Obstetric and nonmalignant gynecologic bleeding: treatment with angiographic embolization

Eight patients (seven post partum, one post abortion) with massive pelvic hemorrhage related to pregnancy and one patient with uncontrollable bleeding following a cervical biopsy underwent angiography to facilitate the identification and treatment of bleeding sites. In all nine patients pelvic hemorrhage was successfully controlled with embolization under angiographic guidance. Angiographic embolization allowed preservation of the uterus in six patients referred prior to hysterectomy, and one patient subsequently became pregnant. When conservative measures and minor surgical repairs have failed, embolization should be the next step in the treatment of postpartum hemorrhage to avoid major surgery in an unstable patient and to maintain reproductive function.     

Chronic daily headache with medication overuse: a randomized follow-up by neurologist or PCP

Several studies have shown the benefit of withdrawal therapy when medication overuse headache (MOH) is suspected. Our aim was to compare the effect of withdrawal therapy in patients followed by a neurologist (group A, n  = 42) and a primary care physician (PCP) (group B, n  = 38). Patients were randomized to A or B, and follow-up was at 3, 6 and 12 months. Calculated mean headache (MH at 6 months + MH at 12 months)/2 (primary end-point) was similar; A 1.04 (0.87, 1.21) and B 1.02 (0.82, 1.21) ( P  = 0.87). The number of patients with 50% improvement of headache days was also similar; 14/42 in group A vs. 12/34 in B ( P  = 0.86) at 3 months, 15/42 vs. 11/33 ( P  = 0.83) at 6 months and 15/42 vs. 14/38 ( P  = 0.92) at 12 months. Days without headache during the last 9 months of follow-up were 123 (96, 150) in group A and 137 (112, 161) in B ( P  = 0.62). After 3 months one-third were classified as MOH. Patients with MOH improved similarly in group A and B, and so did patients without MOH. Within 1 year 7/42 in A and 9/38 in B had recurrent medication overuse ( P  = 0.43). In summary, there were no significant differences in follow-up results between the two groups.     

Marijuana exposure and pulmonary alterations in primates.

As part of a large multidisciplinary study, we examined lungs from 24 periadolescent male rhesus monkeys that were sacrificed seven months after daily marijuana smoke inhalation of 12 months duration. Animals were divided into four exposure groups: A) high-dose (one marijuana cigarette 7 days/week), B) low-dose (one marijuana cigarette 2 days/week and sham smoke 5 days/week), C) placebo (one extracted marijuana cigarette 7 days/week), and D) sham (sham smoke 7 days/week). Lungs, removed intact, were formalin inflated, sectioned and examined. Several pathological alterations, including alveolitis, alveolar cell hyperplasia and granulomatous inflammation, were found with higher frequency in all cigarette-smoking groups. Other alterations, such as bronchiolitis, bronchiolar squamous metaplasia and interstitial fibrosis, were found most frequently in the marijuana-smoking groups. Alveolar cell hyperplasia with focal atypia was seen only in the marijuana-smoking animals. These changes represent mostly early alterations of small airways. Additional follow-up studies are needed to determine their long-term prognostic significance.     

Effects of chronic delta-9-THC treatment on cardiac beta-adrenoceptors in rats

This study was designed to determine if chronic treatment with delta-9-tetrahydrocannabinol (THC) alters cardiac beta-adrenoceptors in the rat. Following daily oral administration of 10 or 20 mg/kg THC or an equivalent volume of control solvent for 90 days, rats were sacrificed, and sarcolemmal membranes were prepared from ventricular myocardium. Beta-adrenoceptor density and binding affinity estimated with (-)[3H]dihydroalprenolol; a beta-adrenergic antagonist, were not significantly affected by treatment with THC when compared to vehicle controls. These results suggest that the tolerance to cardiovascular effects of THC which develops during chronic exposure in the rat is not associated with alterations in cardiac beta-adrenoceptors as monitored by radiolabeled antagonist binding.     

No alterations in the performance of two interval timing operant tasks after alpha-difluoromethylornithine (DFMO)-induced cerebellar stunting.

The cerebellum is critically involved in temporal processes in the millisecond range and may be involved in longer time estimations (i.e. in the seconds range). Estimates in the millisecond range are impaired after developmentally induced cerebellar alterations, however, little is known about the effects of similar alterations on longer timing performance. Appropriately timed DFMO treatment reliably causes cerebellar stunting in rats, however, its effects on temporal estimation performance are unknown. Here, male and female Sprague-Dawley rats were treated with subcutaneous injections of 500 mg/kg DFMO on postnatal days 5-12, causing a 10% cerebellar weight reduction at adulthood. As adults, subjects were tested under one of two paradigms - a differential reinforcement of low response rate (DRL) task requiring that subjects withhold a lever press response for 10-14 s or a temporal response differentiation (TRD) task requiring that subjects maintain a lever press response for 10-14 s. Training and steady-state performance of the DRL and TRD tasks were not significantly altered by DFMO treatment. Performance after acute challenges with two dopaminergic agonists (2.00-7.50 mg/kg methylphenidate and 0.10-1.00 mg/kg d-amphetamine) was measured after which all subjects underwent behavioral extinction. Generally, performance after methylphenidate and d-amphetamine was similar in control and DFMO-treated rats and DFMO treatment had no differential effects on performance during extinction. These results support findings from an earlier study [Ferguson SA, Paule MG, Holson RR. Neonatal dexamethasoneon day 7 in rats causes behavioral alterations reflective of hippocampal, but not cerebellar, deficits. Neurotoxicol Teratol, 2001; 23:57-69] indicating that developmental cerebellar stunting has few effects on time estimation within the range of seconds.     

Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity.

The NMDA receptor has been widely investigated in recent years as a target for the pharmacological management of seizures, pain and a variety of neurological disorders. Its role in normal central nervous system (CNS) activity and development, as well as in the development of CNS abnormalities and neurodegeneration has also been of interest. The NMDA receptor is one of three pharmacologically distinct subtypes of ionotropic receptor channels that are sensitive to the endogenous excitatory amino acid, L-glutamate. The ontogeny of the NMDA receptor, a multiple tetrameric and heteromeric channel complex with at least six known subunits, is controlled by three gene families and varies in developmental profile with species and regional brain area. NMDA receptors play a role in excitatory synaptic transmission, in the activity-dependent synaptic plasticity underlying learning and memory, and in pre- and postnatal CNS development, including brain cell differentiation, axonal growth and degeneration of unused neurons. The results of recent studies suggest that sustained alteration of NMDA receptor activation during critical periods of development may have deleterious effects on normal CNS development and function. Neonatal rats administered the NMDA receptor antagonists 2-amino-5-phosphonovalerate (AP5) and MK-801 during the first two weeks of life develop abnormal axonal arborization in the retinal connections to the superior colliculus, interfering with normal visual responses. Results from monkey studies suggest that chronic developmental exposure to high doses of a NMDA antagonist, remacemide, has pronounced and long-lasting effects on learning. Recent findings indicate that if NMDA receptors are blocked during a specific period in neonatal life (first two weeks postnatally in the rat), massive apoptotic neurodegeneration results, due not to excitotoxic overstimulation of neurons but to deprivation of stimulation. These observations require further laboratory evidence and support in order to establish their relevance to drug-induced human neurodevelopmental concerns. It is necessary to investigate the relevance of these findings in other animal species in addition to the rat, most notably, nonhuman primates, where neuronal cytoarchitecture and development are significantly different than the rodent but more like the human.     

Dystrophic calcification and mineralization during bone induction: biochemical differences

The calcification of implants of glutaraldehyde-cross linked collagenous tissues and collagen was studied in young and old rats and compared to bone induction by non-crosslinked osteogenically active demineralized bone matrix (DBM). Glutaraldehyde-crosslinked implants of DBM, tendon, and cartilage calcified in young but not in old animals and accumulated only trace amounts of BGP (Bone Gla protein, osteocalcin). Alkaline phosphatase activity and BGP was high in implants of DBM and undetectable in crosslinked implants. To try and understand why bone formation is so significantly reduced in older Fischer 344 rats, we developed a system which consists of cylinders of DBM sealed at the ends with a Millipore filter. Cells originating from 20 day old embryo donors were introduced into the chambers prior to subcutaneousmplantation. After 4 weeks of implantation in 26 month old rats, the cylinders containing embryonic calvaria or muscle cells were found to be full of bone and/or cartilage.     

Multiple behavioral effects of diazepam in rhesus monkeys

The acute effects of diazepam (Valium) were assessed using a battery of complex food-reinforced operant tasks that included responding in delayed matching to sample (DMTS, n = 5), conditioned position response (CPR, n = 7) progressive ratio (PR, n = 8), temporal response differentiation (TRD, n = 4), and incremental repeated acquisition (IRA, n = 9) tests. Diazepam (0.25-4.0 mg/kg IV) produced significant dose-dependent decreases in the number of reinforcers obtained in the TRD and IRA tasks only. TRD accuracy was significantly decreased at doses of 0.25, 1.0, 2.0, and 4.0 mg/kg when compared to vehicle injections. Significant decreases in IRA accuracy generally did not occur at doses below 1.0 mg/kg. DMTS accuracy was decreased at 0.5 mg/kg for some time delays but showed no clear dose-delay interaction. Performance in the CPR and PR tests showed no significant effects of diazepam exposure over the dose range tested. These results indicate that diazepam selectively disrupts performance of operant tasks in monkeys designed to model human correlates of time perception, learning ability and visual attention/short-term memory while not affecting tasks designed to model motivation and position/color discrimination.     

A comparison of interoceptive and exteroceptive discrimination in the pigeon

In pigeons performing a conditional discrimination under a second-order, color-tracking procedure, stimulus control of responding was established using a blinking versus a nonblinking light as exteroceptive stimuli (light-discrimination group). Another group performing under the same second-order schedule of reinforcement was trained to discriminate the interoceptive stimuli produced by an IM injection of 1.5 mg/kg phencyclidine (PCP) versus saline (drug-discrimination group). In the drug-discrimination group, administration of PCP or pentobarbital resulted in dose-dependent increases in PCP-appropriate responding, while, in general, d-amphetamine did not result in appreciable drug-appropriate responding. In the light-discrimination group, all three drugs over the same dose ranges resulted in decreased discriminative control over responding. In both groups, doses of PCP and pentobarbital which resulted in intermediate (30 to 70%) levels of stimulus-appropriate responding were associated with responding at a single key position rather than tracking a key color. In contrast, intermediate responding after d-amphetamine administration was not associated with position responding in either group. These results emphasize the similarity between discriminative control maintained by interoceptive drug stimuli and exteroceptive visual stimuli.