Effect of impurities on estradiol crystallization in a sustained-release implant.

During the development of a silicone rubber implant for the delivery of estradiol 17-beta some batches of implants made from a certain lot of commercial estradiol inexplicably developed surface crystals of estradiol after several days of storage. An impurity profile was obtained for 28 lots of estradiol by a newly developed HPLC method. One or more impurities may have had a role in the spontaneous crystal growth on the surface of the implants, because the one lot of estradiol that initially had surface crystals on aging produced acceptable implants after multiple recrystallizations. Attempts to isolate suspected impurities for characterization were unsuccessful. During the manufacture of the implants, temperatures sufficient to melt the estradiol (mp, 173-179 degrees C) were used. It was expected that, upon implant cooling, melted impure estradiol would form a thermodynamically more active (i.e., noncrystalline) physical form. This metastable form could have migrated to the implant surface, where ambient conditions favored crystallization. Because melted estradiol of a higher purity tended to crystallize more readily, it was less likely to form a glass upon cooling. The phenomenon of surface crystallization was limited to one lot of estradiol with the highest level of impurities. Data from differential scanning calorimetry studies supported this conclusion.     

Dose-Response Characteristics of Spinal Bupivacaine in Volunteers: Clinical Implications for Ambulatory Anesthesia

Background: Small doses of bupivacaine may be a reasonable choice for spinal anesthesia for patients having ambulatory surgery. However, few dose-response data are available to guide the selection of reasonable doses of bupivacaine for different ambulatory procedures.

Methods: Eight volunteers per group were randomized to receive 3.75, 7.5, or 11.25 mg of 0.75% bupivacaine with 8.25% dextrose in a double-blind manner. Sensory block was assessed with pinprick, transcutaneous electrical stimulation equivalent to surgical incision at the ankle, knee, pubis, and umbilicus, and with duration of tolerance to pneumatic thigh tourniquet. Motor block at the quadriceps and gastrocnemius muscles was assessed with isometric force dynamometry. Times until recovery from spinal anesthesia were recorded. Dose-response relationships were determined by linear regressions. Mean (95% confidence intervals) for durations of sensory and motor block per milligram of bupivacaine administered were calculated from linear regressions.

Results: Significant dose-response relationships (P < 0.006) were determined for sensory block, motor block, and time until recovery (R from 0.6 to 0.9). Within the range of doses studied, each additional milligram of bupivacaine was associated with an increase in duration of tolerance to transcutaneous electrical stimulation of 10 (7 to 13) min, an increase in tolerance to tourniquet of 7 (2 to 11) min, an increase in duration of motor block of 8 (5 to 12) min, and an increase in time until recovery of 21 (17 to 25) min.     

Considerations in the treatment of cerebral palsy patients with spinal deformities

The natural history of spinal deformities in the cerebral palsy patient is different than that in the idiopathic patient. Consequently, the approach to the patient with cerebral palsy and the surgical decision-making are different from that in the idiopathic patient. The present article gives the UTMB approach to the treatment of the cerebral palsy patient and the unique considerations that must be taken into account when treating these patients. Specific references are made to the use of L-rod instrumentation to stabilize the spinal deformity in the cerebral palsy patient.     

Short-term morbidity and mortality of implantation of automatic implantable cardioverter-defibrillator

Over the 3-year period from Jan. 1, 1986, through Dec. 31, 1988, we have implanted 101 automatic implantable cardioverter-defibrillators into patients with life-threatening ventricular arrhythmias. There were 82 male patients and 19 female patients. The mean age was 58 years with a range of 25 to 82 years. The indication for implantation was ventricular fibrillation in 89 patients and recurrent ventricular tachycardia in 12 patients. Seventy-seven patients had a history of prior myocardial infarction or coronary artery disease, or both. Eighteen patients had nonischemic cardiomyopathy. One patient had a prolonged QT syndrome and five patients had no evidence of preexisting structural heart disease. The mean injection fraction was 37% +/- 17%. Forty-one of the automatic implantable cardioverter-defibrillator implantations were associated with procedures necessitating cardiopulmonary bypass. The hospital mortality rate was 4% and the morbidity rate was 15%. The only statistical difference between those patients who did and did not have postoperative complications was a history of a prior myocardial infarction (90% versus 54%, p less than 0.05). Twenty percent of patients had new-onset postoperative atrial fibrillation after implantation of the device. Eleven percent of patients had sustained ventricular tachycardia postoperatively. Although there was a trend toward a higher complication/death rate in the patients whose automatic implantable cardioverter-defibrillator was inserted in association with cardiopulmonary bypass (24% versus 15%) and the occurrence of new-onset postoperative atrial fibrillation (27% versus 15%), these findings were not statistically significant. Automatic implantable cardioverter-defibrillator implantation with and without concomitant cardiopulmonary bypass is associated with a clinically important morbidity and mortality rate and development of postoperative arrhythmias.     

Pharmacological analysis of established ventricular fibrillation.

1. The effects of anti-arrhythmic drugs on the power spectrum of established ventricular fibrillation induced by endocardial electrical stimulation, have been studied in greyhounds anaesthetized with sodium pentobarbitone (35 mg kg-1, i.v.). 2. In dogs receiving no drug, initial recording of ventricular fibrillation showed a dominant frequency of 9.9 +/- 0.7 Hz (lead II) and 10.0 +/- 0.6 Hz (endocardium). After 3.3 min the frequency had fallen to 4.0 +/- 0.4 Hz in lead II, but remained high in the endocardium (10.7 +/- 0.5 Hz). 3. Lignocaine significantly reduced the dominant frequency for fibrillation recorded from lead II at (0-80 s), and for endocardial fibrillation at (0-200 s). 4. Pretreatment with propranolol or bretylium had little effect on the time course of the dominant frequency of fibrillation in lead II or the endocardium. 5. Verapamil prevented the fall in frequency seen in lead II after 80 s in the no drug group. A significantly higher frequency was maintained in both lead II (14.7 +/- 0.9 Hz) and the endocardium (14.8 +/- 0.9 Hz) for 3.3 min, compared with the no drug group (P less than 0.01). 6. Activation of fast sodium channels may determine the rapid frequency of the initial stages of ventricular fibrillation. The rapid fall in dominant frequency in lead II after fibrillation for 80 s can be prevented by calcium channel blockade and may be due to intracellular accumulation of calcium.     

Complex Genetic Disease: Can Genetic Strategies in Alzheimer's Disease and New Genetic Mechanisms Be Applied to Epilepsy?

Summary: Strategies used in molecular genetics have changed modern neurology. The gene or genes responsible for several major neurologic diseases have now been identified using "reverse" or positional genetics. Unexpected new genetic mechanisms have been discovered in human neurologic diseases, including (a) identical mutations of the prion protein gene in Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotypic expression directed by an accompanying polymorphism; (b) stable duplications of chromosome 17 in Charcot-Marie-Tooth disease (type 1 A) that involve many genes, only one of which appears to cause neuropathy; and (c) highly variable, dynamic mutations in myotonic dystrophy, fragile X syndrome, and Kennedy's syndrome that modulate variable expressivity in multiple tissues. There is growing recognition that neurologic diseases are often complex genetic diseases with multifactorial rather than simple modes of inheritance. For example, genetic association/linkage strategies have interacted with biochemistry and immunopathology studies to produce new insights into the disease mechanism of late-onset Alzheimer's disease. The role of apolipoprotein E in late-onset Alzheimer's disease is an example of how new analytical techniques of genetic disease can be applied to dissect multiple genes. Similar research strategies are suggested for the study of epilepsy as a complex disease.     

Manipulation of intracellular calcium affects in vitro juvenile hormone synthesis by larval corpora allata of Manduca sexta.

The effect of altering intracellular free Ca2+ on juvenile hormone (JH) and acid synthesis by larval and pupally-committed corpora allata (CA) of fifth stadium Manduca sexta was investigated. Larval CA required extracellular Ca2+ greater than or equal to 0.1 mM for maximal JH synthesis, while JH acid synthesis by glands after pupal commitment was independent of extracellular Ca2+. Free Ca2+ in the hemolymph ranged from 1.4 to 2.1 mM during the fifth stadium. Both calcium ionophores and caffeine, which releases Ca2+ from intracellular stores, inhibited JH synthesis by larval CA but stimulated JH acid synthesis by post-commitment CA. These results suggest that intracellular stores may be the principal source of Ca2+ for the biosynthetic activity of the post-commitment gland. Calcium channel blockers (La3+, Cd2+) and antagonists (verapamil, isradipine and nitrendipine) decreased both JH and JH acid synthesis, indicating the existence of Ca2+ channels in the CA cell membrane. Calmodulin (CaM) antagonists inhibited the activity of both larval and post-commitment CA, suggesting an integral relationship of CaM to the effects of Ca2+ on gland activity. One of these effects is the demonstrated requirement of 0.1 mM extracellular Ca2+ for allatostatin inhibition of JH I synthesis by larval CA.     

MEASUREMENTS OF INTERFACE PRESSURE BETWEEN BODY SITES AND THE SURFACES OF FOUR SPECIALISED AIR MATTRESSES

SUMMARY Four specialised air mattresses had interface pressure measured under six body sites prone to pressure sores in 10 subjects, supine and sitting. The mattresses were the Clinirest (SSI) and FirstStep (KCI) continuous airflow mattress overlays, and Airwave (Pegasus) and Nimbus (Huntleigh) alternating pressure air mattresses. On the mattress overlays, average supine interface pressures were 2.33 kPa (scapula), 4.15 kPa (elbow), 1.94 kPa (sacrum) and 2.79 kPa (buttock), although they were higher at the occiput (7.97 kPa) and heel (11.7 kPa). The alternating pressure air mattresses had an average minimum interface pressure close to zero for three sites, rising to 4.28 kPa under the heel. Average maximum interface pressures were 8.61 kPa (occiput), 5.21 kPa (scapula), 4.90 (elbow), 4.85 kPa (sacrum), 4.61 kPa (buttock) and 13.2 kPa (heel). No accepted scientific method exists for comparing the two types of mattress. Our data suggest a clinical benefit at the occiput and heel (supine) in using an alternating pressure air mattress and a benefit in using a continuous airflow mattress overlay at other sites.     

Long-Term Subdural Strip Electrocorticographic Monitoring of Ictal Déjà Vu

Summary: We report a series of 8 patients with ictal déjà vu. Subdural strip electrocorticographic (ECoG) monitoring localized the ictal epileptogenic focus as follows: right (n = 6) and left (n = 2) mesiotemporal lobe. In all 8 patients, the left hemisphere was dominant for language function based on intracarotid amytal testing. In 6 right-handed patients, ictal déjà vu was associated with a right temporal lobe focus. However, in the 2 left-handed patients, the ictal focus was left temporal lobe. Although ictal déjà vu localizes the epileptic focus to temporal lobe, this experiential phenomenon appears to lateralize to the hemisphere nondominant for handedness.