The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate.

BACKGROUND AND PURPOSE: BAF312 is a next-generation sphingosine 1-phosphate (S1P) receptor modulator, selective for S1P(1) and S1P(5 ) receptors. S1P(1) receptors are essential for lymphocyte egress from lymph nodes and a drug target in immune-mediated diseases. Here, we have characterized the immunomodulatory potential of BAF312 and the S1P receptor-mediated effects on heart rate using preclinical and human data. EXPERIMENTAL APPROACH: BAF312 was tested in a rat experimental autoimmune encephalomyelitis (EAE) model. Electrophysiological recordings of G-protein-coupled inwardly rectifying potassium (GIRK) channels were carried out in human atrial myocytes. A Phase I multiple-dose trial studied the pharmacokinetics, pharmacodynamics and safety of BAF312 in 48 healthy subjects. KEY RESULTS: BAF312 effectively suppressed EAE in rats by internalizing S1P(1) receptors, rendering them insensitive to the egress signal from lymph nodes. In healthy volunteers, BAF312 caused preferential decreases in CD4(+) T cells, T(naïve) , T(central memory) and B cells within 4-6 h. Cell counts returned to normal ranges within a week after stopping treatment, in line with the elimination half-life of BAF312. Despite sparing S1P(3) receptors (associated with bradycardia in mice), BAF312 induced rapid, transient (day 1 only) bradycardia in humans. BAF312-mediated activation of GIRK channels in human atrial myocytes can fully explain the bradycardia. CONCLUSION AND IMPLICATIONS: This study illustrates species-specific differences in S1P receptor specificity for first-dose cardiac effects. Based on its profound but rapidly reversible inhibition of lymphocyte trafficking, BAF312 may have potential as a treatment for immune-mediated diseases.

A three-dimensional mathematical model of temporomandibular joint loading.

OBJECTIVE: A mathematical model of the temporomandibular joint was developed to study the magnitude and direction of the compressive loading experienced at the temporomandibular joint during clenching. DESIGN: The model was based on the principles of static equilibrium in three dimensions. BACKGROUND: Direct measurement of temporomandibular joint loading in humans is extremely difficult. Animal models have provided an alternative in the past. However, evidence suggests that primates are not the most accurate human analogues for temporomandibular joint studies. A mathematical model was used as an alternative to direct measurement. METHODS: The EMG activity of two masticatory muscles was combined with their cross-sectional areas to calculate the force exerted by each muscle. Experimentally determined forces were implemented into a quadratic programming model to solve for the compressive forces on the joint. Two objective functions were chosen and their ability to predict muscle and joint forces was evaluated. RESULTS: The maximum bite forces for normal men, normal women, and women with temporomandibular joint disorders were 300 N (SD 102 N), 210 N (SD 57.7 N), and 120 N (SD 77.1 N), respectively. The calculated joint force for normal males was 260 N (SD 84.1 N). Normal females and female temporomandibular joint disorder patients produced temporomandibular joint forces of 172 N (SD 37.5 N) and 152 N (SD 44.2 N), respectively.

Correlates of adolescents' satisfaction with mental health services.

While there has been increased attention to consumers' satisfaction with mental health services as an indicator of quality of care, little is known about the construct of consumer satisfaction, especially for youth. The goal of this study was to examine potential correlates of adolescents' satisfaction with mental health services. One hundred eighty adolescents who had received out-patient mental health services completed a multidimensional satisfaction scale and measures of behavior problems, attitudes and expectations about treatment, perceived choice/motivation in seeking treatment, and service use history. Results indicate that the strongest unique correlates of satisfaction are severity of behavior problems, positive expectations about services, and perceived choice in seeking services. Satisfaction with services was also associated with service site, length of time in treatment, and reason for entering treatment. Demographic variables were not related to satisfaction. A discussion of the appropriateness of using satisfaction as an indicator of quality of care is included.

Combined effects of caffeine and prostaglandin E2 on the proliferation of osteoblast-like cells (UMR106-01).

BACKGROUND: The general public widely consumes caffeine (1,3,7-trimethylxanthine), which is contained in various foods, beverages and over-the-counter medications. We have shown previously that caffeine intake could affect bone metabolism in vivo. METHODS: Because prostaglandin E2 (PGE2) is shown to be elevated in the periodontally diseased site, the possible interaction between caffeine and PGE2 was investigated in the present study using UMR106-01 rat osteoblast-like cells in vitro. RESULTS: Although neither 0.1 mM caffeine nor 0.1 microg/ml of PGE2 alone showed any inhibitory effects on cell proliferation, the combination of caffeine and PGE2 showed significant inhibition. However, in order to have inhibitory effects, both caffeine and PGE2 had to be present at least 72 or 96 hours in the medium. Addition of the endogenous PGE2 synthesis inhibitor, indomethacin, showed no effects on cell proliferation. Neither cAMP-inducing agent IBMX (0.01 mM and 0.1 mM) nor forskolin (0.001 mM) inhibited cell proliferation, but combined with PGE2 these agents strongly inhibited proliferation as was observed with the combination of caffeine and PGE2, suggesting possibly that the increase of intracellular cAMP concentration plays an important role in the inhibitory effects of cell proliferation. CONCLUSIONS: The present data for the first time demonstrate the possible implication of routine caffeine intake in the acceleration of pathological conditions of periodontitis. Thus, we propose that chronic caffeine intake is one of the possible risk factors in the advancement of pathology in the periodontitis patient. Further research in this area is warranted.

Controlled release of antibodies for long-term topical passive immunoprotection of female mice against genital herpes.

Current methods for sexually transmitted diseases (STD) prophylaxis, which can be disruptive and inconvenient, must be used before each act of sexual intercourse, so a method that provides protection over the course of many acts is desirable. We used a mouse model of vaginally-transmitted herpes simplex virus 2 (HSV-2) infection to test polymeric controlled-release devices for sustained passive immunoprotection. Vaginal disks were prepared by dispersing a monoclonal antibody to HSV-2 (III-174) within a matrix of poly(ethylene-co-vinyl acetate); these disks released 2 to 40 micrograms/day of antibody into buffered water. When disks were placed in the vagina, large amounts of III-174 (5 to 3,000 ng) were recovered from the vaginal fluid over the next 8 days. Mice were vaginally challenged with 10 ID50 of HSV-2 either 3 or 7 days after disk placement; no mice receiving III-174 disks became infected, while 65% of control mice receiving identical disks with nonspecific IgG did. Controlled-release disks with III-174 provided significant protection against HSV-2 infection (p < 0.005). This new technology for long-term STD prophylaxis should increase user compliance, a factor limiting the efficacy of current methods.

Combined effects of caffeine and alcohol during pregnancy on bones in newborn rats.

The combined effects of caffeine and alcohol on mineral contents of fetal mandibles and femurs were studied. Pregnant rats were divided into four groups: group 1, control; group 2, caffeine; group 3, alcohol; and group 4, caffeine-plus-alcohol. Alcohol (1.0 g ethanol/kg body weight) was intubated twice daily, beginning at day 9 of gestation. Caffeine (2 mg/100 g body weight) was given as a dietary supplement. Groups 1 and 2 were intubated with isocaloric sucrose solution. At birth, randomly selected pups were killed and the mandible and femur were removed and dried. Ca, P, Mg, Zn and hydroxyproline in these bones were measured. Notwithstanding the dams' intake of caffeine and alcohol administered separately, the present results suggest that the combination of caffeine and alcohol exhibited the most detrimental effects.

Volunteers as customers: a service quality perspective.

Not-for-profit service firms depend upon volunteer employees for the success of their programs. This article offers a change in perspective--volunteer as customer instead of employee--to stimulate insights and provide recommendations about attracting and retaining volunteers. The volunteer is viewed as a customer, the service purchased is the volunteer experience, paid for in the currency of donated time and energy, and the not-for-profit service firm is seen as being in the business of designing, managing, communicating, and delivering a quality volunteer experience.

Effect of metoclopramide in diabetic gastroparesis.

The aims of our study were to: determine the effect of metoclopramide parenterally and orally on delayed gastric emptying of a radionuclide test meal in symptomatic patients with diabetic gastroparesis not explained by ulceration or other mechanical problems; and evaluate in a double-blind crossover fashion the efficacy of metoclopramide in relieving the symptoms of diabetic gastroparesis. Thirteen patients with subjective evidence of gastric stasis had delayed gastric emptying of an isotope-labeled semisolid meal which was significantly accelerated (p less than 0.05) after 10 mg of metoclopramide parenterally. Patients then received metoclopramide 10 mg and placebo before meals and prior to retiring for 3 weeks in a randomized double-blind crossover design. During metoclopramide therapy nausea, vomiting, anorexia, fullness, and bloating were significantly (p less than 0.05) ameliorated compared to placebo with an overall mean symptom reduction of 52.6%. Gastric emptying studies after completion of the trial is seven patients, subjectively improved and receiving open-labeled metoclopramide, showed significantly less gastric retention. Individual improvements in gastric emptying after parenteral or oral metoclopramide, however, could not be correlated with symptom change during the treatment trial. We conclude that metoclopramide is an important therapeutic adjunct in the management of diabetic gastroparesis and its therapeutic effects are mediated through its prokinetic properties as well as centrally mediated antiemetic actions.

Treatment of impending pathological fractures of the femur with flexible intramedullary nails.

Thirty-nine patients with fifty impending pathological fractures of the femur were prophylactically stabilized with flexible intramedullary nails. Indications included lesions causing unremitting pain and either measuring greater than 2.5 cm in diameter or involving more than 50% cortical destruction. Painful lesions not meeting these radiographic criteria were also considered for prophylactic nailing if radiation therapy failed to relieve pain. Ninety-five percent of patients experienced marked pain relief after nailing, and 92% were ambulatory with or without assistive devices at discharge. Complications included one fracture at the nail insertion site and three cases with nondisabling knee pain. There were no infections.

Comparison of effects of two dosage regimens of phenylpropanolamine on blood pressure and plasma levels in normal subjects under steady-state conditions.

Plasma levels and blood pressure responses to two dosage regimens of phenylpropanolamine (PPA)-25-mg, immediate-release tablets three times per day and a 75-mg, controlled-release capsule once per day--were compared in 14 normal subjects. To obtain steady-state conditions, subjects were given the test materials for four-day periods, and blood pressure and plasma PPA levels were measured on day 4. The dosage forms were equally bioavailable, based on a 95-percent confidence coefficient, and neither produced hypertensive effects. The highest diastolic pressure was 96 mm Hg three hours after a 25-mg dose. Mean PPA plasma levels showed no correlation with mean blood pressure readings at any point during a 12-hour test period. These data show that, in these subjects, a daily dosage of PPA 75 mg, either in divided doses of 25 mg each or in a dependable controlled-release formula, produces no indication of pressor effects.

Diabetes and the stomach.

Abnormalities in the function of the stomach in patients with long-standing diabetes mellitus, usually insulin-dependent, may provide difficult management problems. There is a reduced frequency of peptic ulcer disease in diabetics. Gastric atrophy, often with parietal cell antibodies, is common and the frequency of pernicious anemia with its expected intrinsic factor antibodies is increased. Gastric analysis results have been conflicting but generally suggest that long-standing diabetics have lower acid levels than normals, possibly secondary to vagal neuropathy. Gastric atony occurring in a small but significant number of patients with longstanding insulin-dependent diabetes, usually with a clinically apparent peripheral neuropathy, has been associated with upper abdominal discomfort, vomiting, and a clinical picture of gastric outlet obstruction. Various degrees of subclinical delays in gastric emptying are probably present in many asymptomatic patients and, indeed, are underemphasized contributors to poor control of blood sugar levels. Studies utilizing radioactive-labeled physiological meals have demonstrated abnormalities in the gastric emptying of solids, in particular, and sometimes liquids in the latter stages of the disease. Metoclopramide, a dopamine antagonist, which stimulates upper gastrointestinal smooth musculature, results in accelerated gastric emptying; clinical trials have shown that it is capable of alleviating symptoms related to diabetic gastroparesis and with its recent approval and release in this country, it promises improved management of this entity. Another agent, domperidone, a selective peripheral dopamine antagonist with no appreciable side effects, is in this country an investigational drug which has shown clinical efficacy in Europe in improving gastric stasis syndromes.

Progression of cimetidine-treated reflux esophagitis to a Barrett's stricture.

A patient is described who developed a peptic stricture of the esophagus associated with Barrett's epithelium while receiving continuous cimetidine therapy. At this time, the role of cimetidine in the treatment of gastroesophageal reflux is evolving and, although it may provide symptomatic relief on some occasions, this report suggests that its role in improving the histological changes related to esophagitis or influencing complications of this disease has not been clarified.