis that ventilatory drive in hypoxia and hypercapnia is inversely correlated with the number of hypopneas and obstructive apneas per hour of sleep (obstructive apnea hypopnea index, OAHI) in children. METHODS: Fifty children, 6 to 12 years of age were studied. Participants had an in-home unattended polysomnogram to compute the OAHI. We subsequently estimated ventilatory drive in normoxia, at two levels of isocapnic hypoxia, and at three levels of hyperoxic hypercapnia in each subject. Experiments were done during wakefulness, and the mouth occlusion pressure measured 0.1 seconds after inspiratory onset (P(0.1)) was measured in all conditions. The slope of the relation between P(0.1 )and the partial pressure of end-tidal O(2 )or CO(2 )(P(ET)O(2 )and P(ET)CO(2)) served as the index of hypoxic or hypercapnic ventilatory drive. RESULTS: Hypoxic ventilatory drive correlated inversely with OAHI (r = -0.31, P = 0.041), but the hypercapnic ventilatory drive did not (r = -0.19, P = 0.27). We also found that the resting P(ET)CO(2 )was significantly and positively correlated with the OAHI, suggesting that high OAHI values were associated with resting CO(2 )retention. CONCLUSIONS: In awake children the OAHI correlates inversely with the hypoxic ventilatory drive and positively with the resting P(ET)CO(2). Whether or not diminished hypoxic drive or resting CO(2 )retention while awake can explain the severity of sleep-disordered breathing in this population is uncertain, but a reduced hypoxic ventilatory drive and resting CO(2 )retention are associated with sleep-disordered breathing in 6–12 year old children

A review of the current treatment methods for posthaemorrhagic hydrocephalus of infants

Posthaemorrhagic hydrocephalus (PHH) is a major problem for premature infants, generally requiring lifelong care. It results from small blood clots inducing scarring within CSF channels impeding CSF circulation. Transforming growth factor – beta is released into CSF and cytokines stimulate deposition of extracellular matrix proteins which potentially obstruct CSF pathways. Prolonged raised pressures and free radical damage incur poor neurodevelopmental outcomes. The most common treatment involves permanent ventricular shunting with all its risks and consequences

The CD14+/lowCD16+ monocyte subset is more susceptible to spontaneous and oxidant-induced apoptosis than the CD14+CD16− subset

Human monocytes can be classified into two subsets with distinctive characteristics. In this study, we report a difference in apoptotic potential between these two subsets with CD14+/lowCD16+ monocytes being more susceptible than CD14+CD16− monocytes to undergo spontaneous apoptosis and apoptosis induced by reactive oxygen species (ROS). By global transcriptomic and proteomic approaches, we observed that CD14+/lowCD16+ monocytes expressed higher levels of pro-apoptotic genes and proteins such as TNFα, caspase 3, Bax and cytochrome c and showed more caspases 3 and 7 activities. They also exhibited greater aerobic respiration resulting in a higher production of ROS from the mitochondria. CD14+CD16− monocytes, in contrast, showed higher expression of glutathione (GSH)-metabolizing genes such as GSH peroxidase and microsomal GSH S-transferase and were more resistant to oxidative stress than CD14+/lowCD16+ monocytes. The apoptosis of CD14+/lowCD16+ monocytes was ROS dependent as reducing ROS levels significantly reduced cell death. This is the first report of a differential apoptotic propensity of human monocyte subsets, and gaining a better understanding of this process may help to provide a better understanding of the roles of these subsets during homeostasis and under pathological conditions, particularly in situations in which high levels of oxidants are present

Production of Transgenic Pigs Mediated by Pseudotyped Lentivirus and Sperm

Sperm-mediated gene transfer can be a very efficient method to produce transgenic pigs, however, the results from different laboratories had not been widely repeated. Genomic integration of transgene by injection of pseudotyped lentivirus to the perivitelline space has been proved to be a reliable route to generate transgenic animals. To test whether transgene in the lentivirus can be delivered by sperm, we studied incubation of pseudotyped lentiviruses and sperm before insemination. After incubation with pig spermatozoa, 62±3 lentiviral particles were detected per 100 sperm cells using quantitative real-time RT-PCR. The association of lentivirus with sperm was further confirmed by electron microscopy. The sperm incubated with lentiviral particles were artificially inseminated into pigs. Of the 59 piglets born from inseminated 5 sows, 6 piglets (10.17%) carried the transgene based on the PCR identification. Foreign gene and EGFP was successfully detected in ear tissue biopsies from two PCR-positive pigs, revealed via in situ hybridization and immunohistochemistry. Offspring of one PCR-positive boar with normal sows showed PCR-positive. Two PCR-positive founders and offsprings of PCR-positive boar were further identified by Southern-blot analysis, out of which the two founders and two offsprings were positive in Southern blotting, strongly indicating integration of foreign gene into genome. The results indicate that incubation of sperm with pseudotyped lentiviruses can incorporated with sperm-mediated gene transfer to produce transgenic pigs with improved efficiency

Global gene expression analysis of canine osteosarcoma stem cells reveals a novel role for COX-2 in tumour initiation

Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs), which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05), and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation

The HELLP syndrome: Clinical issues and management. A Review

<p>Abstract</p> <p>Background</p> <p>The HELLP syndrome is a serious complication in pregnancy characterized by haemolysis, elevated liver enzymes and low platelet count occurring in 0.5 to 0.9% of all pregnancies and in 10–20% of cases with severe preeclampsia. The present review highlights occurrence, diagnosis, complications, surveillance, corticosteroid treatment, mode of delivery and risk of recurrence.</p> <p>Methods</p> <p>Clinical reports and reviews published between 2000 and 2008 were screened using Pub Med and Cochrane databases.</p> <p>Results and conclusion</p> <p>About 70% of the cases develop before delivery, the majority between the 27th and 37th gestational weeks; the remainder within 48 hours after delivery. The HELLP syndrome may be complete or incomplete. In the Tennessee Classification System diagnostic criteria for HELLP are haemolysis with increased LDH (> 600 U/L), AST (≥ 70 U/L), and platelets < 100·10⁹/L. The Mississippi Triple-class HELLP System further classifies the disorder by the nadir platelet counts. The syndrome is a progressive condition and serious complications are frequent. Conservative treatment (≥ 48 hours) is controversial but may be considered in selected cases < 34 weeks' gestation. Delivery is indicated if the HELLP syndrome occurs after the 34th gestational week or the foetal and/or maternal conditions deteriorate. Vaginal delivery is preferable. If the cervix is unfavourable, it is reasonable to induce cervical ripening and then labour. In gestational ages between 24 and 34 weeks most authors prefer a single course of corticosteroid therapy for foetal lung maturation, either 2 doses of 12 mg betamethasone 24 hours apart or 6 mg or dexamethasone 12 hours apart before delivery. Standard corticosteroid treatment is, however, of uncertain clinical value in the maternal HELLP syndrome. High-dose treatment and repeated doses should be avoided for fear of long-term adverse effects on the foetal brain. Before 34 weeks' gestation, delivery should be performed if the maternal condition worsens or signs of intrauterine foetal distress occur. Blood pressure should be kept below 155/105 mmHg. Close surveillance of the mother should be continued for at least 48 hours after delivery.</p

Pheochromocytoma multisystem crisis treated with emergency surgery: a case report and literature review

Background: Pheochromocytoma is a neuroendocrine tumor that predominantly presents with hypertension, palpitations, and tachycardia due to excessive catecholamine excretion. Although pheochromocytoma multisystem crisis (PMC) is relatively rare, urologists and clinicians should focus on early diagnosis as delay in initiating the appropriate treatment can lead to mortality Case presentation: A 70-year-old man developed ileus after a few days of medication for hypertension. Computed tomography incidentally revealed a left adrenal mass. This finding together with his clinical course was compatible with pheochromocytoma. An α-blocker was administered immediately, and his blood pressure was well controlled. However, his general condition and laboratory data deteriorated rapidly, and the patient was diagnosed with PMC with lethal status. Thus, emergency adrenalectomy was performed without confirmation of catecholamine levels. From the resected specimen, his tumor was judged as pheochromocytoma. On immunohistochemical analysis, the proliferation index evaluated by Ki-67 staining was 9.7 %. This case report was approved by the Human Ethics Review Committee of the Nagasaki University Hospital. Conclusion: The present case of PMC was successfully treated with emergency surgery. The benign pheochromocytoma also presented with high cell proliferation potential, which may be a cause of the extreme aggressiveness of PMC