Inhibition of nitric oxide synthesis extends cerebrovascular autoregulation during hypertension

In anesthetized intact rats, cerebral blood flow is autoregulated until mean arterial blood pressure (MAP) exceeds 150 mmHg. At higher pressures cerebral blood flow breaks through autoregulation and rapidly increases. However, interruption of the arterial baroreceptor reflex eliminates breakthrough of autoregulation. Thus, breakthrough may reflect active rather than passive vasodilatation. We, therefore, sought to determine if breakthrough depends upon synthesis of the vasodilator nitric oxide. Thirty-eight anesthetized adult male Sprague-Dawley rats were studied. In all, MAP was raised by slow i.v. infusion of phenylephrine. In rats pretreated with the nitric oxide synthase inhibitor L-nitroarginine (L-NA; 22 mg/kg i.v.) or with a combination of L-NA plus D-arginine (D-Arg; 240 mg/kg i.v.), breakthrough did not occur even when MAP exceeded 185 mmHg (L-NA) and 165 mmHg (D-Arg). In contrast, breakthrough occurred in rats treated with L-NA plus L-arginine (L-Arg; 240 mg/kg i.v.) and in rats whose basal vascular tone had been increased by pretreatment with arginine vasopressin prior to infusion of phenylephrine. Removal of sympathetic innervation to cerebral vessels attenuated, but did not eliminate, effects of L-NA on breakthrough. Thus, vasodilatation seen with breakthrough of autoregulation depends upon release of nitric oxide or a nitric oxide donor.     

Phenotypic diversity and kinetics of proliferating microglia and astrocytes following cortical stab wounds

Brain injury induces reactive gliosis, characterized by increased expression of glial fibrillary acidic protein (GFAP), astrocyte hypertrophy, and hyperplasia of astrocytes and microglia. One hypothesis tested in this study was whether ganglioside GD3+ glial precursor cells would contribute to macroglial proliferation following injury. Adult rats received a cortical stab wound. Proliferating cells were identified by immunostaining for proliferating cell nuclear antigen (PCNA) and by [3H]-thymidine autoradiography, and cell phenotypes by immunocytochemical staining for GD3, GFAP, ED1 (for reactive microglia) and for Bandeiraea Simplicifolia isolectin-B4 binding (all microglia). Animals were labeled with thymidine at 1,2,3, and 4 days postlesion (dpl) and sacrificed at various times thereafter. Proliferating cells of each phenotype were quantified. A dramatic upregulation of GD3 on ramified microglia was seen in the ipsilateral hemisphere by 2 dpl. Proliferating cells consisted of microglia and fewer astrocytes. Microglia proliferated maximally at 2-3 dpl and one third to one half were GD3+. Astrocytes proliferated maximally at 3-4 dpl, and some were also GD3+. Both ramified and ameboid forms of microglia proliferated and by 4 dpl all GD3+ microglia were ED1+ and vice versa. In the contralateral cortex microglia expressed neither GD3 nor ED1. Thus they acquired these antigens when activated. Neither microglia nor astrocytes that were thymidine-labeled at 2, 3, or 4 dpl changed in number in subsequent days. Most thymidine+ astrocytes were large GFAP+ reactive cells that clearly arose from pre-existing astrocytes, not from GD3+ glial precursors. In this model of injury microglia proliferate earlier and to a much greater extent than astrocytes, they can divide when in ramified form, and GD3 is up-regulated in most reactive microglia and in a subset of reactive astrocytes. We also conclude that microglial proliferation precedes proliferation of invading blood-borne macrophages.     

Single-strand conformational polymorphism analysis of the M(r) 170,000 isozyme of DNA topoisomerase II in human tumor cells

Five cell lines selected for resistance to the cytotoxicity of inhibitors of DNA topoisomerase II have point mutations in the gene that codes for the M(r) 170,000 form of this enzyme. In each case, the mutation results in an amino acid change in or near an ATP binding sequence of the M(r) 170,000 isozyme of topoisomerase II. We used single-strand conformational polymorphism analysis to screen for similar mutations in other drug-resistant cell lines or in leukemic cells from patients previously treated with etoposide or teniposide. We also analyzed the region of the gene that codes for amino acids adjacent to the tyrosine at position 804 of topoisomerase II which binds covalently to DNA. CEM/VM-1, CEM/VM-1-5, and HL-60/AMSA human leukemic cell lines were used as controls; 3 of 3 known mutations were detected by migration differences of polymerase chain reaction products from the RNA extracted from these three lines. A previously unknown mutation was found in the tyrosine 804 region of the M(r) 170,000 topoisomerase II expressed by CEM/VM-1 and CEM/VM-1-5 cells. Sequence analysis showed that substitution of a T for a C at nucleotide 2404 resulted in an amino acid change of a serine for a proline at amino acid 802. No mutations in any of the ATP binding sequences or in the tyrosine 804 region were detected in polymerase chain reaction products from RNA extracted from human leukemia HL-60/MX2 or CEM/MX1 cells (both cell lines selected for resistance to mitoxantrone) or in human myeloma 8226/Dox1V cells (selected for resistance by simultaneous exposure to doxorubicin and verapamil). No mutations were detected in polymerase chain reaction products from RNA extracted from blasts of 15 patients with relapsed acute lymphocytic leukemia, previously treated with etoposide or teniposide. We conclude that: (a) single-strand conformational polymorphism analysis is useful for screening for mutations in topoisomerase II; (b) resistance to the cytotoxicity of inhibitors of DNA topoisomerase II is not always associated with mutations in ATP binding sequences or the active site tyrosine region of M(r) 170,000 topoisomerase II; and (c) mutations similar to those detected in drug resistant cells selected in culture have not been identified in blast cells from patients with relapsed acute lymphocytic leukemia, previously treated with etoposide or teniposide.     

Occipitocervical fusion with a five-millimeter malleable rod and segmental fixation

Although occipitocervical fusion is frequently used for instability of the upper cervical spine and the occipitocervical articulation, most currently used techniques have one or more of the following disadvantages: the necessity for sublaminar wires, the use of occipital screws, a fixed angle of instrumentation, or the necessity for routine postoperative halo immobilization. Moreover, many reported techniques are associated with a high rate of nonunion or instrumentation failure. We present our experience with a technically simple method of obtaining rigid occipitocervical arthrodesis using a 5-mm malleable rod that is fixed to the skull by a pair of wires passed through four suboccipital burr holes. Segmental spinal fixation is achieved with Wisconsin interspinous wires and is occasionally supplemented with sublaminar wires. Supplemental autogenous bone graft is used in all cases. A cervical collar is routinely used for postoperative immobilization. The results of treatment were retrospectively reviewed in 16 patients with an average age of 49.4 years (range, 9-69). Mean follow-up was 24 months (range, 12-36 mo). The indication for fusion was instability of the occiput-C1-C2 complex as a result of Chiari malformation, rheumatoid disease, skull base tumor resection, basilar invagination, ankylosing spondylitis, Down's syndrome, cervical laminectomy, and trauma. The average number of levels fused was 5.4 (range, O-C3 to O-T3). Successful occipitocervical arthrodesis was achieved in all but one of the surviving patients. The single patient with a pseudarthrosis was successfully managed with supplemental bone grafting and halo immobilization. There were two deaths from medical complications in chronically ill patients. Other complications included one postoperative instrumentation loosening, one myocardial infarction, and one superficial occipital decubitus. In conclusion, rodding and segmental interspinous wiring is an effective, technically simple method of obtaining rigid occipitocervical fixation, which obviates the need for bulky orthoses.     

2-Hydroxypropyl-beta-cyclodextrin enhances phorbol ester effects on glucose transport and/or protein kinase C-beta translocation to the plasma membrane in rat adipocytes and soleus muscles

In rat adipocytes and soleus muscles, 2-hydroxypropyl-beta-cyclodextrin (CD) was found to have a relatively small or no effect on basal or insulin-stimulated hexose uptake, but markedly enhanced hexose uptake effects of phorbol esters and/or diacylglycerol. In rat adipocytes, the CD-induced enhancement of hexose uptake during concurrent phorbol ester treatment was not associated with an increase in GLUT4 glucose transporter translocation to the plasma membrane, which was stimulated comparably by insulin and phorbol esters. Moreover, CD appeared to activate or facilitate the activation of glucose transporters subsequent to their translocation to the plasma membrane during ongoing phorbol ester treatment. In rat adipocytes, CD also enhanced the translocation of protein kinase C (PKC)-beta to the plasma membrane during the action of phorbol esters, which alone had little or no effect on this specific PKC translocation. Although it is uncertain how CD alters the function of plasma membranes to enhance the translocation of PKC-beta to, and the activation of glucose transporters within, this subcellular fraction during phorbol ester treatment, our findings provide direct support for a two-step model in the activation of glucose transport. In addition, it seems clear that, at least in some cell types, simple phorbol ester treatment does not necessarily serve as a ubiquitous activator of all activable PKC pools and all potential PKC-mediated responses.     

Antecedents and outcomes of work-family conflict: Testing a model of the work-family interface.

A comprehensive model of the work–family interface was developed and tested. The proposed model extended prior research by explicitly distinguishing between work interfering with family and family interfering with work. This distinction allowed testing of hypotheses concerning the unique antecedents and outcomes of both forms of work–family conflict and a reciprocal relationship between them. The influence of gender, race, and job type on the generalizability of the model was also examined. Data were obtained through household interviews with a random sample of 631 individuals. The model was tested with structural equation modeling techniques. Results were strongly supportive. In addition, although the model was invariant across gender and race, there were differences across blue- and white-collar workers. Implications for future research on the work–family interface are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prolonged poststrike elevation in tongue-flicking rate with rapid onset in gila monster,Heloderma suspectum: Relation to diet and foraging and implications for evolution of chemosensory searching

Experimental tests showed that poststrike elevation in tongue-flicking rate (PETF) and strike-induced chemosensory searching (SICS) in the gila monster last longer than reported for any other lizard. Based on analysis of numbers of tongue-flicks emitted in 5-min intervals, significant PETF was detected in all intervals up to and including minutes 41–45. Using 10-min intervals, PETF lasted though minutes 46–55. Two of eight individuals continued tongue-flicking throughout the 60 min after biting prey, whereas all individuals ceased tongue-flicking in a control condition after minute 35. The apparent presence of PETF lasting at least an hour in some individuals suggests that there may be important individual differences in duration of PETF. PETF and/or SICS are present in all families of autarchoglossan lizards studied except Cordylidae, the only family lacking linguallly mediated prey chemical discrimination. However, its duration is known to be greater than 2-min only in Helodermatidae and Varanidae, the living representatives of Varanoidea. That prolonged PETF and SICS are typical of snakes provides another character supporting a possible a varanoid ancestry for Serpentes. Analysis of 1-min intervals showed that PETF occurred in the first minute. A review of the literature suggests that a pause in tongue-flicking and delay of searching movements are absent in lizards and the few nonvenomous colubrid snakes tested. The delayed onset of SICS may be a specific adaptation of some viperid snakes to allow potentially dangerous prey to be rendered harmless by venom following voluntary release after envenomation and preceding further physical contact with the prey.     

Continuous extrapleural intercostal nerve block for post thoracotomy analgesia in children

The influence of the nicotine antagonist dihydro-beta-erythroidine (DH beta E) was examined on various behavioural effects of nicotine in rats. Motor activity was recorded in photocell cages whereas discriminative stimulus effects were examined using two-lever drug discrimination procedures with a tandem schedule of food reinforcement (n = 8 throughout). DH beta E (0.1-3.2 mg/kg) failed to antagonise the decreases in motor activity that nicotine (0.4-0.6 mg/kg) produced in experimentally naive rats, whereas mecamylamine (1.5 mg/kg) completely blocked this effect of nicotine. DH beta E (0.1-3.2 mg/kg) antagonised the increases in motor activity that nicotine (0.4 mg/kg) produced in rats with extensive previous exposure to both nicotine and the photocell apparatus. In rats trained to discriminate either 0.1 or 0.4 mg/kg nicotine from saline, DH beta E (0.1-3.2 mg/kg) blocked the discriminative stimulus effect of nicotine. The block of the discriminative effect could be reversed by increasing the dose of nicotine; DH beta E (1.6 mg/kg) shifted the dose-response curve for nicotine discrimination to the right by a factor of 9.4. In addition, nicotine in doses of 0.32-0.64 mg/kg decreased the overall rate of lever pressing but DH beta E (1.6 mg/kg) did not influence the dose-response curve for this effect. Thus, DH beta E potently blocked the locomotor activating and discriminative stimulus effects of nicotine at doses that did not antagonise its locomotor depressant and operant response rate-reducing effects. This selective blockade supports the involvement of different subtypes of nicotinic receptor in the mediation of diverse behavioural effects. Furthermore, the rightward shift of the dose-response curve for nicotine discrimination suggested a competitive mode of action for DH beta E.