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Biomedical subjects

J E Welsh

Publications and source records attributed to J E Welsh.

At least 19 recordsLinked to original sources
PubMed2001

A non-calcemic sulfone version of the vitamin D(3) analogue seocalcitol (EB 1089): chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin.

Novel side-chain diene sulfones 5, analogues of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol, 1), were designed to incorporate some of the therapeutically most favorable structural features of the Leo Pharmaceutical Company's drug candidate diene EB 1089 (seocalcitol, 4) and of the Hopkins' non-calcemic side-chain sulfone analogues 2 and 3. Synthesis of diene sulfones 5 features selective Swern oxidation of a primary silyl ether in the presence of a secondary silyl ether (9-->10) and Horner-Wadsworth-Emmons aldehyde addition by a 1-phosphonyl-3-sulfonyl stabilized carbanion regiospecifically at the 1-position to form E,E-diene sulfone 11. Sulfone diene analogue 5a with natural 1alpha,3beta-diol functionality, but not its diastereomer 5b with unnatural A-ring stereochemistry, is antiproliferative in vitro toward murine keratinocytes and malignant melanoma cells, as well as toward MCF-7 human breast cancer cells. Combining diene sulfone 5a with the currently used anticancer drug adriamycin (ADR) caused a noteworthy 3-fold enhancement of ADR antiproliferative potency in MCF-7 cells. Sulfone diene analogue 5a is weakly active transcriptionally in MCF-7 and ROS 17/2.8 cells, binds poorly but measurably to the vitamin D receptor (VDR), and desirably is non-calcemic in vivo at a daily dose (7 days) of 10 microg/kg of rat body weight.

Animals↗
PubMed1997

Use of the KTP-532 laser in acoustic neuroma surgery.

The potassium titanyl phosphate (KTP-532) laser has been applied to otologic surgery with a proven record of both safety and efficacy. The aim of this study was to demonstrate the use, safety, and advantages of laser dissection in the surgical treatment of acoustic neuromas. The authors' experience with 111 patients in whom laser surgery was used in acoustic neuroma is presented, with emphasis on surgical technique employed and facial nerve functional outcome. The method of laser dissection did not result in deleterious neurologic sequelae or laser-specific complications. In addition, laser dissection afforded certain advantages to traditional techniques, especially in larger tumors. The facial nerve functional outcome as assessed by the House-Brackmann grading system revealed that 90.2% of small tumors, 72.2% of medium tumors, and 75.0% of large tumors achieved satisfactory (grades I and II) functional results. These results compare favorably with the literature describing nonlaser dissection techniques. The observations and results reported in this article demonstrate the safety of the KTP-532 laser in the posterior cranial fossa, and specific advantages that this technology may offer to the surgical armamentarium of the neuro-otologist are outlined.

Facial Nerve↗
PubMed1997

A multifactorial analysis of facial nerve results in surgery for cerebellopontine angle tumors.

Preserving the function of the facial nerve remains a paramount objective in acoustic neuroma surgery. This study was undertaken to determine the influence of four independent variables on facial nerve outcome by means of a retrospective review of 111 surgical cases: 1) tumor size; 2) use of intraoperative facial nerve monitoring (IFNM); 3) completeness of tumor resection; and 4) surgical approach used. Partial tumor resection appeared to result in improved facial nerve outcome for patients with large tumors. Results indicated that tumor size did not correlate with facial nerve functional outcome, with no statistically significant differences observed among the three size categories. Facial nerve function was not found to depend on selection of either a translabyrinthine (n = 47) or a suboccipital (n = 55) surgical approach in that results were similar for both groups. Outcome data showed a trend in support of the use of IFNM, especially for large tumors, even though the differences between monitored and unmonitored groups were not statistically significant. This study describes the independent impact of the four factors generally thought to affect facial nerve outcome and, in addition, recommends the use of data stratification in reporting facial nerve function results.

Adult↗
PubMed1997

Value of intraoperative threshold stimulus in predicting postoperative facial nerve function after acoustic tumor resection.

OBJECTIVE: The objective of this study was to determine the predictive value of intraoperative threshold stimulus and postoperative facial nerve outcome in acoustic neuroma surgery. This is a retrospective case review of 116 consecutive procedures to remove acoustic neuromas using either a retrosigmoid or translabyrinthine approach. STUDY DESIGN: Retrospective study. SETTINGS: The Tertiary Referral Center at The California Ear Institute in Palo Alto, California. PATIENTS: These were consecutive presenting patients with acoustic neuroma in the senior author's practice. Patients were not categorized into age, sex, race, or other demographic features. INTERVENTION: All patients had acoustic neuromas detected via magnetic resonance imaging, and they underwent surgery at the hands of the same neurootologic team, Drs. Nissen and Welsh. MAIN OUTCOME MEASURE: The electrophysiological monitoring reports of 81 cases of acoustic tumors. Measures in which intraoperative facial nerve monitoring was performed provided the data for this article. RESULTS: The patients were categorized by postoperative facial nerve function evaluated a minimum of 6 months after surgical removal. Group I was composed of those patients with facial nerve grades of I or II. The median threshold stimulus voltage required to produce measurable facial nerve activity at the root entry zone (REZ) immediately after tumor removal in this group was 0.100 V. Patients in group II had postoperative facial nerve grades of III to VI. Median threshold stimulus in this group was 0.7250 V. The difference in median threshold stimulus voltage at the REZ after tumor removal between these two groups was found to be statistically significant in using the nonparametric Mann-Whitney U test. CONCLUSIONS: The results of this study strongly support the continued use of intraoperative facial monitoring as a predictor of postoperative facial nerve outcome after acoustic tumor surgery.

Electromyography↗
PubMed1994

Induction of calbindin D-28K in Madin-Darby bovine kidney cells by 1,25(OH)2D3.

Renal calbindin D-28K is a calcium binding protein, localized to the distal nephron, whose expression is reduced in vitamin D deficiency and increased upon administration of 1,25(OH)2D3, the active form of vitamin D. Investigation into the molecular regulation of renal calbindin D-28K expression has been limited by the lack of an established cell line which expresses calbindin D-28K in a vitamin D responsive manner. In the studies described here, we compared the expression of calbindin D-28K and the vitamin D receptor (VDR) in four renal cell lines: Madin-Darby bovine kidney (MDBK) cells, Madin-Darby canine kidney (MDCK) cells, LLC-PK1 pig kidney cells and opossum kidney (OK) cells. We report that MDBK cells express the highest relative levels of calbindin D-28K and the VDR, and that 1,25(OH)2D3 increases calbindin D-28K expression in these cells. No expression of calbindin D-28K was detected in MDCK, LLC-PK1 or OK cells. Kinetic studies indicated that calbindin D-28K protein increased with time for up to 24 hours after a single dose of 1,25(OH)2D3 (10(-7) M) in MDBK cells. Immunofluorescence studies indicated that in control MDBK cells, the majority of calbindin D-28K was localized in cytosol, with a definite concentration in the peri-nuclear region. In 1,25(OH)2D3 treated cells, calbindin D-28K was enhanced in cytosol and was detected within the nucleus. In contrast to heterogeneous primary culture systems, in which a minority of cells express calbindin D-28K, virtually all MDBK cells expressed calbindin D-28K, even in the absence of 1,25(OH)2D3.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effects of in vivo and in vitro insulin on renal 25 (OH) D3 hydroxylation in insulin dependent diabetic rats.

Renal production of 1,25(OH)2D3 and 24,25(OH)2D3 was assessed in proximal tubules derived from two distinct rat models of insulin dependent diabetes. In both streptozotocin (STZ) induced and spontaneously diabetic BB rats, low plasma 1,25(OH)2D3 was associated with comparable decreases in in vitro 1,25(OH)2D3 synthesis. Diabetes was also associated with reduced in vitro 24,25(OH)2D3 synthesis in proximal tubules, suggesting that impaired 1,25(OH)2D3 synthesis was not secondary to enhanced 24-hydroxylase activity resulting in shunting of 25(OH)D3 towards 24,25(OH)2D3 or enhanced conversion of 1,25(OH)2D3 to 1,24,25(OH)3D3. Plasma 1,25(OH)2D3 and impaired 1,25(OH)2D3 synthesis were normalized in STZ diabetic rats within three days of exogenous insulin therapy. In contrast, preincubation for up to 18 hours with insulin did not significantly increase 1,25(OH)2D3 synthesis in proximal tubules from diabetic or control animals, suggesting that either insulin does not directly modulate 1,25(OH)2D3 synthesis, or that insulin acts synergistically with other factors to regulate 1,25(OH)2D3 synthesis in vivo. The correlation between low plasma 1,25(OH)2D3 and impaired 1,25(OH)2D3 production in vitro during diabetes emphasizes the advantages of proximal tubules as a model system for probing interactions between insulin and other modulators of 1-OHASE activity.

Animals↗
PubMed1993

Fibrin glue in otology and neurotology.

The recent development of simple, low-cost methods for producing autologous fibrin glue have given rise to a variety of uses in routine otologic and neurotologic procedures. Some of the current applications used by the authors are discussed, and a brief review of the literature is presented. Included are methods of positioning and securing implants, closure of wound edges, and application as an adjunct to achieving watertight dural closures with intracranial procedures. Representative cases are presented. No adverse reactions or specific problems related to the glue have been noted. A simple production method is included, as well as comparison with other commonly available tissue glue products.

Female↗
PubMed1992

Active cell death in hormone-dependent tissues.

Active cell death (ACD) in hormone-dependent tissues such as the prostate and mammary gland is readily induced by hormone ablation and by treatment with anti-androgens or anti-estrogens, calcium channel agonists and TGF beta. These agents induce a variety of genes within the hormone-dependent epithelial cells including TRPM-2, transglutaminase, poly(ADP-ribose) polymerase, Hsp27 and several other unidentified genes. Not all epithelial cells in the glands are equally sensitive to the induction of ACD. In the prostate, the secretory epithelial cells that are sensitive to hormone ablation are localized in the distal region of the prostatic ducts, and are in direct contact with the neighboring stroma. In contrast, the epithelial cells in the proximal regions of the ducts are more resistant to hormone ablation, probably because the permissive effects of the stroma are attenuated by the presence of the basal epithelial cells, which are intercalated between the epithelium and stroma. The underlying biology of ACD in prostate and mammary glands, and its relevance to hormone resistance, is discussed in this review.

Animals↗
PubMed1992

Activation of protein kinase C modulates dihydroxycholecalciferol synthesis in rat renal tubules.

1,25(OH)2D3, the biologically active metabolite of vitamin D, is produced from 25(OH)D3 by the renal mitochondrial 25(OH)D3 1 alpha-hydroxylase. Several studies have implicated reversible phosphorylation and a possible role for protein kinase C (PKC) in acute regulation of 1,25(OH)2D3 production. In the experiments described here, we studied 1,25(OH)2D3 production in freshly isolated rat renal tubules treated with activators and inhibitors of PKC. In this mammalian system, TPA, but not its inactive analogue 4 alpha PDD, inhibited 1,25(OH)2D3 production in a dose-dependent fashion within 20 min. The acute inhibition of 1,25(OH)2D3 production by TPA exposure was preceded by an increase in membrane associated PKC activity, which was paralleled by a decrease in cytosolic PKC activity. Pre-incubation of tubules with staurosporine, a PKC inhibitor, abolished the inhibitory effect of TPA on 1,25(OH)2D3 production. Chronic (18 h) exposure of tubules to high dose TPA resulted in down regulation of both membrane and cytosolic PKC activity and re-exposure to TPA did not affect PKC translocation or 1,25(OH)2D3 production in down regulated tubules. Our data strongly suggest that modulation of renal PKC activity may be an important mechanism for acute regulation of 1,25(OH)2D3 production.

Alkaloids↗
PubMed1981

Cardiac catheters for diagnosis and treatment of venous air embolism: a prospective study in man.

One hundred consecutive patients undergoing neurosurgical procedures in the seated position were monitored for venous air embolism with a Swan-Ganz pulmonary artery (PA) catheter, precordial Doppler ultrasound device, and continuous end-tidal CO2 (FETCO2) analysis. Simultaneous determinations of right atrial and pulmonary capillary wedge pressures were also performed during each operation. Although 80 episodes of air embolism were detected by changes in Doppler sounds, only 36 were associated with increased PA pressure, and only 30 developed a decrease in FETCO2. Changes in PA pressure and FETCO2 agreed closely (r = 0.86), and only marked changes were associated with systemic hypotension. Air was recovered from the right atrium and PA only in small amounts (2 to 20 ml) during air embolism, although it was possible to aspirate large quantities of blood. Twenty-nine patients were found to have right atrial pressures that were higher than pulmonary capillary wedge pressures. Paradoxical air embolism from a probe-patent foramen ovale was possible in these patients, and one developed signs and symptoms of systemic air embolism postoperatively. We conclude that noninvasive monitoring with the combination of a precordial Doppler device and end-tidal CO2 analysis is satisfactory for rapid detection of clinically significant venous air embolism. The unique advantage of Swan-Ganz monitoring, however, is that it permits identification of patients who may sustain paradoxical air embolism, and that it differentiates the hemodynamic effects of brain-stem manipulation from those caused by air embolism.

Blood Pressure↗
PubMed1980

Brain adenosine production in rat during sustained alteration in systemic blood pressure.

Brain production of adenosine and its metabolites, inosine and hypoxanthine was determined in 46 rats during sustained (5 min) reduction in mean arterial blood pressure (MABP) caused by hemorrhage. Also measured were ATP, ADP, AMP, phosphocreatine (PCr), and lactate. Brain tissue was obtained by the freeze-blowing technique. Ventilation was controlled to maintain constant arterial O2 tension, CO2 tension, and pH. When MABP was decreased from 135 + 3 (SE) mmHg to 72 +/- 2 mmHg, within the range of cerebral autoregulation, brain adenosine concentration doubled from 0.55 +/- 0.12 to 1.16 +/- 0.13 nmol/g (P < 0.015). Unlike the changes in adenosine concentrations, adenine nucleotides and PCr remained stable. Lactate varied inversely with MABP. With moderate to severe hypotension (MABP = 45 +/- 3 mmHg), adenosine levels increased almost sixfold. The increment in brain adenosine concentration within the autoregulatory range supports a role for this potent dilator of pial vessels in the regulation of cerebral blood flow.

Adenine Nucleotides↗
PubMed1980

Changes in brain adenosine during bicuculline-induced seizures in rats. Effects of hypoxia and altered systemic blood pressure.

We analyzed brain tissue in 139 rats for adenosine and its metabolites, inosine and hypoxanthine, during the initial 120 seconds of seizures induced by bicuculline. We also measured ATP, ADP, AMP, phosphocreatine (PCr), and lactate. We divided the rats into four groups by adjustment of their preictal arterial oxygen tension: group I, PaO2 > 200 mm Hg; group II PaO2 = 50 mm Hg; and group III: PaO2 = 100 mm Hg. We treated a fourth group whose PaO2 = 100 mm Hg with phentolamine to block the 44% rise in blood pressure which occurred with the onset of seizures. PaCO2 was maintained between 30 anf 40 mm Hg in all groups. Brain tissue was sampled rapidly after 0, 10, 20, 30, 60, and 120 seconds of seizures by the freeze-blow technique. With normoxia (PaO2 = 100 mm Hg) or hyperoxia (PaO2 > 200 mm Hg), adenosine increased within ten seconds of the onset of seizures and remained elevated even after 120 seconds. Elevations in inosine and hypoxanthine were delayed compared to the increases in adenosine. A reduction in PaO2 (50 mm Hg) or systemic blood pressure during seizures caused a further augmentation in the increase in brain adenosine levels. During the seizure period, transient changes in adenine nucleotides and energy charge were observed, but PCr remained depressed and lactate continued to rise. The rapid and sustained increase in cerebral adenosine levels, temporally paralleling the changes in cerebral blood flow, supports the role for adenosine in the regulation of cerebral blood flow.

Adenosine↗
PubMed1980

Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. Alterations with penicillin and methylprednisolone.

Acute bacterial meningitis may be associated with increased intracranial pressure, neurological sequelae such as communicating hydrocephalus, and a slow response to antibiotic therapy. Alterations in cerebrospinal hydrodynamics are at least partially responsible for these complications. Constant, low-flow short-duration manometric infusion studies through a hollow-bore pressure monitoring device in direct continuity with the supracortical subarachnoid space were performed in rabbits with experimental meningitis. Maximal resistance to cerebrospinal fluid (CSF) outflow from the subarachnoid to vascular space was markedly increaed in acute pneumococcal meningitis when compared to control, uninfected animals (6.77 +/- 3.52 vs. 0.26 +/- 0.04 mm Hg/microliter per min, P less than 0.001). Similar elevations (8.93 +/- 4.15 mm Hg/microliter per min were found in experimental Escherichia coli meningitis. Despite eradication of viable bacteria from the CSF by penicillin therapy during the acute stage of pneumococcal meningitis, resistance remained elevated (6.07 +/- 4.68 mm Hg/microliter per min) and had not returned to normal up to 15 d later. Administration of methylprednisolone during the early stages of acute pneumococcal meningitis reduced mean peak outflow resistance towards control values (0.59 mm Hg/microliter per min) and no "rebound" effect was apparent 24 h later. These hydrodynamic alterations in experimental meningitis prevent normal CSF absorption and decrease the ability of the bran to compensate for changes in intracranial volume and pressure.

Animals↗
PubMed1980

Intraventricular extension of a ruptured basilar artery aneurysm.

Penetration of the floor of the third ventricle by a saccular basilar bifurcation aneurysm accounted for a primary intraventricular hemorrhage in a 75-year-old women. This unusual relationship between the aneurysm and the third ventricle was clearly demonstrated by a computed tomographic (CT) scan only after the interface between the aneurysm and the ventricle was projected in a plane parallel to the ventricular floor. The CT scan interpretation was corroborated by an autopsy study. The principle of varying the plane of projection in order to obtain optimum delineation of the relationships of an aneurysm is well established in angiography, but has not previously been reported in the study of aneurysms by CT scan.

Aged↗
PubMed1979

Primary cerebellar nocardiosis. Report of two cases.

The authors describe two cases of primary cerebellar nocardiosis. Confinement of Nocardia abscesses to a localized, accessible portion of the central nervous system should favor surgical cure of this aggressive and often fatal disease. In our two cases multilocularity, tenuous encapsulation, and proximity to the brain stem prevented complete primary excision. Nevertheless, the infections were effectively treated by intensive postoperative antibiotic therapy and, in one case, a second operation to excise the residual abscess. The need for the latter was suggested by the results of sequential computerized tomographic brain scans that were used to monitor the response to antibiotic therapy. In the absence of any apparent extracranial focus of infection and any overt condition that might impair immunological competence, nocardiosis is likely to be omitted from the preoperative differential diagnosis of a posterior fossa space-occupying lesion.

Adult↗