Effect of acute hypoglycemia on visual information processing in adults with type 1 diabetes mellitus

Acute hypoglycemia in people with type 1 (insulin-dependent) diabetes mellitus causes general impairment in cognitive performance. The effects on more specific cognitive processes are less well defined. Acute hypoglycemia has been shown to impair visual information processing in nondiabetic human subjects and has now been examined in 16 adult subjects with type 1 diabetes. All subjects had normal visual acuity and no diabetic retinopathy, and their median (range) age was 24 (18-47) years with a median (range) duration of type 1 diabetes of 8 (2-18) years and a mean (SD) HbA1c of 8.5 (1.3)%. A hyperinsulinemic glucose clamp technique was used to maintain arterialized blood glucose at 5.0 mmol l(-1), and on separate test days, either euglycemia was continued or hypoglycemia (2.6 mmol l(-1)) was induced. During each condition subjects performed tests of visual processing and cognitive function. Hypoglycemia caused a significant disruption in general cognitive ability as assessed by digit symbol (p < 0.001) and trail-making B (p < 0.05) tasks. Conventional measures of visual acuity were unaffected by hypoglycemia, but visual information processing deteriorated significantly as indexed by inspection time (p < 0.005) and visual change detection (p < 0.01). Contrast sensitivity tended to deteriorate during hypoglycemia (p = 0.06). In conclusion, hypoglycemia impairs important aspects of early visual information processing and contrast sensitivity in adults with type 1 diabetes. Further research is needed to evaluate the functional relevance of such changes for everyday tasks that require the intake of visual information at speed and under conditions of low contrast.     

Suppression of tumorigenicity and metastasis of human renal carcinoma cells by infection with retroviral vectors harboring the murine inducible nitric oxide synthase gene

The purpose of this study was to determine whether retrovirus-mediated transfer of the murine macrophage inducible nitric oxide synthase (iNOS) gene can inhibit tumorigenicity and metastasis of human renal cancer cells. Retroviral vectors encoding murine macrophage iNOS were constructed in the pLXSN retroviral vector with the iNOS gene under the control of a long terminal repeat promoter and a neomycin resistance gene under the control of an internal simian virus 40 promoter. Highly metastatic human renal carcinoma SN12PM6 cells were infected with control or iNOS retrovirus. Expression of iNOS was confirmed by Northern and Western blot analyses, and expression of the functional iNOS protein, i.e., production of nitric oxide (NO), was determined by measuring nitrite accumulation in culture supernatants. Noninfected or control cells produced large orthotopic tumors in the kidney of nude mice and a larger number of experimental lung metastases, whereas iNOS-infected cells produced small tumors in the kidneys and few to no lung metastases. The data indicate that the infection of human renal cancer cells by retroviruses harboring the murine iNOS gene can induce the production of high levels of NO, which is associated with autocytotoxicity, suppression of tumorigenicity, and abrogation of metastasis.     

Behavior and behavioral needs

An understanding of behavior is important in any consideration of poultry welfare. Behavior is a good indicator of states of suffering such as fear, frustration, and pain. It might also be possible to use social interactions as indicators of welfare. The possibility of using "luxury" behavior, such as play and exploratory behavior, as an indicator of positive emotional states, requires investigation. Important welfare consequences arise from the fact that some behavior may be so strongly motivated as to constitute a "need". A behavioral need will arise in the case of behavior, such as nesting, that is controlled largely by internal factors, because these factors will be present no matter what type of environment is provided. Behavior triggered largely by external stimuli, such as responses to predators, will not give rise to a need if the external factors can be removed from the environment. Dustbathing is an example of behavior controlled by complex interactions between internal and external factors; the extent to which this constitutes a need is still being debated. If a behavioral need arises, then it is important that the environment provided allows it to be performed without damage to the performer or other birds. It should also be remembered that birds may need to perform behavior, including appetitive as well as consummatory elements, although the functional consequences of these are no longer required for survival. Finally, the performance of certain behavior leads to an increase in health or physical condition that improves welfare later in life.     

Conduct of phase I trials in children with cancer

PURPOSE AND METHODS: Future progress in the care of children with cancer requires appropriate evaluations of promising new agents for pediatric indications, beginning with well-conducted phase I trials. This report summarizes current guidelines for the conduct of pediatric phase I trials and represents a consensus between American and European investigators. The primary objective of pediatric phase I trials is to define safe and appropriate doses and schedules of new agents that can subsequently be used in phase II trials to test for activity against specific childhood malignancies. Prioritization of agents for evaluation in children is critical, since many more investigational agents are evaluated in adult patients than can be systematically evaluated in children. Considerations used in prioritizing agents include activity in xenograft models, novel mechanism of action, favorable drug-resistance profile, and activity observed in adult trials of the agent. RESULTS AND CONCLUSION: Distinctive characteristics of pediatric phase I trials, in comparison to adult phase I trials, include the necessity for multiinstitutional participation and their higher starting dose (typically 80% of the adult maximum-tolerated dose [MTD]), both of which reflect the relative unavailability of appropriate patients. The application of uniform eligibility criteria and standard definitions for MTD and dose-limiting toxicity (DLT) help to assure that pediatric phase I trials are safely conducted and reliably identify appropriate doses and schedules of agents for phase II evaluation. Where possible, pediatric phase I trials also define the pharmacokinetic behavior of new agents in children.     

Modulating mechanisms of neuroendocrine cell activity: the LHRH pulse generator

1. Luteinizing hormone-releasing hormone (LHRH), synthesized in specialized neurons in the hypothalamus, is the prime regulator of reproduction. In its absence, reproductive development is arrested and disorders of LHRH secretion result in several reproductive dysfunctions. 2. The LHRH neuronal network plays a paramount role in the regulatory loop controlling gonadal homeostasis. LHRH input to the pituitary gland maintains gonadotropin secretion, which, in turn, is responsible for gonadal trophism. Steroidal and peptidergic hormones from the gonad close the regulatory system by establishing negative (male and females) and positive (females) feedback loops. 3. Interestingly, LHRH input to the pituitary is intermittent rather than continuous. In fact, continuous exposure to LHRH results in paradoxical hypogonadism. Several studies in animals have provided direct evidence for episodic secretion of LHRH into the hypophyseal portal system. However, the nature of the system(s) responsible for the generation of the LHRH pulsatile profile is not currently known. The recent observation that immortalized LHRH neurons secrete LHRH in a pulsatile manner suggests that the pulse generating mechanism resides within the LHRH neuronal network. 4. In this overview, we compile several lines of evidence supporting this notion and put this characteristic of LHRH neurons in perspective with gonadal influences both internal and external to the LHRH neuronal network. Some recent data regarding the site of action of gonadal steroids on the LHRH neuronal system, the functional significance of galanin colocalization with LHRH, and the role of nitric oxide in the pulse generating mechanism are also discussed.     

Regulation of distinct steps of angiogenesis by different angiogenic molecules

This study was designed to determine the relative activity of basic fibroblast growth factor (bFGF), vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), platelet-derived growth factor (PDGF), platelet-derived endothelial cell growth factor (PD-ECGF), hepatocyte growth factor (HGF), and interleukin-8 (IL-8) in regulating endothelial cell division, migration, degradation of the extracellular matrix (ECM), morphogenesis, and survival. Human umbilical vein endothelial cells (HUVEC) were treated with different concentrations of the six cytokines. bFGF was the most potent mitogen followed by VEGF/VPF and PD-ECGF. VEGF/VPF and bFGF also enhanced the survival of the endothelial cells in serum-free medium. Interstitial collagenase (MMP-1) and urokinase plasminogen activator (uPA) were significantly upregulated only by bFGF. HGF, bFGF, and VEGF/VPF induced chemotactic migration of the endothelial cells, but only HGF (scatter factor) enhanced nondirectional motility. The organization of endothelial cells to form tubes on Matrigel was induced by bFGF and, to a lesser extent, by VEGF/VPF and IL-8. Permeability across endothelial cell monolayers was induced only by VEGF/VPF. These data demonstrate that different angiogenic molecules differentially regulate distinct steps in the process of angiogenesis, suggesting that any given molecule may be necessary but in itself insufficient for establishment of a viable vasculature.     

Organization and development of facial motor neurons in the kreisler mutant mouse

The adult facial nerve contains the axons from two populations of efferent neurons. First, the branchiomotor efferent neurons that innervate the muscles of the second arch. These neurons project out of the hindbrain in the motor root and form the facial motor nuclei. Second, the preganglionic efferent neurons that innervate the submandibular and pterygopalatine ganglia. These neurons project from the hindbrain via the intermediate nerve and form the superior salivatory nucleus. The motor neurons of the facial nerve are known to originate within rhombomeres 4 and 5. In the kreisler mouse mutant there is a specific disruption of the hindbrain rhombomeres 5 and 6 appear to be absent. To investigate changes in the organization of the facial motor neurons in this mutant, we have used lipophilic dyes to trace the facial motor components both retrogradely and anterogradely. As expected, facial motor neurons are missing from rhombomere 5 in this mutant. In addition, the loss of these neurons correlates with the specific loss of the superior salivatory nucleus. In contrast, the branchiomeric neurons, that originate in rhombomere 4, appear to develop normally. This includes the caudal migration of their cell bodies forming the genu of the facial nerve. Our studies confirm that rhombomeres are critical to hindbrain development and that they are the fundamental unit at which motor neurons are specified.     

Dependence of aortic pulse wave assessments on behavioural state in normal term fetus

To investigate any influence of behavioural states on the pulse waves in the descending aorta, 21 human fetuses were studied in utero in uncomplicated gestation at the age of 36-41 weeks. The fetal behavioural states were identified using two real-time scanners and one cardiotocograph. The aortic waveform data and pulse wave velocity (PWV) were recorded by means of two double phase-locking echo-trackers. The PWV of the fetal aorta was significantly lower in fetal behavioural state (FBS) 2F than in FBS 1F, when the fetus was apnoeic, and was also reduced in both states during fetal breathing. The calculated pulse pressure showed the same trend as the PWV. The fetal aortic end diastolic diameter and the pulse amplitude did not alter, when the two states changed. Our data suggest that the central haemodynamics in term fetuses are independently influenced by their behavioural state as well as by fetal breathing. The study of pulse waves in the fetal aorta should preferably be performed during apnoea in state 1F, when neither gross body movements nor breathing movements disturb the recording.     

NGF involvement in pain induced by chronic constriction injury of the rat sciatic nerve

Chronic constriction injury (CCI) of the rat sciatic nerve, which within 3 days induces thermal and mechanical hyperalgesia and mechanical allodynia, is used as a model for pain resulting from nerve injury. Involvement of nerve growth factor (NGF) in the development of this hyperalgesia is suggested by the increase in the level of mRNA encoding NGF in cells in the injured area and in dorsal root ganglia at the level of the lesion and the greatly increased NGF levels (determined by ELISA) in the ganglia ipsilateral to the CCI. Application of anti-serum to NGF at the site of CCI delayed the appearance of hyperalgesia, whereas pre-immune serum appeared to enhance it. These results are consistent with the view that NGF is an important factor in the appearance of hyperalgesia associated with unilateral mononeuropathy.     

Exceptional convergent evolution in a virus

Replicate lineages of the bacteriophage phiX 174 adapted to growth at high temperature on either of two hosts exhibited high rates of identical, independent substitutions. Typically, a dozen or more substitutions accumulated in the 5.4-kilobase genome during propagation. Across the entire data set of nine lineages, 119 independent substitutions occurred at 68 nucleotide sites. Over half of these substitutions, accounting for one third of the sites, were identical with substitutions in other lineages. Some convergent substitutions were specific to the host used for phage propagation, but others occurred across both hosts. Continued adaptation of an evolved phage at high temperature, but on the other host, led to additional changes that included reversions of previous substitutions. Phylogenetic reconstruction using the complete genome sequence not only failed to recover the correct evolutionary history because of these convergent changes, but the true history was rejected as being a significantly inferior fit to the data. Replicate lineages subjected to similar environmental challenges showed similar rates of substitution and similar rates of fitness improvement across corresponding times of adaptation. Substitution rates and fitness improvements were higher during the initial period of adaptation than during a later period, except when the host was changed.