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Biomedical subjects

R Page

Publications and source records attributed to R Page.

At least 19 recordsLinked to original sources
PubMed2005

Intraneuronal Abeta, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer's disease.

We have developed models of Alzheimer's disease in Drosophila melanogaster by expressing the Abeta peptides that accumulate in human disease. Expression of wild-type and Arctic mutant (Glu22Gly) Abeta(1-42) peptides in Drosophila neural tissue results in intracellular Abeta accumulation followed by non-amyloid aggregates that resemble diffuse plaques. These histological changes are associated with progressive locomotor deficits and vacuolation of the brain and premature death of the flies. The severity of the neurodegeneration is proportional to the propensity of the expressed Abeta peptide to form oligomers. The fly phenotype is rescued by treatment with Congo Red that reduces Abeta aggregation in vitro. Our model demonstrates that intracellular accumulation and non-amyloid aggregates of Abeta are sufficient to cause the neurodegeneration of Alzheimer's disease. Moreover it provides a platform to dissect the pathways of neurodegeneration in Alzheimer's disease and to develop novel therapeutic interventions.

Alzheimer Disease↗
PubMed2005

Molecular mousetraps and the serpinopathies.

Members of the serine proteinase inhibitor or serpin superfamily inhibit their target proteinases by a remarkable conformational transition that involves the enzyme being translocated more than 70 A (1 A = 10(-10) m) from the upper to the lower pole of the inhibitor. This elegant mechanism is subverted by point mutations to form ordered polymers that are retained within the endoplasmic reticulum of secretory cells. The accumulation of polymers underlies the retention of mutants of alpha(1)-antitrypsin and neuroserpin within hepatocytes and neurons to cause cirrhosis and dementia respectively. The formation of polymers results in the failure to secrete mutants of other members of the serpin superfamily: antithrombin, C1 inhibitor and alpha1-antichymotrypsin, to cause a plasma deficiency that results in the clinical syndromes of thrombosis, angio-oedema and emphysema respectively. Understanding the common mechanism underlying the retention and deficiency of mutants of the serpins has allowed us to group these conditions as the serpinopathies. We review in this paper the molecular and structural basis of the serpinopathies and show how this has allowed the development of specific agents to block the polymerization that underlies disease.

Animals↗
PubMed2004

A response time model for judging order relationship between two symbolic stimuli.

The response time to judge the order relationship between two symbolic stimuli is frequently modeled as the time spent in a (constant-rate) accumulative sampling process until a threshold is reached. We will show that empirical descriptions of observed effects in number comparisons suggest an accrual process that reaches the threshold at an exponential rate. The model accrual equations and stopping conditions have an immediate interpretation in terms of a simple quantitative connectionist network. The encoded stimuli and thresholds are inputs to the network. The former are considered to result from the participant's learning history, and the latter modulate the rearrangement of the network parts; each arrangement models a different task. We have found a good correlation between model predictions and other authors' experimental data, both in number comparisons and in experiments in which the ordering of the symbolic stimuli has been artificially induced. Incorrect answers are discussed, and predictions are compared with data. We will explore differences and similarities with other approaches, such as random walk and the symbolic comparison model. In a limit case, our model becomes identical to the discriminability model.

Humans↗
PubMed2002

Furin expression in squamous cell carcinomas of the oral cavity and other sites evaluated by tissue microarray technology.

Furin is a proprotein convertase that activates many cancer development-related substrates such as growth factors, growth factor-receptors, adhesion molecules, and matrix degrading enzymes. Furin expression was studied in sections from tissue microarrays (TMA) and conventional paraffin blocks in a collection of squamous cell carcinomas (SCC) from three different sites. A total of 118 SCCs from the oral cavity, lung and esophagus as well as 34 precursor lesions (intraepithelial neoplasia) from the oral and bronchial mucosae were studied by immunohistochemistry. Furin expression was notably higher in most precursor lesions than in normal epithelia. Tumors from either the TMAs or the conventional blocks showed significant differences when compared to the mostly negative normal epithelia. High levels of furin expression were observed in approximately 50% SCCs of three different sites as well as in precursor lesions of the oral and bronchial mucosae. In addition another 30% showed low furin expression that was localized in all tumor cells including those in a basaloid position. Normal epithelia sometimes showed low level expression but the normal basal cells were always negative. These results show that furin is up-regulated in SCCs from three different organs and validates its use as a tumor marker in both invasive and pre-invasive neoplasia.

Biomarkers, Tumor↗
PubMed2001

Atypical right atrial flutter patterns.

BACKGROUND: The purpose of our study was to define the incidence and mechanisms of atypical right atrial flutter. METHODS AND RESULTS: A total of 28 (8%) of 372 consecutive patients with atrial flutter (AFL) had 36 episodes of sustained atypical right AFL. Among 24 (67%) of 36 episodes of lower loop reentry (LLR), 13 (54%) of 24 episodes had early breakthrough at the lower lateral tricuspid annulus, whereas 11 (46%) of 24 episodes had early breakthrough at the high lateral tricuspid annulus, and 9 (38%) of 24 episodes showed multiple annular breaks. Bidirectional isthmus block resulted in elimination of LLR. A pattern of posterior breakthrough from the eustachian ridge to the septum was observed in 4 (14%) of 28 patients. Upper loop reentry was observed in 8 (22%) of 36 episodes and was defined as showing a clockwise orientation with early annular break and wave-front collision over the isthmus. Two patients had atypical right AFL around low voltage areas ("scars") in the posterolateral right atrium. CONCLUSIONS: Atypical right AFL is most commonly associated with an isthmus-dependent mechanism (ie, LLR or subeustachian isthmus breaks). Non-isthmus-dependent circuits include upper loop reentry or scar-related circuits.

Aged↗
PubMed2001

Enhancement of bone growth by sustained delivery of recombinant human bone morphogenetic protein-2 in a polymeric matrix.

PURPOSE: The purpose of this study was to develop a polymeric sustained delivery system for recombinant human bone morphogenetic protein-2 (BMP-2) and to evaluate local bone growth induced by the sustained release of BMP-2 in an animal model. METHODS: BMP-2 was incorporated in biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microspheres to obtain different release rates. Two sustained and an immediate release implants were produced by suspending the BMP-2 loaded PLGA microspheres in aqueous sodium carboxymethylcellulose (CMC), lyophilizing, and cutting the dried materials to the size of the animal bone defects. The local in vivo release at the implantation site in rat calvarial defects was determined by gamma scintigraphy using radiolabeled BMP-2. The local bone induction in the critical size of rabbit calvarial defects was evaluated six weeks post implantation. RESULTS: The immediate release implant showed about 65% initial drug release within 24 h and the remaining BMP-2 quickly exhausted from the implantation site within 7 days. The sustained release implants, showing 45-55% initial release followed by a prolonged release for 21 days, released a greater amount of BMP-2 at the implantation site and maintained higher serum BMP-2 for the longer period of time compared to the immediate release implant. Significant bone growth was observed in all BMP-2 treated defects while the defects without treatment or with BMP-2-free implant showed minimal bone healing. 75-79% of rabbit calvarial defect area was healed with newly induced bone matrix by the sustained release implants in 6 weeks as compared to 45% recovery from the immediate release implant. CONCLUSION: The sustained delivery of BMP-2 based on the biodegradable PLGA microsphere system resulted in faster and more complete bone healing in the animal model.

Animals↗
PubMed2001

15-Lipoxygenase-2 expression in benign and neoplastic sebaceous glands and other cutaneous adnexa.

15-Lipoxygenase-2 has a limited tissue distribution in epithelial tissues, with mRNA detected in skin, cornea, lung, and prostate. It was originally cloned from human hair rootlets. In this study the distribution of 15-lipoxygenase-2 was characterized in human skin using immunohistochemistry and in situ hybridization. Strong uniform 15-lipoxygenase-2 in situ hybridization (n = 6) and immunostaining (n = 16) were observed in benign cutaneous sebaceous glands, with expression in differentiated secretory cells. Strong 15-lipoxygenase-2 immunostaining was also observed in secretory cells of apocrine and eccrine glands. Variable reduced immunostaining was observed in skin-derived sebaceous neoplasms (n = 8). In the eyelid, Meibomian glands were uniformly negative for 15-lipoxygenase-2 in all cases examined (n = 9), and sebaceous carcinomas apparently derived from Meibomian glands were also negative (n = 12). The mechanisms responsible for differential expression in cutaneous sebaceous vs eyelid Meibomian glands remain to be established. In epidermis, positive immunostaining was observed in the basal cell layer in normal skin, whereas five examined basal cell carcinomas were negative. Thus, the strongest 15-lipoxygenase-2 expression is in the androgen regulated secretory cells of sebaceous, apocrine, and eccrine glands. This compares with the prostate, in which 15-lipoxygenase-2 is expressed in differentiated prostate secretory cells (and reduced in the majority of prostate adenocarcinomas). The product of 15-lipoxygenase-2, 15-hydroxyeicosatetraenoic acid, may be a ligand for the nuclear receptor peroxisome proliferator activated receptor-gamma, which is expressed in sebocytes, and contribute to secretory differentiation in androgen regulated tissues such as prostate and sebaceous glands.

Adenoma↗
PubMed2001

Internet relationships: people who meet people.

Current research suggests that the Internet has become a popular medium for forming interpersonal relationships. Not only are many people developing cyberfriendships, but some move beyond virtual communication and interact more directly through telephone contact and face-to-face encounters. This pilot study examined the personality characteristics of 30 participants (17 men and 13 women) who were regular Internet users and who had used the Internet to meet people mainly through chat rooms. The findings of this study suggest that people who use the Internet meet others tend to be truthful in general in their interactions although both men and women often did not reveal their true names. Eighty percent of the subjects formed casual or friendly relationships, whereas 6% formed intimate or romantic relationships. Approximately one-third of the subjects made some form of offline contact, with 40% talking on the telephone and 33.3% meeting face-to-face. Furthermore, examination of personality styles indicated that cyberfriends tend to be socially skilled, have strong verbal skills, and demonstrate empathy for others. Most subjects were careful about protecting their anonymity, and none of the subjects who met face-to-face did so without first talking on the phone. This suggests that individuals who make friends via the Internet tend to take appropriate precautions and find this medium an effective and safe way to interact with others and to expand one's social system.

Adult↗
PubMed2000

Comparative in vivo activity of gemifloxacin in a rat model of respiratory tract infection.

The in vivo efficacy of the novel quinolone gemifloxacin (SB-265805) was examined in a rat respiratory tract infection (RTI) model against four strains of Streptococcus pneumoniae and two strains of Haemophilus influenzae with varying susceptibilities to standard antimicrobial agents. Animals were infected intrabronchially to produce pneumonia and therapy with oral gemifloxacin, amoxycillin-clavulanate, ciprofloxacin, cefuroxime, azithromycin, trovafloxacin, grepafloxacin or levofloxacin was started 24 h after infection. The doses administered were chosen to approximate in the rat the serum or tissue concentrations measured in humans following therapeutic dosing. Therapy continued once- or twice-daily for 3 days, and approximately 17 h after the end of therapy the lungs were excised for bacterial enumeration. Following infection with strains of S. pneumoniae, gemifloxacin produced a 3-5 log reduction in bacterial numbers compared with untreated animals. Gemifloxacin was as effective as amoxycillin- clavulanate, and was as potent or more potent than all other comparators. Notably, the quinolone agents trovafloxacin, ciprofloxacin, grepafloxacin and levofloxacin were significantly less effective (P < 0.01) than gemifloxacin: these agents reduced bacterial numbers by < or =3 log compared with untreated animals. Gemifloxacin produced a marked response against H. influenzae infection, reducing bacterial numbers significantly (P < 0.01) compared with untreated controls. Gemifloxacin was significantly more potent than cefuroxime and azithromycin. None of the other comparator agents was more potent than gemifloxacin. The excellent efficacy seen in these experimental models of RTI with S. pneumoniae and H. influenzae confirms the in vitro activity of gemifloxacin against these organisms. This indicates that gemifloxacin may be of significant benefit in the treatment of RTI.

Animals↗
PubMed2000

Comparative efficacy of gemifloxacin in experimental models of pyelonephritis and wound infection.

Gemifloxacin (SB-265805) is a potent, novel fluoroquinolone with broad-spectrum antimicrobial activity. In this study, the efficacy of gemifloxacin was studied in experimental models of Gram-negative pyelonephritis (caused by Escherichia coli or Proteus mirabilis) and Gram-positive wound infection resulting from Streptococcus pyogenes, Staphylococcus epidermidis or Staphylococcus aureus. Gemifloxacin activity against these pathogens was compared with those of amoxycillin-clavulanate, ciprofloxacin, cefuroxime, azithromycin, trovafloxacin, grepafloxacin, levofloxacin and tosufloxacin. Oral treatment was initiated 1 h after infection and continued once or twice daily for 3 days. Around 17 h after the end of treatment, animals were killed and the infected kidneys or the skin around the wound site were excised for the enumeration of viable bacteria. In the pyelonephritis model (either microorganism), gemifloxacin reduced bacterial numbers significantly (P < 0.01) compared with no treatment. No comparator agent had a greater effect than gemifloxacin. Notably, grepafloxacin and azithromycin were significantly less effective (P < 0.01) than gemifloxacin against E. coli pyelonephritis, and amoxycillin-clavulanate, azithromycin and trovafloxacin were inferior (P < 0.01) against P. mirabilis infection. In the S. pyogenes wound infection model, gemifloxacin, amoxycillin-clavulanate, cefuroxime and azithromycin reduced bacterial numbers significantly compared with controls (P < 0.01). Results for the comparator quinolones were not significantly different from untreated controls (P > 0.05). Gemifloxacin was also effective against staphylococcal infection, as were grepafloxacin and levofloxacin, while ciprofloxacin, trovafloxacin and tosufloxacin were significantly less effective against these pathogens than gemifloxacin (P < 0.01). No comparator agent had greater activity than gemifloxacin against S. pyogenes or S. aureus infections. These data demonstrate the potential benefit of gemifloxacin in the treatment of Gram-negative urinary tract infection and Gram-positive skin and soft tissue infection.

Animals↗
PubMed1998

Domain motions in actin.

Previous crystallographic investigations have shown that actin can undergo large conformational changes, even when complexed to the same actin binding protein. We have conducted a formal analysis of domain motions in actin, using the four available crystal structures, to classify the mechanism as either hinge or shear and to quantify the magnitude of these changes. We demonstrate that actin consists of two rigid cores, a semi-rigid domain and three conformationally variable extended loops. Confirming predictions about the nature of the domain rotation in actin based on its structural similarity to hexokinase, we show, using an algorithm previously used only to identify protein hinges, that residues at the interface between the two rigid cores undergo a shear between alternative conformations of actin. Rotations of less than 7 degrees in the torsion angles of five residues in the polypeptides that connect the rigid cores enable one actin conformation to be transformed into another. Because these torsion angle changes are small, the interface between the domains is maintained. In addition, we show that actin secondary structure elements, including those outside the rigid cores, are conformationally invariant among the four crystal structures, even when actin is complexed to different actin binding proteins. Finally, we demonstrate that the current F-actin models are inconsistent with the principles of actin conformational change identified here.

Actins↗
PubMed1998

The laryngeal mask airway reduces blood flow in the common carotid artery bulb.

PURPOSE: The introduction of the laryngeal mask airway (LMA) has had a major impact on anaesthetic practice in the last ten years. Previous authors have demonstrated pressures equivalent to mean arterial blood pressure within the cuff of the LMA. This study examined the effects of cuff inflation on the cross sectional area, flow and velocity of blood flow at the level of the carotid sinus. METHODS: Seventeen patients scheduled to have LMAs inserted as part of routine anaesthetic management were recruited into the study. Measurements of the common carotid artery bulb area, peak velocity and blood flow were performed upon LMA cuff inflation and deflation using a 5 MHz pulse wave Doppler probe. RESULTS: Deflation of the cuff resulted in an increase in the cross sectional area (from 0.58 +/- 0.05 to 0.64 +/- 0.04 cm2; P < 0.005), an increase in blood flow (from 65.6 +/- 5.6 to 73.9 +/- 5.6 cm3.sec-1; P < 0.05) and a slight but non significant increase in velocity of blood flow. CONCLUSION: This study demonstrates that inflation of the cuff on the LMA results in a decrease in carotid bulb cross sectional area which results in a decrease in blood flow.

Adult↗
PubMed1998

Index finger lengthening by gradual distraction and bone grafting.

We present the case of an 18-year-old woman with a shortened right index finger. The digit was stabilized and lengthened a total of 18 mm by external fixation and iliac bone grafting. A distal interphalangeal fixed flexion deformity of 60 degrees was corrected with external fixation and intermedullary wiring.

Adolescent↗
PubMed1998

Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer.

PURPOSE: To evaluate the efficacy of an abbreviated treatment plan consisting of two cycles of chemotherapy plus thoracic irradiation in a population of limited-stage small-cell lung cancer (LSCLC) patients who were elderly, infirm, or noncompliant with standard-duration therapy. PATIENTS AND METHODS: Fifty-five LSCLC patients (median age, 73) were treated with one cycle of cyclophosphamide, doxorubicin, and vincristine (CAV) followed 3 weeks later by one cycle of etoposide and cisplatin (EP). Both regimens were administered at conventional full dose. Thoracic irradiation (20 to 30 Gy) was delivered concurrently with EP. RESULTS: Complete response occurred in 28 patients (51%) and partial response in 21 (38%). The median survival time was 54 weeks; the 2-year survival rate was 28% and the actual 5-year survival rate was 18%. Three patients died of toxicity. CONCLUSION: Elderly, infirm, or noncompliant LSCLC patients who are unable to receive standard-duration chemotherapy may have useful palliation and potential for long-term survival with abbreviated chemotherapy (two cycles) and thoracic irradiation.

Aged↗