Pharmacological evaluation of the cholinergic system in progressive supranuclear palsy

Severe cholinergic loss occurs in the brains of patients with progressive supranuclear palsy. To evaluate the functional implications of this neuronal deficit, dose-response curves were obtained in patients with progressive supranuclear palsy and normal control subjects undergoing intravenous cholinergic blockade (scopolamine) and stimulation (physo-stigmine). Physostigmine had no significant neurobehavioral effects at any does in patients with progressive supranuclear palsy. Scopolamine, at low and medium doses, significantly impaired memory performance of both groups, but worsened the gait of only the patients. High-dose scopolamine, which could not be tolerated by the patients, resulted in gait deterioration among control subjects. Thus, patients with progressive supranuclear palsy have increased sensitivity to cholinergic blockade compared to control subjects. Since loss of cholinergic neurons appears to contribute to the pathogenesis of certain cognitive and motor deficits found in progressive supranuclear palsy, the use of oral anticholinergics should ordinarily be avoided in this disorder. On the other hand, physostigmine at clinically tolerated dose levels seems to be terapeutically ineffective.     

Voltage-gated Currents in Rabbit Retinal Astrocytes

The voltage-gated currents of the astrocytes associated with the retinal capillaries of the rabbit retina were studied using whole-cell patch clamp recording. The resting potential of these cells was −70 ± 4.8 mV (mean ± SEM; n = 54), and the input resistance and cell capacitance were 558 ± 3.6 MΩ and 19.5 ± 1.8 pF respectively. Depolarization to potentials positive to −50 mV evoked rapidly activating inward and outward currents. The inward current was transient, eliminated by substitution of choline for Na⁺ in the bathing solution, and reduced by 50% in the presence of 1 μM tetrodotoxin. The time-to-peak of the Na⁺ current was more than twice that for the Na⁺ current found in retinal neurons. The glial Na⁺ current was half-inactivated at −55 mV. A transient component of the outward K⁺ current was blocked by external 4-aminopyridine while a more sustained component was blocked by external tetraethylammonium. At potentials between −150 and −50 mV the membrane behaved Ohmically. Voltage-gated currents in retinal astrocytes recorded in situ appear qualitatively similar to those described for some glial cells in vitro.     

Preoperative oral naproxen for pain relief after day-case laparoscopic sterilization

Analgesia with preoperative naproxen after laparoscopic sterilization was assessed in a prospective, double-blind, randomized study of 80 women; 42 women received oral naproxen 1 g, approximately 90 min before surgery, and 38 received placebo. Preoperative naproxen did not significantly influence postoperative pain scores, but was associated with a reduction in parenteral opioid administration (P = 0.04).      

Toxicology screening of the trauma patient: a changing profile

STUDY OBJECTIVES: To determine the current ingestants found in the multiply injured trauma patient and to determine if this select group of ingestants affected the resuscitation, evaluation, or convalescent management of these patients. DESIGN: A one-year retrospective analysis was performed on all patients who were admitted to an urban trauma center with a discharge diagnosis of multiple trauma and who received a comprehensive toxicology screening test. MAIN RESULTS: One hundred twenty-seven of the 177 patients (72%) who fulfilled the criteria had positive toxicology screens. Ethyl alcohol was the only drug present in 26 of these patients (20%); 57 (45%) were positive for drugs other than ethyl alcohol. A combination of ethyl alcohol and at least one other drug was quantified in 44 patients (35%). The most often encountered substances were ethyl alcohol (55%), marijuana (24%), and cocaine (21%). Twelve drug screens (9%) demonstrated pharmaceuticals (eg, acetylsalicylic acid, acetaminophen, or cyclic antidepressants) that may require specific antidotal treatment. CONCLUSION: The ingestant profile found in this subgroup of trauma patients differed from those of previous studies. Although a select group of these ingestants requires specific treatment or affects the physical assessment of the patient, none of these trauma patients received more than supportive care.     

Anti-leukemia effect of perillyl alcohol in Bcr/Abl-transformed cells indirectly inhibits signaling through Mek in a Ras- and Raf-independent fashion.

PURPOSE: Perillyl alcohol (POH) displays preventive and therapeutic activity against a wide variety of tumor models, and it has been suggested that this might be associated with the ability of POH to interfere with Ras prenylation. POH also selectively induces G(1) arrest and apoptosis in Bcr/Abl-transformed hematopoietic cells. Because signaling through Ras is necessary for Bcr/Abl transformation, we examined whether POH induces its anti-leukemia effect by inhibiting Ras signaling. EXPERIMENTAL DESIGN: The ability of POH to inhibit posttranslational farnesylation and signaling from Ras as well as signaling through the Raf-Mek-Erk cascade was examined in Bcr/Abl-transformed and mock-transformed cells and related to the anti-leukemia effect of POH. RESULTS: POH does not affect Ras prenylation or Ras activity, but it blocks signaling downstream of Ras by reversing the state of activation of the Erk kinase, Mek. POH affects Mek activity only when it is added to intact cells. Treatment of either cell lysates or of purified Mek with POH has no effect on Mek activity. Inhibition of the Mek-Erk pathway seems to be related to the POH anti-leukemia effect for the following reasons: (a) the concentration of POH needed to block the Erk pathway, as well the kinetics with which POH inhibits this signaling cascade, both correlate with the anti-leukemia effect of POH; (b) both U0126 (a specific Mek inhibitor) and POH induce similar anti-leukemia effects; and (c) mock-transformed hematopoietic cells are simultaneously resistant to POH anti-leukemia effects and inhibition of the Mek-Erk pathway. CONCLUSION: Blocking Mek is sufficient to induce growth arrest and apoptosis in Bcr/Abl-transformed cells; therefore, POH represents a novel small molecule inhibitor of Mek that might be effective for treating Bcr/Abl leukemias.     

Predictive power of various models for longitudinal attachment level change

Abstract Several statistical models that have been suggested in the periodontal literature for describing longitudinal attachment level changes, such as the gradual loss, single-burst, multiple-burst, and random walk models as well as other models introduced in this paper are compared by their power to predict future attachment loss. The data used in this analysis is from 1061 sites of 8 subjects, with moderate to severe periodontal disease, monitored monthly for about a year. This study found that none of the suggested models could significantly outperform the naive mean predictor, which predicts the future attachment level from the past mean. It was also found that no single model, such as the burst, gradual, or random walk, together with measurement error can fully explain the variation in the data. These results indicate that in the course of one year, the attachment level change may not follow the same model. Consequently, a model that fits well to past data cannot be accurately extended to the future.     

Provider attitudes regarding use of an immunization information system to identify children with asthma for influenza vaccination.

OBJECTIVES: Despite longstanding national guidelines, many children with asthma do not receive annual influenza vaccinations. Information from Medicaid-administrative claims data was integrated into the Michigan Care Improvement Registry (MCIR) to prompt providers regarding influenza vaccination among children with high-risk conditions such as asthma. The attitudes of pediatric primary care providers regarding the implementation of this system were assessed. METHODS: A survey was sent in February 2006 to office-based general pediatricians (n = 300) and family physicians (n = 300) in Michigan. The survey focused on influenza vaccination during the 2005-2006 influenza season and attitudes regarding a reminder system for providers using the MCIR. RESULTS: Overall response rate was 67 percent. MCIR participation was high (91%) among respondents, and most (83%) had MCIR information available to them prior to visits with pediatric patients. Most physicians (75%) considered the MCIR high-risk indicator for influenza vaccination a feature that they would find helpful. Some respondents reported concerns that the reminder system is limited to Medicaid patients only (44%) and regarding the completeness of Medicaid data to identify children with asthma (24%). CONCLUSIONS: Physicians have a positive overall view of a statewide registry-based automated reminder system to assist in identifying children with asthma for influenza vaccination, albeit with specific areas of concern.     

Physical fitness and all-cause mortality. A prospective study of healthy men and women

We studied physical fitness and risk of all-cause and cause-specific mortality in 10,224 men and 3120 women who were given a preventive medical examination. Physical fitness was measured by a maximal treadmill exercise test. Average follow-up was slightly more than 8 years, for a total of 110,482 person-years of observation. There were 240 deaths in men and 43 deaths in women. Age-adjusted all-cause mortality rates declined across physical fitness quintiles from 64.0 per 10,000 person-years in the least-fit men to 18.6 per 10,000 person-years in the most-fit men (slope, -4.5). Corresponding values for women were 39.5 per 10,000 person-years to 8.5 per 10,000 person-years (slope, -5.5). These trends remained after statistical adjustment for age, smoking habit, cholesterol level, systolic blood pressure, fasting blood glucose level, parental history of coronary heart disease, and follow-up interval. Lower mortality rates in higher fitness categories also were seen for cardiovascular disease and cancer of combined sites. Attributable risk estimates for all-cause mortality indicated that low physical fitness was an important risk factor in both men and women. Higher levels of physical fitness appear to delay all-cause mortality primarily due to lowered rates of cardiovascular disease and cancer.