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Biomedical subjects

John Davis

Publications and source records attributed to John Davis.

At least 37 records · Page 2Linked to original sources
PubMed2004

Suppressing orthotopic pancreatic tumor growth with a fiber-modified adenovector expressing the TRAIL gene from the human telomerase reverse transcriptase promoter.

An adenoviral vector with RGD-modified fibers and expressing the human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene from the human telomerase reverse transcriptase (hTERT) promoter (designated Ad/TRAIL-F/RGD) was constructed, and its antitumor activity was evaluated in vitro and in vivo. An in vitro study showed that treatment with Ad/TRAIL-F/RGD elicited a high rate of apoptosis in human pancreatic and colon cancer cell lines that were either susceptible or resistant to conventional adenovectors. In vivo study showed that direct administration of Ad/TRAIL-F/RGD to an orthotopic implantation tumor model established in the pancreatic tails of nu/nu mice significantly suppressed tumor growth: tumors in the animals treated with Ad/TRAIL-F/RGD were approximately eight times smaller than those in animals treated with a control vector. We also evaluated hTERT promoter activity and the effect of Ad/TRAIL-F/RGD on mesenchymal stem cells. Our results showed that transgene expression from the hTERT promoter in human bone marrow mesenchymal stem cells was minimal. No adverse effect was observed in mesenchymal stem cells treated with Ad/TRAIL-F/RGD. Together, our results suggest that Ad/TRAIL-F/RGD could become a potent therapeutic agent for the management of pancreatic cancer.

Adenoviridae↗
PubMed2004

Embryonic development in the mouse is enhanced via microchannel culture.

Microfluidic devices (microchannels) have been fabricated and tested for embryo culture. Three different microfabrication materials (silicon, polydimethylsiloxane (PDMS), and borosilicate) were used to fabricate the microchannels. The objective of this study was to determine if static microchannels permitted culture of mouse embryos to the blastocyst stage. Groups of 10 two-cell ICR x B6SJL/F1 mouse embryos were cultured for 96 hours in 4 different physical culture systems: 1) silicon/borosilicate microchannels, 2) PDMS/borosilicate microchannels, and 3) standard microdrops. Embryos cultured in the silicon/borosilicate and PDMS/borosilicate microchannels exhibited a faster rate of cleavage (P < 0.05), and produced more blastocysts (P < 0.01) than control microdrops. Furthermore, microchannels had a lower percentage of degenerated embryos than control embryos (P < 0.01). The results suggest that the microchannel culture systems may provide a culture environment that more closely mimics the in vivo environment.

Animals↗
PubMed2004

Interpretation and optimization of the dissolution specifications for a modified release product with an in vivo-in vitro correlation (IVIVC).

This article considers the in vivo significance attached to in vitro dissolution testing. Almost invariably, the in vitro dissolution test is interpreted in terms of bioequivalence. The literature that describes methods for setting in vitro dissolution specifications is reviewed. The most common interpretation of these specifications is a deterministic one, that is, those batches passing the dissolution specifications would be bioequivalent with the reference if tested in vivo and those failing the dissolution specifications would not be bioequivalent if tested in vivo. Due to random variation, the deterministic interpretation is not appropriate. Instead, we need to consider the conditional probability that a batch that has passed the in vitro dissolution test would demonstrate bioequivalence if tested in vivo, and that a batch known to have failed the in vitro dissolution test would demonstrate bioinequivalence if tested in vivo. One way to estimate these probabilities is by means of a simulated experiment in which the production and testing (in vivo and in vitro) of a large number of batches is computer simulated. Such a simulation can only be performed if the relationship between the in vitro dissolution characteristics and the in vivo performance of the product has been modeled. These models are generally referred to as in vivo-in vitro correlations (IVIVC). The results of one such experiment are described. The above-mentioned conditional probabilities are shown to depend on the choice of dissolution specifications. This result leads to the notion of optimal dissolution specifications. However, both of the conditional probabilities cannot be maximized simultaneously. The probability of making a correct decision on the basis of the in vitro dissolution test is introduced as a possible optimality criterion. This probability is a linear combination of the two conditional probabilities of interest. Using this criterion, the optimal dissolution specifications can be found by searching over the multidimensional space defined by the half width of each interval used in the specifications to find the combination that maximizes this probability. This process is demonstrated using the Nelder-Mead search routine. The choice of dissolution specifications has profound implications for the routine production of the product because if the specifications were very narrow the probability of a batch passing would be low, resulting in a low hit rate. The same computer program used to perform the simulation experiment can be used to estimate the hit rate. Furthermore, it can be used to explore the magnitude of changes required in the parameters describing the test product (particularly variability) to increase a low hit rate to an acceptable level.

Biological Availability↗
PubMed2004

Imidazenil: a potent and safe protective agent against diisopropyl fluorophosphate toxicity.

Convulsions are major and life-threatening signs of organophosphate (OP) nerve agents induced neurotoxicity. Thus, early intervention with anticonvulsant drugs to control seizure propagation and the consequent irreversible neuronal damage that may occur during OP exposure is essential. Diazepam is the standard anticonvulsant used in the therapeutic management of OP poisoning. However, its use has been associated with several unwanted effects including, sedation, amnesia, and in the large doses used for such treatment, respiratory depression. Moreover, protracted administration of diazepam has been associated with tolerance and dependence liabilities. In this study, we compared the efficacy and safety of diazepam (full allosteric modulator of GABA action) to that of imidazenil (partial, selective allosteric modulator of GABA action) as preventive treatment against diisopropyl fluorophosphate (DFP)-induced convulsions and mortality. Our results show that imidazenil is more potent and efficacious than diazepam in protecting rats against DFP-induced convulsions and death. Moreover, imidazenil was effective at doses (1 and 0.5 mg/kg) we have previously shown to be devoid of sedation, amnesia, respiratory depression, or tolerance and/or dependence. In contrast, diazepam was effective at doses (5 and 2.5 mg/kg) that produce sedation, amnesia, and ataxia. Furthermore, the combination of imidazenil with atropine was more potent and efficacious than that with diazepam.

Animals↗
PubMed2004

Minimally invasive total knee replacement through a mini-midvastus incision: an outcome study.

Total knee replacement traditionally has been done through an anterior incision approximately 18 cm long, using a capsular incision that separates the interval between the rectus femoris and vastus medialis musculature. Although giving excellent exposure, this incision also disrupts the suprapatellar pouch and may lead to adhesions and difficulty with rapidly regaining flexion. It is hypothesized that, by using a more minimally invasive incision, there will be a more rapid return of flexion and the patient will require fewer narcotic medications postoperatively. This retrospective review compared 32 total knee replacements done through a minimally invasive mini-midvastus approach with 26 total knee replacements done through the standard medial parapatellar approach. Preoperative Knee Society scores and postoperative functional outcomes were compared. Postoperative flexion was measured daily during hospitalization and at a 6-week and 3-month followup. Pain was assessed by a visual analog scale and the amount of pain medication used during hospitalization. Implant position was measured. The MIS group had an average skin incision length of 12.8 cm. Passive flexion on a daily basis was significantly higher in the MIS group compared with the standard group. At 6 weeks postoperatively, the change in Knee Score was statistically higher in the MIS group and the average visual analog pain score and the total amount of pain medication was lower. The radiographic alignment and position of all the components was normal in all patients in both groups. The limited disruption of the extensor mechanism results in more rapid restoration of the quadriceps muscle control.

Aged↗
PubMed2004

Nonlinear oral pharmacokinetics of the alpha-antagonist 4-amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)-perhydro-1,4-diazepin-1-yl]quinoline in humans: use of preclinical data to rationalize clinical observations.

4-amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)-perhydro-1,4-diazepin-1-yl]quinoline (UK-294,315) is an antagonist of the human alpha1-adrenoceptor and exhibits nonlinear oral pharmacokinetics in humans. Superproportional increases in Cmax occur (220-fold, over a 1- to 50-mg dose range), area under the curve increases linearly, but time to maximum concentration decreases with dose, suggesting variation in rate but not extent of absorption. Oral absorption in humans is extensive, with only 14% of an orally administered (20 mg) radiolabeled dose excreted unchanged in the feces. In rats and dogs, UK-294,315 is partially eliminated as unchanged drug in feces (29 and 14% of an intravenous dose, respectively). Oral bioavailability is low in rats (11%) and high in dogs (71%), in keeping with systemic clearance. Fecal elimination of unchanged drug was 60% after oral administration to rats, indicating incomplete absorption in this species, whereas absorption in dogs is complete. UK-294,315 is a P-glycoprotein (P-gp) substrate (Km, 15 microM) exhibiting polarized flux in Caco-2 cell monolayers, saturable across a concentration range of 5 to 200 microM. Furthermore, the observations in vitro occurred at similar concentrations to those estimated in the gut lumen in clinical trials (dose range, 1-100 mg). It is considered that P-gp acts as a saturable absorption barrier to UK-294,315, slowing the rate of absorption at low doses, and is responsible for the observed nonlinearity in oral disposition in humans. Rat and dog pharmacokinetic studies offered limited insight into the process(es) driving nonlinear pharmacokinetics in humans. Our current understanding of the functional effects of P-gp in the human intestine, in combination with in vitro studies at clinically relevant concentrations, has helped rationalize the clinical data for UK-294,315.

Administration, Oral↗
PubMed2004

Karyometric image analysis for intraepithelial and invasive cervical lesions.

OBJECTIVE: To derive an objective, numeric measure for the progression of intraepithelial and invasive squamous cell cervical lesions. STUDY DESIGN: Thin-layer cervical cytology preparations from colposcopically confirmed normal cervix, low grade squamous intraepithelial lesions, high grade squamous intraepithelial lesions and carcinoma were identified from a cross-sectional study. Fifty-nine cases representing 4 diagnostic categories were selected, and 2,375 nuclei from epithelial cells representative of the diagnostic category were randomly selected for imaging and measurement from these cases. Additionally, 1,378 visually normal appearing intermediate cells from low and high grade squamous intraepithelial lesions, as well as from carcinoma cases, were identified for analysis. The nuclei were quantitatively characterized, and discriminant analyses were performed to derive a progression curve from normal cytology to carcinoma. RESULTS: The lesion signatures show a clear increase in nuclear abnormality with increasing progression. A progression curve was derived based on mean discriminant function scores for each diagnostic category and on the mean nuclear abnormality values for the nuclei in each category, as expressed by their deviation in feature values from normal reference nuclei. CONCLUSION: A numeric assessment of lesion progression for cervical precancerous and cancerous lesions based on karyometric measurements is possible and may provide an objective, precise characterization of each lesion as well as a basis for improved performance in automated cytology-based cervical cancer screening.

Cell Nucleus↗
PubMed2003

Mechanisms of thermal adaptation revealed from the genomes of the Antarctic Archaea Methanogenium frigidum and Methanococcoides burtonii.

We generated draft genome sequences for two cold-adapted Archaea, Methanogenium frigidum and Methanococcoides burtonii, to identify genotypic characteristics that distinguish them from Archaea with a higher optimal growth temperature (OGT). Comparative genomics revealed trends in amino acid and tRNA composition, and structural features of proteins. Proteins from the cold-adapted Archaea are characterized by a higher content of noncharged polar amino acids, particularly Gln and Thr and a lower content of hydrophobic amino acids, particularly Leu. Sequence data from nine methanogen genomes (OGT 15 degrees -98 degrees C) were used to generate 1111 modeled protein structures. Analysis of the models from the cold-adapted Archaea showed a strong tendency in the solvent-accessible area for more Gln, Thr, and hydrophobic residues and fewer charged residues. A cold shock domain (CSD) protein (CspA homolog) was identified in M. frigidum, two hypothetical proteins with CSD-folds in M. burtonii, and a unique winged helix DNA-binding domain protein in M. burtonii. This suggests that these types of nucleic acid binding proteins have a critical role in cold-adapted Archaea. Structural analysis of tRNA sequences from the Archaea indicated that GC content is the major factor influencing tRNA stability in hyperthermophiles, but not in the psychrophiles, mesophiles or moderate thermophiles. Below an OGT of 60 degrees C, the GC content in tRNA was largely unchanged, indicating that any requirement for flexibility of tRNA in psychrophiles is mediated by other means. This is the first time that comparisons have been performed with genome data from Archaea spanning the growth temperature extremes from psychrophiles to hyperthermophiles.

Adaptation, Physiological↗
PubMed2003

Treatment of systemic lupus erythematosus-associated type B insulin resistance syndrome with cyclophosphamide and mycophenolate mofetil.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immunologic self-tolerance and the subsequent development of autoantibodies. These antibodies are thought to be important in relation to the clinical manifestations of the disease. One example is the development of multiple cytopenias secondary to cytolytic or cytotoxic antibodies directed toward red blood cells, platelets, and white blood cells. Other antibodies may mediate abnormal cellular mechanisms such as those seen with neuropsychiatric manifestations of SLE. We report the occurrence of autoantibodies directed toward insulin receptors and the subsequent development of type B insulin resistance syndrome in a woman with SLE. This syndrome was treated successfully with cyclophosphamide and mycophenolate mofetil.

Adult↗
PubMed2003

Cross-sectional study of patient- and physician-collected cervical cytology and human papillomavirus.

OBJECTIVE: To compare the performance of patient- and physician-obtained cytology and human papillomavirus (HPV) testing for the detection of high-grade cervical intraepithelial neoplasia. METHODS: A cross-sectional study was performed involving 334 women seen at three colposcopy clinics (Tucson, Arizona; Hermosillo, Mexico; and Lima, Peru). All women used a cytobrush to self-collect specimens for cervical cytology and HPV testing. Subjects subsequently underwent physician collection for cytology and HPV, followed by a complete colposcopic evaluation with directed biopsy. Cytology was processed using thin-layer technology, and HPV was determined using the polymerase chain reaction technique. Test performance characteristics were determined using the histopathologic diagnosis as the reference standard and designating high-grade cervical intraepithelial neoplasia as clinically significant disease for the purpose of the analysis. RESULTS: The sensitivity of patient-collected cytology was significantly lower (55.0%) and specificity was significantly better (84.1%) than those of physician-directed sampling (85.2% and 73.4%, respectively). Patient-collected HPV had significantly lower sensitivity (49.0%) than physician sampling (82.2%), although specificity did not significantly differ. CONCLUSION: Patient collection is a feasible although inferior alternative to physician-collected cervical cytology and HPV testing.

Adolescent↗
PubMed2003

Contrasting lives, contrasting views? Understandings of health inequalities from children in differing social circumstances.

Children's differing socio-economic, cultural and familial circumstances and experiences are part of the pathways implicated in health and illness in adulthood. However, in the existing, mainly survey based, work children's own voices tend to be absent and adult-defined data about health and illness accumulated. Little is known about the social and cultural processes, in children's very different childhoods, which underpin and ultimately constitute these epidemiological findings. This paper reports findings from a qualitative study examining the socio-economic and cultural contexts of children's lifestyles and the production of inequalities in health, carried out in a large Scottish city. Two rounds of semi-structured interviews, using a range of child-friendly techniques (photographs, drawings, vignettes), were carried out with 35 girls and boys aged 9-12 years living in two contrasting but contiguous areas, one relatively advantaged and one relatively disadvantaged. Thirty of their parents were also interviewed and community profiling and observational work undertaken. Children and parents described often starkly contrasting lives and opportunities, regularly involving material differences. However, children appeared to locate inequalities as much in relationships and social life as in material concerns; in this their direct experiences of relationships and unfairness were central to their making sense of inequality and its impact on health. Although children from both areas highlighted several different inequalities, including those related to material resources, they also spoke of the importance of control over their life world; of care and love particularly from parents; of friendship and acceptance by their peer group. Many children challenged straightforward causal explanations for future ill-health, privileging some explanations, such as psychological or lifestyle factors. The accounts of children from both areas displayed considerable resilience to and downplaying of the effects of both relationship and material inequalities; also showing how familial and personal challenges, such as bullying, divorce, learning difficulties, cut across structurally based differences.

Attitude to Health↗
PubMed2003

Combination of TRAIL gene therapy and chemotherapy enhances antitumor and antimetastasis effects in chemosensitive and chemoresistant breast cancers.

We recently found that breast cancer cell lines that are resistant to chemotherapy or to the recombinant TRAIL protein are susceptible to TRAIL gene therapy. However, it is unclear whether a combination of TRAIL gene therapy and chemotherapy will have enhanced antitumor activity or can be used for the treatment of metastasis. In this study, we investigated the combined effect of TRAIL gene therapy and chemotherapeutic agents, including doxorubicin, paclitaxel, vinorelbine, gemcitabine, irinotecan, and floxuridine, in different breast cancer cell lines. In all the cell lines tested, including a breast cancer cell line that is resistant to chemotherapy, the combination of TRAIL gene therapy and cytotoxic agents had either a synergistic or an additive effect. An in vivo study showed that aerosolized administration of an adenovector expressing the GFP-TRAIL fusion protein from the human telomerase reverse transcriptase promoter (designated Ad/gTRAIL) also decreased the number of lung metastases from both doxorubicin-sensitive and doxorubicin-resistant breast cancer cell lines. The combination of TRAIL gene therapy and chemotherapy resulted in a further reduction of lung metastatic nodules with minimal toxicity. These results suggest that a combination of TRAIL gene therapy and chemotherapy is effective in the treatment of metastatic diseases.

Antibiotics, Antineoplastic↗
PubMed2003

Factors that affect the quality of cytologic cervical cancer screening along the Mexico-United States border.

OBJECTIVE: The purpose of this study was to identify the factors that affect the quality of cytologic cervical cancer screening conducted in public sector clinics in Sonora, Mexico. STUDY DESIGN: We assessed the quality of cervical cytology before and after a 2-hour training session and the implementation of cervical spatulas and endocervical brushes. Additionally, we conducted a cross-sectional study of reproductive aged women who attended public clinics in paired border communities in Sonora and Arizona. Cervical cytologic specimens (n=2436) were collected and compared for adequacy and cytologic diagnosis and for the prevalence of human papillomavirus infection. RESULTS: The training intervention achieved significantly improved the rates of satisfactory but limited smears and unsatisfactory smears. The cross-sectional study revealed comparable quality indicators for cytologic specimens that were collected in Sonora and Arizona clinics. CONCLUSION: A high-quality cytology-based cervical cancer screening program is possible in public sector clinics in Sonora, with indicators similar to those achieved in comparable Arizona clinics.

Adult↗
PubMed2003

The use of topical tacrolimus (FK506/Protopic) in cutaneous manifestations of autoimmune diseases.

The cutaneous manifestations of autoimmune diseases, including systemic lupus erythematosus, are common and often recalcitrant to treatment. Unfortunately, therapy for lupus and other autoimmune skin diseases has not advanced and relies heavily on the use of oral and topical corticosteroids. Frequently, treatments prove less than ideal, either from toxicity or lack of efficacy. A topical form of the immunomodulating transplant medication, tacrolimus (FK-506, Protopic), has recently been developed and approved for use in treating atopic dermatitis. Its mechanism of action and local route of administration render tacrolimus a potentially attractive novel therapeutic alternative for the treatment of various autoimmune dermatologic conditions. We report our successful experience using this drug in 3 patients with autoimmune dermatologic disease who were referred to a tertiary care subspecialty clinic.

Journal Article↗
PubMed2003

Data reduction using a discrete wavelet transform in discriminant analysis of very high dimensionality data.

We present a method of data reduction using a wavelet transform in discriminant analysis when the number of variables is much greater than the number of observations. The method is illustrated with a prostate cancer study, where the sample size is 248, and the number of variables is 48,538 (generated using the ProteinChip technology). Using a discrete wavelet transform, the 48,538 data points are represented by 1271 wavelet coefficients. Information criteria identified 11 of the 1271 wavelet coefficients with the highest discriminatory power. The linear classifier with the 11 wavelet coefficients detected prostate cancer in a separate test set with a sensitivity of 97% and specificity of 100%.

Data Compression↗
PubMed2003

Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance staff using the face arm speech test.

BACKGROUND AND PURPOSE: Timely referral of appropriate patients to acute stroke units is necessary for effective provision of skilled care. We compared the characteristics of referrals with suspected stroke to an academic acute stroke unit via 3 primary referral routes: ambulance paramedics using a rapid ambulance protocol and stroke recognition instrument, the Face Arm Speech Test; primary care doctors (PCDs); and emergency room (ER) referrals. METHODS: Patient characteristics, final diagnosis, and admission delay were recorded in all suspected acute stroke referrals in a 6-month period. RESULTS: Four hundred eighty-seven patients (356 strokes/transient ischemic attacks) were admitted by the 3 routes: 178 by ambulance, 216 by PCDs, and 93 through the ER. The proportion of nonstrokes admitted by each route was similar (23%, 29%, and 29%, respectively). Ambulance paramedics' stroke diagnosis was correct in 144 of 183 (79%) stroke patients who initially presented to them. Thirty-nine of 66 strokes/transient ischemic attacks referred via ER were taken there following initial ambulance assessment. Compared with PCDs, paramedics referred more total anterior circulation (39% versus 14%, P<0.0001) and fewer lacunar strokes (14% versus 31%, P<0.001) and admitted more patients (46% versus 12%, P<0.01) within 3 hours of symptom onset. The most common nonstroke conditions were seizures, infections and confusion, cardiovascular collapse, and cerebral tumors. Paramedics admitted more patients with seizures. CONCLUSIONS: Misdiagnosis of stroke is common in the ER and by PCDs. Paramedics using the Face Arm Speech Test achieved high levels of detection and diagnostic accuracy of stroke.

Adult↗
PubMed2003

Thin-layer cytology and histopathology in the evaluation of abnormal uterine bleeding.

OBJECTIVE: To compare thin-layer endometrial cytology to endometrial biopsy and surgical pathology in women with abnormal uterine bleeding. STUDY DESIGN: We performed a prospective study of 103 women. Patients underwent endometrial cytologic evaluation using an endometrial brush, followed by either endometrial biopsy, hysteroscopy with dilation and curettage, or hysterectomy, as clinically indicated. Test performance characteristics and adequacy of cytology and endometrial biopsy were assessed. Ki-67 immunocytochemical expression was evaluated in a random subset of 60 specimens. RESULTS: Cytologic sampling demonstrated a sensitivity of 78%, a specificity of 96%, a positive predictive value of 78% and a negative predictive value of 96% for the detection of endometrial abnormalities. The unsatisfactory rate of uterine cytology was 15% as compared to 26% for endometrial biopsy. Of adenocarcinoma cases, 83% expressed Ki-67, as compared to 30% in benign cases. CONCLUSION: Endometrial cytology may be useful in the detection of endometrial hyperplasia and neoplasia and provides adequate material for the assessment of Ki-67.

Adenocarcinoma↗