Biomedical subjects
D Goldfarb
Publications and source records attributed to D Goldfarb.
Two-state transition between molten globule and unfolded states of acetylcholinesterase as monitored by electron paramagnetic resonance spectroscopy.
Cys-231 of Torpedo californica acetylcholinesterase (EC 3.1.1.7) was selectively labeled with the mercury derivative of a stable nitroxyl radical. In 1.5 M guanidinium chloride, this conjugate exists in a molten globule state (MG), whereas in 5 M denaturant, it is in an unfolded state (U). The transition between the two states is reversible. In the MG, the label is highly immobilized, whereas in the U, it is almost freely rotating. The clearly distinct electron paramagnetic resonance (EPR) spectra of the two states permits the study of this transition. Upon elevating the guanidinium chloride concentration, a decrease in the EPR signal of the MG occurs concomitantly with an increase in the U signal, the total intensity of the EPR spectra remaining constant. This behavior is characteristic of a two-state transition. The thermodynamic characteristics of this transition (delta G0 and m), whether estimated directly from the EPR data or from both CD and fluorescence data analyzed by assuming a two-state scheme, are in good agreement.
Epidemiologic and clinical comparison of renal artery stenosis in black patients and white patients.
PURPOSE: This study was undertaken to compare the epidemiologic and clinical features of renal artery stenosis (RAS) in black patients and white patients. METHODS: Data on all patients identified with 50% or greater RAS from 1984 to 1990 were collected and analyzed. The study was conducted at the Cleveland Clinic Foundation, which is a referral center for patients with renal artery disease. Eight hundred nineteen patients with RAS were identified from an institutional registry that records information on patients with this disease. This group comprises 40 black patients (4.9%) and 779 white patients (95.1%). The presence of RAS was determined by abdominal aortography in all patients. Black patients and white patients with RAS were compared with respect to their age, sex, presence and severity of hypertension, renal function, type and extent of renal artery disease, extrarenal vascular disease, and risk factors such as history of smoking, diabetes, and hyperlipidemia. RESULTS: The mean age of black patients and white patients was 62 years; however, a greater proportion of black patients were women (p = 0.01). RAS was due to atherosclerosis in 95% and 92% of blacks and whites, respectively. Although the extent and severity of RAS were equivalent in black patients and white patients, more blacks were diagnosed with severe (p = 0.01) or refractory (p = 0.05) hypertension. Extrarenal vascular disease was present in 95% and 70% of blacks and whites, respectively (p < 0.01). The incidence of coronary artery disease (p < 0.01), cerebrovascular disease (p < 0.01), and peripheral vascular disease (p < 0.01) was greater among black patients. A history of smoking was more common among black patients (p < 0.01). Serum total cholesterol and low-density lipoprotein cholesterol levels were equivalent among black patients and white patients; however, black patients had higher high-density lipoprotein cholesterol (p = 0.03) and lower triglyceride (p < 0.01) levels. CONCLUSIONS: There are significant differences between black patients and white patients with RAS. The basis for these findings and their relationship to the cause and true prevalence of RAS in blacks requires further study.
The impact of adjuvant nephrectomy on multimodality treatment of metastatic renal cell carcinoma.
Multimodality treatment of metastatic renal cell carcinoma with biological response modifiers and cytoreductive surgery has produced durable responses. The timing and impact of cytoreductive surgery on the success of immunotherapy require further study. We reviewed the treatment of 62 patients with metastatic renal cell carcinoma and primary tumors in place who qualified for multimodality treatment comprising adjuvant nephrectomy and biological response modifier protocols at our institution between 1987 and 1992. Of the patients 37 were scheduled to undergo initial adjuvant nephrectomy followed by biological response modifier therapy. A total of 25 patients underwent initial biological response modifier therapy with planned delayed adjuvant nephrectomy if a response to treatment was demonstrated. Of the 37 patients undergoing initial adjuvant nephrectomy, 8 (22%) were unable to enter induction of immunotherapy because of perioperative complications (1), medical contraindications (2), tumor progression (4) or death (1). Three patients in the initial adjuvant nephrectomy group (8%) had a partial response and the median survival in this group was 12 months (range 1 to 57). In the initial biological response modifier group 3 patients (12%) with an objective response (2 complete and 1 partial) to biological response modifier therapy underwent nephrectomy. The median survival for the initial biological response modifier group was 14 months (range 1 to 48). These results add to our understanding of the impact of adjuvant nephrectomy on patients with metastatic renal cell carcinoma considered for immunotherapy protocols.
Magnetic resonance imaging of pelvic tumors in children.
Pelvic tumors in children may be large, complex and of unknown origin. Preoperative radiological information regarding tumor localization and extent becomes essential in these cases for proper staging and surgical planning. Magnetic resonance imaging (MRI) offers the ability to enhance the surgical preparation of children who present with a pelvic mass. Advantages of MRI over computerized tomography include improved soft tissue characterization, signal enhancement of neuroendocrine tumors and multiplanar imaging. These features better define the origin, size and extent of tumors. In addition, no ionizing radiation is required. Several examples of pelvic tumors are presented. The new anatomical information provided by MRI altered surgical planning previously based on computerized tomography findings alone.
A new triple-balloon, four-channel vascular catheter for use in renal transplantation.
While current surgical techniques of renal transplantation afford excellent results, some steps of the operation are associated with potential morbidity. Application of vascular clamps on an atherosclerotic recipient artery can cause plaque fracture or atheroembolism. atheroembolism. Prolonged revascularization time may aggravate ischemic allograft damage. Based on the premise that arterial occlusion by an intraluminal balloon is less damaging to the vascular endothelium than an external vascular clamp, a new three-balloon, four-channel vascular catheter has been developed for use in renal transplantation. Catheters are inserted by the Seldinger technique, one catheter being positioned in each recipient external iliac artery and external iliac vein. Vascular control of the recipient vessels is obtained by inflation of the balloons. A pilot study in four dogs has confirmed the technical feasibility of using this catheter during renal transplantation. A description of the catheter, technique of surgical placement, advantages and potential uses is presented.
Use of the thoracic aorta for renal arterial reconstruction.
PURPOSE: Thoracic aortorenal bypass is a new technique for surgical renal revascularization in patients with severe atherosclerosis of the abdominal aorta. In such cases, the thoracic aorta is often free of disease. METHODS: From 1989 to 1992, thoracic aortorenal bypass was performed in 23 patients with hypertension, abdominal aortic atherosclerosis, and celiac artery stenosis; in 21 patients, renal artery stenosis was present bilaterally or in a solitary kidney. RESULTS: There was one operative death. Among the remaining 22 patients, hypertension was cured or improved after operation in 19 (86%), and renal function was improved or stable in 21 (95%). CONCLUSIONS: Thoracic aortorenal bypass has several advantages and is a useful alternative to abdominal aortic replacement in selected older patients who require renal arterial reconstruction.
Laryngeal pacing as a treatment for vocal fold paralysis.
We summarize etiologies of vocal fold paralysis and current treatments. The recent literature involving electrical stimulation of the larynx is reviewed. Four canines were involved in a study to test a new laryngeal pacemaker system. This system was used to stimulate both the lateral cricoarytenoid and thyroarytenoid muscles. The data are taken from two of these canines. One of the goals was to stimulate the paralyzed side of the larynx based on the activity of the normal (nonparalyzed) side of the larynx. The best stimulation parameters for full addition of the paralyzed vocal cord were 3-7 V, pulse duration of 0.5 ms at a frequency of 84-100 Hz. Principles for electrode design and electrophysiologic parameters pertaining to laryngeal pacing are discussed. We believe that unilateral vocal fold paralysis may someday be treated by stimulating the paralyzed lateral cricoarytenoid and thyroarytenoid muscles to move in synchrony with the normal, unparalyzed, lateral cricoarytenoid and thyroarytenoid muscles.
Reduced nuclear import of human immunodeficiency virus type 1 preintegration complexes in the presence of a prototypic nuclear targeting signal.
Nuclear import of the retroviral preintegration complex and integration of retroviral with host cell DNA are essential steps for completion of the virus life cycle. The preintegration complex of the lentivirus human immunodeficiency virus type 1 (HIV-1) displays karyophilic properties and, as a consequence, is rapidly directed to the host cell nucleus by an energy-dependent transport pathway. The karyophilic properties of nuclear proteins are governed by a nuclear localization sequence, the targeting function of which can be inhibited in the presence of excess targeting signals. Here we present evidence that the nuclear import of a large karyophile--the preintegration complex of HIV-1--is inhibited in the presence of a prototypic nuclear targeting signal of simian virus 40 T antigen. This points to a novel strategy which prevents establishment of the provirus by interrupting nuclear localization of HIV-1 DNA.
Lyme disease: a review for the otolaryngologist.
Lyme disease is an important consideration in the differential diagnosis of patients seen by the otolaryngologist. Facial paralysis is the most common sign. The otolaryngologist may also see patients with temporal mandibular joint pain, cervical lymphadenopathy, facial pain, headache, tinnitis, vertigo, decreased hearing, otalgia and sore throat. The incidence is increasing and known to be endemic to certain areas of the United States and abroad. This paper reviews the various ways Lyme disease appears to the otolaryngologist. Three cases along with a discussion including epidemiology, vector, animal host relationship, clinical manifestations and pathophysiology are included. The literature is reviewed and the treatment discussed.
Quantitative flow cytometry cross-matching for precise measurement of donor-specific alloreactivity.
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A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells.
Permissiveness of the host cell to productive infection by oncoretroviruses is cell-cycle dependent, and nuclear localization of viral nucleoprotein preintegration complexes will occur only after cells have passed through mitosis. In contrast, establishment of an integrated provirus after infection by the lentivirus HIV-1 is independent of host cell proliferation. The ability of HIV-1 to replicate in non-dividing cells is partly accounted for by the karyophilic properties of the viral preintegration complex which, after virus infection, is actively transported to the host cell nucleus. Here we report that the gag matrix protein of HIV-1 contains a nuclear localization sequence which, when conjugated to a heterologous protein, directs its nuclear import. In addition, HIV-1 mutants containing amino-acid substitutions in this nuclear localization signal integrate and replicate within dividing but not growth-arrested cells, and thus display a phenotype more representative of an oncoretrovirus.
Regulation of RNA processing and transport by a nuclear guanine nucleotide release protein and members of the Ras superfamily.
The RCC1 gene of mammals encodes a guanine nucleotide release protein (GNRP). RCC1 and a homolog in Saccharomyces cerevisiae (MTR1/PRP20/SRM1) have previously been implicated in control of mRNA metabolism and export from the nucleus. We here demonstrate that a temperature-sensitive fission yeast mutant which has a mutation in a homologous gene, and two of three additional (mtr1/prp20/srm1) mutants accumulate nuclear poly(A)+ RNA at 37 degrees C. In S.cerevisiae, maturation of rRNA and tRNA is also inhibited at 37 degrees C. Nevertheless, studies with the corresponding BHK-21 cell mutant indicate that protein import into the nucleus continues. MTR1 homologs regulate RNA processing at a point which is distinct from their regulation of chromosome condensation since: (i) poly(A)+ RNA accumulation in the fission yeast mutant precedes chromosome condensation, and (ii) unlike chromosome condensation, accumulation of nuclear poly(A)+ RNA does not require p34cdc28 kinase activation or protein synthesis. Moreover, experiments involving inhibition of DNA synthesis indicate that the S.cerevisiae homolog does not govern cell cycle checkpoint control. Since RCC1p acts as GNRP for Ran, a small nuclear GTPase of the ras superfamily, we have identified two homologs of Ran in S.cerevisiae (CNR1 and CNR2). Only CNR1 is essential, but both code for proteins extremely similar to Ran and can suppress mtr1 mutations in allele-specific fashion. Thus, MTR1 and its homologs appear to act as GNRPs for a family of conserved GTPases in controlling RNA metabolism and transport. Their role in governing checkpoint control appears to be restricted to higher eukaryotes.
Efficacy of herbal tea preparation in infantile colic.
We evaluated the effect of an herbal tea preparation on infantile colic in a prospective double-blind study. The use of tea eliminated the colic in 19 (57%) of 33 infants, whereas placebo was helpful in only 9 (26%) of 35 (p < 0.01). The mean colic score was significantly improved in tea-treated infants. No significant differences were noted between groups regarding number of night wakings.
Microinjected U snRNAs are imported to oocyte nuclei via the nuclear pore complex by three distinguishable targeting pathways.
The inhibitory effects of wheat germ agglutinin and mAb 414 on the nuclear import of all types of U snRNAs indicate that they cross the nuclear envelope through the nuclear pore complex. However, the import of different U snRNAs occurs by kinetically distinct targeting pathways that can be distinguished from one another by the competitive effects of free trimethylguanosine cap dinucleotide (m3GpppG) and P(Lys)-BSA, an efficient synthetic karyophile based on the nuclear localization signal of SV40 large T antigen. The import of U snRNAs that contain 5' m3GpppN caps and are complexed by Sm proteins (U1, U2, U4, and U5) is competed by coinjection with free m3GpppG, indicating a shared transport factor, but not by P(Lys)-BSA. The import of U6 snRNA, which lacks a m3GpppN cap and is not complexed by the Sm proteins, is competed by P(Lys)-BSA but not by free m3GpppG. Thus, by the criterion of kinetic competition, U6 snRNA import is identical to that of the karyophilic proteins P(Lys)-BSA and nucleoplasmin. Uniquely, the import of U3 snRNA, which contains a m3GpppN cap but does not bind Sm proteins is not competed by either free m3GpppG or P(Lys)-BSA. Thus, U3 snRNA appears to be imported by a novel third kinetic pathway.
[Anemia in children: hemoglobin changes in mild, acute infections].
Anemia is commonly discovered in children when a complete blood count is routinely performed during acute and febrile illnesses. In this study-recovery of hemoglobin levels in children after acute infections was evaluated. Hemoglobin levels were measured in capillary blood of 70 patients who visited a community primary pediatric clinic with an acute infectious illness (37 boys, 33 girls; mean age 22 months, mode 18; 58 had fever of 38 degrees or higher). The most frequent diagnoses were upper respiratory tract infection, acute otitis media and pharyngitis. Follow-up hemoglobin measurements were performed after at least 3 days without fever and when the children were considered well by their parents. The average time between the 2 measurements was 12 +/- 9 days.
Pathways for the nuclear transport of proteins and RNAs.
The nuclear pore complex catalyses the import and export of both proteins and RNAs. The molecular mechanisms of RNA and protein translocation through the nuclear pore are likely to be similar; however, their signals and targeting apparatus may differ. Recent insights into RNA transport have come from studies of kinetic control mechanisms and the preconditions for translocation that include processing, RNP assembly, and a targeting function for 5' caps.
[Intracranial hemorrhage complicating acute disseminated staphylococcal disease in a child].
Acute disseminated staphylococcal disease may develop in previously healthy children below the age of 15 years. It progresses rapidly and may cause death in a significant number. The diagnostic criteria are infection in 2 or more anatomical sites and isolation of a coagulase-positive Staphylococcus aureus from the blood or from a site of infection. We present an 11.5-year-old boy with disseminated staphylococcal disease with evidence of cellulitis, osteomyelitis and endocarditis. He developed intracranial hemorrhage as a complication and survived, but with mild residual hemiparesis. Nervous system involvement, such as meningitis and brain abscess, have been described in this particularly severe disease. This is the only known report of intracranial hemorrhage as a complication of the disease.