Role of a p53 polymorphism in the development of human papillomavirus-associated cancer

The E6 oncoprotein derived from tumour-associated human papillomaviruses (HPVs) binds to and induces the degradation of the cellular tumour-suppressor protein p53. A common polymorphism that occurs in the p53 amino-acid sequence results in the presence of either a proline or an arginine at position 72. The effect of this polymorphism on the susceptibility of p53 to E6-mediated degradation has been investigated and the arginine form of p53 was found to be significantly more susceptible than the proline form. Moreover, allelic analysis of patients with HPV-associated tumours revealed a striking overrepresentation of homozygous arginine-72 p53 compared with the normal population, which indicated that individuals homozygous for arginine 72 are about seven times more susceptible to HPV-associated tumorigenesis than heterozygotes. The arginine-encoding allele therefore represents a significant risk factor in the development of HPV-associated cancers.     

Combined supra/infratentorial-transsinus approach to large pineal region tumors

OBJECT: The authors sought to confirm that the combined supra/infratentorial-transsinus approach offers a safer means of resecting large pineal region tumors than other approaches currently being used. The aforementioned method provides a wider exposure of the pineal region with less brain retraction than the infratentorial-supracerebellar or the occipital-transtentorial approach alone and is applicable to some large and giant tumors of this area. This combined approach was used in six patients to remove large pineal region tumors including four tentorial meningiomas, one pineocytoma, and one epidermoid cyst. METHODS: The transverse sinus and tentorium were sectioned after review of preoperative angiographic studies, after taking intraoperative measurements of the venous pressure in the nondominant transverse sinus before and after clipping and while monitoring the somatosensory evoked potentials. The occipital lobe cortex and cerebellum were retracted slightly along the tentorium. Deep veins of the galenic system, the quadrigeminal area, and the tumor were well exposed. Before it was used for tumor resection the approach was studied in five cadaveric head specimens, and the projection of different approaches was compared radiologically. The tumors were removed in a gross-total manner in all patients, and none of the major veins of the galenic system was injured. Resuturing of the nondominant transverse sinus was performed postoperatively in one patient. One of the six patients experienced transient visual loss, and another suffered mild right sixth cranial nerve paresis; however, both recovered in 3 weeks. The wide exposure of the combined approach was also confirmed on radiological and anatomical studies. CONCLUSIONS: The combined supra/infratentorial-transsinus approach is preferred for the resection of certain large pineal region tumors.     

Comparison of urinary bone resorption markers in women of 40-70 years; day-to-day and long-term variation in individual subjects

Pethidine is an effective epidural opioid for the treatment of acute pain. Its use has been well described in Australian and New Zealand practice, particularly in the field of obstetric anaesthesia. Reported methods of delivery have included bolus injection, continuous infusion and patient-controlled epidural analgesia. Areas of application have included treatment of postoperative pain, labour pain and intraoperative pain. Because of its intermediate lipid solubility, pethidine may have advantages over many other epidural opioids. However, potential for accumulation of norpethidine limits its use to relatively short durations of treatment.     

The design of instructional multimedia in e-Learning: A Media Richness Theory-based approach

The rapid development of computer and Internet technologies has made e-Learning become an important learning method. There has been a considerable increase in the needs for multimedia instructional material in e-Learning recently as such content has been shown to attract a learner’s attention and interests. The multimedia content alone, however, does not necessarily result in significant positive learning performance and satisfaction. Moreover, it is expensive to design and develop multimedia instructional material. There is a lack of extant research to address the critical issue of how to develop effective multimedia instructional content that leads to desirable learning performance and satisfaction. The objective of our paper is to propose and empirically test a model that examines the impact of the fitness of instructional content and media on a learner’s performance and satisfaction.     

Efficient flooding with passive clustering-an overhead-free selective forward mechanism for ad hoc/sensor networks

High capacity real-time data communications in sensor networks usually require multihop routing and ad hoc routing protocols. Unfortunately, ad hoc routing protocols usually do not scale well and cannot handle dense situations efficiently. These two issues-scalability and density-are the major limitations when we apply ad hoc routing schemes to sensor networks. Passive clustering (PC) classifies ad hoc/sensor nodes into critical and noncritical nodes without any extra transmission. By 2-b piggybacking and monitoring user traffic (e.g., data polling requests from a sink), PC deploys the clustering structure "for free". Moreover, PC makes even the first flooding as efficient as all subsequent floodings (i.e., no initialization overhead). PC introduces many benefits, including efficient flooding and density adaptation. As a result, PC reduces control overhead of ad hoc routing protocols significantly and, as a consequence, enables ad hoc routing in large, dense sensor networks. The resulting structure can be utilized in cluster-based ad hoc network/sensor networking as well as for active node selection.     

An evolutionarily conserved cysteine protease, human bleomycin hydrolase, binds to the human homologue of ubiquitin-conjugating enzyme 9

Bleomycin hydrolase (BH) is a highly conserved cysteine proteinase that deamidates and inactivates the anticancer drug bleomycin. Yeast BH self-assembles to form a homohexameric structure, which resembles a 20 S proteasome and may interact with other proteins. Therefore, we searched for potential human BH (hBH) partners using the yeast two-hybrid system with a HeLa cDNA library and identified the full-length human homologue of yeast ubiquitin-conjugating enzyme 9 (UBC9). Cotransformation assays using hBH deletion mutants revealed that the carboxyl terminus of hBH (amino acids 356-455), which contains two of the three essential catalytic amino acids, was not critical for protein binding in the yeast two-hybrid environment. In vitro translated human UBC9 was precipitated by glutathione S-transferase-hBH fusion protein but not by glutathione S-transferase. Efficient in vitro binding occurred in the absence of the first 24 amino acids of UBC9 and the catalytic Cys93 of UBC9. We confirmed that hBH and UBC9 interacted in vivo by affinity copurification of proteins overexpressed in mammalian cells. Using immunocytochemical analysis, hBH was colocalized with UBC9. Coexpression of hBH and UBC9 in mammalian cells did not markedly alter the bleomycin-hydrolyzing activity of hBH or apparent small ubiquitin-related modifier 1 addition. This is the first reported heteromeric interaction with hBH, and it suggests a role for hBH in intracellular protein processing and degradation.     

Olfactory-evoked regional cerebral blood flow in Alzheimer's disease.

Olfaction is impaired in Alzheimer's disease (AD). It was hypothesized that AD would reduce olfactory-evoked perfusion in mesial temporal olfactory (piriform) cortex, where neuropathology begins. Seven AD patients and 8 elderly controls (ECs) underwent olfactory threshold and identification tests and olfactory stimulation during positron emission tomography. Odor identification was impaired in AD, but threshold was not. Olfactory stimulation in ECs activated right and left piriform areas and right anterior ventral temporal cortex. AD patients had less activation in right piriform and anterior ventral temporal cortex but not in the left piriform area. Although orbital cortex did not activate in ECs, there was a significant between-groups difference in this area. Right piriform activation correlated with odor identification. Impaired odor identification likely reflects sensory cortex dysfunction rather than cognitive impairment. Given olfactory bulb projections to the mesial temporal lobe, olfactory stimulation during functional imaging might detect early dysfunction in this region. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Recovery of growth hormone release from suppression by exogenous insulin-like growth factor I (IGF-I): evidence for a suppressive action of free rather than bound IGF-I

To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) suppression, 11 healthy adults (18-29 yr) received, in randomized order, 4-h i.v. infusions of recombinant human IGF-I (rhIGF-I; 3 microg/kg-h) or saline (control) from 25.5-29.5 h of a 47.5-h fast. Serum GH was maximally suppressed within 2 h and remained suppressed for 2 h after the rhIGF-I infusion; during this 4-h period, GH concentrations were approximately 25% of control day levels [median (interquartile range), 1.2 (0.4-4.0) vs. 4.8 (2.8-7.9) microg/L; P < 0.05]. A rebound increase in GH concentrations occurred 5-7 h after the end of rhIGF-I infusion [7.6 (4.6 -11.7) vs. 4.3 (2.5-6.0) microg/L; P < 0.05]. Thereafter, serum GH concentrations were similar on both days. Total IGF-I concentrations peaked at the end of the rhIGF-I infusion (432 +/- 43 vs. 263 +/- 44 microg/L; P < 0.0001) and remained elevated 18 h after the rhIGF-I infusion (360 +/- 36 vs. 202 +/- 23 microg/L; P = 0.001). Free IGF-I concentrations were approximately 140% above control day values at the end of the infusion (2.1 +/- 0.4 vs. 0.88 +/- 0.3 microg/L; P = 0.001), but declined to baseline within 2 h after the infusion. The close temporal association between the resolution of GH suppression and the fall of free IGF-I concentrations, and the lack of any association with total IGF-I concentrations suggest that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for this suppression. The rebound increase in GH concentrations after the end of rhIGF-I infusion is consistent with cessation of an inhibitory effect of free IGF-I on GH release.     

NF-kappaB-mediated inhibition of apoptosis is required for encephalomyocarditis virus virulence: a mechanism of resistance in p50 knockout mice

Apoptosis is a central host defense mechanism to eliminate virus-infected cells. Activation of NF-kappaB suppresses apoptosis following some types of stimulation in vitro. To test the physiological importance of this pathway in vivo, we studied murine encephalomyocarditis virus (EMCV) infection in mice and cell lines defective in NF-kappaB1 (p50) signaling. As previously reported, we find that all p50 knockout (p50 -/-) mice survive an EMCV infection that readily kills normal mice. By introducing the p50 mutation into interferon (IFN) type I receptor knockout (IFNRI -/-) mice, we find that this resistance is not mediated by IFN-beta as previously thought. While no IFNRI -/- mice survive, the double-knockout mice survive 60% of the time. The survival is tightly linked to the animals' ability to clear the virus from the heart in vivo. Using murine embryonic fibroblasts (MEF) derived from wild-type, p50 -/-, and p65 -/- embryos, we found that NF-kappaB is not required for the replication cycle of EMCV. However, during these experiments we observed that p50 -/- and p65 -/- MEF infected with EMCV undergo enhanced, premature cytotoxicity. Upon examination of this cell death, we found that EMCV infection induced both plasma membrane and nuclear changes typical of apoptosis in all cell lines. These apoptotic processes occurred in an accelerated and pronounced way in the NF-kappaB-defective cells, as soon as 6 h after infection, when virus is beginning to be released. Previously, only the RelA (p65) subunit of NF-kappaB has been shown to play a role in suppressing apoptosis. In our studies, we find that p50 is equally important in suppressing apoptosis during EMCV infection. Additionally, we show that suppression of apoptosis by NF-kappaB1 is required for EMCV virulence in vivo. The attenuation in p50 -/- mice can be explained by rapid apoptosis of infected cells which allows host phagocytes to clear infected cells before the viral burst leading to a reduction of the viral burden and survival of the mice.     

Role of glutathione in the beneficial effect of dietary restriction on bile formation in young, mature, and old rats

We investigated the contribution of bile salts and glutathione (GSH) to the generation of bile flow in young, mature, and old female Sprague-Dawley rats, either fed ad libitum (AL) or subjected to a 40% dietary restriction (DR), which was supplemented or not with vitamins and minerals, starting from weaning. An age-related decline in bile flow was observed in the AL group. DR increased bile flow compared to age-matched AL rats, resulting in a twofold increase in the old animals. This was associated with a statistically significantly higher biliary GSH secretion rate and a moderate increase in the bile salt secretory rate. The apparent GSH-dependent flow was significantly increased in DR groups of all ages. Hepatic GSH concentration was closely related to the GSH secretion rate. These results indicate that the increase in biliary GSH content produced by DR is the major mediator of the increased bile flow, resulting in enhanced GSH and GSH-derived thiols supply to the intestinal lumen.