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Biomedical subjects

B E Shapiro

Publications and source records attributed to B E Shapiro.

At least 19 recordsLinked to original sources

Graphical method for force analysis: macromolecular mechanics with atomic force microscopy.

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.

Connectin↗

Hysteresis in force probe measurements: a dynamical systems perspective.

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.

Animals↗

Adult botulism.

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Botulism↗

Delayed radiation-induced bulbar palsy.

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.

Adult↗

A dose-ranging pharmacokinetics study of sodium diethyldithiocarbamate in normal healthy volunteers.

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.

Adult↗

Neuropathic findings in oculopharyngeal muscular dystrophy. A report of seven cases and a review of the literature.

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.

Aged↗

Applicability of teicoplanin dosage adjustment guidelines for renally impaired patients over the range of 3 to 30 mg kg-1.

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.

Aged↗

Disposition of cefpodoxime proxetil in hemodialysis patients.

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)

Administration, Oral↗

Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal disease.

Tazobactam is an irreversible inhibitor of many beta-lactamases. In combination with piperacillin, tazobactam exhibits synergy against many beta-lactamase-producing bacteria. The pharmacokinetics of piperacillin and tazobactam were evaluated in eight normal volunteers and in 52 patients with renal dysfunction. Plasma and urine were obtained for up to 30 hours after an infusion of piperacillin and tazobactam (3 and 0.375 gm, respectively). Dialysate samples were collected from patients undergoing dialysis. Piperacillin and tazobactam concentrations were determined by high-performance liquid chromatography. Noncompartmental methods were used for pharmacokinetic analysis. Piperacillin and tazobactam total body clearance, area under the curve, and terminal elimination rate correlated with renal function. Hemodialysis removed 31% and 39% of piperacillin and tazobactam, respectively. During continuous ambulatory peritoneal dialysis, 5.5% of the piperacillin and 10.7% of the tazobactam was recovered in the dialysate over 28 hours. Peak plasma concentrations of both drugs increased minimally with decreasing creatinine clearance. Dosage alterations for creatinine clearance values less than 40 ml/min are recommended.

Adult↗

Disposition of cefpodoxime proxetil in healthy volunteers and patients with impaired renal function.

The disposition of cefpodoxime in 24 subjects with various degrees of renal function after administration of a single oral dose of 200 mg of cefpodoxime proxetil (equivalent to 200 mg of cefpodoxime activity) was studied. Subjects were assigned to one of four groups (six per group): group I, normal renal function (creatinine clearance [CLCR], greater than ml/min); group II, mild renal impairment (CLCR, 50 to 80 ml/min); group III, moderate renal impairment (CLCR, 30 to 49 ml/min); or group IV, severe renal impairment (CLCR, 5 to 29 ml/min). Although cefpodoxime terminal elimination half-life in group I (2.55 +/- 0.25 h [mean +/- standard deviation]) was not significantly different from that in group II (3.53 +/- 0.74 h), the half-life values for group III (5.90 +/- 1.67 h) and group IV (9.80 +/- 1.21 h) were significantly prolonged compared with those of group I. The mean absorption rate constant was similar among groups and ranged from 0.68 to 0.85 h-1. All groups exhibited absorption lag-times which were comparable (0.30 to 0.41 h), and the apparent volume of distribution was similar among groups. Cefpodoxime apparent total body clearance (CLP/F) values in groups II, III, and IV (132 +/- 29, 112 +/- 41, and 55.7 +/- 9.9 ml/min, respectively) were significantly lower than that in group I (238 +/- 44 ml/min). Cefpodoxime CLP/F was positively correlated with CLCR (r2 = 0.79; P less than 0.05): CLP/F = (1.9 CLCR) + 18.4. Renal clearance also declined with decreasing renal function. Adjustments in cefpodoxime organism and on the site and severity of infection. Simulated plasma concentration-time data from this study suggest that 200 mg of cefpodoxime proxetil administered every 12 to 24 h to subjects with CLcr between 30 and 49 ml/min and 200-mg dose taken every 24 h by subjects with CLcr between 5 and 29 ml/min will maintain cefpodoxime concentration in plasma similar to those in subjects with normal renal function who receive a standard dosage mg every 12 h.

Acute Kidney Injury↗

Isepamicin disposition in subjects with various degrees of renal function.

The disposition of isepamicin, an investigational aminoglycoside antibiotic, was evaluated in 30 subjects with various degrees of renal function. The subjects were divided into five groups: those with normal renal function (creatinine clearance [CLCR], greater than 80 ml/min/1.73 m2), those with mild renal insufficiency (CLCR, 50 to 80 ml/min/1.73 m2), those with moderate renal insufficiency (CLCR, 30 to 49 ml/min/1.73 m2), those with severe renal insufficiency (CLCR, 5 to 29 ml/min/1.73 m2), and those maintained on hemodialysis (CLCR, less than 5 ml/min/1.73 m2). Subjects on hemodialysis were studied both during hemodialysis and during an interdialytic period. The volumes of distribution of isepamicin were not significantly different among the five groups of patients. The total body clearance (CLP) and renal clearance (CLR) of isepamicin significantly decreased as CLCR decreased. The CLP of isepamicin and CLCR were significantly related [(COP = 0.391.[CLCR] + 1.83; r2 = 0.878)]. Nonrenal clearance of isepamicin did not differ between groups. Hemodialysis augmented the CLP of isepamicin by approximately 25-fold. The amount of isepamicin recovered in the dialysate was 60.6 +/- 15.8% of the dose administered. The maximal rebound of the isepamicin concentration in plasma after cessation of hemodialysis was observed at 0.78 +/- 0.7 h. Concentrations in plasma increased 32.7 +/- 22.9% over that measured at the end of hemodialysis. These data indicate that dosage adjustments are necessary in subjects with decreased renal function.

Adult↗

Hemispheric threshold differences for motor evoked potentials produced by magnetic coil stimulation.

A brief monophasic pulse through an electromagnetic coil preferentially activates motor pathways of each hemisphere, depending on the direction of coil current flow. Using the preferred direction for each hemisphere, the minimum stimulus intensity (threshold) that evoked compound muscle action potentials in the contralateral abductor digiti minimi (ADM) muscle was significantly less for the left hemisphere than the right. Threshold for biceps on each side was significantly higher than ADM, but there was no side-to-side difference. Assessing handedness using a standard handedness index, those who had less tendency to use the right hand for everyday tasks had greater differences between hemispheres for ADM thresholds. The lower threshold of the left-hemisphere projection to hand muscles is probably related to the asymmetry of corticomotoneuronal monosynaptic connections; a greater number project to the motor neuron pool of the right- than left-hand muscles.

Action Potentials↗

Renal protective effects of angiotensin-converting enzyme inhibition.

Nephron loss is a common progression of a diverse range of kidney diseases. Recent experimental models of chronic renal disease have suggested that hemodynamic and nonhemodynamic mechanisms play key roles in progressive renal injury. Extensive renal ablation in the rat was followed by development of altered glomerular hemodynamics. Albuminuria and histologic damage leading to focal glomerulosclerosis were preceded by the development of increased glomerular pressures and were prevented by interventions such as severe dietary protein restriction and angiotensin-converting enzyme (ACE) inhibitor therapy. Both experimental interventions ameliorated glomerular hypertension. It was therefore concluded that these interventions ameliorated injury by glomerular hemodynamic effect. Similar findings were obtained in a rat model of type I diabetes mellitus induced by streptozotocin in which glomerular hemodynamic factors appeared important to the development of progressive renal disease. Recent studies have suggested that nonhemodynamic factors have important roles in the progression of glomerular injury. For example, although the predominant effects of ACE inhibitor therapy appear to be hemodynamically mediated, data are emerging which suggest that these agents may also influence growth/proliferation of glomerular cells. Because hyperplasia/hypertrophy may influence glomerular susceptibility to injury, this may also be a potential mechanism whereby ACE inhibitor therapy influences glomerular damage. In addition, a variety of studies have suggested that hyperlipidemia, which is frequent accompaniment of glomerular disease, is an important modulator of glomerular injury independent of glomerular hemodynamic effects. Coagulation factors, calcium phosphorus balance, as well as the genetic susceptibility of the glomerulus to injury, all appear to contribute to progressive nephron destruction.

Angiotensin-Converting Enzyme Inhibitors↗