Biomedical subjects
Publications and source records attributed to B E Shapiro.
The authors conducted a retrospective and brief prospective study of adverse effects of approximately 350 medications in 44 adults with late-onset Tay-Sachs disease (LOTS). Some medications were relatively safe, whereas others, particularly haloperidol, risperidone, and chlorpromazine, were associated with neurologic worsening.
BACKGROUND: Late-onset Tay-Sachs disease (LOTS) is an adult-onset, autosomal recessive, progressive variant of GM2 gangliosidosis, characterized by involvement of the cerebellum and anterior horn cells. OBJECTIVE: To determine the range of visual and ocular motor abnormalities in LOTS, as a prelude to evaluating the effectiveness of novel therapies. METHODS: Fourteen patients with biochemically confirmed LOTS (8 men; age range 24 to 53 years; disease duration 5 to 30 years) and 10 age-matched control subjects were studied. Snellen visual acuity, contrast sensitivity, color vision, stereopsis, and visual fields were measured, and optic fundi were photographed. Horizontal and vertical eye movements (search coil) were recorded, and saccades, pursuit, vestibulo-ocular reflex (VOR), vergence, and optokinetic (OK) responses were measured. RESULTS: All patients showed normal visual functions and optic fundi. The main eye movement abnormality concerned saccades, which were "multistep," consisting of a series of small saccades and larger movements that showed transient decelerations. Larger saccades ended earlier and more abruptly (greater peak deceleration) in LOTS patients than in control subjects; these changes can be attributed to premature termination of the saccadic pulse. Smooth-pursuit and slow-phase OK gains were reduced, but VOR, vergence, and gaze holding were normal. CONCLUSIONS: Patients with late-onset Tay-Sachs disease (LOTS) show characteristic abnormalities of saccades but normal afferent visual systems. Hypometria, transient decelerations, and premature termination of saccades suggest disruption of a "latch circuit" that normally inhibits pontine omnipause neurons, permitting burst neurons to discharge until the eye movement is completed. These measurable abnormalities of saccades provide a means to evaluate the effects of novel treatments for LOTS.
Biologists are increasingly recognising that computational modelling is crucial for making sense of the vast quantities of complex experimental data that are now being collected. The systems biology field needs agreed-upon information standards if models are to be shared, evaluated and developed cooperatively. Over the last four years, our team has been developing the Systems Biology Markup Language (SBML) in collaboration with an international community of modellers and software developers. SBML has become a de facto standard format for representing formal, quantitative and qualitative models at the level of biochemical reactions and regulatory networks. In this article, we summarise the current and upcoming versions of SBML and our efforts at developing software infrastructure for supporting and broadening its use. We also provide a brief overview of the many SBML-compatible software tools available today.
MOTIVATION: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. RESULTS: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. AVAILABILITY: The specification of SBML Level 1 is freely available from http://www.sbml.org/
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We present a graphical method for a unifying, quantitative analysis of molecular bonding-force measurements by atomic force microscopy (AFM). The method is applied to interpreting a range of phenomena commonly observed in the experimental AFM measurements of noncovalent, weak bonds between biological macromolecules. The analysis suggests an energy landscape underlying the intermolecular force and demonstrates that many observations, such as "snaps-on," "jumps-off," and hysteresis loops, are different manifestations of a double-well energy landscape. The analysis gives concrete definitions for the operationally defined "attractive" and "adhesive" forces in terms of molecular parameters. It is shown that these operationally defined quantities are usually functions of the experimental setup, such as the stiffness of the force probe and the rate of its movement. The analysis reveals a mechanical instability due to the multistate nature of molecular interactions and provides new insight into macromolecular viscosity. The graphical method can equally be applied to a quantitative analysis of multiple unfolding of subunits of the giant muscle protein titin under AFM.
Macromolecular binding forces between single protein-ligand pairs have been directly measured with the Atomic Force Microscope (AFM) in several recent experiments. In a typical measurement, the AFM probe, or cantilever, is attached to the ligand and exerts a disruptive force on the bond between the macromolecular pair while the receptor is held fixed; the probe is then moved away from the substrate until the bond is broken. When the bond actually breaks, the tip is observed to slip; in fact, the ligand is jumping to a new equilibrium point determined purely by the cantilever, as if the receptor had been instantaneously moved to infinity. This "jumping-off" or "minimum rupture force" is determined by measuring cantilever deflection. In a similar manner, the two molecules can be brought together and the "jumping-on" force can be determined. These two measurements will result in different estimates of the binding force due to hysteresis. This hysteresis is caused by a cusp catastrophe in the space defined by probe position and cantilever stiffness. The phenomena of "jumping-off" in macromolecular rupture experiments and "jumping-on" when molecules are brought together occur when the system passes through a saddle-node bifurcation as the probe position is varied. Probe approach and withdrawal result in different post-bifurcation equilibria, different energy dissipation, and different force measurements.
Force measurements on and within single macromolecular complexes utilizing techniques such as atomic force microscopy, optical trapping, flexible glass fibers, and magnetic beads provide a rich source of quantitative data on biomolecular processes. Stochastic thermal fluctuations, an undesirable source of noise in macroscopic biochemical experiments, are an essential element of these sensitive and novel experiments. With the proper analysis, a great deal of information can be gleaned from measurements of these fluctuations. A quantitative framework for analyzing such measurements, based on Kramers' theory of molecular dissociation, is developed. The analysis reveals the kinetic origin and stochastic nature of the measurements. This framework is presented in the context of protein-ligand separation with the atomic force microscope.
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We report a man with a slowly progressive bulbar palsy 14 years after radiation therapy for nasopharyngeal carcinoma. Electromyography demonstrated prominent myokymic and neuromyotonic discharges in muscles innervated by the lower cranial nerves. Late effects of radiation therapy can occur in the cranial nerve musculature that are similar to well-recognized syndromes affecting the brachial plexus and spinal cord.
Sodium diethyldithiocarbamate (DDTC) is an investigational modulator of the toxicity produced by cisplatin. The pharmacokinetics of DDTC were evaluated after administration of 200 mg/m2/hr (n = 8) and 400 mg/m2/hr (n = 7) DDTC as 4-hour intravenous infusions to normal male healthy volunteers. Diethyldithiocarbamate concentration at steady-state (Cpss) increased disproportionally from 27.0 +/- 7.6 microM for the low dose to 74.8 +/- 19.3 microM for the high dose, whereas total body clearance decreased from 23.83 +/- 8.23 mL/min/kg for the low dose to 15.48 +/- 2.72 mL/min/kg for the high dose (P < 0.05). However, the volume of distribution in the terminal phase remained unchanged. Diethyldithiocarbamate terminal elimination half-life (t1/2 beta) increased from 3.74 +/- 1.10 minutes for the low dose to 6.08 +/- 1.07 minutes for the high dose (P < 0.005). The data were then fitted using a one-compartment open model with zero-order infusion and Michaelis-Menten elimination kinetics. The Km for DDTC was estimated to be 124.3 +/- 19.9 microM, whereas the Vm was estimated to be 3.67 +/- 1.15 mumol/min/kg. However, DDTC t1/2 beta was independent of DDTC concentrations, suggesting that the nonlinearity in DDTC kinetics does not exactly follow Michaelis-Menten elimination kinetics. Thus, DDTC pharmacokinetics are dose dependent and may not be concentration dependent. Clinically, DDTC Cpss will increase nonlinearly with an increase in dose.
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We describe seven patients with clinical evidence of oculopharyngeal muscular dystrophy. Four of these patients were members of the same Italian-American family. The age at onset was after the fourth decade in all patients. All seven patients had extraocular muscle involvement, and six of the seven patients had clinical, electrophysiological, and/or pathological evidence of neuropathy in addition to features that were suggestive of myopathy. An autopsy was performed on one patient. We discuss the significance of the concurrence of neuropathic features with oculopharyngeal muscular dystrophy in relation to these patients and previously reported cases.
The pharmacokinetics of teicoplanin were investigated in 13 subjects with various degrees of renal impairment using a randomized two-period crossover design; 11 subjects completed both periods. Doses of 3 and 30 mg kg-1 were administered as single dose, 60-min constant rate intravenous infusions. Blood samples were obtained over 28 days and urine was collected over 48 h. Serum and urine were analyzed using a microbiological assay. As previously observed in studies conducted in renally impaired subjects, teicoplanin total and renal clearance significantly decreased with decreasing creatinine clearance (p < 0.0001). However, for these parameters, no differences between doses were observed. Dosage adjustment guidelines for renally impaired patients are usually developed using the ratio of total clearance in renally impaired patients to the total clearance in patients with normal renal function. Since no dose-related differences existed in the relationship between teicoplanin total clearance and creatinine clearance, initial dosage adjustment guidelines for renally impaired patients developed at 3 or 30 mg kg-1 are applicable over the range of 3 to 30 mg kg-1.
The disposition of cefpodoxime after single, oral 200-mg doses of cefpodoxime proxetil (cefpodoxime equivalents) was investigated in an open-label study of six patients with end-stage renal disease currently maintained on hemodialysis. Subjects were randomly assigned to one of two treatment groups, which differed in the sequence of the interdialytic and intradialytic periods. Doses were separated by at least 2 weeks. Blood samples were serially collected for 48 hours after each treatment; if obtainable, urine was also collected over this same period. During the intradialytic period, hemodialysis was scheduled to begin approximately 3 hours after dosing, and dialysate was collected before and until the end of dialysis. Average cefpodoxime elimination half-life for the interdialytic period was 18.0 +/- 6.5 hours; apparent total body clearance was 28.6 +/- 13 mL/minute. The half-life during hemodialysis, 2.66 +/- 0.74 hours, was considerably shorter than that after hemodialysis, 19.2 +/- 3.5 hours, in the intradialytic period of the study. Hemodialysis clearance of cefpodoxime was 120 +/- 31 mL/minute, which was 57.1 +/- 13% and 71.7 +/- 25% of the hemodialysis clearance for urea nitrogen and creatinine, respectively. The 2.86 +/- 0.25 hour hemodialysis session removed 22.4 +/- 2.9% of the administered dose, as assessed by cefpodoxime recovery in dialysate. A maximum rebound in cefpodoxime plasma concentration of 0.41 +/- 0.33 mcg/mL was observed, at about one-half hour after the end of hemodialysis. Based on these results, dosage adjustment is not required, but extension of the dosing interval is warranted.(ABSTRACT TRUNCATED AT 250 WORDS)