Carotid body size on CTA: correlation with comorbidities.

AIM: To test the hypothesis that computed tomographic angiography (CTA) can identify carotid body enlargement in patients with sympathetically mediated diseases. MATERIALS AND METHODS: A retrospective chart review of all patients obtaining CTAs of the cervical vasculature at University of Utah Health Sciences Center over a 6-month period was performed. Widest axial measurements of both carotid bodies were performed on a picture archiving and communication system (PACS). Statistical analysis was then performed to compare the mean carotid body size between control patients and patients with diabetes mellitus, hypertension, and congestive heart failure. RESULTS: Measurements were performed on 288 patients, with 134 controls. Of the remaining 154, 72 patients had diabetes mellitus, 46 had congestive heart failure, and 130 had hypertension. The control patients had a mean carotid body diameter of 2.3 mm. There was a statistically significant (p < 0.01) 20-25% increase in mean diameter with diabetes mellitus (2.8 mm), hypertension (2.7 mm), and congestive heart failure (2.7 mm; p < 0.01). CONCLUSIONS: This study found a 20-25% larger mean carotid body size in patients with diabetes mellitus, hypertension, and congestive heart failure relative to controls. However, this small enlargement should not mimic other carotid body diseases, such as a paraganglionoma. Moreover, these findings further support the proposed functional relationship between the carotid body and sympathetically mediated disease states.

Oral histories document community mobilisation to participate in decision-making regarding a hazardous waste thermal treatment facility.

Colfax, Louisiana hosts a commercial hazardous waste thermal treatment (TT) facility, which treats fireworks, explosives, and military ordnances by open-burn/open-detonation one mile from the edge of the nearest community. Seventy-one percent of Colfax's residents are Black, and forty-six percent live below poverty, indicating the community's structural vulnerability. This community-based study originated at the behest of Colfax community members. We hypothesized that the close relationships among members of this enclave may have enhanced the community's ability to mobilize in opposition to the TT facility. We conducted semi-structured oral history interviews with nineteen community members and examined the social and interorganizational networks used by the Colfax community to claim its role in decision-making regarding the TT facility after years of exclusion from this process. Interview transcripts were analyzed through the lens of community capacity theory to gain insight into how interactions among community members about the environmental hazards led to social mobilization and improved participation in the decision-making process using codes for communication, organization, and outcome. Additionally, we reviewed Louisiana Department of Environmental Quality records for complaints about the facility to gauge public participation. One notable theme across several interviews was exclusion from the initial decision-making process related to the facility. However, interviewees noted a sustained effort was made among community members to educate themselves about the facility, organize a response through neighbor-to-neighbor contact, and take action by submitting formal complaints and participating in public hearings. Through the lens of environmental justice, this study illustrates an evolving condition of procedural justice.

Indirect comparison of clobazam and other therapies for Lennox-Gastaut syndrome.

OBJECTIVE: In the absence of head-to-head trials, it is not feasible to make direct comparisons of antiepileptic therapies for the treatment of Lennox-Gastaut syndrome (LGS). We conducted indirect comparisons of the relative efficacies of clobazam, felbamate, lamotrigine, topiramate, and rufinamide as adjunctive treatments for LGS. METHODS: Clinical studies of LGS patients were identified in a 2009 Cochrane review and by electronic database search. Five randomized controlled trials were included in this systematic review, which reports findings from indirect comparisons between clobazam and other approved adjunctive LGS therapies (felbamate, lamotrigine, topiramate, rufinamide) in the United States and Europe. As outcomes were not uniformly reported across studies, the primary efficacy endpoint from each trial was transformed into Cohen's d effect size, to facilitate indirect comparisons. Typical interpretations of Cohen's d results are as follows: d < 0.2, change not detectable; 0.2 ≤ d < 0.5, small change; 0.5 ≤ d < 0.8, moderate change; and 0.8 ≤ d, large change. RESULTS: High-dosage clobazam (1.0 mg/kg/day) was found to have the strongest treatment effect vs placebo (effect size 0.80), with moderate effects (effect sizes >0.50) for medium-dosage clobazam (0.5 mg/kg/day) and rufinamide. Felbamate, lamotrigine, and topiramate had low effect sizes. Indirect comparisons of numbers of total seizures and tonic-atonic seizures ('drop attacks') demonstrated superiority of both clobazam dosages over all comparators. CONCLUSIONS: High- and medium-dosage clobazam was estimated to be more efficacious than other LGS treatments. Our analysis relied on published data and could not draw on direct head-to-head data of clobazam with alternatives. Further comparative research is ongoing to assess the usefulness of clobazam for LGS.

Non-interventional surveillance study of adverse events in patients with epilepsy.

OBJECTIVES: Compare adverse events (AEs) in patients with epilepsy taking different antiepileptic drugs (AEDs) using standardized physician-completed questionnaires. MATERIALS AND METHODS: Multicenter, observational, cross-sectional study in epilepsy patients aged ≥4 , stable on 1-2 AED(s) for ≥3 months. RESULTS: One thousand and nineteen patients were evaluated: 28.7% took newer, 71.3% older (or older + newer) AED(s); 56.9% monotherapy; 43.1% polytherapy. Overall, 68.3% reported ≥1 AE (61.3% newer; 71.1% older AEDs), most commonly: cognitive function disturbances, sedation, psychological problems. Patients taking newer AEDs were significantly less likely to report ≥1 AE (OR [95% CI]: 0.64 [0.46-0.89], P = 0.008). Treatment/dose changed at study visit: 22.8% (17.5% newer; 24.9% older AEDs) because of (newer/older); lack of efficacy (6.2%/7.8%); AEs (4.1/8.4%); absence of seizures (3.8/4.0%). Patients receiving levetiracetam or lamotrigine were significantly less likely to report AEs/modify treatment. CONCLUSION: Patients taking newer AEDs were significantly less likely to report AEs, although the non-randomized study design does not allow the lower rate of AEs to be attributed with certainty to the use of newer AEDs. A standardized AE questionnaire appeared useful for monitoring AEs/optimizing AED therapy.

Limitations of T2*-Gradient Recalled-Echo and Susceptibility-Weighted Imaging in Characterizing Chronic Subdural Hemorrhage in Infant Survivors of Abusive Head Trauma.

A possible misconception among radiologists is that chronic subdural hemorrhage should show some degree of blooming on T2*-gradient recalled-echo or susceptibility-weighted sequences such as SWI and susceptibility-weighted angiography, which is not necessarily true. We present 5 cases of chronic subdural hemorrhages in infants, demonstrating intensity near or greater than that of CSF with variable amounts of hemosiderin staining along the neomembranes. We review the physiology and MR imaging physics behind the appearance of a chronic subdural hemorrhage, highlighting that the absence of a BBB can allow hemosiderin to be completely removed from the subdural compartment. Finally, we stress the importance of reviewing all multiplanar sequences for the presence of neomembranes, which can be quite subtle in the absence of hemosiderin staining and are critical for making the diagnosis of chronic subdural hemorrhage.

Kinetic and mechanistic studies with bovine testicular hyaluronidase.

Bovine testicular hyaluronidase exhibits hydrolase and transglycosylase activity. To assess the magnitude of each type of reaction, the time-course of hyaluronidase catalysed hyaluronic acid degradation was followed using a sensitive and specific HPLC method. The kinetic parameters Km and Vmax were calculated for purified short chain hyaluronic acid oligomers and native hyaluronic acid based on the appearance of unreactive hyaluronic acid tetrasaccharide. For hyaluronic acid oligomers, as substrate size increased Km decreased from 2.06 to 1.09 mM while Vmax remained about the same, indicating a 5-fold increase in the enzyme-substrate association constant, k1 (kcat/Km). The values of k2 (kcat), the enzyme-substrate disassociation constant, for native hyaluronic acid and hyaluronic acid decasaccharide were similar. The value of k1 for native hyaluronic acid, however, was larger by 70-fold. Kinetic degradation mechanisms for each hyaluronic acid oligomer, using chemical-reaction kinetics, were proposed and evaluated by computer curve fitting analysis of the experimental time vs. concentration data. The derived rate constants, together with mass balance calculations, revealed that transglycosylation plays a significant role in the degradation of all hyaluronic acid oligomers studied.

Reversible trifluoroacetic acid-induced conformational changes in glycophorin A as detected by proton nuclear magnetic resonance spectroscopy.

High-field (270 MHz) 1H-NMR has been employed to study the solution conformation of glycophorin A, a sialoglycoprotein which spans the human erythrocyte membrane. Glycophorin A is one of the most fully characterized integral membrane proteins known, making it an excellent model for the study of membrane-bound proteins. This protein consists of three distinct domains: a glycosylated extracellular N-terminus, a hydrophobic intramembranous segment, and a polar cytoplasmic C-terminus. These domains contain aromatic residues which serve as convenient 1H-NMR conformational probes. The aromatic region of the NMR spectrum of glycophorin A in 2H2O shows single, well-resolved His and Tyr resonances. No resonances are observed, however, for the Phe residues which are located in or near the hydrophobic domain. These observations suggest that considerable heterogeneity with respect to segmental motions exists within the protein. This is consistent with circular dichroism data showing the intramembranous segment to be completely helical with the extremities of the protein being predominantly random coils. The helix of the hydrophrobic domain is remarkably resistant to conventional denaturing conditions including variations in pH, and temperature, and treatment with guanidine hydrochloride. However, in trifluoroacetic acid, which strongly solvates peptide backbones, there is extensive reversible unfolding of the helical structure as evidenced by the appearance of Phe resonances. Solvent titration experiments indicate that approximately a 1 : 1 volume ratio of trifluoroacetic acid to 2H2O is required to initiate unfolding of the helix.

Compliance declines between clinic visits.

Adherence to prescribed drug dosing regimens declined substantially during the interval between clinic visits and drug level tests. Using microelectronic monitors to observe pill-taking habits, 20 patients averaged 88% compliance before and 86% compliance after the visit, but this dropped to 67% compliance a month later. These data indicate that spot drug levels do not represent long-term "steady-state" drug serum concentrations.

Barbiturate-related connective tissue disorders.

Development of Dupuytren's contractures, frozen shoulder, Ledderhose's syndrome, Peyronie's disease, fibromas, and general joint pain has been linked in retrospective studies and case reports to the use of antiepileptic drugs. We undertook a prospective survey of the incidence of connective tissue disorders in 622 patients newly treated with carbamazepine, phenobarbital, phenytoin sodium, or primidone. Ten of the 406 patients who were treated for 6 months or more developed connective tissue disorders. All affected patients were taking a barbiturate (primidone, 4 patients; phenobarbital, 6 patients). Seven of the 10 problems occurred during the first year of treatment. These data are prospective evidence of a statistically significant relationship between barbiturate use and the development of connective tissue disorders, and timing of appearance.

Safe coadministration of terbinafine and terfenadine: a placebo-controlled crossover study of pharmacokinetic and pharmacodynamic interactions in healthy volunteers.

The pharmacokinetic and pharmacodynamic interactions of terbinafine (Lamisil) and terfenadine (Seldane) were assessed in 26 healthy volunteers randomized to receive either terbinafine (250 mg tablet) or its placebo (terbinafine placebo), which were administered in a double-blind manner once daily for 18 days. On days 12 through 18, terfenadine was coadministered (60 mg twice daily, unblinded). Pharmacokinetic profiles were obtained for terbinafine and its desmethyl metabolite on day 11 (in the absence of terfenadine), day 12, and day 18. Terfenadine and terfenadine acid metabolite levels were also assayed on days 12 and 18. After a 4-week washout period, subjects were crossed over to the alternate treatment (terbinafine or terbinafine placebo). Pharmacodynamic measures were electrocardiographic (ECG) rhythm abnormalities, corrected QT interval (QTc), and plasma ALT levels. Terfenadine levels were evaluated; however, only eight of 1502 samples assayed were above the limit of quantitation. No effect of terbinafine administration on pharmacokinetic parameters for the terfenadine acid metabolite was observed, except for a decrease of approximately 20% in through terbinafine concentrations (C0hr; p < 0.05) on the last day of terfenadine plus terbinafine coadministration. Pharmacokinetic parameters for terbinafine were unchanged on the first day of terfenadine coadministration, and only small increases in area under the plasma concentration versus time curve from 0 to 24 hours and peak plasma concentrations (16.1%[p < 0.01] and 6.63% [p < 0.05]) were observed on the last day of terfenadine and terbinafine coadministration. Values for C0hr were also about 20% to 25% higher (p < 0.05). Steady-state levels of the terfenadine acid metabolite were achieved after 2 days of terfenadine coadministration, and steady-state levels of terbinafine and its desmethyl metabolite were achieved after 14 days of terbinafine administration. The incidence of ECG rhythm abnormalities was not significantly higher in any treatment group; however, the incidence of prolongation of QTc > 10% above baseline was significantly higher in the groups treated with terfenadine. No QTc prolongation occurred in the absence of terfenadine treatment. Both terbinafine and terfenadine were well tolerated when coadministered during this study, as indicated by the low incidence of complaints, abnormalities, and adverse events. The results of this study indicate that terbinafine and terfenadine can be safely coadministered.

The relationship of neuropsychological functioning to quality of life in epilepsy.

OBJECTIVE: To examine the relationship of objectively assessed cognitive functioning to self-reported quality of life. DESIGN: Correlational, multiple regression, and factor analytic comparisons of a new self-report quality of life inventory with neuropsychological tests of cognition and mood. SUBJECTS: Two hundred fifty-seven patients with epilepsy. SETTING: Twenty-five epilepsy centers and neurology clinics across the United States. MEASURES: A recently developed self-report (ie, Quality of Life in Epilepsy-89 inventory) and objective tests of memory, verbal abilities, spatial functions, psychomotor and cognitive processing speed, cognitive flexibility, and mood. RESULTS: Factors that assessed mood, psychomotor speed, verbal memory, and language correlated significantly with selected scales of the Quality of Life in Epilepsy-89 inventory (P < .0001) and were predictive of overall quality of life (P < .002 to P < .0001). The mood factor showed the highest correlations (r = -.20 to r = -.73) and was the strongest predictor of quality of life in regression analyses (46.7% explained variance, P < .0001). CONCLUSIONS: Mood may be adversely affected by diminished quality of life, or perceived quality of life may be affected by mood disturbance. Quantitative quality of life assessments can be used in conjunction with formal neuropsychological testing of mood and cognition when evaluating patients with epilepsy.

Effect of valproate on cognitive functioning. Comparison with carbamazepine. The Department of Veterans Affairs Epilepsy Cooperative Study 264 Group.

OBJECTIVE: To assess the effects of carbamazepine vs valproate sodium on cognitive functioning in patients with epilepsy compared with normal control subjects. DESIGN: Patients with recently diagnosed, previously unmedicated seizures participated in a prospective randomized double-blind Department of Veterans Affairs multicenter study of the efficacy and toxicity of carbamazepine vs valproate. MAIN OUTCOME MEASURE: A behavioral toxicity battery was administered prior to treatment and again 6 and 12 months after the initiation of antiepileptic medication. RESULTS: There were no significant differences in the effect of carbamazepine vs valproate on motor speed and coordination, memory, or concentration and mental flexibility, and there was no significant decline in neuropsychological performance from pretreatment baseline levels for either drug. No significant differences in performance were found between patients with low (mean, 52.8 micrograms/mL) vs high (mean, 94.4 micrograms/mL) serum valproate levels within the therapeutic range. Patients treated with either carbamazepine or valproate did not show practice effects experienced by normal controls, a finding that may reflect a subtle compromise in cognitive functioning. CONCLUSION: The impact of carbamazepine and valproate monotherapy on cognitive functioning is similar: both drugs produce minimal negative effects compared with pretreatment baseline performance.

Optimizing long-term patient compliance.

The key elements for enhancing patient compliance when prescribing are selecting the fewest number of daily doses (taking patient's other medications into consideration), scheduling when doses are to be taken, and helping the patient select an appropriate reminder or "cue." Developing reminder cues, such as clock time, meal time, or bathroom ritual, requires only a few minutes of careful planning to mesh with the patient's lifestyle. If one type of cue is not successful, another or combinations of cues are tried over time. Asking patients about their cues at each visit not only helps patients develop personalized cuing systems, but also reminds them that their physician has a consistent interest in the way they take their medication. Unfortunately, no single specific strategy will enhance compliance in all patients. Physicians have the greatest influence on medication compliance when they provide specific suggestions that fit into the patient's lifestyle.

Quality of life assessment in clinical practice.

Health-related quality of life (HRQOL) includes aspects of physical, psychological, and social well-being issues for people with epilepsy. QOLIE questionnaires can be used to assess the effects of seizures and medications on cognitive function, memory, mood, physical health, and health perceptions. Monitoring HRQOL in epilepsy allows patients to express their concerns about a variety of issues affected by the diagnosis that often are not brought to the attention of the physician.

Prognosis for total control of complex partial and secondarily generalized tonic clonic seizures. Department of Veterans Affairs Epilepsy Cooperative Studies No. 118 and No. 264 Group.

BACKGROUND: Two prospective observations of adults with symptomatic, localization-related (partial) epilepsy included 1,102 patients in VA multicenter studies (VA-118 and VA-264). Analyses assessed the likelihood of remaining seizure free for 12 and 24 months after initiating adequate antiepileptic drug therapy. METHODS: Patients were grouped as having only secondarily generalized tonic-clonic seizures (GTC), only complex partial seizures (CPS), or both types (MIXED) at entry. The cumulative proportion of patients remaining seizure free with standard antiepileptic drug therapy was determined by actuarial life table methods. RESULTS: At 12 months, 70% and 61% of GTC patients (VA-118 and VA-264, respectively) had no further GTC; 53% and 50% of MIXED, predominantly GTC patients had no further GTC, 21% and 28% of CPS patients had no further CPS and 98% and 91% were seizure free for GTC; 32% and 35% of MIXED, predominantly CPS patients had no further CPS, and 62% and 51% of patients with MIXED seizure types remained seizure free for CPS for 12 months after enrollment. CONCLUSIONS: The overall prognosis for control of seizures of any type for 12 months was best for those who had only GTC at entry (55% and 48%), worst for those who had only CPS at entry (23% and 26%), and intermediate for those with MIXED seizures at entry (32% and 25%) (all p < 0.0001). Prognosis can be based on the predominant seizure type in patients with multiple types.

Measurement of carbamazepine and carbamazepine epoxide in the human brain using in vivo microdialysis.

We report the first study of carbamazepine and carbamazepine-10,11-epoxide concentrations determined by using intracerebral microdialysis in three patients undergoing depth electrode studies for the evaluation of medically intractable epilepsy. Very small microdialysis catheters, affixed to and inserted with the depth electrodes, sampled drug concentration in the extracellular environment. We perfused artificial extracellular fluid continuously, and varied the perfusion rate to permit estimation of the absolute drug concentration in the extracellular space. Serum samples were obtained simultaneously. The relation between dialysate and extracellular concentration (recovery fraction) depended, in vivo but not in vitro, on the relative lipophilicity of the compounds, suggesting that diffusion of the drug within the brain is a major determinant of microdialysate drug concentration. When this is taken into account, the steady-state extracellular concentrations of these compounds closely mirror their unbound serum concentrations.

A design for the prospective evaluation of the efficacy and toxicity of antiepileptic drugs in adults.

The design for the comparative evaluation of the efficacy and toxicity of phenobarbital, phenytoin, primidone, and carbamazepine is outlined. A double-blind prospective study of a sufficient number of patients can determine the optimum drug to use initially for partial and generalized tonic-clonic seizures in adults. The rationale for methods defines the major parameters that should be addressed in order to determine optimum drug for longterm seizure therapy. Major problems in the function of such a project include aspects of sample size attainment, screening/recruitment, non-drug-related losses, and adjustments to the ongoing protocol. The design, with modifications, can be used to study other antiepileptic drugs and other types of seizures.

Treatment of seizures with medroxyprogesterone acetate: preliminary report.

Medroxyprogesterone acetate (MPA), a synthetic progesterone, was added to the antiepileptic drug regimen of 14 women who had uncontrolled seizures. Of the 11 women who developed amenorrhea, 7 reported fewer seizures during MPA therapy. Overall reductions in seizure frequency averaged 30% (n = 11), declining from a baseline 8.3 +/- 5.8 seizures per month to 5.1 +/- 4.1 seizures per month (p = 0.02). No serious side effects were encountered, but spotting was common. These preliminary data suggest further evaluation of MPA for catamenial seizures.

PIP: In Connecticut, physicians followed 19 women with tractable epilepsy for 3-5 months to determine baseline seizure frequency. 14 women agreed to enter a clinical trial evaluating synthetic medroxyprogesterone acetate's (MPA) ability to reduce seizure frequency by adding MPA to the usual antiepileptic drug regimen. They all received 10 mg MPA pills 2-4 times each day. 6 women who did experience amenorrhea later received 120-150 mg intramuscular MPA injections (Depo-Provera) every 6-12 weeks instead of oral MPA. The physicians followed the women for 12 months. 11 women eventually experienced amenorrhea and always had low levels of serum progesterone ( or = ng/ml). Seizure frequency fell significantly from a mean of 8.3 seizures/month before MPA administration to 5.1 seizures/month after MPA administration, equaling 39% fewer seizures (p = .02). 7 women who experienced obvious improvement had 52% fewer seizures on average (25-71%) reduction. All women who had fewer seizures did experience partial seizures, however. MPA did not affect the steady state levels of antiepileptic drugs. MPA levels were higher in women receiving oral MPA than they were in those receiving MPA injections (5.2 ng/ml vs. 2.6 ng/ml). Most women had some spotting, particularly during the first few months of the study. Some of these women discontinued treatment because of this side effect, especially women who did not appear to benefit from the treatment. Menstruation returned in 6-12 months in women receiving MPA injections. Further research on MPA's effect on catamenial seizures is needed.

Crossover from polytherapy to monotherapy in primary generalized epilepsy.

Patients with primary generalized tonic-clonic seizures can obtain equal or superior seizure control and fewer side effects when managed with valproate than when taking multiple antiepileptic drugs. The conversion from polytherapy to valproate monotherapy must be done carefully if side effects and seizure exacerbation are to be avoided. A gradual crossover, often requiring several months, is usually necessary. A well-developed plan and understanding by the patient, coupled with close follow-up, are essential. The major improvement in quality of life that results for the majority of patients after completing such a conversion fully warrants the extra time and effort required.

Evaluation of liposome-entrapped radioactive tracers as scanning agents. Part 1: Organ distribution of liposome (99mTc-DTPA) in mice.

We describe the use of liposomes as a delivery system for radiopharmaceutical localization. Liposomes [99mTc-DTPA] were injected intravenously in mice and showed preferential uptake in the liver and spleen. There was a steady decline of activity in all organs, suggestive of destruction of liposomes with subsequent release of 99mTc-DTPA into the circulation. Alteration of uptake from liver to spleen, lung, and bone marrow was achieved by prior loading of the circulation with nonradioactive liposomes. The same effect was produced in dogs and demonstrated with scintigraphy. We also showed scintigraphically in dogs how 99mTc-DTPA, when administered entrapped in liposomes, follows the pattern of distribution of liposomes. Liposomes seem to be suitable carriers for radiopharmaceuticals. Further studies should show the possibility of directing liposomes to specific targets.