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Biomedical subjects

M A Davies

Publications and source records attributed to M A Davies.

At least 19 recordsLinked to original sources
PubMed2006

Comparison of cervical disk implants and cervical disk fusion treatments in human cadaveric models.

Articulating cervical disk implants have been proposed as an alternative to disk fusion in the treatment of cervical disk disease. To examine the mechanical effect of articulating cervical disk implants (ACDI) versus simulated cervical disk fusion, a mechanical test device was constructed and cadaveric tests were carried out. While results show little effect on the pressures above and below the treatment level, the percent hysteretic behavior of the specimens trended to be higher for the ACDI, indicating that these implants retain more of the natural energy absorption capability of the cervical spine.

Aged↗
PubMed2001

Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN.

Human gliomas are highly invasive, and remain to be a major obstacle for any effective therapeutic remedy. Among many other factors, gliomas express elevated levels of matrix metalloproteinases (MMPs), which have been implicated to play an important role in tumor invasion as well as neovascularization. The tumor suppressor gene mutated in multiple advanced cancers/phosphatase and tensin homologue (MMAC/PTEN) has been shown to inhibit cell migration, spreading, and focal adhesion. In this study, we determined whether MMAC/PTEN inhibits tumor invasion by modulating MMP-2 activity. Our results showed that reintroduction of the MMAC/PTEN gene into human glioma U251 and U87 cells modified their phenotype and growth characteristics. The ability of MMAC/PTEN to induce anoikis in U251 cells was accompanied by a significant inhibition of in vitro invasion (70%). Expression of MMAC/PTEN in U251 and U87 cells inhibited MMP-2 enzymatic activity as determined by zymography. Furthermore, MMAC/PTEN expression strongly decreased MMP-2 mRNA levels, which correlated well with the inhibition of invasion capacity in these cells. Concomitant with MMP-2 expression and activity, MMP-2 promoter activity was also reduced in MMAC/PTEN expressing cells. Our observations suggest that MMAC/PTEN inhibits tumor cell invasion in part by regulating MMP-2 gene transcription and thereby its enzymatic activity. Further characterization of this regulation will facilitate the development of MMAC/PTEN based gene therapy for gliomas.

Anoikis↗
PubMed2001

Differential effects of phosphatidylinositol-3/Akt-kinase inhibition on apoptotic sensitization to cytokines in LNCaP and PCc-3 prostate cancer cells.

Alterations in phosphatidylinositol 3'-kinase (PI3'-kinase) and Akt activation frequently occur in prostate cancer and may disrupt apoptotic induction by such cytokines as tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL). To examine the role of PI3' phosphorylation in the cellular response to cytokines, two prostate cancer cell lines with constitutively activated PI3'-kinase cascades (LNCaP and PC-3) were examined for direct sensitivity to cytokines. TNF or TRAIL alone failed to activate apoptosis in either LNCaP or PC-3 cells, and drug-mediated inhibition of the PI3k/Akt cascade caused only minimal activation of apoptosis in either cell line. Suppression of PI3'-kinase/Akt signaling markedly enhanced the apoptotic activity of both TNF and TRAIL in LNCaP cells but not in PC-3 cells. Adenovirus-mediated PTEN/MMAC1 expression in LNCaP cells reduced Akt activation, activated apoptosis, and sensitized cells to TNF but not to TRAIL. Together, these results suggest that PI3'-kinase signaling inhibits both TNF-mediated and TRAIL-mediated apoptosis but may represent one of several apoptotic resistance mechanisms that inhibit cytokine-mediated killing of prostate cancer cells.

Androstadienes↗
PubMed2000

MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells.

The development and progression of bladder cancer is associated with multiple alterations in the genome, including loss of chromosome 10. Recently, MMAC1/PTEN, a phosphatidylinositol phosphatase, has been mapped to chromosome 10q23. We previously demonstrated that MMAC1/PTEN has tumor suppressive properties in glioblastoma and prostate cancer. To investigate the efficacy of gene therapy with MMAC1/PTEN, we examined whether the exogenous introduction of MMAC1/PTEN via an adenoviral vector (Ad-MMAC) can inhibit tumor growth and reverse drug resistance to doxorubicin in human bladder cancer cells. Human bladder cancer cell lines UM-UC-3 and T24 were infected with Ad-MMAC to induce exogenous expression of MMAC1/PTEN. The cells were then analysed for cell growth and expression of phosphorylated protein kinase B (Akt/PKB) and MMAC1/PTEN. UM-UC-6dox, a doxorubicin resistant subline, was infected with Ad-MMAC to evaluate its role in reversing drug resistance to doxorubicin. We found that MMAC1/PTEN suppressed tumor growth in UM-UC-3 and T24 cells with arrest in the G1 phase of the cell cycle. We also showed that gene therapy with MMAC1/PTEN abrogated phosphorylated Akt/PKB expression in UM-UC-3, T24 and UMUC-6dox cells, and restored doxorubicin sensitivity in UM-UC-6dox. These data demonstrate that MMAC1/PTEN can induce growth suppression and increase sensitivity to doxorubicin in bladder cancer cells and suggest that the MMAC1/PTEN gene and its pathways can be therapeutic targets for bladder cancer.

Adenoviruses, Human↗
PubMed1999

The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells.

The PTEN/MMAC1/TEP (PTEN) tumor suppressor gene at 10q23.3 is mutated in multiple types of sporadic tumors including breast cancers and also in the germline of patients with the Cowden's breast cancer predisposition syndrome. The PTEN gene encodes a multifunctional phosphatase capable of dephosphorylating the same sites in membrane phosphatidylinositols phosphorylated by phosphatidylinositol 3'-kinase (PI3K). We demonstrate herein that loss of PTEN function in breast cancer cells results in an increase in basal levels of phosphorylation of multiple components of the P13K signaling cascade as well as an increase in duration of ligand-induced signaling through the P13K cascade. These alterations are reversed by wild-type but not phosphatase inactive PTEN. In the presence of high concentrations of serum, enforced expression of PTEN induces a predominant G1 arrest consistent with the capacity of PTEN to evoke increases in the expression of the p27Kip1 cyclin dependent kinase inhibitor. In the presence of low concentrations of serum, enforced PTEN expression results in a marked increase in cellular apoptosis, a finding which is consistent with the capacity of PTEN to alter the phosphorylation, and presumably function, of the AKT, BAD, p70S6 kinase and GSK3 alpha apoptosis regulators. Under anchorage-independent conditions, PTEN also induces anoikis, a form of apoptosis that occurs when cells are dissociated from the extracellular matrix, which is enhanced in conjunction with low serum culture conditions. Together, these data suggest that PTEN effects on the PI3K signaling cascade are influenced by the cell stimulatory context, and that depending on the exposure to growth factors and other exogenous stimuli such as integrin ligation, PTEN can induce cell cycle arrest, apoptosis or anoikis in breast cancer cells.

Apoptosis↗
PubMed1999

Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN.

Understanding the functional roles of the molecular alterations that are involved in the oncogenesis of prostate cancer, the second most frequent cause of cancer-related deaths among men in the United States is the focus of numerous investigations. To examine the possible significance of alterations associated with the tumor suppressor gene, MMAC/PTEN, in prostate carcinoma, the biological and biochemical effects of MMAC/PTEN expression were examined in LNCaP cells, which are devoid of a functional gene product. Acute expression of MMAC/PTEN via an adenoviral construct resulted in a dose-dependent and specific inhibition of Akt/PKB activation, consistent with the phosphatidylinositol phosphatase activity of MMAC/PTEN. MMAC/PTEN expression induced apoptosis in LNCaP cells, although to a lesser extent than that observed with p53 via an adenoviral construct. However, MMAC/PTEN expression produced a growth inhibition that was significantly greater than that achieved with p53. Overexpression of Bcl-2 in LNCaP cells blocked MMAC/PTEN- and p53-induced apoptosis but not the growth-suppressive effects of MMAC/ PTEN, suggesting that the growth regulatory effects of MMAC/PTEN involve multiple pathways. These studies further implicate the loss of MMAC/PTEN as a significant event in prostate cancer and suggest that reintroduction of MMAC/PTEN into deficient prostate cancer cells may have therapeutic implications.

Apoptosis↗
PubMed1998

Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis.

The MMAC/PTEN tumor suppressor gene encodes for a phosphatase that recently has been shown to have phosphotidylinositol phosphatase activity, implicating its possible involvement in phosphatidylinositol 3'-kinase-mediated signaling. To investigate possible alterations in growth factor-mediated signal transduction, an adenovirus containing MMAC/PTEN, Ad-MMAC, previously shown to inhibit growth and tumorigenicity in glioma cells, was used to acutely express the transgene. Human glioma cells infected with Ad-MMAC but not with control adenoviruses exhibited an inhibition of phosphorylation of both activating residues of Akt, Ser-473, and Thr-308, along with Akt's serine/threonine kinase activity, without significantly altering Akt expression. The effects of functional MMAC/PTEN expression were relatively specific, because members of several other growth factor-mediated signaling pathways showed no altered responses. The presence of MMAC/PTEN also inhibited phosphorylation of BAD, although no evidence of apoptosis in the in situ treated cells was observed. However, U251 glioma cells infected with Ad-MMAC were induced to undergo anoikis at a significantly higher rate than U251 cels treated with control viruses or mock infected with media. These results demonstrate that the acute administration of MMAC/PTEN results in the inhibition of Akt-mediated signaling, growth inhibition, and anoikis, implying that loss of MMAC/PTEN increases cellular proliferation and significantly augments a cell's survival potential during cellular processes that are associated with malignancy.

Adenoviridae↗
PubMed1997

The efficacy of treatment for malignant epidural spinal cord compression.

The aims of this study were to document the efficacy of treatment and to identify factors that were predictive of the outcome in malignant epidural spinal; cord compression. The medical records of patients treated at the Prince Henry and Prince of Wales Hospitals in the period 1980-1989 with a diagnosis of malignant epidural spinal cord compression were reviewed. A total of 94 patients were eligible for the study and were treated by radiotherapy alone (37), surgery alone (19) and surgery followed by radiotherapy (38). Efficacy was determined by measuring complete resolution of symptoms and signs at 1 month after presentation, and also by using an overall functional improvement score (FIS). Complete resolution of individual pre-treatment symptoms that were measured 1 month after treatment occurred as follows: pain (30/88), sensory disturbance (12/61), weakness (8/17), bladder dysfunction (10/42), and bowel dysfunction (10/36). Complete resolution of motor deficit occurred in 7/82 and of sensory deficit in 9/73. The ability to walk was regained in 19/51 previously non-ambulatory patients, and bladder function improved sufficiently to remove an indwelling catheter in 9/32 previously catheterized patients. As judged by FIS, 67 patients improved, 15 patients remained stable and 12 patients deteriorated. Of the treatments given, a combination of surgery followed by radiotherapy was associated with the greatest functional improvement (P = 0.001). The coexistence of 'liver failure' was the only patient-related factor identified which was associated with outcome (P = 0.041). The treatment of malignant spinal cord compression appears to be worthwhile; however, the outcome of treatment is not easy to predict from pretreatment factors. A 'functional improvement score' may be useful in assessing treatment efficacy.

Activities of Daily Living↗
PubMed1996

The validity of classification for the clinical presentation of intracranial dural arteriovenous fistulas.

A number of classification schemes for intracranial dural arteriovenous fistulas (AVFs) have been published that claim to predict which lesions will present in a benign or aggressive fashion based on radiological anatomy. We have tested the validity of two proposed classification schemes for the first time in a large single-institution study. A series of 102 intracranial dural AVFs in 98 patients assessed at a single institution was analyzed. All patients were classified according to two grading scales: the more descriptive schema of Cognard, et al. (Cognard) and that recently proposed by Borden, et al. (Borden). According to the Borden classification, 55 patients were Type I, 18 Type II, and 29 Type III. Using the Cognard classification, 40 patients were Type I, 15 Type IIA, eight Type IIB, 10 Type IIA+B, 13 Type III, 12 Type IV, and four Type V. Intracranial hemorrhage (ICH) or nonhemorrhagic neurological deficit was considered an aggressive presenting clinical feature. A total of 16 (16%) of 102 intracranial dural AVFs presented with hemorrhage. Eleven of these hemorrhages (69%) occurred in either anterior cranial fossa or tentorial lesions. When analyzed according to the Borden classification, none (0%) of 55 Type I intracranial dural AVFs, two (11%) of 18 Type II, and 14 (48%) of 29 Type III intracranial dural AVFs presented with hemorrhage (p < 0.0001). After exclusion of visual or cranial nerve deficits that were clearly related to cavernous sinus intracranial dural AVFs, nonhemorrhagic neurological deficits were a feature of presentation in one (2%) of 55 Type I, five (28%) of 18 Type II, and nine (31%) of 29 Type III patients (p < 0.0001). When combined, an aggressive clinical presentation (ICH or nonhemorrhagic neurological deficit) was seen most commonly in intracranial dural AVFs located in the tentorium (11 (79%) of 14) and the anterior cranial fossa (three (75%) of four), but this simply reflected the number of higher grade lesions in these locations. Aggressive clinical presentation strongly correlated with Borden types: one (2%) of 55 Type I, seven (39%) of 18 Type II, and 23 (79%) of 29 Type III patients (p < 0.0001). A similar correlation with aggressive presentation was seen with the Cognard classification: none (0%) of 40 Type I, one (7%) of 15 Type IIA, three (38%) of eight Type IIB, four (40%) of 10 Type IIA+B, nine (69%) of 13 Type III, 10 (83%) of 12 Type IV, and four (100%) of four Type V (p < 0.0001). No location is immune from harboring lesions capable of an aggressive presentation. Location itself only raises the index of suspicion for dangerous venous anatomy in some intracranial dural AVFs. The configuration of venous anatomy as reflected by both the Cognard and Borden classifications strongly predicts intracranial dural AVFs that will present with ICH or nonhemorrhagic neurological deficit.

Adolescent↗
PubMed1995

Management of traumatic cerebrospinal fluid fistula.

Cerebrospinal fluid fistulae present a common management problem for the surgeon managing craniofacial trauma. Controversies exist concerning various aspects of treatment. These controversial management issues include cerebrospinal fluid drainage, antibiotic prophylaxis, timing of surgical intervention, and techniques of repair. Although most cerebrospinal fluid fistulae cease spontaneously, some fistulae persist, resulting in the potential for life-threatening complications. A review of these issues is presented, together with a suggested management protocol.

Algorithms↗
PubMed1993

Hemispherectomy: a further modification using omentum vascularized free flaps.

This report describes the authors' technique designed to further prevent the late complications of hemispherectomy. A vascularized omental free flap is used to fill the extradural dead space left following the procedure advocated by Adams. This procedure may provide further stability to the residual brain and reduce infective complications.

Adult↗
PubMed1993

Cost effectiveness of clozapine in neuroleptic-resistant schizophrenia.

OBJECTIVE: The goal of this study was to determine whether clozapine is a cost-effective treatment for treatment-resistant schizophrenia. METHOD: Data were collected on 96 treatment-resistant patients with schizophrenia for 2 years before they entered a clozapine treatment study and for at least 2 years after they entered the study. Information about the cost of inpatient and outpatient treatment, housing costs, other costs, and family burden through direct interview or questionnaire of these patients and their families were available for 47 of the 96 patients. Data on lost income and Social Security disability insurance were also obtained. Outcome measures included psychopathology, quality of life, global functioning, work function, and rehospitalization. RESULTS: The cost of treatment was significantly decreased in the patients who continued clozapine treatment for at least 2 years. This was primarily due to a dramatic decrease in the frequency and cost of rehospitalization. Costs were nonsignificantly lower in patients who dropped out of treatment. The estimated total 2-year cost for the 59 patients who continued clozapine treatment, the 34 patients who dropped out, and the three who interrupted treatment decreased from $7,390,206 to $5,719,463, a savings of $8,702/year per patient. There was a decrease in total costs of $22,936/year for the 37 patients who continued clozapine treatment for whom cost data were available. There were no significant changes in lost income or Social Security disability insurance payments in either group. Clozapine produced a marked improvement in Brief Psychiatric Rating Scale total scores as well as positive negative symptom scores, Global Assessment Scale scores, Quality of Life Scale scores, work functioning, capacity for independent living, and rehospitalization rates. CONCLUSIONS: Clozapine is a cost-effective treatment for treatment-resistant schizophrenic patients. Cost savings result almost exclusively from the reduced cost of hospitalization.

Adult↗
PubMed1992

Acyl chain conformational ordering in 1,2 dipalmitoylphosphatidylethanolamine. Integration of FT-IR and 2H NMR results.

The extent of trans-gauche isomerization at the 4 and 4' positions of the acyl chains of fully hydrated 4,4,4',4'-d4 1,2-dipalmitoylphosphatidylethanolamine (4-d4 DPPE) bilayers was quantitatively evaluated from the infrared (IR) intensity of the CD2 rocking modes. About 20% gauche conformers were observed at 72 degrees C (above Tm), while at 23 degrees C, well below Tm, about 4% were noted. The order parameter SC-D was determined from 2H nuclear magnetic resonance (NMR) quadrupolar splittings. SC-D is the product of a segmental order parameter (S gamma), which depends on conformational order, and a chain order parameter (S alpha) which depends on slower motions such as chain wobble. The IR-determined percentage of gauche forms was converted into a segmental order parameter and factored out of the measured value for SC-D to yield an estimate of S alpha = 0.59 for L alpha phase DPPE. A comparison with S alpha for 1,2-dipalmitoylphosphatidylcholine (DPPC) suggests that increased wobble is responsible for enhanced motional averaging of the quadrupolar splittings in the latter at a similar reduced temperature. The extent of conformational disordering [at the 4(4') position] is essentially unchanged between the two molecules. The current study demonstrates the advantage of integrating quantitative IR with 2H NMR data, for elucidation of the contributions of the individual motions that average the NMR quadrupolar splittings.

Deuterium↗
PubMed1991

CD2 rocking modes as quantitative infrared probes of one-, two-, and three-bond conformational disorder in dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylcholine/cholesterol mixtures.

The use of CD2 rocking modes in the IR spectrum as quantitative probes of phospholipid conformational disorder has recently been described for aqueous dispersions of 1,2-dipalmitoylphosphatidylcholine (DPPC) and DPPC/cholesterol mixtures [Mendelsohn et al. (1989) Biochemistry 28, 8934-8939; Davies et al. (1990) Biochemistry 29, 4368-4373]. Initial studies focused at the 4, 6, and 10 acyl chain positions of DPPC. In the current work, the method is extended to the 2, 3, 12, and 13 positions. Conformational disorder in the L alpha phase is approximately the same (about 20% gauche) at positions 4, 10, and 13, but an unexpected higher value is observed (about 30%) at the 6 position. Cholesterol (33 mol%) restricts gauche rotamer formation by factors ranging from 6 to 9 at positions 4 and 6, respectively, to 1.5-2 at positions 10, 12, and 13. Quantitative analysis for the DPPC/cholesterol "liquid-ordered" phase indicates the occurrence of 1.2 gauche bonds/chain, a marked reduction from the 3.6-4.2 gauche bonds/chain for DPPC alone. Proximity to the ester moiety at acyl chain position 3 perturbs the vibrational coupling patterns of the CD2 rocking modes and eliminates their sensitivity to conformational change. In addition, the feasibility of a method based on the conformation-dependent coupling between CD2 rocking frequencies of two successive CD2 groups for the quantitative detection of specific, position-dependent king (gtg') and isolated gauche (gtt) conformers is demonstrated. Finally, comparisons between IR measurements and explicit theoretical predictions of acyl chain conformational order are presented.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1991

Results of ulnar neuropathy at the elbow treated by decompression or anterior transposition.

A retrospective study was conducted on 148 patients with ulnar neuropathy at the elbow, who underwent surgical treatment between 1981 and 1989. Of the 178 nerves operated on, 105 underwent subcutaneous anterior transposition, and 73 were decompressed without transposition. We compared the surgical results of these two groups, and factors influencing prognosis. Overall, 92% of patients improved postoperatively. Pre-operatively, electrophysiological assessment corresponded well to clinical findings, and to macroscopic findings at operation in 95% of cases. The severity of pre-operative clinical findings, advancing age, duration of symptoms and the presence of intraneural fibrosis did not predict an adverse outcome. A satisfactory outcome in 72% of those decompressed compared with 60% of those who were transposed was not statistically significant. However, there was a lower percentage of those with unsatisfactory results in the decompressed series. Thus, we advise that, except where there is persistent deformity or a mass lesion in the region of the ulnar groove, decompression is the operation of choice.

Adult↗
PubMed1990

Effects of cholesterol on conformational disorder in dipalmitoylphosphatidylcholine bilayers. A quantitative IR study of the depth dependence.

A method originally proposed by Snyder and Poore [(1973) Macromolecules 6, 708-715] as a specific probe of trans-gauche isomerization in hydrocarbon chains and recently applied [Mendelsohn et al. (1989) Biochemistry 28, 8934-8939] to the quantitative determination of phospholipid acyl chain conformational order is utilized to monitor the effects of cholesterol at various depths in dipalmitoylphosphatidylcholine (DPPC) bilayers. The method is based on the observation that the CD2 rocking modes from the acyl chains of specifically deuterated phospholipids occur at frequencies in the Fourier transform infrared spectrum which depend upon the local geometry (trans or gauche) of the C-C-C skeleton surrounding a central CD2 group. Three specifically deuterated derivatives of DPPC, namely, 4,4,4',4'-d4 DPPC (4-d4 DPPC), 6,6,6',6'-d4 DPPC (6-d4 DPPC), and 12,12,12',12'-d4 DPPC (12-d4 DPPC), have been synthesized, and the effects of cholesterol addition at 2:1 DPPC/cholesterol (mol:mol) on acyl chain order at various temperatures have been determined. At 48 degrees C, cholesterol inhibits gauche rotamer formation by factors of approximately 9 and approximately 6 at positions 6 and 4, respectively, of the acyl chains, thus demonstrating a strong ordering effect in regions of the bilayer where the sterol rings are presumed to insert parallel to the DPPC acyl chains. In contrast, the ability of the sterol to order the acyl chains is much reduced at the 12-position. The sterol demonstrates only a slight disordering of phospholipid gel phases. Finally, the contributions of different classes of gauche conformers to the spectra have been determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholesterol↗
PubMed1990

A quantitative infrared determination of acyl chain conformation in gramicidin/dipalmitoylphosphatidylcholine mixtures.

A quantitative infrared characterization of phospholipid acyl chain disordering in 6,6,6'6'-d4 dipalmitoylphosphatidylcholine/ Gramicidin D bilayers has been made. Three CD2 rocking modes, at 622 cm-1, 646-649 cm-1, and 651-653 cm-1, assigned to particular conformers, were used to determine disorder in the presence of peptide, as well as percentages of particular classes of conformer within the total gauche population. At 44C, the gauche percentages in 10:1 and 30:1 lipid/peptide mixtures were 15% and 17%, respectively. At 34C, the corresponding values were 9.8% and 2.6%. The percentage of (single gauche bend + kink) conformers, relative to multiple gauche forms, decreases dramatically from 78% in the 30:1 mixture to 15% in the 10:1 mixture at 44C. These data provide the first quantitative measure of the extent to which a membrane-spanning peptide disorders phospholipid gel phases and orders liquid crystal phases.

1,2-Dipalmitoylphosphatidylcholine↗