Ultrastructural transformation in mitochondria isolated from kidneys of normal and lead-intoxicated rats.

Mitochondria isolated from kidneys of lead-intoxicated rats have been shown to have decreased oxidative and phosphorylative abilities. The purpose of this study was to determine whether these abnormal mitochondria would undergo ultrastructural transformation during controlled respiration in the absence of phosphate acceptor (State IV), as previously demonstrated for normal liver mitochondria. It was first shown that normal rat kidney mitochondria transforms from a condensed ultrastructural conformation to an orthodox conformation after 5 min of State IV respiration with pyruvate-malate substrate. Reversal to a condensed conformation follows stimulation of respiration with adenosine diphosphate (ADP). A large portion of kidney mitochondria from lead-poisoned rats do not change from condensed to orthodox conformation during State IV respiration. Other mitochondria do transform to the orthodox form but they rapidly degenerate. State IV respiration decreases as these few orthodox mitochondria disintegrate. The conclusion is that those mitochondria that do not undergo change in ultrastructure have impairment of electron transport, and that those that do become orthodox have increased membrane lability and undergo degeneration.

Antenatal dexamethasone exposure differentially affects distinct cortical neural progenitor cells and triggers long-term changes in murine cerebral architecture and behavior.

Antenatal administration of synthetic glucocorticoids (sGC) is the standard of care for women at risk for preterm labor before 34 gestational weeks. Despite their widespread use, the type of sGC used and their dose or the dosing regimens are not standardized in the United States of America or worldwide. Several studies have identified neural deficits and the increased risk for cognitive and psychiatric disease later in life for children administered sGC prenatally. However, the precise molecular and cellular targets of GC action in the developing brain remain largely undefined. In this study, we demonstrate that a single dose of glucocorticoid during mid-gestation in mice leads to enhanced proliferation in select cerebral cortical neural stem/progenitor cell populations. These alterations are mediated by dose-dependent changes in the expression of cell cycle inhibitors and in genes that promote cell cycle re-entry. This leads to changes in neuronal number and density in the cerebral cortex at birth, coupled to long-term alterations in neurite complexity in the prefrontal cortex and hippocampus in adolescents, and changes in anxiety and depressive-like behaviors in adults.

Treatment of status epilepticus with lorazepam.

Twenty-one episodes of status epilepticus (SE) were each treated with 1 to 9 mg (mean, 4 mg) of intravenous lorazepam. All patients with generalized tonic-clonic ( GTC ) SE responded within 15 minutes. Nine (82%) of the 11 patients with episodes of partial SE with altered responsiveness responded poorly. Respiratory depression occurred in five instances (two requiring intubation) and was associated with transient loss of brain-stem reflexes, hypotension, and decorticate posturing in three cases. Generalized tonic-clonic SE was transformed into partial SE with altered responsiveness in three patients. In an additional four patients, marked lethargy developed. Lorazepam appears effective in controlling GTC SE but only occasionally effective in partial SE with altered responsiveness.

The GABA-agonist progabide for spasticity in multiple sclerosis.

Thirty-two patients with spasticity due to multiple sclerosis were entered into a randomized, double-blinded, placebo-controlled crossover trial of the gamma-aminobutyric acid agonist, progabide. Each patient was treated with a maximum of 45 mg/kg of progabide during each of two four-week treatment periods, separated by a two-week washout. Twenty-five participants completed the study; seven failed to complete the study due to adverse events. Progabide was associated with lessened spasticity. There was no loss of motor power associated with progabide. The physician, patients, and study nurse coordinator all declared preferences for progabide for treatment of spasticity. Ten participants (40%) chose to remain on progabide in an open, long-term follow-up protocol. Seven serious adverse events occurred. One consisted of fever and weakness without infection; the other six consisted of elevated aspartate aminotransferase and alanine aminotransferase levels, four of which were asymptomatic. All adverse events resolved entirely when the drug was stopped. Progabide is an effective antispastic agent and its antispastic effect is not accompanied by increased motor weakness. The use of the drug, however, is associated with a high incidence of adverse events, which will likely limit progabide's therapeutic usefulness.

Synovial sarcoma: a clinical, pathological, and ultrastructural study of 26 cases supporting the recognition of a monophasic variant.

Twenty-six cases of synovial sarcoma (14 biphasic, 12 monophasic) were subjected to a clinicopathological study that included electron-microscopic examination of six tumors. Monophasic tumors were composed predominantly of uniform, densely packed, small spindle cells with scant cytoplasm identical to those of the "stromal" elements of typical biphasic tumors. The arrangement of these cells into narrow interlacing fascicles, forming tight whorls and showing little collagenization, was distinctive for this tumor. Major clinical differences between the two types of synovial sarcoma were the tendency for monophasic tumors to arise in distal extremity locations (seven of 10), and the poorer prognosis of monophasic tumors, 30% surviving 5 years compared to 58% for biphasic tumors. At the ultrastructural level, monophasic tumors and the spindle-cell components of biphasic tumors were identical. Both were composed of spindle or polygonal cells attached by numerous desmosomes. Prominent Golgi, abundant RER, perinuclear microfilaments, and glycogen aggregates were characteristic. Intercellular spaces containing elongated cytoplasmic filopodia were observed consistently, as were fragments of basement membrane-like material. The EM findings concur with those described previously in normal and pathologic synovium, and support a synovioblastic origin for the monophasic variant of synovial sarcoma.

Dose response effects of zolpidem in normal geriatric subjects.

The dose-related hypnotic effects and effects on memory, performance, and daytime alertness of zolpidem 5, 10, 15, and 20 mg were compared with those of placebo in 30 elderly non-insomniac volunteers in a randomized, placebo-controlled, three-period crossover study. Subjects were randomized into two groups and received either placebo, zolpidem 5 mg, or zolpidem 15 mg or placebo, zolpidem 10 mg, or zolpidem 20 mg for 2 consecutive nights followed by 1 night of placebo during the same 3 nights of 3 consecutive weeks. Polysomnographic results showed statistically significant decreases in sleep latency and increases in sleep efficiency at all doses. Subjective reports also showed improved sleep latency, total sleep time, and sleep quality. REM percent was slightly decreased at doses of 10 and 20 mg. No consistent effects on memory or performance were observed, and the Multiple Sleep Latency Test showed no effects on daytime sleepines. There was no objective evidence of rebound insomnia upon drug discontinuation.

Low-grade mucoepidermoid carcinoma of the breast.

Two cases of primary breast carcinoma morphologically identical to low-grade mucoepidermoid carcinoma of salivary gland origin occurred. To our knowledge, this article represents the first description of this tumor type in the breast. Both lesions were well circumscribed, wholly or partially cystic, and composed of intimately associated, well-differentiated, squamous and mucinous glandular epithelium. It is suggested that these may represent an indolent tumor type in the breast analogous to their behavior in the salivary gland.

Limited Wegener's granulomatosis. Unusual cutaneous, radiographic, and pathologic manifestations.

A case of limited Wegener's granulomatosis is presented with unusual black linear and circular digital infarcts, unilateral bursitis and subcutaneous nodules, interstitial pneumonitis, and unusual pulmonary pathology. Response to cyclophosphamide was curative.

State of the controlled clinical trial enterprise in the United States.

We undertook a survey of the current capability in the United States to conduct controlled clinical trials. The intention was to use the results as a foundation for understanding how to create a controlled clinical trial capability sufficient to meet future needs of US health care. For this purpose, using the results from an advanced search of ClinicalTrials.gov on 16 August 2009, we created a database consisting of actively recruiting interventional trials having at least one US investigator center. As of 16 August 2009, there were 10,974 actively recruiting interventional trials having at least one investigator center in the United States. These trials were seeking to recruit a total of 2.8 million subjects. Of the trials, 68% involved the study of drugs or biologicals. The data indicate that clinical research conducted in the United States is dominated by research on regulated products. We estimated that 1 of every 200 persons in the United States would need to participate as a subject in a clinical trial if the current clinical research portfolio is to be successfully completed.

Tubular carcinoma of the breast.

Retrospective pathologic review of 636 breast carcinomas from 611 patients revealed twelve tumors which were pure low grade tubular carcinoma (TC) and nineteen tumors with features combining both low grade tubular carcinoma and invasive duct carcinoma (T&D). A control group of 23 cases consisted of invasive duct carcinoma with at least a third of the tumor surface area showing tubular formation, but without the low grade features of tubular carcinoma. Life table analysis at 15 years showed a 100%, 72%, and 33% survival for TC, T&D, and controls, respectively. Eight percent of TC and 21% of T&D had axillary metastases compared to 67% for controls. Axillary metastases had no detrimental effect on TC or T&D survival. There were no recurrences in the TC group. Patients with T&D with tumor diameter 1.0 cm or less with 50% or greater low grade tubular carcinoma component are alive and well. The mean age of T&D was 7 years greater than TC. The combined TC and T&D group showed a significant incidence of multiple cancers in the ipsilateral breast and a significant trend toward bilateral cancers when compared to controls. Tubular carcinoma has an inherently low malignant potential with a histological and biological spectrum.

Knowledge-engineering software. A demonstration of a high-end tool.

Many investigators wanting to apply knowledge-based systems (KBSs) as consultants for cancer diagnosis have turned to tools running on personal computers. While some of these tools serve well for small tasks, they lack the power available with such high-end KBS tools as KEE (Knowledge Engineering Environment) and ART (Automated Reasoning Tool). These tools were originally developed on Lisp machines and have the full functionality of the Lisp language as well as many additional features. They provide a rich and highly productive environment for the software developer. This paper illustrates the capability of one of these high-end tools. First, a table showing the classification of benign soft tissue tumors was converted into a KEE knowledge base. The tools available in KEE were then used to identify the tumor type for a hypothetical patient.

Pseudomonas aeruginosa ExoT is a Rho GTPase-activating protein.

Transient intracellular expression of ExoT in CHO cells stimulated cell rounding and actin reorganization. Biochemical studies showed that ExoT was a GTPase-activating protein for RhoA, Rac1, and Cdc42. Together, these data show that ExoT interferes with Rho signal transduction pathways, which regulate actin organization, exocytosis, cell cycle progression, and phagocytosis.

Vertebrobasilar ischemia after total repair of tetralogy of Fallot: significance of subclavian steal created by Blalock-Taussig anastomosis. Vertebrobasilar ischemia after correction of tetralogy of Fallot.

Patients who have undergone a Blalock-Taussig anastomosis for treatment of congenital heart disease may have the vascular anatomy of the subclavian steal syndrome. Cerebral ischemia has been reported in such patients, but not when total surgical correction has eliminated other predisposing factors. We report a patient who developed vertebrobasilar insufficiency 31 years after Blalock-Taussig anastomosis and 4 years after total intracardiac repair of tetralogy of Fallot. He had angiographically proven subclavian steal and no other known predisposing factor for cerebral ischemia. This case suggests that symptomatic subclavian steal may be a late risk of surgical treatment of congenital heart disease that leaves the vascular anatomy of subclavian steal intact. Vascular reconstructive surgery can be effective treatment for these patients and may be indicated prophylactically at the time of intracardiac repair if subclavian steal syndrome becomes a more frequently recognized sequela of prior Blalock-Taussig anastomosis.

Trials with the FEMCEPT method of female sterilization and experience with radiopaque methylcyanoacrylate.

A previous report described the development of a blind method to deliver methylcyanoacrylate (MCA) transcervically. Using 0.6 ml of a stable MCA whose polymerization time was closely controlled, we reported a 78% bilateral tubal closure rate in 23 cases with hysterosalpingographic control. Subsequent to the previous report, we initiated a study in which patients were randomly assigned to one of three treatment groups: a single MCA injection, a single MCA injection after uterine lavage, or two MCA injections 1 month apart. In addition, a radiopaque MCA has been developed with which it is possible to determine tubal entry after its application by means of the FEMCEPT device. Patients treated with radiopaque MCA have been studied to determine whether it is possible to predict tubal closure on the basis of tubal entry and distribution patterns. The results of these studies and their implications for contraceptive effectiveness of the FEMCEPT/MCA system will be reported.

Double-blind withdrawal of phenytoin and carbamazepine in patients treated with progabide for partial seizures.

Of 30 patients who completed a study of progabide (PGB) as an add-on to both phenytoin (PHT) and carbamazepine (CBZ), 11 volunteered for a double-blind withdrawal protocol in which the PHT and CBZ were to be withdrawn. All patients were receiving 24-32 mg/kg/day PGB in combination with PHT and CBZ. Each patient was randomly assigned to withdrawal of either CBZ or PHT in the first block, and then withdrawal from the other in the second block in an attempt to achieve PGB monotherapy. Seizure occurrence was monitored by sequential analysis, and if a significant increase over baseline seizure frequency occurred, the dose of PGB was increased to a maximum of 45 mg/kg/day. If seizure frequency remained above baseline, the drug being withdrawn was added back and an attempt made to withdraw the other. The study was terminated if these adjustments were not successful in decreasing seizure frequency to baseline. At the conclusion of the study, three patients were being treated with PGB and PHT, two with CBZ and PGB, and six with all three. This study demonstrated the applicability of sequential analysis to antiepileptic drug trials.

Conduction velocity depression and drug-induced ventricular tachyarrhythmias. Effects of lidocaine in the intact canine heart.

Depression of myocardial conduction velocity can be an important mechanism of action of antiarrhythmic drugs but it can also facilitate arrhythmogenesis. We used lidocaine in an anesthetized canine preparation to address the hypothesis that drug-induced rate-dependent conduction velocity depression causes ventricular tachyarrhythmias. A closely spaced square array of 64 electrodes was used to determine conduction velocity longitudinal and transverse to epicardial ventricular fiber direction. Lidocaine caused rate-dependent decreases in conduction velocity that were proportionately greater in the longitudinal direction at the shortest pacing cycle lengths. Conduction velocity depression developed rapidly in the presence of lidocaine with a new steady state present by the second beat of the rapid train. Recovery from rate-dependent depression of conduction velocity was exponential with a time constant of 122 +/- 20 msec (mean +/- SD) in the longitudinal direction and 114 +/- 30 msec in the transverse direction; this difference was not significant. The relation between conduction velocity depression and ventricular arrhythmias was assessed by pacing for 3 minutes at cycle lengths of 1,000, 500, 300, and 250 msec, and for 1 minute at a cycle length of 200 msec. Arrhythmias did not occur in the baseline period in the dogs that received lidocaine, nor in 12 control dogs that were subjected to the same stimulation protocol except that saline was administered in place of lidocaine. Sustained polymorphic ventricular tachycardia (VT) occurred in six of 16 dogs given lidocaine. VT occurred in the presence of relatively high plasma lidocaine concentrations (8.4 +/- 2.3 micrograms/ml) and only at pacing cycle lengths of 300 msec or shorter. The dogs that developed VT demonstrated greater rate-dependent depression of conduction velocity than the other dogs, and activation patterns obtained just before the onset of VT showed marked conduction disturbances. Furthermore, QRS prolongation, loss of one-to-one capture, and increasingly distorted activation patterns preceded the onset of VT during fixed-rate pacing, suggesting progressive sodium channel block. In summary, rate-dependent conduction velocity depression and nonuniform activation were associated with VT in this model and can be responsible for some arrhythmias induced by antiarrhythmic drugs.