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Biomedical subjects

T J Wieman

Publications and source records attributed to T J Wieman.

At least 37 records · Page 2Linked to original sources
PubMed1994

Effects of photodynamic therapy using mono-L-aspartyl chlorin e6 on vessel constriction, vessel leakage, and tumor response.

The effect of photodynamic therapy using mono-L-aspartyl chlorin e6 (NPe6) on both direct cytotoxicity and vascular damage was examined. Sprague-Dawley rats bearing chondrosarcoma tumor were given i.v. injections of 5 or 10 mg/kg NPe6 and exposed to 135-J/cm2 664-nm laser light either 4 or 24h after NPe6 injection. The percentage of viable tumor cells was estimated either immediately after the completion of light treatment or 24 h after treatment using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Measurements of arteriole constriction and venule leakage in normal cremaster tissues were made during and 1 h after the light treatment. Tumor response was evaluated for the 4 different NPe6 dose and time combinations. Both direct tumor cytotoxicity and vascular stasis were observed during light treatment. Vessel leakage did not occur. Blood flow stasis was a result of platelet aggregation and the mechanical obstruction of flow rather than vessel constriction. The magnitude of direct cytotoxicity and vascular response was dependent on both the amount of NPe6 delivered and the delay between injection and light treatment. Tumor cure was found in animals either when given high NPe6 doses or when treated early after NPe6 injection. Treatment regimens which maximized the effect of both vascular stasis and direct tumor cytotoxicity were found to produce the best tumor response. Dose combinations which produced vascular stasis with minimal early cytotoxicity did not result in cure. The combined mechanisms of damage after photodynamic therapy using NPe6 suggests that this photosensitizer may have specific advantages for clinical use and provides a benchmark for the development of new photosensitizers.

Animals↗
PubMed1994

A new model for the study of pulmonary microcirculation: determination of pulmonary edema in rats.

Traditional studies of the lung microcirculation and pulmonary edema commonly employ indirect measurements of vascular hemodynamics or the examination of isolated lung segments. We have developed a new model which allows the direct investigation of the microcirculation at the surface of the lung in rats. A pulmonary window chamber of novel design was implanted into the chest wall of Sprague-Dawley rats to allow both short- and long-term observation of the pulmonary microvasculature in living animals. Pulmonary edema was induced by i.v. injection of either oleic acid or compound 48/80. The progression of pulmonary edema and alveolar flooding was assessed by monitoring the leakage of fluorescein-labeled albumin and rhodamine dye from the pulmonary capillaries into the alveoli. Animals given oleic acid or compound 48/80 showed progressive leakage of both fluorescein-labeled albumin and rhodamine. The greatest leakage occurred over the first 30 min of observation. No changes in pulmonary capillary permeability were observed in control animals over the period of observation.

Animals↗
PubMed1994

Effect of metatarsal head resection for diabetic foot ulcers on the dynamic plantar pressure distribution.

Diabetic neuropathic ulcers are thought to arise from repetitive injury during normal walking in areas of high plantar pressures. It has been suggested that metatarsal head (MTH) resection alleviates elevated pressures at the site of the ulcer and, thus, expedites healing and prevents recurrence. We investigated the effect of MTH resection on plantar pressure distribution and ulcer healing. Sixteen diabetic patients with neuropathic plantar ulcers present for a mean of 36 +/- 28 weeks undergoing MTH resection were studied. Plantar pressure distribution was measured preoperatively and postoperatively using the EMED-SF pressure sensor platform (Novel, Munich, Germany). The data showed that 68.8% of the patients had mean peak plantar pressures (MPPs) elevated (greater than 500 kilopascal (kPA)) at sites of plantar ulceration. The MPPs following MTH resection were significantly reduced irrespective of the site (p = 0.002). There was maximal MPP reduction following the resection of the 1st MTH (70%) and a lower reduction with 2nd-3rd MTH (39.9%) and 4th-5th MTH (45.8%) resections. We found no significant transfer of pressure to adjacent metatarsal heads following resection of the 1st MTH (p = 0.87), 2nd-3rd MTH (p = 0.11), and 4th-5th MTH (p = 0.75). All patients achieved complete ulcer healing within 8 +/- 2 weeks after surgery. We concluded that reduction of plantar pressure is crucial for plantar ulcer healing, and we have demonstrated definitively that MTH resection leads to reduced peak plantar pressure, thus, expediting ulcer healing.

Adult↗
PubMed1994

Detection of epidermal growth factor receptor mRNA in tissue sections from biopsy specimens using in situ polymerase chain reaction.

Human epidermal growth factor (EGF) receptor mRNA was detected in cryopreserved tissue sections adherent to whole glass slides using in situ reverse transcriptase polymerase chain reaction. EGF receptor cDNA was synthesized in situ by reverse transcription using an EGF receptor-specific oligonucleotide primer. In situ polymerase chain reaction amplification in the presence of digoxigenin-11-dUTP and subsequent binding with an antidigoxigenin antibody conjugated to alkaline phosphatase allowed direct visualization. Because DNase, RNase, or proteinase K are not required, tissue integrity is maintained. EGF receptor mRNA is expressed in the basal layer of normal human skin epithelium and is significantly overexpressed in squamous cell tumor specimens, which is consistent with conventional analysis of EGF receptor expression. The assay is semiquantitative, quicker, more sensitive, and void of the nonspecific binding associated with in situ hybridization. In situ reverse transcriptase polymerase chain reaction using whole glass slides is ideally suited for detecting moderate to infrequently expressed transcripts in biopsy specimens.

Antisense Elements (Genetics)↗
PubMed1993

The effects of aspirin on microvasculature after photodynamic therapy.

The effects of aspirin (acetylsalicylic acid: ASA) on vessel behavior and tumor response were measured during and after photodynamic therapy (PDT). Changes to vessel constriction, macromolecular leakage, tumor interstitial pressure, and tumor response were examined. Animals were randomly placed into treatment groups and injected with 0-25 mg/kg Photofrin and given 0 or 135 J/cm2 light treatment. The light treatment was standardized to 75 mW/cm2 at 630 nm over a 30 min treatment interval (135 J/cm2). The treatment groups were further subdivided to receive Photofrin alone or Photofrin plus 100 mg/kg ASA. A cremaster muscle model in Sprague-Dawley rats was used to directly observe microvascular response and changes in vessel permeability to macromolecules. A tumor interstitial pressure model was designed to measure pressure changes in a chondrosarcoma tumor over time. This model indirectly measures macromolecular leakage, among other factors, in the tumor tissue. Groups of 10-20 rats were implanted subcutaneously with chondrosarcoma and were subjected to PDT to assess tumor response to the various treatments. Statistically significant differences in vessel leakage and changes in interstitial pressure were observed between animals given ASA plus PDT as compared to animals given PDT alone. The administration of ASA significantly inhibited venule leakage of albumin and reduced increases in interstitial pressure after treatment. The use of ASA had no effect on vessel constriction or tumor response after PDT. These findings suggest that the increases in vessel permeability observed during and after PDT, using Photofrin, do not significantly contribute to tumor response.

Animals↗
PubMed1993

The effects of photodynamic therapy using differently substituted zinc phthalocyanines on vessel constriction, vessel leakage and tumor response.

The effects of four different zinc phthalocyanines were studied during and after photodynamic therapy (PDT). Measurements of vessel constriction, vessel leakage, tumor interstitial pressure, eicosanoid release, and tumor response of chondrosarcoma were made in Sprague-Dawley rats. Animals were injected intravenously with 1 mumol/kg of mono-, di-, or tetrasulfonated zinc phthalocyanine, or 1 mumol/kg of a zinc phthalocyanine substituted with four tertiary butyl groups. Tissues were exposed to 400 J/cm2 670 nm light 24 h after photosensitizer injection. An additional group of animals was given indomethacin before treatment. The use of the monosulfonated and tertiary butyl substituted zinc phthalocyanines in PDT caused the release of specific eicosanoids, caused vessel constriction, and induced venule leakage and increases in tumor interstitial pressure. Tumor cures of 27% and 7% were observed. Photodynamic therapy using the disulfonated zinc phthalocyanine did not induce vessel constriction or the release of eicosanoids, however, tumor cure was 43%. The use of the tetrasulfonated zinc phthalocyanine caused intermediate effects between the mono- and disulfonated compounds. The administration of indomethacin to animals completely inhibited the effects of PDT using the monosulfonated compound but had minimal effects on treatment using the disulfonated compound. This suggests that the monosulfonated and disulfonated compounds act by different mechanisms of destruction.

Animals↗
PubMed1993

The effects of thromboxane inhibitors on the microvascular and tumor response to photodynamic therapy.

Vascular stasis and tissue ischemia are known to cause tumor cell death in several experimental models after photodynamic therapy (PDT); however, the mechanisms leading to this damage remain unclear. Because previous studies indicated that thromboxane release is implicated in vessel damage, we further examined the role of thromboxane in PDT. Rats bearing chondrosarcoma were injected with 25 mg/kg Photofrin (intravenously) 24 h before treatment. Light (135 J/cm2, 630 nm) was delivered to the tumor area after injection of one of the following inhibitors: (1) R68070: a thromboxane synthetase inhibitor; (2) SQ-29548: a thromboxane receptor antagonist; and (3) Flunarizine: an inhibitor of platelet shape change. Systemic thromboxane levels were determined. Vessel constriction and leakage were evaluated by intravital microscopy. Tumor response was assessed after treatment. Thromboxane levels were decreased more than 50% with SQ-29548 as compared to controls. Thromboxane levels in animals given R68070 and Flunarizine remained at baseline levels. SQ-29548 and R68070 reduced vessel constriction compared to controls, while Flunarizine totally prevented vessel constriction. R68070 and SQ-29548 inhibited vessel permeability compared to PDT controls; Flunarizine did not. Animals given these inhibitors showed markedly reduced tumor cure. These results indicate that the release of thromboxane is linked to the vascular response in PDT.

Animals↗
PubMed1993

Use of endoscopic retrograde cholangiopancreatography in the management of biliary complications after laparoscopic cholecystectomy.

BACKGROUND: Current options in the management of bile duct injuries caused by laparoscopic cholecystectomy include diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP) and open laparotomy with direct repair. The goal of this review was to clarify the role and evaluate the potential of endoscopic techniques to diagnose and treat bile duct injuries. METHODS: The records of all patients undergoing biliary tract surgery at our hospitals for the period from December 1989 to February 1993 were reviewed. Twenty-five patients were identified with bile duct injuries during laparoscopic cholecystectomy. RESULTS: ERCP was performed for diagnostic or therapeutic purposes in 22 of the 25 patients; successful opacification of the biliary tree was achieved in 21 (95%) of the 22 patients. In these 21 patients the location and nature of the injury were identified correctly in 19 (90%). In six of the 25 cases, interventional ERCP was used as the primary treatment of these injuries. Successful treatment was achieved in five (83%) of the six cases, although laparotomy was required in two to drain the abscess cavity better. Open surgical repair was performed as the primary treatment in the remaining 19 patients. Interventional ERCP with stenting was required in six and transhepatic stenting in one of these patients as an adjunctive treatment for stricture or persistent fistula. Six (86%) of these seven patients have been treated successfully to date in this manner. CONCLUSIONS: ERCP is a uniquely helpful diagnostic and therapeutic technique in the management of laparoscopic biliary complications. Open surgical repair remains the procedure of choice for patients with loss of bile duct tissue or long complex strictures. ERCP with sphincterotomy, balloon dilatation, and stenting is an accepted alternative approach for bile leaks (fistulas) and treatment of shorter strictures resulting from either the initial laparoscopic injury or the initial repair.

Adolescent↗
PubMed1992

The role of microvascular damage in photodynamic therapy: the effect of treatment on vessel constriction, permeability, and leukocyte adhesion.

Intravital microscopy of the rat cremaster muscle was used to evaluate changes in vessel constriction, vessel permeability, and leukocyte adhesion during and after photodynamic therapy (PDT). Animals were given Photofrin doses of 0-25 mg/kg i.v. 24 h before treatment. Cremaster muscles were exposed to 135 J/cm2 light at 630 nm. Animals given 5 mg/kg Photofrin showed no vessel constriction or increase in vessel permeability to albumin. Doses of 10 and 25 mg/kg Photofrin caused a dose-related constriction of arterioles which was observed within the first minutes of illumination at the higher drug dose. After the initial constriction, arteriole response to PDT was biphasic in nature, with some vessels relaxing to nearly control levels while others remained fully constricted. Constriction of venules occurred only at the highest porphyrin dose studied (25 mg/kg) and was delayed in comparison to arteriole constriction. Photofrin doses which produced arteriole constriction also caused an increase in venule permeability to albumin, which occurred shortly after the start of light treatment and was progressive with time. Leakage began at specific sites along the venule wall but became uniform along the entire length of the venule by 1 h after treatment. Changes in the adherence of polymorphonuclear leukocytes to venule endothelium were also observed with PDT. Photofrin doses of 25 mg/kg and 45 J/cm2 light were sufficient to cause polymorphonuclear leukocytes to become adherent to the vessel wall. A second group of animals was given indomethacin trihydrate to examine the involvement of cyclooxygenase products such as thromboxane in vessel response to PDT. Animals given 5 mg/kg indomethacin intraarterially 1 h before light treatment showed no constriction of arterioles or venules at all Photofrin and light doses studied. No increases in venule permeability to albumin were seen in this group of animals. This suggests that cyclooxygenase products including thromboxane are important in causing vessel constriction and changes in permeability during PDT. The initiating event which causes the release of these vasoactive agents remains unknown.

Animals↗
PubMed1992

Implications of a pre-existing tumor hypoxic fraction on photodynamic therapy.

The presence of oxygen in tissue is a requirement for photodynamic therapy (PDT)-induced destruction of solid tumors, otherwise no cell death occurs. Since many tumors have been shown to have significant populations of hypoxic cells, it is of clinical interest to determine if pre-existing tumor hypoxia limits phototherapy. This question was examined using RIF tumors where tumor response to PDT of completely oxygenated tumors was compared to tumors with an induced hypoxic fraction. Tumor hypoxia was induced by using vasoactive drugs (epinephrine, chlorpromazine, or isoproterenol), given 30 min prior to PDT, or by a surgical method. PDT consisted of 5 mg/kg Photofrin II ip 24 hr prior to treatment and 135 J/cm2 630-nm light. The administration of the various vasoactive agents induced hypoxic fractions of 2.2 to 10%. The surgical method induced hypoxic fractions of 35%. Tumor response and cure in animals given vasoactive agents did not differ from controls, suggesting that low levels of pre-existing tumor hypoxia do not limit photodynamic therapy in this tumor model. Animals with tumors made hypoxic by a surgical method showed significantly reduced tumor response to PDT. Only 14% of these animals had tumors which became flat and necrotic by the day following PDT, compared to nearly 100% for animals given vasoactive drugs or controls. Furthermore, no tumor cure was observed in animals treated by this method. The higher level of tumor hypoxia in these animals likely represents one point where large proportions of PDT-resistant cells can survive after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Photodynamic therapy.

Photodynamic therapy is an experimental method for treating malignant tumors. Injection of a tumor-localizing and photosensitizing agent and its subsequent activation by an appropriate wavelength of light can lead to tumor destruction, apparently through disruption of the vascular integrity of the neoplasm. The mechanism by which the blood vessels are destroyed appears to involve damage to the endothelium and release of vasoactive substances including thromboxane. The clinical utility has yet to be completely established, but the modality seems likely to play a role in the management of a variety of neoplasms. The diagnostic potential of this technology also appears to hold considerable promise. Advances in technological support for the clinical use of photodynamic therapy seem to hold the key to its wide clinical application.

Humans↗
PubMed1992

Management of diabetic midfoot ulcers.

Diabetic midfoot ulcers are caused by bone and joint disruption that occur as a consequence of progressive peripheral neuropathy associated with this disease. This results in osseus deformities and areas of high pressure on the plantar surface of the midfoot, which cause the ulcers. These lesions are difficult to heal and frequently lead to amputation. In a series of 348 patients, 40 developed 54 midfoot ulcers. Limb preservation was achieved in 33 (61%). Wound closure was achieved in 32 (60%). The amputation rate was highest (83%) in the 10 of 12 patients with peripheral vascular disease. Successful therapy for limb preservation most often included an operation combining resection of underlying osseus deformities with debridement of affected soft tissues.

Diabetic Neuropathies↗
PubMed1992

Meticulous attention to foot care improves the prognosis in diabetic ulceration of the foot.

Ulceration of the foot is a major cause of morbidity in patients with diabetes, and its treatment has become a significant part of general surgical practice. It is, therefore, important to develop an efficient and effective approach to the care of this complication. We established a clinic dedicated to the care and prevention of foot ulcers in diabetic patients and since its inception in 1985, 343 patients have been seen. We provide regular prophylactic care and education to patients without ulcers, as well as treating those with ulcers. To assess the effectiveness of the clinic, we compared two groups of patients. Group 1 contained those who had ulcers while attending our prophylactic care program. Group 2 comprised those who were referred to us with lesions already present. There were 21 patients in group 1 and 150 in group 2. There were no statistical differences between the two groups with respect to age, sex, type and duration of diabetes, smoking history, prevalence of peripheral neuropathy, peripheral vascular disease, renal impairment and retinopathy. The sites and sizes of lesions were also no different between the groups. In spite of these similarities, however, patients in group 1 had a significantly better prognosis than those in group 2. The over-all number of lesions per patient was lower (1.52 +/- 0.98, compared with 2.06 +/- 1.33, p less than 0.05), the mean time required for lesions to heal was shorter (111.9 +/- 80.5 days compared with 160.5 +/- 151.3 days, p less than 0.05). The major amputation rate was lower and fewer patients required partial foot amputation. Prior to the opening of the clinic, the mean length of inpatient treatment was 30 days. This now has been reduced to 12.9 +/- 12.8 days. We conclude that the improved prognosis for those in group 1 can be attributed to the earlier detection and treatment of both potential and actual foot lesions. These results support the contention that the establishment of a dedicated diabetic foot care clinic and regular patient review can reduce the morbidity associated with diabetic foot ulceration.

Diabetes Complications↗
PubMed1991

Cardiac sympathetic tone in anaesthetized diabetics.

To assess cardiac sympathetic nervous function in diabetics, the heart rates attained following a pharmacological dose of intravenous atropine, 23 micrograms.kg-1, were studied under N2O, isoflurane anaesthesia in diabetics (n = 21) and nondiabetics (n = 30). Atropine-induced heart rate in diabetics was significantly lower than that in nondiabetics (95 +/- 14 (SD) bpm vs 109 +/- 12 bpm, P less than 0.001) and were closely related to preoperative orthostatic diastolic blood pressure change (r = 0.60, P less than 0.01). There was some correlation between the atropine-induced heart rate and preoperative RR-variation in diabetics (r = 0.50, P less than 0.05). The findings suggest that cardiac sympathetic function may also be impaired in diabetics with orthostatic hypotension.

Adolescent↗
PubMed1991

The influence of photodynamic therapy on the ultrastructure of the normal rat bladder.

Reduced bladder capacity is a major side effect for patients receiving photodynamic therapy (PDT) for bladder cancer. A rat bladder model has been developed to address both the vascular and tissue effects of the photodynamic treatment of the urinary bladder. Bladders were exteriorized and positioned in a plexiglass tissue bath. Effects on microvasculature were assessed during PDT of the bladder by recording luminal diameter changes in arterioles and venules. Animals receiving Photofrin II (10 mg kg-1) 30 min prior to PDT scored a statistically significant reduction in the diameter of the red blood cell column in the vessels, whereas administration of Photofrin II 48 h prior to PDT was ineffective. Morphological changes included significant endothelial and vascular myocyte damage in the 30 min PDT group alone. Among the other tissue components, the mucosal lining was minimally affected and the response of the muscularis was highly variable. Smooth muscle cell changes ranged from mild contraction to frank necrosis with many of the affected cells located near the altered vascular beds. These data suggest that the clinical symptoms of reduced bladder capacity can be accounted for by vascular damage and myocyte sensitivity. Further refinements in the Photofrin II and light doses used in therapy may reduce bladder complications and allow for better management of bladder cancer.

Animals↗
PubMed1991

Changes in tumor interstitial pressure induced by photodynamic therapy.

This study has examined the changes in tumor interstitial pressure exhibited during and after photodynamic therapy (PDT). The kinetics of these changes are marked by an initial decrease, followed by a rapid rise in tumor interstitial pressure. We have also employed two inhibitory agents to evaluate the different components of the pressure curve. Specially designed pressure chambers were seeded with chondrosarcoma and implanted subcutaneously in rats. Animals were injected with 0-50 mg/kg Photofrin II (i.v.) 7 days post-implantation and tumors were exposed to 0-540 J/cm2 630 nm 24 h later. Interstitial pressure was monitored via a transducer connected to the implanted chamber. Additional groups of animals were injected with either indomethacin (an inhibitor of thromboxane synthesis) or Ketanserin (a serotonin antagonist) before light treatment. Porphyrin doses of 10 mg/kg and above (135 J/cm2), or light doses of 135 J/cm2 and above (25 mg/kg Photofrin II) were effective in modifying interstitial pressure. Porphyrin doses greater than 25 mg/kg, or light doses greater than 270 J/cm2 produced no further increases in interstitial pressure. Animals given indomethacin (10 mg/kg i.p.) exhibited the initial decrease in pressure during light treatment, but showed no increase past baseline levels. Animals given Ketanserin (10 mg/kg i.p.) demonstrated no decrease in pressure during PDT, but showed the same elevations in pressure as controls. This suggests that two independent mechanisms account for the different components of the pressure curve, and that serotonin release may occur during PDT.

Animals↗
PubMed1990

Role of thromboxane and prostacyclin release on photodynamic therapy-induced tumor destruction.

Thromboxane and prostacyclin levels in serum were measured following photodynamic therapy (PDT) to assess the role of these vasoactive agents on vascular damage and tumor destruction. Sprague Dawley rats were given injections i.v. of Photofrin II doses ranging from 0 to 25 mg/kg. Twenty-four h later, the right hindlimbs of animals bearing chondrosarcoma tumor or controls were exposed to 0-135 J/cm2 630 nm light. Serum concentrations of thromboxane and prostacyclin were determined by radioimmunoassay. A dose-response relationship was established between the amount of photosensitizer administered and the light dose delivered with the release of thromboxane immediately following PDT. Treatment of tumor induced higher levels of thromboxane than did the treatment of tumor-free tissue, suggesting that tumor is more sensitive to PDT-induced damage. The porphyrin and light doses found to induce the release of thromboxane into serum were the same as those required to evoke vascular stasis and tumor destruction. Prostacyclin release was not altered by PDT. The administration of indomethacin (10 mg/kg, i.p.) 3 h before light treatment was found to suppress the intravascular release of thromboxane at the highest porphyrin and light doses studied. Indomethacin treatment also inhibited PDT-induced vascular stasis and tumor destruction, suggesting that the release of thromboxane is linked to these events. Since prostacyclin levels in serum were unchanged following PDT treatment of tumor and controls, thromboxane release appears to be a specific response to PDT and may mediate the vascular stasis observed following PDT.

Animals↗