Randomised placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis

BACKGROUND: Rotavirus is the most common cause of acute childhood gastroenteritis. Vaccination with live oral heterologous rotavirus vaccines may prevent rotavirus gastroenteritis. We assessed the efficacy of rhesus-human reassortant rotavirus tetravalent vaccine (RRV-TV) against severe rotavirus gastroenteritis in Finnish children in a randomised placebo-controlled double-blind trial. METHODS: Placebo or RRV-TV (titre 4x10(5) plaque-forming units) was given to infants at ages 2, 3, and 5 months. The children were followed up for one or two rotavirus epidemic seasons. The main outcome measure was protection against severe rotavirus gastroenteritis (score > or =11 on a 20-point severity scale). 2398 children were enrolled and received at least one dose of RRV-TV (n=1191) or placebo (n=1207). The primary efficacy analysis was based on children who received three doses of RRV-TV (n=1128) or placebo (n=1145). FINDINGS: 256 episodes of rotavirus gastroenteritis occurred at any time during the study; 65 were among 1191 RRV-TV recipients, and 191 among 1207 placebo recipients (vaccine efficacy 66% [95% CI 55-74]; intention-to-treat analysis). 226 episodes were included in the primary efficacy analysis of fully vaccinated children (54 among 1128 RRV-TV recipients, 172 among 1145 placebo recipients; vaccine efficacy 68% [57-76]). 100 episodes were severe, eight in RRV-TV recipients and 92 in placebo recipients (vaccine efficacy 91% [82-96]). INTERPRETATION: RRV-TV vaccine was highly effective against severe rotavirus gastroenteritis in young children. Incorporation of this vaccine into routine immunisation schedules of infants could reduce severe rotavirus gastroenteritis by 90% and severe gastroenteritis of all causes in young children by 60%.     

Rotavirus

Rotavirus, the most common diarrheal pathogen in children worldwide, causes approximately one third of diarrhea-associated hospitalizations and 800,000 deaths per year. Because natural infection reduces the incidence and severity of subsequent episodes, rotavirus diarrhea might be controlled through vaccination. Serotypespecific immunity may play a role in protection from disease. Tetravalent rhesus-human reassortant rotavirus vaccine (RRV-TV) (which contains a rhesus rotavirus with serotype G3 specificity and reassortant rhesus-human rotaviruses with G1, G2, and G4 specificity) provides coverage against the four common serotypes of human rotavirus. In clinical trials in industrialized countries, RRV-TV conferred 49% to 68% protection against any rotavirus diarrhea and 61% to 100% protection against severe disease. This vaccine was licensed by the U.S. Food and Drug Administration on August 31, 1998, and should be cost-effective in reducing diarrheal diseases in industrialized countries. The vaccine's efficacy and cost-effectiveness in developing countries should be evaluated.     

Comparative evaluation of reactogenicity and immunogenicity of two dosages of oral tetravalent rhesus rotavirus vaccine. US Rhesus Rotavirus Vaccine Study Group

OBJECTIVE: To compare the safety and immunogenicity of two dosages of tetravalent rhesus rotavirus vaccine (RRV-TV) and the effect of age at dosing. METHODS: A total of 195 infants were stratified by age into 2 groups, 6 to 12 weeks and 16 to 24 weeks, and randomly assigned to receive a single dose of placebo or RRV-TV containing either 4 x 10(5) or 4 x 10(6) plaque-forming units (pfu). Symptoms were recorded for 5 days after vaccination. Anti-rotavirus IgA and neutralizing antibody to human rotavirus serotypes G1 to G4 and RRV were measured in serum obtained pre- and postvaccination. RESULTS: Rates of fever > 38 degrees C (9%), diarrhea (6%) and vomiting (8%) were similar in all groups. IgA (69% vs. 49%, P = 0.02) and RRV (85% vs. 66%, P = 0.004) seroconversion rates were significantly higher in the 4 x 10(6) pfu vaccine group as were antibody titers to RRV (440.2 vs. 263.7, P = 0.04). Older infants demonstrated significantly higher seroconversion rates and antibody titers for IgA (71% vs. 52%, P = 0.03; and 110.6 vs. 54.8, P = 0.004) and RRV (92% vs. 66%, P = 0.05 and 498.3 vs. 205.6, P = 0.01) at either dose level than did the younger infants. There were no significant differences in seroconversion rates or antibody titers to human rotavirus types G1 to G4 between the two vaccination groups. CONCLUSIONS: RRV-TV at a dose of 4 x 10(6) pfu can be safely administered to infants 6 to 24 weeks of age. A single dose of 4 x 10(6) pfu of RRV-TV was significantly more immunogenic than a single dose of 4 x 10(5) pfu but did not improve responses to the human serotypes. Older vaccine recipients demonstrated significantly higher IgA and neutralizing antibody seroconversion rates and antibody titers than younger infants independent of dosage.     

Rotavirus vaccines against diarrhoeal disease

Rotaviruses are responsible for more diarrhoeal disease-associated mortality than any other single agent. Vaccination may therefore hold the key to combating diarrhoeal disease worldwide. Natural immunity to rotavirus infection indicates that rather than protection from reinfection such immunity gives rise to less severe and less frequent attacks of diarrhoea. Early attempts to design a rotavirus vaccine with bovine rotavirus failed because of poor efficacy in some developing countries. Research into rhesus rotavirus, particularly the high-titre rhesus rotavirus tetravalent (RRV-TV) vaccine, has given slightly better results. A stumbling block to truly effective oral vaccines seems to be immunogenicity in developing countries. If efficacy can be ensured by trials in the developing countries, money spent on rotavirus vaccines will be well spent.     

The role of endothelin-1 as a mediator of the pressure response after air embolism in blood perfused lungs

BACKGROUND: Irritable bowel syndrome is a common cause of abdominal pain and discomfort and may be related to disordered gastrointestinal motility. Our aim was to assess the effects of long-term treatment with a prokinetic agent, cisapride, on postprandial jejunal motility and symptoms in the irritable bowel syndrome (IBS). METHODS: Thirty-eight patients with IBS (constipation-predominant, n = 17; diarrhoea-predominant, n = 21) underwent 24-h ambulatory jejunal manometry before and after 12 week's treatment [cisapride, 5 mg three times daily (n = 19) or placebo (n = 19)]. RESULTS: In diarrhoea-predominant patients significant differences in contraction characteristics were observed between the cisapride and placebo groups. In cisapride-treated diarrhoea-predominant patients the mean contraction amplitude was higher (29.3 +/- 3.2 versus 24.9 +/- 2.6 mm Hg, cisapride versus placebo (P < 0.001); pretreatment, 25.7 +/- 6.0 mm Hg), the mean contraction duration longer (3.4 +/- 0.2 versus 3.0 +/- 0.2 sec, cisapride versus placebo (P < 0.001); pretreatment, 3.1 +/- 0.5 sec), and the mean contraction frequency lower (2.0 +/- 0.2 versus 2.5 +/- 0.4 cont./min, cisapride versus placebo (P < 0.001); pretreatment, 2.5 +/- 1.1 cont./min] than patients treated with placebo. No significant differences in jejunal motility were found in the constipation-predominant IBS group. Symptoms were assessed by using a visual analogue scale before and after treatment. Symptom scores relating to the severity of constipation were lower in cisapride-treated constipation-predominant IBS patients [score, 54 +/- 5 versus 67 +/- 14 mm, cisapride versus placebo (P < 0.05); pretreatment, 62 +/- 19 mm]. Diarrhoea-predominant IBS patients had a higher pain score after cisapride therapy [score, 55 +/- 15 versus 34 +/- 12 mm, cisapride versus placebo (P < 0.05); pretreatment, 67 +/- 19 mm]. CONCLUSION: Cisapride affects jejunal contraction characteristics and some symptoms in IBS.     

One-year economic evaluation of intensive vs conventional patient education and supervision for self-management of new asthmatic patients

The purpose was to compare the short-term cost-effectiveness of intensive vs conventional education and supervision for the self-management of mild asthmatic patients. Consecutive newly diagnosed asthmatic patients (n = 162) were randomized into an intervention group (IG) and a control group (CG) with 1 yr of treatment and follow-up. Intensive education was given to 77 patients at visits every third month in the outpatient clinic. Eighty CG patients received conventional education and advice at the baseline visit only. All patients received similar inhaled anti-inflammatory treatment. At baseline and at 12 months standard clinical lung functions and health-related quality of life (HRQOL) were measured, the latter by the disease-specific St George's Respiratory Questionnaire and the generic 15D. Furthermore, the use of extra health care services, medication and sickness days were recorded. The IG experienced a significant improvement in all clinical and HRQOL outcome variables. The same applied to the CG except spirometric values. The groups differed significantly only in terms of FEV1 (P < 0.05) in favour of the IG. There was a significant difference between the groups in extra costs. The mean cost was FIM 2351 per patient (294 Pounds sterling) in the CG and FIM 2757 per patient (345 Pounds) in the IG, of which the intervention cost was FIM 1978 per patient (247 Pounds). In 1 yr follow-up the intensive education programme did not prove to be cost effective but was dominated by the conventional one regardless of what effectiveness measure was used. Also, a purely monetary cost-benefit calculation showed that the intervention resulted in a negative net benefit (loss) of FIM 406 per patient (51 Pounds). A longer follow-up may be needed before definitive conclusions about the cost-effectiveness of this kind of intervention can be drawn.     

Immune response to three doses of quadrivalent rotavirus vaccine: 1-year follow-up

Twenty-eight children who received three doses of the quadrivalent rotavirus vaccine with 4 x 10(5) plaque-forming units (p.f.u.) were followed during a year after vaccination. Serum samples were obtained and evaluated for rotavirus IgA and neutralizing antibodies against vaccine and human rotavirus strains. At the end of the study, up to 61% of the children showed an increase in circulating IgA antibody levels. Nearly all of the vaccinated children increased their neutralizing antibody titres against the vaccine strains, and 25-54% against human rotavirus serotypes. After comparing the vaccinees with a population of children naturally infected with serotype G1 in the same study area, we conclude that three doses of 4 x 10(5) p.f.u. of the quadrivalent vaccine should prepare the child against future severe rotavirus diarrhea.     

The human dead ringer/bright homolog, DRIL1: cDNA cloning, gene structure, and mapping to D19S886, a marker on 19p13.3 that is strictly linked to the Peutz-Jeghers syndrome

A 2-year trial was conducted to evaluate the cost-effectiveness of heliotherapy for psoriasis. The course and cost of psoriasis of 46 Finnish patients were first closely monitored for 1 year, then the patients received a 4-week supervised heliotherapy treatment in the Canary Islands, Spain, after which they continued to be followed for another year. Heliotherapy dramatically reduced the severity of psoriasis and also seemed to have favourable long-term effects on psoriasis. The mean direct cost of the 4-week heliotherapy for one patient was FIM12,289 (1 Pound = FIM7.0 in 1989). The cost of flights and half-board in Spain formed nearly 60% (FIM7033) of the total cost. In the year preceding heliotherapy, the mean direct annual cost of antipsoriasis therapy was FIM7335 and in the year after FIM5700, a reduction of 22% in annual costs; this change was not statistically significant because there were large variations in costs among patients. The costs of heliotherapy exceeded manyfold the mean monthly cost of conventional psoriasis therapy. There were no overall savings using heliotherapy in those patients suffering mainly from moderately severe psoriasis. Heliotherapy saved costs only in those patients with severe psoriasis that required expensive medication or ward treatment. Although heliotherapy cannot be regarded as an economical treatment for the average patients with psoriasis, it clears psoriasis effectively and is preferred by patients. Thus, heliotherapy constitutes an alternative for patients suffering severe psoriasis.     

Enteric pathogens in severe forms of acute gastroenteritis in Ghanaian children

Diarrheal disease is the major cause of childhood morbidity in developing countries. Although malnutrition is known as a risk factor for severe gastroenteritis, the role of enteric pathogens in the clinical severity is unclear. The present study was conducted in well nourished Ghanaian preschool children during a 3 month period of the rainy season to assess the relationship between enteric pathogens and severe gastroenteritis. Two hundred and twenty-five children with acute gastroenteritis and 64 age-matched control children were prospectively examined for the severity of dehydration and enteric pathogens in their stools. Of the 225 children with gastroenteritis, 69.8% (157/225) had mild dehydration and 30.2% (68/225) had severe dehydration. Bacteria were similarly isolated in stool samples from children with mild and severe dehydration and controls. Rotavirus accounted for 20.6% of children with severe dehydration and was more often isolated in stools from patients with severe dehydration than those from controls. Furthermore, the mixed infections associated with rotavirus and bacteria were more often found in patients with severe dehydration than those with mild dehydration or controls. Parasites were similarly found at low incidences among the three groups. The present study implied that rotavirus was more responsible for severe gastroenteritis than bacteria or parasites. However, factors other than enteric pathogens must be sought in a considerable number of severe cases. A large scale study throughout a year is recommended to obtain more precise information that would reflect the seasonal variation of rotavirus infections.     

Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure. A double-blind, placebo-controlled, randomized crossover trial

BACKGROUND: The pharmacological effects of infusion of human brain natriuretic peptide (hBNP) in patients with severe congestive heart failure have not been characterized previously. METHODS AND RESULTS: Twenty patients with severe congestive heart failure were randomized in a double-blind, placebo-controlled, crossover trial to receive incremental 90-minute infusions of hBNP (0.003, 0.01, 0.03, and 0.1 microgram/kg per minute) or placebo on 2 consecutive days. At the highest completed dose of the hBNP, mean pulmonary artery pressure decreased from 38.3 +/- 1.6 to 25.9 +/- 1.7 mm Hg; mean pulmonary capillary wedge pressure decreased from 25.1 +/- 1.1 to 13.2 +/- 1.3 mm Hg; mean right atrial pressure decreased from 10.9 +/- 1 to 4.8 +/- 1.0 mm Hg; mean arterial pressure decreased from 85.2 +/- 2.0 to 74.9 +/- 1.7 mm Hg; and cardiac index increased from 2.0 +/- 0.1 to 2.5 +/- 0.1 L/min per square meter (all P < .01 versus placebo). Urine volume and urine sodium excretion increased significantly during hBNP infusion when compared with placebo infusion (90 +/- 38 versus 67 +/- 27 mL/h and 2.6 +/- 2.4 versus 1.4 +/- 1.2 mEq/h, respectively, both P < .05 versus placebo), whereas creatinine clearance and urinary potassium excretion did not change. CONCLUSIONS: Infusion of incremental doses of hBNP is associated with favorable hemodynamic and natriuretic effects in patients with severe congestive heart failure.     

Biomarkers of immunotoxicity in fish and other non-mammalian sentinel species: predictive value for mammals?

Despite considerable experience with single-dose, live, oral cholera vaccine CVD 103-HgR in Asia, Europe, and the Americas, the vaccine had not been evaluated in sub-Saharan Africa or on individuals infected with human immunodeficiency virus (HIV). We therefore conducted a randomized, placebo-controlled, double-blind, cross-over clinical trial in 38 HIV-seropositive (without clinical acquired immunodeficiency syndrome (AIDS)) and 387 HIV-seronegative adults in Mali to assess its safety and immunogenicity. Adverse reactions (fever, diarrhoea and vomiting) were observed with similar frequency among vaccine and placebo recipients. The vaccine strain was not isolated from the coprocultures of any subject. The baseline geometric mean titre (GMT) of serum vibriocidal antibody was significantly lower in HIV-seropositives (1:23) than in HIV-seronegatives (1:65) (P = 0.002). Significant rises in vibriocidal antibody were observed in 71% of HIV-seronegatives and 58% of HIV-seropositives, and in 40% of HIV-seropositives with CD4+ counts below 500 per microliter. Following immunization, the peak vibriocidal GMT in HIV-seronegatives was 1:584 versus 1:124 in HIV-seropositives (P = 0.0006); in HIV-seropositives with CD4+ counts < 500 per microliter, the peak vibriocidal GMT was 1:40 (P = 0.03 versus other HIV-seropositives). CVD 103-HgR was safe in HIV-infected Malian adults, although serological responses were significantly attenuated among HIV-seropositives (particularly in those with CD4+ counts < 500 per microliter) relative to HIV-seronegatives. These results encourage further evaluations of this single-dose, oral cholera vaccine in high-risk populations such as refugees in sub-Saharan Africa.     

Which vertebrae should be assessed in diagnosing osteoporosis by plain radiography? Comparative study of radiographic findings and bone mineral density measured by dual energy X-ray absorptiometry

OBJECTIVE: To determine rates of hospitalisation of young children for acute gastroenteritis in Australia, and to estimate the proportion of these admissions caused by rotavirus infection. DESIGN: Analysis of hospital admission records, and parallel, prospectively collected data on rotavirus-positive admissions. SETTING: Hospitals admitting young children in all Australian States and Territories in 1993-1996. PATIENTS: All children under five years admitted to hospital for acute gastroenteritis (International Classification of Diseases, ninth revision principal diagnosis codes 003.0, 004.0-009.3 and 558.9). MAIN OUTCOME MEASURES: Rate of hospital admission per 1000 children per year by State, and the proportion of admissions caused by rotavirus infection. RESULTS: There were almost 20,000 hospital admissions annually in Australia for acute gastroenteritis in children under five years, at an average rate of 15/1000. An estimated 50% of these were attributable to rotavirus infection, implying a rate of hospitalisation for rotavirus-related gastroenteritis of 7.5/1000/year. Among children under two years this rate was 11.6/1000. Rotavirus incidence rates generally followed a typical seasonal pattern in temperate regions of the country, with sharp peaks in mid to late winter. Rates of hospitalisation varied markedly, even between States with apparently similar patterns of disease, while the incidence in the Northern Territory was 3-5 times higher than other States. CONCLUSIONS: Rotavirus-related gastroenteritis is a major cause of hospital admissions in young children, and large savings to the healthcare system are possible if it can be prevented at reasonable cost. Variation in treatment practices between States may be worth studying in greater detail as another source of potential savings.     

Protection against rotavirus disease after natural rotavirus infection. US Rotavirus Vaccine Efficacy Group

Determination of protective efficacy after natural rotavirus infection is important as a basis for evaluating rotavirus vaccines. Therefore, placebo recipients in a large 2-year rotavirus vaccine trial conducted across the United States were followed to determine the protection afforded by natural rotavirus infection. Serotype 1 rotaviruses predominated (93% year 1, 66% year 2), but isolates of all four major human rotavirus serotypes circulated during both years. Of the 45 placebo recipients with documented rotavirus illnesses in year 1, 1 developed rotavirus disease in year 2 compared with 29 of the other 235 placebo recipients (P = .03). Serologic data were available for 171 placebo recipients, and 37 of 140 without rotavirus illnesses in year 1 had evidence of asymptomatic rotavirus infection. None of these 37 experienced rotavirus disease in year 2 compared with 22 of the remaining 103 (P < .001). Overall efficacy after natural rotavirus infection was 93% (95% confidence interval, 50%-99%).     

Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery

BACKGROUND: Atrial fibrillation occurs commonly after open-heart surgery and may delay hospital discharge. The purpose of this study was to assess the use of preoperative amiodarone as prophylaxis against atrial fibrillation after cardiac surgery. METHODS: In this double-blind, randomized study, 124 patients were given either oral amiodarone (64 patients) or placebo (60 patients) for a minimum of seven days before elective cardiac surgery. Therapy consisted of 600 mg of amiodarone per day for seven days, then 200 mg per day until the day of discharge from the hospital. The mean (+/-SD) preoperative total dose of amiodarone was 4.8+/-0.96 g over a period of 13+/-7 days. RESULTS: Postoperative atrial fibrillation occurred in 16 of the 64 patients in the amiodarone group (25 percent) and 32 of the 60 patients in the placebo group (53 percent) (P=0.003). Patients in the amiodarone group were hospitalized for significantly fewer days than were patients in the placebo group (6.5+/-2.6 vs. 7.9+/-4.3 days, P=0.04). Nonfatal postoperative complications occurred in eight amiodarone-treated patients (12 percent) and in six patients receiving placebo (10 percent, P=0.78). Fatal postoperative complications occurred in three patients who received amiodarone (5 percent) and in two who received placebo (3 percent, P= 1.00). Total hospitalization costs were significantly less for the amiodarone group than for the placebo group ($18,375+/-$13,863 vs. $26,491+/-$23,837, P=0.03). CONCLUSIONS: Preoperative oral amiodarone in patients undergoing complex cardiac surgery is well tolerated and significantly reduces the incidence of postoperative atrial fibrillation and the duration and cost of hospitalization.     

Laparoscopic resection of a benign true cyst of the spleen with the harmonic scalpel producing high levels of CA 19-9 and carcinoembryonic antigen

BACKGROUND: Oral ingestion of immunoglobulins in humans has been shown to be effective as prophylaxis against enteric infections. However, its therapeutic effect in children with infectious diarrhea has hitherto not been proven. We treated children with rotavirus diarrhea with immunoglobulins extracted from immunized bovine colostrum (IIBC) containing high titers of antibodies against four rotavirus serotypes. METHODS: In this double blind placebo-controlled trial, 80 children with rotavirus diarrhea were randomly assigned to receive orally either 10 g of IIBC (containing 3.6 g of antirotavirus antibodies) daily for 4 days or the same amount of a placebo preparation. The daily stool output (grams/kg/day), intake of oral rehydration solution (ml/kg/day), stool frequency (number of stools/day) and presence of rotavirus in stool were monitored for the 4 days during treatment. RESULTS: Children who received IIBC had significantly less daily and total stool output and stool frequency and required a smaller amount of oral rehydration solution than did children who received placebo (P < 0.05). Clearance of rotavirus from the stool was also earlier in the IIBC group compared with the placebo group (mean day, 1.5 vs. 2.9, P < 0.001). No adverse reactions from the colostrum treatment were observed. CONCLUSIONS: Treatment with antirotavirus immunoglobulin of bovine colostral origin is effective in the management of children with acute rotavirus diarrhea.     

Bidirectional shunt flow across a ventricular septal defect: pulsed Doppler echocardiographic analysis

Pulsed Doppler echocardiographic and hemodynamic examinations were performed in 31 patients (mean age 17.8 years) with isolated ventricular septal defect (VSD). Three groups were studied: group I (n = 6) patients had severe pulmonary vascular obstructive disease (PVOD); group II (n = 12) patients had pulmonary hypertension (PH) without severe PVOD; group III (n = 13) patients had no PH. Bidirectional shunting was detected in 9 VSD patients (6 in group I and 3 in group II). Patients with low to moderately elevated right ventricular pressures demonstrated left-to-right shunting across the defect throughout the cardiac cycle. When systolic pressure in the right ventricle reached approximately 60% of the left ventricular pressure, right-to-left shunting occurred across the defect during early and mid diastole. However, in patients with Eisenmenger syndrome (group I) the right-to-left shunting occurred during late systole with continuation during the early and mid diastolic period. The earlier occurrence of right-to-left shunting (index < 0.5 second) signifies the presence of severe PVOD.     

Randomized, double-blind, placebo-controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homocysteine levels in healthy postmenopausal women

OBJECTIVE: To investigate the long-term effects of raloxifene on fasting plasma homocysteine levels in postmenopausal women compared with conjugated equine estrogen (CEE). DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Outpatient department of a university hospital. PATIENT(S): Fifty-two hysterectomized, healthy postmenopausal women. INTERVENTION(S): Oral raloxifene in two dosages (60 mg/d [n=13] and 150 mg/d [n=13]), oral CEE (0.625 mg/d [n=13], and placebo (n=13) were given for 24 months. MAIN OUTCOME MEASURE(S): Fasting plasma homocysteine concentrations. RESULT(S): Plasma homocysteine levels were not altered in the placebo group. After 12 months, a significant reduction versus baseline in the mean plasma homocysteine level (-16%) was found only in the raloxifene 150-mg group. The mean change in plasma homocysteine levels within this group also was significantly different from the changes versus baseline found in the placebo group (+2%) and the raloxifene 60-mg group (-2%), but not different from those found in the CEE group (-8%). After 24 months, plasma homocysteine levels were decreased significantly in the raloxifene 150-mg and CEE groups compared with both baseline (-13% and -10%, respectively) and placebo values (-15% and -11%, respectively). No significant change in plasma homocysteine levels was observed in the raloxifene 60-mg group. CONCLUSION(S): Raloxifene has a favorable, dose-related effect on plasma homocysteine levels in postmenopausal women.     

A double-masked comparison of Naprelan and nabumetone in osteoarthritis of the knee. Naprelan Study Group

The efficacy and safety of Naprelan (naproxen sodium) 1000 mg once daily (QD) and nabumetone 1500 mg QD were compared in a multicenter, randomized, parallel-group, placebo-controlled, double-masked, 4-week study of adult outpatients with active osteoarthritis (OA) of the knee. Nabumetone 1500 mg was chosen for comparison because it is commonly prescribed in a QD dosing regimen for OA. After a washout period free of nonsteroidal anti-inflammatory drugs, 279 patients were enrolled and assigned randomly to treatment with either Naprelan 1000 mg QD (n = 92), nabumetone 1500 mg QD (n = 93), or placebo (n = 94). All treatments were evaluated for efficacy and safety at baseline and at weeks 2 and 4 of the treatment period or at discontinuation. Demographic characteristics were comparable among all treatment groups. As might be expected in a study of OA of the knee, a majority of patients enrolled were women (68.8%), and many were obese (mean weight, 195.6 lb; mean height, 66 in). Significantly fewer patients (13) treated with Naprelan prematurely discontinued the study than did patients treated with placebo (27); there was a lower rate of discontinuation for insufficient therapeutic effect in the Naprelan group compared with the nabumetone and placebo groups. Using an intent-to-treat model, the overall distribution of scores in all three primary efficacy assessments (investigator's global assessment of OA, patient's global assessment of OA, and walking pain) at week 2 and at the last visit was significantly better for the Naprelan group compared with both the nabumetone and placebo groups. The mean improvement from baseline was also significant for Naprelan compared with the nabumetone and placebo groups for all three assessments at week 2 and for investigator's global assessment of OA and walking pain at the last visit. The nabumetone-treated group showed significant improvement over the placebo-treated group in only one primary assessment: mean change from baseline in patient's global assessment of OA at week 2. At week 2, significant differences favoring Naprelan versus nabumetone and placebo were measured in overall distribution of scores for joint tenderness and nighttime pain. Distribution of quality of sleep and inactivity stiffness scores also improved relative to placebo at week 2. At the last visit, nighttime pain scores were still significantly better for patients receiving Naprelan versus nabumetone and placebo. Patients receiving nabumetone had statistically significant improvement from baseline in inactivity stiffness compared with placebo at week 2. There were no clinically important differences among treatment groups in the occurrence of adverse events or laboratory abnormalities. The results of this 4-week study of Naprelan 1000 mg QD compared with nabumetone 1500 mg QD demonstrate at least equal efficacy (superior efficacy was demonstrated for several parameters) and equal safety in adult outpatients with active OA of the knee.     

Hepatitis A vaccination

The safety and immunogenicity of an inactivated hepatitis A virus vaccine were assessed in 101 healthy adults. Seronegative persons with normal serum aminotransferase levels were grouped according to age: Group 1 (n = 24) and group 3 (n = 22) were between 18 and 40 years of age, and group 2 (n = 25) and group 4 (n = 30) were older than 40 years. Groups 1 and 2 received vaccine on a 0-, 1-, and 2-month schedule (schedule A), and groups 3 and 4 received the vaccine on a 0-, 1-, and 12-month schedule (schedule B). Of the 101 vaccinated subjects, 98 (97%) seroconverted with antibody titers to hepatitis A virus of > or = 20 IU per liter after the first dose, and all subjects seroconverted after the second dose. The geometric mean titers a month after the third vaccine dose were significantly greater (P < .03) on both schedules for younger subjects (schedule A, 1,743 IU per liter, and schedule B, 7,882 IU per liter) than for older subjects (schedule A, 826 IU per liter, and schedule B, 4,279 IU per liter). Also, the differences in geometric mean titers a month after the third dose were significantly greater (P < .001) for subjects in both age groups on schedule B (group 3, 7,882 IU per liter, and group 4, 4,279 IU per liter) than for those on schedule A (group 1, 1,743 IU per liter, and group 2, 826 IU per liter). The hepatitis A virus was well tolerated, with mild discomfort at the injection site being the main side effect. This vaccine is both safe and highly immunogenic.     

Quality of life in patients with benign anorectal disorders

BACKGROUND: Benign proctological conditions are very common in Western civilization. However, to date quality of life in these patients has not been evaluated comprehensively. The aim of this study was to investigate whether the Gastrointestinal Quality of Life Index (GIQLI) is a useful instrument for measuring quality of life in these patients, and subsequently to establish baseline values for different anorectal disorders. METHODS: The questionnaire was completed by 325 consecutive patients (182 men; mean age 49 years) seen at the proctology outpatient clinic. For further analysis patients were classified into nine subgroups according to the primary diagnosis: group 1, haemorrhoids (n=96); group 2, anal fissure (n=38); group 3, fistula in ano (n=22); group 4, severe constipation (n=14); group 5, faecal incontinence (n=35); group 6, symptomatic anterior rectocele (n=12); group 7, perianal abscess (n=7); group 8, perianal thrombosis (n=7); and group 9, miscellaneous conditions (e.g. skin tags, anal papillomas, mild constipation, rectal polyps) (n=94). The GIQLI scores were compared between the subgroups. In addition the GIQLI scores of age-matched healthy controls, derived from data in the literature, were compared with the patients' scores. RESULTS: The mean GIQLI score for all patients was 113 (78.5 per cent of the maximum score of 144). Mean scores for the nine diagnostic subgroups were: group 1, 120; group 2, 104; group 3, 119; group 4, 94; group 5, 93; group 6, 112; group 7, 115; group 8, 129; and group 9, 117. Age-matched controls from a series published previously had a significantly higher GIQLI score compared with all patients (P < 0.0001). However, only the subgroups of patients with miscellaneous conditions, fissures, severe constipation and faecal incontinence had a significantly poorer quality of life than age-matched healthy individuals. CONCLUSION: The GIQLI is a valuable instrument for measuring quality of life in patients with benign anorectal disorders. Although certain diseases do not seem to affect quality of life profoundly, certain subgroups of patients, most notably those with incontinence and severe constipation, are extremely compromised. Severely constipated individuals exhibit the same poor quality of life as patients with faecal incontinence.