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Biomedical subjects

R Dowell

Publications and source records attributed to R Dowell.

12 recordsLinked to original sources
PubMed2000

The development of speech perception in children using cochlear implants: effects of etiologic factors and delayed milestones.

HYPOTHESIS: Speech perception outcomes for cochlear implantation of children vary over a wide range, and it is hypothesized that central pathologic states associated with certain causes of hearing impairment account for a substantial part of the variance. STUDY DESIGN: A retrospective analysis was carried out to ascertain the relationships between speech perception, etiologic factors, and central pathologic states as indicated by preoperative delayed motor milestones and/or cognitive delays. SETTING: Data were obtained from the pre- and postoperative records of patients attending a hospital cochlear implant clinic. PATIENTS: Results for 75 consecutive patients up to age 5 years who underwent implantation were included in the study. INTERVENTION: Patients received a 22-electrode cochlear prosthesis and were seen by the clinic for regular tune-up and assessments. Home- and school-based habilitation was recommended by the clinic. MAIN OUTCOME MEASURES: Speech perception measures were classified on a five-point scale to allow for different evaluation procedures at different ages and developmental stages. RESULTS: The incidence of motor and cognitive delays were fairly evenly spread across etiologic factors, except for cytomegalovirus, which had a much higher than average incidence. Children with motor and/or cognitive delays were significantly slower than other children in the development of speech perception skills after implantation. Etiologic factors did not have a statistically significant effect on speech perception outcome. CONCLUSIONS: It is likely that central pathologic states account for a substantial part of the variance among children using cochlear implants. Specific indicators of central pathologic states should be used to assess a child's prognosis in preference to less specific information based on etiologic factors alone.

Child, Preschool↗
PubMed2000

Effect of increasing lipid loads on the ability of the endoplasmic reticulum to transport lipid to the Golgi.

We have previously shown (Mansbach, C. M. and P. J. Nevin, 1998. J. Lipid Res. 39: 963;-968) that after the development of a mass steady state with respect to triacylglycerol absorption in rats, the introduction of radiolabeled trioleoylglycerol, while maintaining the input rate of trioleoylglycerol constant at 135 micromol/h, was followed by a slow (60 min) achievement of a radiolabel steady state in the intestinal endoplasmic reticulum (ER). We hypothesized that this was due to the large input load and that the time to steady state would be shorter at lower lipid loads. Rats were infused intraduodenally with 22.5, 45, 90, or 135 micromol trioleoylglycerol/h for 6 h to obtain a mass steady state in the intestine. [(3)H]trioleoylglycerol was added to the infusate and the ER and Golgi were isolated from the proximal intestine after 5;-60 min of radiolabel infusion. The time required to reach a radiolabel steady state in the ER lengthened from 10 min at the 22.5 micromol/h infusion rate to 60 min at the 135 micromol/h rate. Similar data were obtained for the Golgi. Incubation of the ER with lipase reduced the ER;-triacylglycerol amount by 43% and increased its specific activity by 73%. The amount of [(3)H]TG-dpm in the ER was not reduced unless taurocholate, 10 mm, and colipase were added. We conclude that as the rate of triacylglycerol infusion is increased, TG movement from the ER to the Golgi progressively lengthens until finally all the triacylglycerol infused cannot be transported. A portion of this triacylglycerol is disposed on the cytoplasmic face of the ER and thus able to be attacked by lipase whereas another fraction is sequestered in the ER lumen and immune to lipase attack unless the ER membrane is solubilized.

Animals↗
PubMed1995

Optimization of alkylating agent prodrugs derived from phenol and aniline mustards: a new clinical candidate prodrug (ZD2767) for antibody-directed enzyme prodrug therapy (ADEPT).

Sixteen novel potential prodrugs derived from phenol or aniline mustards and their 16 corresponding drugs with ring substitution and/or different alkylating functionalities were designed. The [[[4-]bis(2-bromoethyl)-(1a), [[[4-[bis(2-iodoethyl)-(1b), and [[[4-[(2-chloroethyl)-[2-(mesyloxy)ethyl]amino]phenyl]oxy] carbonyl]-L-glutamic acids (1c), their [[[2- and 3-substituted-4-[bis(2-chloroethyl)amino]phenyl]oxy]carbonyl]-L- glutamic acids (1e-1), and the [[3-substituted-4-[bis(2-chloroethyl)amino]phenyl]carbamoyl]-L- glutamic acids (1o-r) were synthesized. They are bifunctional alkylating agents in which the activating effect of the phenolic hydroxyl or amino function is masked through an oxycarbonyl or a carbamoyl bond to a glutamic acid. These prodrugs were designed to be activated to their corresponding phenol and aniline nitrogen mustard drugs at a tumor site by prior administration of a monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in antibody-directed enzyme prodrug therapy (ADEPT). The synthesis of the analogous novel parent drugs (2a-r) is also described. The viability of a colorectal cell line (LoVo) was monitored with the potential prodrugs and the parent drugs. The differential in the cytotoxicity between the potential prodrugs and their corresponding active drugs ranged between 12 and > 195 fold. Compounds 1b-d,f,o exhibited substantial prodrug activity, since a cytotoxicity differential of > 100 was achieved compared to 2b-d,f,o respectively. The ability of the potential prodrugs to act as substrates for CPG2 was determined (kinetic parameters KM and kcat), and the chemical stability was measured for all the compounds. The unsubstituted phenols with different alkylating functionalities (1a-c) proved to have the highest ratio of the substrates kcat:KM. From these studies [[[4-[bis(2-iodoethyl)amino]phenyl]oxy]carbonyl]-L-glutamic acid (1b) emerges as a new ADEPT clinical trial candidate due to its physicochemical and biological characteristics.

Antibodies, Monoclonal↗
PubMed1987

The reno-hepatic axis of blood pressure control: further studies.

A reno-hepatic axis of blood pressure (BP) control has been proposed primarily by two developments: the lag period between the injection of the antihypertensive neutral renomedullary lipid (ANRL) into the vena cava and the beginning of the drop of the BP is significantly reduced by injection of this lipid into the portal vein; and a reno-portal shunt (RPS) accelerates markedly the drop of the BP following unclipping the Goldblatt hypertensive rat. In the present studies, three maneuvers were performed: perfusion of the isolated, blood-drained rat liver with plasma containing ANRL and delivery of the plasma into the jugular vein of a hypertensive rat; injection of captopril, establishment of a RPS of a hypertensive rat (one-kidney, one-clip) followed by unclipping; and establishment of a RPS in a normal rat. The blood-drained liver was capable of decreasing significantly the lag period of ANRL. Captopril did not potentiate the antihypertensive action of the kidney when RPS was coupled with unclipping. Following the RPS, the BP of the normal rat dropped modestly over a 3-hour period. These results further support the concept of reno-hepatic axis of BP control.

Animals↗
PubMed1987

Selachyl alcohol as an oral antihypertensive agent: a preliminary note.

Selachyl alcohol (SA) is a mono-oleyl glyceryl ether. It has certain biologic activities similar to those of the antihypertensive neutral renomedullary lipid (ANRL) derived from the renal papilla and its renomedullary interstitial cells (RIC). These include a vaso-depressor effect following bolus injection and a requirement for hepatic activation for the development of biological activity. In view of this similarity to ANRL, it appeared worthwhile to test the antihypertensive action of SA when given via the GI tract. Accordingly, pure SA was given either by gavage or by tube into the stomach or duodenum of one-kidney, one-clip hypertensive rats (5-10 mg per dose). The role of hepatic activation was demonstrated by comparing the BP response to bolus injection of SA and ANRL with and without the presence of an intact circulation to the liver. Administration of SA via the GI tract resulted in a significant decline in BP without tachycardia or weight loss. In the absence of a circulation to the liver, neither SA nor ANRL was active. SA appears to be an effective antihypertensive agent when given via the GI tract.

Animals↗
PubMed1986

The liver converts the antihypertensive hormone of the kidney. The renohepatic axis.

The antihypertensive neutral renomedullary lipid, derived from the renal papilla, causes a vasodepressor effect when injected into a peripheral vein, such as the inferior vena cava, after a lag period of 1 to 2 minutes. The blood pressure tracing is skewed (cuplike effect). The lag period is significantly reduced after injection of the antihypertensive lipid into the portal vein. The vasodepressor configuration (cuplike) is the same whether the lipid is injected into the vena cava or portal vein. Removal of the liver from the circulation prevents the depressor effect. Thus, passage through the liver is essential for antihypertensive lipid activity. Renoportal shunting of blood potentiates the antihypertensive function of the kidney after unclipping in the one-kidney, one clip hypertensive rat. Lack of a hepatic circulation prevents the antihypertensive function of the kidney after unclipping. Antihypertensive neutral renomedullary lipid and the renal venous effluent after unclipping have the same biological behavior. We conclude that antihypertensive neutral renomedullary lipid is a promolecule, the putative prohormone of the renal papilla and its renomedullary interstitial cells. The liver converts the antihypertensive prohormone of the kidney to an active antihypertensive substance. A renohepatic axis of blood pressure control appears to exist.

Animals↗
PubMed1984

The nucleus multi-channel implantable hearing prosthesis.

The Nucleus Multi-channel Implantable Hearing Prosthesis was developed in conjunction with the University of Melbourne. A 22 channel flexible electrode array is inserted into the cochlea through a round window opening. A cable leads from the electrode array to a demountable connector mounted on the Receiver-Stimulator unit (RSU). A custom CMOS integrated circuit is mounted inside the hermetically sealed titanium and ceramic RSU which is encased in silicone rubber and measures 34.5 mm diameter and 10.5 mm thick. Biphasic current pulse stimuli can be delivered to any selected electrode pairs at rates in excess of 1 kHz. A pocket-sized speech processor extracts spectral information from the incoming acoustic signal, and encodes stimulus information onto the single RF power/data signal transmitted to the RSU through the skin. The Speech Processor includes electronic memory circuits which are programmed with the information mapping acoustic parameters to stimulation parameters for each electrode for each patient. This MAP is established as a result of psychophysical experiments performed by the audiologist using the Diagnostic and Programming System based on a customized microcomputer.

Cochlear Implants↗
PubMed1982

Development of microvascular rarefaction in the spontaneously hypertensive rat.

Using stereological methods in vivo, we have investigated the rarefaction of arterioles and capillaries in male spontaneously hypertensive rats (SHR) and the Wistar-Kyoto controls (WKY) at 6-8, 12-14, and 16-18 wk of age. Under chloralose-urethan anesthesia, the gracilis muscle was isolated for microscopic observation. Vessel length and surface area per unit volume of tissue (density) were determined during three consecutive states: innervation, denervation, and vasodilation with nitroprusside. Arteriolar wall-to-lumen ratio was measured after vasodilation. At 6-8 wk capillary density was reduced in the SHR. At 12-14 wk there was a reduction of arteriole and capillary density under innervated and denervated conditions but not after vasodilation (a state of functional rarefaction). At 16-18 wk there was a reduction of arteriolar and capillary density under all three conditions (a state of anatomical rarefaction). At 12-14 and 16-18 wk there was an elevated level of arteriolar vasoconstriction in the SHR that was masked in any one state by the closure of the smaller arterioles. Arteriolar wall-to-lumen ratio was not elevated in the SHR at any time. Arteriolar closure was not reversed by acute denervation.

Aging↗