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Biomedical subjects

C J Mathias

Publications and source records attributed to C J Mathias.

284 records · Page 16Linked to original sources
PubMed1975

Plasma catecholamines, plasma renin activity and plasma aldosterone in tetraplegic man, horizontal and tilted.

1. Plasma catecholamines, plasma renin activity, plasma aldosterone and haematocrit were measured in four subjects with physiologically complete cervical spinal cord transections, before, during and after head-up tilt to 45 degrees for 30 min. Plasma catecholamines were measured in five normal male volunteers in the supine position and after head-up tilt to 45 degrees for 10 min. 2. After 10 min of head-up tilt, the plasma noradrenaline rose 14% in the tetraplegic patients and 115% in the control subjects. These findings indicate a failure of sympathetic activity in response to head-up tilt in the tetraplegic patients, probably caused by interruption of pathways by which the brain normally controls sympathetic outflow. 3. In the tetraplegic patients the resting plasma renin activities were above normal, and rose more quickly and greater on head-up tilt than in published studies of normal subjects. It is likely that the renal baroreceptors are important in the control of renin release. 4. In the tetraplegic patients, there was a late rise in plasma aldosterone which was probably due to the elevation in plasma renin activity.

Adult↗
PubMed1975

Plasma prostaglandin E during neurogenic hypertension in tetraplegic man.

1. Arterial blood pressure and heart rate were measured before, during and after cutaneous and visceral stimulation in subjects tetraplegic due to severe cervical spinal cord damage. Stimulation resulted in marked hypertension as a result of reflex sympathetic overactivity. 2. Mixed venous blood from a catheter situated in the right atrium was obtained before and after stimulation and plasma prostaglandin E and prostaglandin F were measured. A consistent and significant rise in plasma prostaglandin E, but not plasma prostaglandin F, accompanied the hypertension. 3. It is suggested that prostaglan ding E is released during this sympathetic nervous activity and may be related to neurogenic hypertension.

Adult↗
PubMedDate not supplied

The relationship between blood flow and pulsatility index in the superior mesenteric artery at rest and during constrictor stimuli in normal subjects.

The relationships between superior mesenteric artery blood flow (SMABF) and pulsatility index (PI) measurement during rest (25 subjects) and stimuli constricting the SMA (16 subjects) have been studied in normal subjects. At rest and during constrictor stimuli, SMABF and PI were highly reproducible (r = 0.89, p < 0.01 for SMABF, and r = 0.97, p < 0.001 for PI) between two observers. There was significant correlation between changes in SMABF, PI, and SMA vascular resistance during the constrictor stimuli, except during head-up tilt when PI was unchanged. Both PI and SMABF measurements are reproducible and can be used to monitor physiological changes in suitable (18 of 25) subjects. PI measurement, although semiquantitative, by itself can also be used to monitor these changes. This may be also of importance in pathological situations such as intestinal ischemia, where measurement of volume blood flow may be less accurate due to irregularities of the vessel wall. PI measurement, however, ideally should not be used in studies involving postural change.

Adult↗
PubMedDate not supplied

Clinical manifestations of malfunctioning sympathetic mechanisms in tetraplegia.

Patients who are tetraplegic with cervical spinal cord transection do not appear to have cerebral control over the sympathetic nervous system. Soon after transection they are often in a state of spinal shock during which even isolated spinal cord sympathetic activity is absent. This affects, in particular, the cardiovascular system and other homeostatic mechanisms which are dependent on appropriate regulation of the vasculature, such as thermoregulation. After a few weeks isolated spinal cord activity returns but the absence of control absence of control by the brain results in sympathetic malfunction of various systems. Inappropriate inactivity therefore occurs during postural change and causes orthostatic hypotension, while over-activity, which results in the syndrome of autonomic dysreflexia and hypertension, occurs if spinal sympathetic reflexes are activated. Examples are provided of clinical effects of sympathetic malfunction in tetraplegics in relation to circulatory, thermoregulatory, pupillary, genital, gastrointestinal and urinary tract function.

Body Temperature Regulation↗
PubMedDate not supplied

N,N'-bis(2-hydroxybenzyl)-1-(4-bromoacetamidobenzyl)-1,2 -ethylenediamine-N,N'-diacetic acid: a new bifunctional chelate for radiolabeling antibodies.

N,N'-Bis(2-hydroxybenzyl)-1-(4-bromoacetamidobenzyl)-1,2 -ethylenediamine-N,N'-diacetic acid (Br phi HBED) was synthesized to bind trivalent metals with high stability constants and to bifunctionally link the radiometal with antibodies (Ab). This ligand has advantages over our previously reported N-(2-hydroxy-3,5-dimethylbenzyl)-N'-(2-hydroxy-5- bromoacetamidobenzyl)ethylenediamine-N,N'-diacetic acid (BrMe2HBED). Br phi HBED has the protein coupling group BrCH2CONH removed from the sterically hindered ring position with the addition of a benzyl group in the linker arm; this provides further distance between the protein and the chelate. We have also observed that the chelate was more stable than BrMe2HBED, so it can be stored longer without loss of observed chemical properties. The improved chelate design allows for more rapid radiolabeling with [111In]indium citrate (1 h at room temperature) with higher radiochemical yields. Br phi HBED was conjugated with an anticolorectal carcinoma monoclonal antibody (1A3) where radiolabeling yields of 75-90% were obtained and the antibody retained its immunoreactivity (ca. 90%) under all labeling conditions studied. Biodistribution studies in a hamster transplanted tumor (GW39) model demonstrated a high tumor uptake when compared to those of 125I-1A3 or 111In-DTPA cyclic anhydride-1A3. Blood clearance of 111In-Br phi HBED-1A3 was rapid and combined with its high target uptake has higher target to nontarget ratios in vivo at various time intervals when compared with that of 1A3 radiolabeled with either 111In-DTPA cyclic anhydride or 125I.

Animals↗
PubMedDate not supplied

Synthesis, purification, and tumor cell uptake of 67Ga-deferoxamine--folate, a potential radiopharmaceutical for tumor imaging.

The vitamin folic acid was covalently linked to the chelating agent deferoxamine (DF) via an amide bond using a simple carbodiimide coupling reaction. A mixture of two isomers, DF--folate(alpha) and DF--folate(gamma), was produced involving the alpha- and gamma-carboxyl group of folic acid, respectively. These two isomers were separated by anion-exchange chromatography using a NH4HCO3 gradient. Competitive binding studies revealed that only the DF-folate(gamma) is recognized by the folate receptor on KB cells, interacting with an affinity comparable to unconjugated folic acid. The DF--folate conjugates were radiolabeled with the gamma-emitting radionuclide 67Ga3+ and tested for uptake by cultured KB cells overexpressing the folate receptor. The cellular accumulation of 67Ga-DF-folate(gamma) tracer exhibited rapid uptake kinetics in cell culture with a t1/2 of approximately 3 min. The KB cell association of 67Ga-DF--folate(gamma) was competitively blocked by free folic acid, indicating that uptake of the 67Ga-DF--folate(gamma) was specifically mediated by the folate receptor. Since the folate receptor is overexpressed on the surfaces of many neoplastic cells, these results suggest that 67Ga-DF--folate(gamma) complex might be useful as a diagnostic agent for noninvasive imaging of folate receptor-positing tumors.

Biological Transport↗
PubMedDate not supplied

Design and synthesis of [111In]DTPA-folate for use as a tumor-targeted radiopharmaceutical.

Folate-conjugated metal chelates have been proposed as potential imaging agents for cancers that overexpress folate receptors. In a previous study, folic acid was linked through its gamma-carboxyl group to deferoxamine (DF), and the 67Ga-labeled complex ([67Ga]DF-folate) was examined for in vivo tumor targeting efficiency in athymic mice with a human tumor cell implant. Although superb tumor-to-background contrast was obtained, slow hepatobiliary clearance would compromise imaging of abdominal tumors such as ovarian cancer. In the present study, folic acid was conjugated to an alternative chelator, diethylenetriaminepentaacetic acid (DTPA), via an ethylenediamine spacer. The desired DTPA-folate (gamma) regioisomer was synthesized by two different approaches, purified by reversed phase column chromatography, and characterized mainly by analytical HPLC, mass spectroscopy, and NMR. In cultured tumor cells, uptake of [111In]DTPA-folate (gamma) was found to be specific for folate receptor-bearing cells, and the kinetics of uptake were similar to those of free folate and other folate-conjugated molecules. In the normal rat, intravenously administered [111In]DTPA-folate (gamma) was found to be rapidly excreted into the urine, giving intestinal levels of radiotracer 10-fold lower than those observed with [67Ga]DF-folate (gamma) at 4 h. In a preliminary mouse imaging study, a folate receptor-positive KB cell tumor was readily visualized by gamma scintigraphy 1 h following intravenous administration of [111In]DTPA-folate (gamma).

Animals↗
PubMedDate not supplied

Synthesis of [(99m)Tc]DTPA-folate and its evaluation as a folate-receptor-targeted radiopharmaceutical.

A DTPA-folate conjugate was radiolabeled with (99m)Tc by stannous chloride reduction of [(99m)Tc]sodium pertechnetate in an aqueous solution of DTPA-folate. The radiochemical purity of the product consistently exceeded 97%, as assessed by thin-layer chromatography employing conditions analogous to those for radiochemical quality control of the radiopharmaceutical [(99m)Tc]DTPA. HPLC demonstrated that the radiolabeled product resulted from the intact DTPA-folate conjugate and not unconjugated DTPA. The ability of [(99m)Tc]DTPA-folate to target folate receptors in vivo was assessed in biodistribution studies with athymic mice bearing subcutaneous folate-receptor-positive human KB cell tumors. As an internal control, previously studied [(111)In]DTPA-folate was coinjected with the [(99m)Tc]DTPA-folate, along with varying amounts of DTPA-folate (0.38 mg/kg, 1.6 mg/kg, or 14 mg/kg). At each DTPA-folate dose, [(99m)Tc]DTPA-folate exhibited tumor uptake comparable to that of the coadministered [(111)In]DTPA-folate, with radiotracer levels declining at the higher DTPA-folate doses due to competitive receptor binding of the unlabeled conjugate. Tumor uptake of both tracers was also competitively blocked by preadministered folic acid dihydrate (2.9 mg/kg). Tumor-to-background tissue contrast obtained with [(99m)Tc]DTPA-folate was generally similar to that obtained with [(111)In]DTPA-folate. The (99m)Tc-labeled DTPA-folate conjugate may have utility as a targeted radiopharmaceutical for imaging neoplastic tissues known to overexpress the folate receptor.

Animals↗