Biomedical subjects

M Michael

Publications and source records attributed to M Michael.

At least 73 records · Page 4Linked to original sources

PubMed1997

Hyperbaric oxygen worsens myocardial low flow ischemia-reperfusion injury in isolated rat heart.

In these experiments rats were exposed to hyperbaric oxygen (100% oxygen; 2.5 atmospheres absolute pressure) for 1, 3 or 6 h. At the end of these periods the hearts were removed and subjected to low flow ischemia (perfusion rate from 12 ml/min to 2 ml/min for 40 min) and reperfusion. Hearts excised from control rats were subjected to the same procedure of ischemia and reperfusion. The data obtained from these experiments clearly indicate that the ischemic picture observed in control hearts is worsened in hearts obtained from hyperbaric oxygen-exposed animals. In fact, after ventricular standstill of the ischemic phase, the left ventricular end-diastolic pressure increased significantly and proportionally according to the time of hyperbaric oxygen exposure. The vasopressor activity of angiotensin II on coronary perfusion pressure was significantly changed, as compared to that in the control preparation: these alterations, well correlated to the time of hyperbaric oxygen exposure, seem to suggest impairment of the vascular endothelium-dependent relaxant function. Furthermore N-acetylcysteine and defibrotide, given orally to the rats before hyperbaric oxygen exposure, prevented the aggravation of the ischemic damage induced in ex vivo hearts.

Acetylcysteine↗

PubMed1997

Mitochondrial D-loop 3' (CA)n repeat polymorphism: optimization of analysis and population data.

We report a dinucleotide repeat polymorphism in the 3' area of the mitochondrial control region. The fragments obtained using a new primer set could be reliably separated by polyacrylamide gel electrophoresis (PAGE) using nondenaturing gels. A total of five alleles [(CA)3 to (CA)7] were detected on silver-stained gels. The 90 bp product corresponds to allele 5. Samples from one African and three European populations were characterized. Significant differences could be demonstrated as to the incidence of single alleles and allele distributions in different populations. These differences were found between the three European and one African Bantu population. For specific forensic questions the mitochondrial CA repeat is well suited. Gene diversities in populations of Germany, Hungary, the Russian Federation and Cameroon were 0.36, 0.40, 0.34, 0.52, respectively.

Africa↗

PubMed1997

Oligonucleotide-directed mutagenesis and subsequent expression of the corresponding recombinant proteins without changing the bacterial vector system.

A new bacterial vector was constructed that combines the attractive features of gene fusion vectors and phagemids. A gene of interest cloned into this new vector can either be expressed as fusion protein or be prepared as single-stranded template DNA within the same system. Thus, time consuming subcloning procedures changing the bacterial vector according to the required method are avoided. As an example sequencing, expression and subsequent purification of site-directed mutants of herpes simplex virus type 1 thymidine kinase are discussed.

Cloning, Molecular↗

PubMed1997

Effects of extended electrical kindling on exploratory behavior and spatial learning.

Short-term electrical kindling, a widely used experimental model of epilepsy, appears to have little effect on behavior. The effects of extended kindling are largely unknown. Rats implanted with kindling electrodes in amygdala (AM) or perforant path (PP) received 300 kindling trials over approximately 7 months, and were tested in the Morris watermaze after a 7-10 day recovery period. Kindled animals were impaired during the initial training on hidden-platform acquisition, but not in retention of platform location. No deficits were found in acquiring a new hidden-platform location, latency to reach a visible-platform, or in swim speed. Open-field activity showed a sustained increase when tested during kindling, but only a transient increase when tested following suspension of kindling. Similar results were obtained for both AM and PP kindled animals. Hence, long-term kindling of both of these sites produced behavioral changes that were transient in nature. Further, these results also indicate that propagation of seizure activity from remote sites can alter hippocampally-mediated or related behavior.

Animals↗

PubMed1997

Phase I dose intensification study of 2-weekly epirubicin with GM-CSF in advanced cancer.

This study investigated dose intensification of epirubicin administered as a 2-weekly regimen with granulocyte-macrophage colony-stimulating factor (GM-CSF) support. The aim was to define the maximally tolerated dose of epirubicin and to assess the efficacy of GM-CSF to ameliorate its toxicity. Patients with anthracycline-responsive advanced malignancies were eligible. Six dose levels, commencing at 90 mg/m2, of epirubicin administered every 2 weeks for four courses were planned with GM-CSF 10 micrograms/kg/day administered for 10 days from the second day of each course. Six patients were to be entered at each dose level, and escalation to the next level was based upon toxicity criteria. Twelve patients were entered, six at dose level 1 (90 mg/m2) and six at dose level 2 (120 mg/m2). Prospectively defined haematological dose-limiting toxicities were noted in one patient at dose level 1 and in five patients at dose level 2. Further dose escalation was not attempted. Significant nonhaematological toxicities included febrile neutropenia in two and four patients at dose levels 1 and 2, respectively. This study has demonstrated that epirubicin can be safely administered at 2 week intervals with GM-CSF at a dose of 90 mg/m2, equivalent to the previously reported maximum tolerated dose intensity of 45 mg/m2/week. Neutropenia was dose-limiting despite the use of GM-CSF.

Adjuvants, Immunologic↗

PubMed1997

Activity and toxicity of docetaxel (Taxotere) in women with previously treated metastatic breast cancer.

BACKGROUND: Metastatic breast cancer is a major cause of cancer death in Australian women. Docetaxel is a new cytotoxic drug that has shown promise in the treatment of metastatic breast cancer in patients who have previously received other chemotherapy, particularly an anthracycline, and has recently been approved for marketing in Australia. AIM: To report the first Australian experience with docetaxel in a group of women with metastatic breast cancer. METHODS: Patients with progressive metastatic breast cancer who had previously received other chemotherapy were treated with docetaxel 75 mg/m2 or 100 mg/m2 given as a one hour infusion every three weeks. All patients received oral dexamethasone for five days starting 24 hours prior to docetaxel as prophylaxis against fluid retention. The patients' response to docetaxel and toxicity were assessed by standard criteria. RESULTS: Twenty-six patients were treated. The major toxicity was neutropenia with 92% of patients experiencing at least one episode of grade 4 (absolute neutrophil count < 0.5 x 10(9)/L) neutropenia. Hospital admission for febrile neutropenia occurred in 44% of patients with one death from sepsis. Cumulative fluid retention was observed but in only one patient was it dose-limiting. Apart from alopecia, other toxicities were infrequent and rarely serious. In 23 patients assessable for response, there were 11 partial responses (48%). Three other patients whose disease could not be assessed for response had clinical improvement. The median survival of all patients treated was eight months. CONCLUSIONS: The response rate observed with docetaxel is comparable to that seen in trials in the United States and Europe and confirms the high activity of this new cytotoxic agent. Neutropenia is the major toxicity, and consideration should be given to the use of prophylactic oral antibiotics or colony stimulating factors to try and prevent febrile episodes. Clinicians will need to balance the benefits, toxicities, and cost of docetaxel in determining the appropriateness of its use in their patients.

Adult↗

PubMed1997

Low-fat papadams from black gram-tapioca blends.

Papadams, made from black gram (Phaseolus mungo) and largely manufactured on cottage scale are popular in the Indian dietary. Escalating prices of black gram coupled with abundant availability of tapioca flour at almost 1/8th the price of black gram prompted the study of papadam characteristics using blends of black gram and tapioca flour. Tapioca flour up to 25% substitution did not alter the sensory attributes. However, the expansibility of the product decreased on addition of tapioca flour; a fact which could be overcome by using carboxymethyl cellulose (CMC) at 3% level of black gram flour. This decreased the oil content to 19.7% and also increased the expansibility to 5.539%.

Bread↗

PubMed1997

Clinical experience with gemcitabine in pancreatic carcinoma.

The treatment of advanced pancreatic carcinoma has been viewed with pessimism. Because of the lack of activity of commonly used agents, there is no consensus regarding a standard chemotherapy regimen. Assessment of response is neither uniform nor reproducible. Debilitating tumor-related symptoms, including pain, anorexia, weight loss, and impaired performance status, are common. Many studies have failed to evaluate the palliative benefit of treatments, although many patients consider such benefit to be of the utmost importance. Tools have been developed to uniformly assess tumor-related symptoms, and the concept of clinical benefit response has been developed as an end point to quantify symptomatic improvement utilizing these tools. Clinical benefit response incorporates palliative measures, such as pain control, analgesic consumption, performance status, and weight gain. In early phase I and II trials, gemcitabine (Gemzar) has shown activity in patients with chemotherapynaive advanced pancreatic carcinoma. In addition to producing some responses and symptomatic benefit, gemcitabine has a favorable toxicity profile. Two recent trials using clinical benefit response as the primary end point have demonstrated that gemcitabine significantly improves disease-related symptoms in approximately one-quarter of patients. These trials also showed improved survival with gemcitabine, as compared with fluorouracil. Additional studies are required to fully assess the role of gemcitabine in both adjuvant and advanced disease settings.

Adenocarcinoma↗

PubMed1996

Sufficient conditions for effective treatment of substance abusing homeless persons.

Treatment efficacy for homeless substance abusers (primarily crack cocaine) was studied in a randomized control design with subjects (n = 176) assigned to usual care (UC) or an enhanced day treatment program plus abstinent contingent work therapy and housing (EC). Subjects met DSM-III-R criteria for Substance Use Disorder and McKinny Act criteria for homelessness. UC involved weekly individual and group counseling. EC involved a day treatment program consisting of daily attendance, transportation, lunch, manualized psychoeducational groups, and individual counseling. A total of 131 (74.4%) subjects (62 UC and 69 EC) were treated and followed. UC subjects attended 28.5% and EC attended 48.4% of expected treatment during the first 2 months. After 2 months, EC subjects experienced up to 4 months of abstinent contingent work therapy (44.9% of EC subjects) and housing (37.7% of EC subjects), with day treatment available two afternoons per week. Longitudinal Wei-Lachin analyses of medians (reported alcohol use, days homeless and employed) and proportions (cocaine toxicologies) were conducted across 2-, 6-, and 12-month follow-up points. EC had 36% fewer positive cocaine toxicologies at 2-months and 18% fewer at 6-months than UC with regression toward baseline at 12-months. EC had 8 days fewer days of reported alcohol use in the past 30 days, 52 fewer days homeless in the past 60 days, and 10 more days employed in the past 30 days from baseline to the 12-months. UC showed no changes except a temporary increase in employment at 6-months. This is one of the first demonstrations that homeless cocaine abusers can be retained and effectively treated.

Adult↗

PubMed1996

Medical supplies donated to hospitals in Bosnia and Croatia, 1994-1995. Report of a survey evaluating humanitarian aid in war.

OBJECTIVE: To evaluate access to and distribution and quality of medical supplies donated by humanitarian aid organizations to hospitals and health services during the war in Bosnia and Croatia. DESIGN: Retrospective survey of 68 representatives of hospitals and field hospitals regularly caring for inpatients between May 1994 and April 1995. SETTING: Three study areas: the Republic and Federation of Bosnia-Herzegovina, Republika Srpska (part of Bosnia-Herzegovina controlled by Bosnian Serbs), and Republika Srpska Krajina (part of Croatia controlled by Croatian Serbs during the study period). PARTICIPANTS: Of 68 hospital representatives, 44 completed the survey (65% response rate). Respondents did not include representatives from 11 hospitals and field hospitals that could not be contacted because of operational obstacles resulting from the ongoing war. RESULTS: Lack of supplies was reported as an important limitation by 62% (26/42) of respondents, followed by lack of staff and security, physical isolation, and lack of infrastructure. Antibiotics were mentioned by 76% (32/42) of respondents as the unavailable drug or item most urgently needed. The majority of drug and medical supplies used to treat patients had been supplied by 5 humanitarian aid organizations. The frequency with which respondents mentioned their ¿own means¿ (eg, from the ministry of health or respective municipalities) was relatively low (9%), reflecting the high degree of dependency on humanitarian aid. All respondents rated the quality of donated supplies and the working relationship with the donating organization as ¿very good¿ or ¿satisfactory¿; 93% 41/44) of respondents indicated that the donated supplies were appropriate. Six of 44 respondents preferred to receive supplies as part of assembled kits; 70% (31/44) preferred to receive such assistance as loose supplies according to demand. CONCLUSION: During war, access and security are beyond the control of humanitarian agencies. Assistance coordination, however, must be provided. Although a consensus on policies and objectives between different humanitarian organizations is difficult to reach, satisfactory complementarity can be achieved. The systematic and continuous gathering of information at the recipient and user level, beginning at the early phase of the conflict, is recommended to maintain appropriate assistance.

Bosnia and Herzegovina↗

PubMed1996

Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel.

Thirty-eight women with epithelial ovarian cancer were treated with gemcitabine, a new antimetabolite. All had previously received platinum, and 27 had also received paclitaxel. Four patients had a partial response giving a response rate of 13% in assessable patients (n = 31) and 11% for all patients entered. Additionally, 6 patients had stable disease with >50% reduction in CA-125 for at least 3 months. Activity was seen in patients resistant to both platinum and paclitaxel. Gemcitabine was well tolerated, with uncomplicated neutropenia the main hematological toxicity. Nonhematological toxicities were generally mild and included fatigue, myalgias, and skin rash. Gemcitabine has some activity in heavily pretreated ovarian cancer patients and deserves further investigation in this malignancy.

Adult↗

PubMed1996

Association of acquired Pelger-Huet anomaly with taxoid therapy.

We describe the occurrence of acquired Pelger-Huet anomaly (APHA) in 23 patients treated with paclitaxel (13) or docetaxel (10). A consistent peak of Pelger-Huet cells (PHC) within a range of 3-9 d after treatment with taxoids was noted. The APHA generally disappeared by day 21 after treatment. Peak PHC values for the first course were significantly different in paclitaxel versus docetaxel versus control groups (P < 0.0001) with the maximum PHC counts being significantly higher for docetaxel compared with paclitaxel (P < 0.001) and for paclitaxel compared with controls (P = 0.007). We conclude that taxoid therapy produces transient APHA which peaks between days 3 and 9 and is more pronounced with docetaxel than with paclitaxel.

Adult↗

PubMed1996

Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study.

OBJECTIVE: To evaluate the effectiveness of systemic hyperbaric oxygen therapy (s HBOT) in addition to a comprehensive protocol in decreasing major amputation rate in diabetic patients hospitalized for severe foot ulcer. RESEARCH DESIGN AND METHODS: From August 1993 to August 1995, 70 diabetic subjects were consecutively admitted into our diabetologic unit for foot ulcers. All the subjects underwent our diagnostic-therapeutic protocol and were randomized to undergo s-HBOT. Two subjects, one in the arm of the treated group and one in the arm of nontreated group, did not complete the protocol and were therefore excluded from the analysis of the results. Finally, 35 subjects received s-HBOT and another 33 did not. RESULTS: Of the treated group (mean session = 38.8 +/- 8), three subjects (8.6%) underwent major amputation: two below the knee and one above the knee. In the nontreated group, 11 subjects (33.3%) underwent major amputation: 7 below the knee and 4 above the knee. The difference is statistically significant (P = 0.016). The relative risk for the treated group was 0.26 (95% CI 0.08-0.84). The transcutaneous oxygen tension measured on the dorsum of the foot significantly increased in subjects treated with hyperbaric oxygen therapy: 14.0 +/- 11.8 mmHg in treated group, 5.0 +/- 5.4 mmHg in nontreated group (P = 0.0002). Multivariate analysis of major amputation on all the considered variables confirmed the protective role of s-HBOT (odds ratio 0.084, P = 0.033, 95% CI 0.008-0.821) and indicated as negative prognostic determinants low ankle-brachial index values (odds ratio 1.715, P = 0.013, 95% CI 1.121-2.626) and high Wagner grade (odds ratio 11.199, P = 0.022, 95% CI 1.406-89.146). CONCLUSIONS: s-HBOT, in conjunction with an aggressive multidisciplinary therapeutic protocol, is effective in decreasing major amputations in diabetic patients with severe prevalently ischemic foot ulcers.

Aged↗

PubMed1995

Site-directed mutagenesis of herpes simplex virus type 1 thymidine kinase opposes the importance of amino acid positions 251, 321 and 348 for selective recognition of substrate analogs.

Seven site-directed mutants representing step-by-step transitions from the thymidine kinase (TK) of Herpes Simplex Virus type 1 (HSV 1) strain F to that one of strain SC16 were constructed, recombinantly produced and kinetically characterized in order to identify which of three differences in the amino acid sequence of these two TKs is/are responsible for their difference in substrate specificity. The preference of these two TKs for the substrate analogs aciclovir and ganciclovir was reported to be in reverse order (4.5), suggesting one of the amino acids in position 251 (cys or gly), 321 (ser or pro) and 348 (val or ile) of the HSV 1 wildtype TKs to be important for selective substrate recognition. However, the results of our study do not support this hypothesis.

Acyclovir↗

PubMed1995

The immunogenicity of MUC1 peptides and fusion protein.

Mucin 1 (MUC1) is highly expressed in breast cancer, has an ubiquitous distribution and, due to altered glycosylation, peptides within the VNTR are exposed. These peptides are the target for anti-MUC1 antibodies, which give a differential reaction on cancer compared with normal tissue. The amino acids, APDTR or adjacent amino acids, are highly immunogenic in mice for antibody production (after immunisation with either breast cancer cells, human milk fat globule (HMFG) or the VNTR peptide). In addition, human studies show that this region of the MUC1 VNTR functions as target epitopes for cytotoxic T cells. We have performed preclinical and clinical studies to examine the immune responses to MUC1 in mice and humans: (a) MUC1+ 3T3 or P815+ 3T3 cells in syngeneic mice are rejected, with the generation of both cytotoxic T lymphocyte (CTL) and DTH responses and a weak antibody response and a weak antibody responses; this type of immunity gives rise to total resistance to re-challenge with high doses of these tumors; (b) immunisation with peptides (VNTR x 2), a fusion protein (VNTR x 5), or HMFG leads to no CTLs, DTH, good antibody production and weak tumour protection (to 10(6) cells, but not 5 x 10(6) cells) (possibly a TH2 type response); (c) immunisation with mannan-fusion protein (MFP) gives rise to good protection (resistance to 50 x 10(6) cells), CTL and DTH responses and weak antibody responses (possibly a TH1 type response, similar in magnitude to that obtained after tumor rejection); (d) established tumors can be rapidly rejected by delayed treatment of MFP; (e) the CTL responses are MHC restricted (in contrast to the human studies); (f) APDTR appears not to be the T cell reactive epitope in mice. On the basis of these findings, two clinical trials are in progress: (a) VNTR x 2 (diphtheria toxoid) which gives rise to some T cell proliferation, DTH and antibody responses in some patients and (b) an MFP trial. The ability to alter the immune response towards cellular immunity with mannan or to humoral immunity with peptides, allows the immune response to be selectively manipulated.

Animals↗

PubMed1995

Development of spontaneous seizures over extended electrical kindling. II. Persistence of dentate inhibitory suppression.

The effect of an extended program of perforant path or amygdala kindling on paired-pulse suppression in the dentate gyrus was studied in male hooded rats. Repeated kindling stimulations were delivered twice or three times daily until either 300 stimuli had been delivered or generalized convulsions had been observed to occur spontaneously. Paired-pulse suppression was monitored prior to and over the course of kindling using a standard variable interval paradigm. We also used a variable intensity paradigm in which the intensity of the conditioning pulse was varied while the test pulse intensity was fixed at 600 microA and the interpulse interval was fixed at 30 ms. Both procedures revealed progressive increases in paired-pulse suppression which persisted over the course of kindling. This increased inhibition also persisted in animals which developed spontaneous seizures. The variable intensity paired-pulse procedure also allowed us to monitor facilitation effects which were relatively uncontaminated by recurrent inhibition (when the conditioning pulse intensity was low). Kindling was found to increase paired-pulse facilitation. With the standard variable interval paradigm, these increases in facilitation masked the increases in suppression.

Amygdala↗

PubMed1995

Treatment outcome as a function of treatment attendance with homeless persons abusing cocaine.

This research examines the influence of treatment attendance at two substance abuse outpatient treatment programs of the Birmingham Substance Abuse Homeless Project on substance abuse, homelessness, and unemployment outcomes with homeless persons abusing primarily crack cocaine. Results revealed that significant reductions across a one year period in alcohol use, cocaine use, and homelessness were more likely to occur in clients who attended an average of 4.1 treatment days per week (High attendance or Enhanced Care group) than clients who attended less than one day a week on the average (Low attendance or Usual Care and Medium attendance groups). These results are consistent with the literature suggesting that more intensive contact early in treatment results in better long-term outcome with cocaine abusers, but has now been demonstrated with homeless cocaine abusers who have additional problems associated with housing and employment.

Adult↗

PubMed1994

Site-directed mutagenesis clarifies the substrate position within the three-dimensional model of the active site of herpes simplex virus type-1 thymidine kinase.

Site-directed mutagenesis was used to experimentally verify the 3D model of the active site of herpes simplex virus type-1 thymidine kinase (HSV 1 TK) obtained by homology modelling. For this purpose, D215 and K317 were replaced by R and G, respectively, at homologous positions in the aciclovir-insensitive bovine herpes virus type-1 thymidine kinase (BHV 1 TK). Wild-type and mutated enzymes were expressed in Escherichia coli using a gene fusion vector and purified to homogeneity. While both mutants had the same Km value for thymidine as the recombinant wild-type enzyme (0.2 microM), Vmax was decreased to 20-25% of the original wild-type value. The recombinant wild-type enzyme was inhibited by the substrate analogue aciclovir with a Ki of 146 microM. Both mutants were able to phosphorylate aciclovir to about the same extent as the wild-type enzyme. These findings suggest that neither D215 nor K317 are directly involved in substrate binding. Therefore, a rearrangement of the 3D model is suggested, concerning the assignment of the substrate-binding site and co-substrate-binding site at the right and left side of the phosphate-binding loop, respectively.

Base Sequence↗