Why quality of life measures should be used in the treatment of patients with respiratory illness

Treatment of airways disease is directed towards improving patients' health and well-being. Measurements of airways function do not reflect all the disease activity present in the airways that may affect the patient. Spirometry correlates poorly with health. Physicians appear to estimate their patients' health using criteria different from the patients themselves. Quality of life questionnaires provide a method of quantifying the effect of disease on patients' lives. They can summarize a number of aspects of the disease and provide an overall estimate of the effect of disease and benefits due to therapy. They have the potential to identify a threshold response to treatment that may be considered "worthwhile", and allow comparison between therapies with respect to the health gain that each provides.     

Visuospatial neglect: the ultimate deconstruction?

Unilateral visuospatial neglect is now widely acknowledged to be a highly heterogeneous condition: The overt manifestations of visual neglect can vary as a function of task, spatial domain, and mode of response (at least). Double dissociations (sometimes of the strong form) have already been reported between most of the components of what was originally thought to be a relatively stable construct within the visual modality. Nonetheless, throughout successive fractionations of neglect, reported cases of bidirectional task-specific neglect after unilateral brain damage are rare. We now report two such cases. After right hemisphere stroke, the first patient reliably showed severe left neglect on cancellation but right neglect on line bisection. After left hemisphere stroke, the second case showed right neglect on cancellation but left neglect on line bisection. Extensive investigation of case 1 confirmed our previous conjecture that the crucial distinction between these tasks lies in the presence or the absence of an overt target. In contrast to cancellation, line bisection demands the internal computation of the location of the "target" (the midpoint), followed by executing a motor response toward the precise location of that "imaginary" midpoint. The relative attentional and premotor contributions of the intact and damaged hemispheres to these forms of bidirectional neglect are also assessed.     

The coxsackievirus-adenovirus receptor protein can function as a cellular attachment protein for adenovirus serotypes from subgroups A, C, D, E, and F

Attachment of an adenovirus (Ad) to a cell is mediated by the capsid fiber protein. To date, only the cellular fiber receptor for subgroup C serotypes 2 and 5, the so-called coxsackievirus-adenovirus receptor (CAR) protein, has been identified and cloned. Previous data suggested that the fiber of the subgroup D serotype Ad9 also recognizes CAR, since Ad9 and Ad2 fiber knobs cross-blocked each other's cellular binding. Recombinant fiber knobs and 3H-labeled Ad virions from serotypes representing all six subgroups (A to F) were used to determine whether the knobs cross-blocked the binding of virions from different subgroups. With the exception of subgroup B, all subgroup representatives cross-competed, suggesting that they use CAR as a cellular fiber receptor as well. This result was confirmed by showing that CAR, produced in a soluble recombinant form (sCAR), bound to nitrocellulose-immobilized virions from the different subgroups except subgroup B. Similar results were found for blotted fiber knob proteins. The subgroup F virus Ad41 has both short and long fibers, but only the long fiber bound sCAR. The sCAR protein blocked the attachment of all virus serotypes that bound CAR. Moreover, CHO cells expressing human CAR, in contrast to untransformed CHO cells, all specifically bound the sCAR-binding serotypes. We conclude therefore that Ad serotypes from subgroups A, C, D, E, and F all use CAR as a cellular fiber receptor.     

Interactions of EGF, Wnt and HOM-C genes specify the P12 neuroectoblast fate in C. elegans

We investigate how temporal and spatial interactions between multiple intercellular and intracellular factors specify the fate of a single cell in Caenorhabditis elegans. P12, which is a ventral cord neuroectoblast, divides postembryonically to generate neurons and a unique epidermal cell. Three classes of proteins are involved in the specification of P12 fate: the LIN-3/LET-23 epidermal growth factor signaling pathway, a Wnt protein LIN-44 and its candidate receptor LIN-17, and a homeotic gene product EGL-5. We show that LIN-3 is an inductive signal sufficient to promote the P12 fate, and the conserved EGF signaling pathway is utilized for P12 fate specification; egl-5 is a downstream target of the lin-3/let-23 pathway in specifying P12 fate; and LIN-44 and LIN-17 act synergistically with lin-3 in the specification of the P12 fate. The Wnt pathway may function early in development to regulate the competence of the cells to respond to the LIN-3 inductive signal.     

Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas

The goal of multimodality therapy for localized pancreatic cancer is to maximize local-regional disease control and patient survival. In contrast to surgery for other solid tumors, prolonged recovery following pancreaticoduodenectomy may prevent the timely delivery of postoperative adjuvant therapy. Therefore, efforts at The University of Texas, M.D. Anderson Cancer Center have focused on the delivery of chemotherapy and radiation therapy prior to surgery in patients with localized pancreatic cancer. Clinical trials have emphasized the use of altered-fractionation schedules of radiation therapy combined with novel radiation-sensitizing agents. All treatment schemes aim to decrease toxicity and treatment time while improving therapeutic efficacy.     

Alpha-2 adrenoceptor subtype causing nitric oxide-mediated vascular relaxation in rats

The alpha-2 adrenoceptor subtype and its signal transduction pathway mediating vascular relaxation in rats were studied in vitro using rings of superior mesenteric arteries. Removal of endothelium or incubation with NG-nitro-L-arginine completely blocked relaxant responses to UK14,304, suggesting endothelium-derived nitric oxide mediates relaxation. The order of potency for full (F) or partial (P) agonists causing relaxation was guanabenz (P) > UK14,304 (F) > clonidine (P) > epinephrine (F) > norepinephrine (F). Affinities (Ka) of alpha-2 adrenoceptor subtype-selective drugs for blocking relaxation were obtained in side-by-side experiments comparing rat mesenteric arteries with pig coronary arteries. Relaxation of pig coronary arteries is known to be mediated by the alpha-2A adrenoceptor subtype. Ka values in nM for rauwolscine (19), WB-4101 (265), SKF-104078 (197), spiroxatrine (128), and prazosin (1531) for blocking relaxation in rat arteries were consistent with their affinities for binding at the alpha-2D adrenoceptor subtype. Ka values for rauwolscine and WB-4101, drugs distinguishing the alpha-2D from the alpha-2A adrenoceptor subtype, were significantly higher in blocking relaxation of rat arteries compared with pig arteries, suggesting the alpha-2D adrenoceptor subtype mediates NO-induced relaxation in rat arteries. We used forskolin to oppose alpha-2 adrenoceptor-mediated inhibition of cAMP formation by directly stimulating cAMP formation in endothelium. Forskolin did not affect the relaxant response to UK14,304, suggesting that cAMP is not involved in the coupling of alpha-2 adrenoceptors to nitric oxide-induced vascular relaxation.     

A novel phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase associates with the interleukin-3 receptor

To gain insight into the intracellular signaling cascades that are activated by the binding of interleukin-3 (IL-3) to its target cells, we have embarked on the identification of proteins that are associated with the IL-3 receptor (IL-3R). In a previous study we reported that a 110-kDa serine/threonine protein kinase is constitutively associated with the IL-3R and activated following IL-3 stimulation. We now report that a phosphatidylinositol-3,4, 5-trisphosphate (PtdIns-3,4,5-P3) 5-phosphatase (5-ptase) is also constitutively associated with the IL-3R. This 5-ptase is magnesium-dependent and removes the 5-position phosphate from PtdIns-3,4,5-P3 but does not metabolize PtdIns-4,5-P2, inositol (Ins)-1,3,4,5-P4, or Ins-1,4,5-P3. This substrate specificity distinguishes it from any previously characterized 5-ptase. Interestingly, it may be bound indirectly via phosphatidylinositol 3-kinase (PI 3-kinase), another enzyme that is constitutively bound to the IL-3R. However, unlike PI 3-kinase which becomes activated following IL-3 stimulation, this receptor-associated 5-ptase activity does not increase following IL-3 stimulation, and its primary function may be to keep the principal in vivo product of PI 3-kinase, PtdIns-3,4,5-P3, at low levels in unstimulated cells, to terminate the PI 3-kinase signal following IL-3 stimulation or to metabolize PtdIns-3,4,5-P3 to a metabolically active second messenger, i.e. PtdIns-3,4-P2.     

Impaired interleukin-12 production is associated with a defective anti-tumor response in colorectal cancer

OBJECTIVE: Spontaneous spinal epidural hematoma (SSEH) is an idiopathic accumulation of blood in the vertebral epidural space without identifiable predisposing factors. First reported in 1869, the clinical outcome in children younger than 18 years old has not been clearly delineated. DESIGN: A comprehensive review of the English language literature revealed 26 patients younger than 18 years old with reported clinical outcomes. The 27th case is presented. RESULTS: Complete neurologic recovery occurred in 14 of 27 (52%) patients, partial recovery in 12 of 27 (44%) patients, and death in 1 of 27 (4%) patients. CONCLUSION: There is an overall good prognosis for neurologic recovery in children who experience SSEH.     

Hypoxia-ischemia induces a rapid elevation of ubiquitin conjugate levels and ubiquitin immunoreactivity in the immature rat brain

Postnatal rats at 7 and 21 days of age were subjected to unilateral hypoxia-ischemia (H/I) by right carotid artery ligation followed by 1.5 to 2 hours of hypoxia (8% oxygen). Brains were frozen at specific intervals of recovery from 0 to 24 hours. Western blots of samples of right and left forebrain were immunodeveloped with a monoclonal antibody specific for ubiquitin, RHUb1. An elevation of ubiquitin conjugate levels in the right compared with the left forebrain of 7-day-old animals was detectable immediately following H/I and increased by close to 60% of control level within 1 hour of recovery. The conjugate immunoreactivity remained at this level for 6 hours but had declined to control levels by 24 hours of recovery. No such increase was observed in response to hypoxia alone. Similar changes were observed in samples from the 21-day-old rat brain. However, the elevation of ubiquitin conjugate levels was of slower onset and persisted longer than observed for the 7-day-old animals. Immunocytochemical studies of brain fixed by immersion in formaldehyde/acetone/methanol showed that ubiquitin-like immunoreactivity was increased in the right, but not left, cerebral cortex and hippocampus of animals subjected to H/I. The data suggest that elevated ubiquitination may represent a neuroprotective response to H/I.