The tau S305S mutation causes frontotemporal dementia with parkinsonism.

Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.

New Alzheimer's disease locus on chromosome 8.

BACKGROUND: Family history is one of the most consistent risk factors for dementia. Therefore, analysis of families with a distinct inheritance pattern of disease can be a powerful approach for the identification of previously unknown disease genes. OBJECTIVE: To map susceptibility regions for Alzheimer's disease. METHODS: A complete genome scan with 369 microsatellite markers was carried out in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least one member with age at onset of < or =65 years. Mutations in known early-onset Alzheimer's disease susceptibility genes have been excluded. All people were genotyped for APOE, but no clear linkage with the epsilon4 allele was observed. RESULTS: Although no common disease locus could be found in all families, in two families an extended haplotype was identified on chromosome 8q shared by all affected members. In one of the families, a non-parametric multimarker logarithm of the odds (LOD) score of 4.2 (p = 0.004) was obtained and analysis based on a dominant model showed a parametric LOD score of 2.4 for this region. All six affected members of this family shared a haplotype of 10 markers spanning about 40 cM. Three affected members in another family also shared a haplotype in the same region. CONCLUSION: On the basis of our data, we propose the existence of a dominantly acting Alzheimer's disease susceptibility locus on chromosome 8.

Qigong reduces stress in computer operators.

UNLABELLED: Chinese research indicates that the Qigong method reduces psychosomatic and physical symptoms through an effect on the sympathetic nervous system. OBJECTIVES: The aim was to investigate the effects of Qigong on stress among computer operators. DESIGN: Ten women were included in a Qigong group and an equal number in a control group. Heart rate, blood pressure, and finger temperature were measured at the beginning and at the end of the working day during 5 weeks. twenty four-hours urine samples were collected in the first and last weeks to measure catecholamine excretion in urine. Participants kept a daily record of psychological measures of strain and weekly measures of stress levels. RESULTS AND CONCLUSIONS: Qigong reduced noradrenaline excretion in urine (p<0.05), and influenced the heart rate and temperature, indicating reduced activity of the sympathetic nervous system. Moreover, Qigong reduced low-back symptoms (p<0.05). In conclusion, Qigong exercise may reduce stress at computerised work.

Effects of salicylates and paracetamol compared to lidocaine on nerve conduction in vitro.

The effects of acetylsalicylic acid, salicylic acid, sodium salicylate and paracetamol on the compound action potentials of the isolated left phrenic nerve of the rat were observed, and compared to that of lidocaine. All drugs depressed the compound action potential in a reversible, dose-dependent way. Lidocaine (inhibition between 0.05 and 10 mM) was more potent than the other drugs and the depression occurred faster. The inhibitory effects of acetylsalicylic acid and salicylic acid were similar to each other (between 1 and 20 mM). Sodium salicylate was less potent (inhibition between 5 and 70 mM). These concentrations cover the plasma levels reported after therapeutic and toxic doses for the salicylates. Inhibition of nerve conduction may therefore contribute to the adverse nervous effects seen after intoxication with salicylates. In contrast, the observed concentrations for inhibition of the compound action potential caused by paracetamol (between 6.7 and 53 mM) were far greater than the plasma concentrations reported after therapeutic doses or after intoxication with paracetamol. Thus, the inhibition of the compound action potential, caused by paracetamol does not contribute to the therapeutic analgesic effects of paracetamol.

Efficacy of paracetamol-esterified methionine versus cysteine or methionine on paracetamol-induced hepatic GSH depletion and plasma ALAT level in mice.

The effect of paracetamol-N-acetyl-DL-methionate (PAM) in preventing paracetamol-induced hepatic glutathione (GSH) depletion and hepatic cell damage assessed by plasma ALAT level, was compared to those of concomitantly administered paracetamol and N-acetyl-L-cysteine (NAC) or N-acetyl-DL-methionine (NAM) and paracetamol 400 mg/kg (P) alone. PAM, NAM and NAC reduced hepatic GSH depletion compared to P. The concomitant administration of GSH precursors in either form apparently maintained hepatic cell integrity as evaluated by plasma ALAT compared to predose and 16 hr control measurements. No statistically significant difference between PAM, NAM and NAC was observed. In group P a statistically significant, but transitory, rise in plasma ALAT level following dosage was seen. NAC was more effective than PAM and NAM in the prevention of GSH depletion 1 hr after dosing but was less effective in promoting de novo GSH synthesis towards 16 hr. There was no statistically significant difference between PAM and NAM with respect to effect on GSH depletion or hepatic cell integrity. PAM and NAM increased the GSH level significantly above control level 16 hr after dosing. PAM is rapidly cleaved to paracetamol and methionine following dosage as shown by the observed plasma paracetamol level. PAM compares favourably in hepatoprophylactic effect, to concomitant administration of equimolar doses of free N-acetyl-DL-methionine added to the paracetamol formulation.

Naproxen 500 mg bid versus acetaminophen 1000 mg qid: effect on swelling and other acute postoperative events after bilateral third molar surgery.

A controlled, randomized, double-blind crossover study, in which the patients acted as their own controls, was carried out to test the efficacy of naproxen 500 mg x 2 versus acetaminophen 1000 mg x 4 for 3 days on the postoperative course following third molar surgery. Acetaminophen reduced the mean swelling on the 3rd postoperative day by 22.4% (p = 0.023) compared to that after naproxen. On the 6th postoperative day, there was 20.9% less mean swelling with naproxen (p = 0.44), although the total swelling measurements were much less than those measured on the 3rd postoperative day. Summed pain intensity (SUMPI3.5-11) on the day of surgery revealed no statistically significant difference between the acetaminophen or naproxen regimen with the exception of 0.5 hours (p = 0.002) and 1 hour (p = 0.009) after first medication when acetaminophen gave less pain than naproxen. Since the drug regimens were different, summed PI for the first acetaminophen dose interval (SUMPI3.5-6) and the first naproxen dose interval (SUMPI3.5-9) was calculated. There was a tendency toward a statistically significant difference in favor of acetaminophen for SUMPI3.5-6 (p = 0.055) but no statistically significant difference (p = 0.41) between the treatments with respect to SUMPI3.5-9. Naproxen was statistically superior (p < or = 0.002) to acetaminophen at 08:00, 12:00, and 16:00 hours on the 1st postoperative day and at 08:00 hours on the 2nd postoperative day, when the pain intensity level was lower than that on the day of surgery. A 3-day acetaminophen regimen reduces acute postoperative swelling better than naproxen on the 3rd postoperative day after third molar surgery but not on the 6th postoperative day when the total swelling is less.

Ketoprofen 75 mg qid versus acetaminophen 1000 mg qid for 3 days on swelling, pain, and other postoperative events after third-molar surgery.

A randomized, double-blind, within-patient, crossover study was carried out after bilateral "identical" surgical procedures using local anesthesia only. A 3-day tablet regime of racemic ketoprofen 75 mg or acetaminophen 1000 mg qid (x 4) was given starting 3 hours after surgery. Ketoprofen reduced objectively measured swelling 27.8% (p < 0.04) better than acetaminophen 3 days after surgery and 70.8% (p < 0.02) better than acetaminophen 6 days after surgery. The pain intensity (PI) was lower after ketoprofen than after acetaminophen from 2 to 6 hours after the first drug intake (all p-values < or = 0.03). Sum PI during the first (SUMPI3.5-6, p = 0.003) and second dose intervals (SUMPI6.5-9, p = 0.007) was lower for ketoprofen than for acetaminophen but not different for the third dose interval (SUMPI9.5-11, p = 0.53). Ketoprofen was a more effective analgesic than acetaminophen on the day of surgery (SUMPI3.5-11, p = 0.005). There was no difference (p > 0.05) between the treatments with respect to mouth opening, drug preference, global evaluation, or adverse reports. Adverse reports included stomach pain and diarrhea in both treatment groups. Ketoprofen 75 mg x 4 for 3 days reduces subjectively assessed pain and objectively measured swelling (i.e., anti-inflammatory effect) following third-molar surgery.

Time to onset of analgesia and analgesic efficacy of effervescent acetaminophen 1000 mg compared to tablet acetaminophen 1000 mg in postoperative dental pain: a single-dose, double-blind, randomized, placebo-controlled study.

This randomized, double-blind, placebo-controlled study compared the time to onset of analgesia and the analgesic efficacy of two formulations of acetaminophen 1000 mg--an effervescent solution and tablet--in 242 patients with moderate or severe pain following dental surgery. Onset of analgesia was determined using a two-stopwatch procedure. Analgesia was assessed over a 4-hour period. Treatments were compared using standard indexes of pain intensity and pain relief and summary measures. Both acetaminophen formulations were significantly more effective than their corresponding placebo for all efficacy assessments. The median time to onset of analgesia was significantly shorter with effervescent acetaminophen (20 minutes) compared to tablet acetaminophen (45 minutes). During the first 45 minutes after administration, effervescent acetaminophen was significantly more effective at each scheduled assessment time than tablet acetaminophen. The median time to meaningful pain relief was significantly shorter with effervescent acetaminophen (45 minutes) compared to tablet acetaminophen (60 minutes). At 4 hours after administration, the pain relief was significantly better with tablet acetaminophen than with effervescent acetaminophen. No other significant differences were observed between the active treatments. In conclusion, effervescent acetaminophen produces a significantly faster onset of analgesia than tablet acetaminophen.

Analgesic dose-response relationship of ibuprofen 50, 100, 200, and 400 mg after surgical removal of third molars: a single-dose, randomized, placebo-controlled, and double-blind study of 304 patients.

The purpose of this single-dose, randomized, placebo-controlled, and double-blind study was to evaluate the analgesic dose-response relationship of 50-mg, 100-mg, 200-mg, and 400-mg doses of ibuprofen after third molar surgery. Patients were instructed to take a single dose of either placebo or 50 mg, 100 mg, 200 mg, or 400 mg of ibuprofen when the postoperative pain was moderate to severe. Acetaminophen 500 mg was used as a rescue medication. Pain intensity, pain relief, and any possible adverse events were recorded on self-administered questionnaires hourly for 6 hours after intake of study medication. If rescue medication was taken, the time of intake was registered. A total of 304 patients entered the study, and 258 complied with the protocol. A positive analgesic dose-response relationship of 50-mg, 100-mg, 200-mg, and 400-mg doses of ibuprofen was observed when evaluated by pain intensity difference, sum of pain intensity difference, pain relief, total pain relief, and survival distribution of patients not taking rescue medication. Although significant pain relief was seen after a dose of 50 mg ibuprofen, ibuprofen 400 mg provided maximum pain relief and the longest duration of analgesic effect. Mild transient adverse events were reported by 6.8% of the patients. However, there was no significant difference in frequency between the placebo and 50 mg, 100 mg, 200 mg, and 400 mg ibuprofen dose groups.

Effects of acetaminophen after bilateral oral surgery: double dose twice daily versus standard dose four times daily.

We compared acetaminophen (APAP) double dose 2000 mg twice a day on the day of oral surgery, decreasing to 1000 mg twice a day for the next 2 days, to a standard dose 1000 mg 4 times a day then 500 mg 4 times a day for 2 days. Compared to the double dose, there was 19% (p = 0.03) less edema after the standard regimen on the third postoperative day. No statistical difference was seen between the two treatments with respect to ability to open the mouth, temperature on the nonoperated versus operated side, or summary analgesic efficacy measures. However, pain intensity scores indicate that APAP double dose gave less analgesia toward the end of the dosing interval than the standard regimen. It is proposed that double-dose APAP twice daily does not have any analgesic and antiedematous advantages over the standard dose 4 times a day. The analgesic and antiphlogistic efficacies of APAP apparently do not coincide.

Analgesic efficacy of acetaminophen 1000 mg, acetaminophen 2000 mg, and the combination of acetaminophen 1000 mg and codeine phosphate 60 mg versus placebo in acute postoperative pain.

Acetaminophen (APAP) 1000 mg, APAP 2000 mg, the combination of APAP 1000 mg plus codeine phosphate 60 mg (APAPCOD), and placebo (PBO) were compared in a 6-hour, randomized, single-dose, double-blind, parallel-group analgesic trial. All active treatments were statistically superior (p less than 0.05) to placebo for 4 hours after medication with respect to pain intensity (PI) and pain intensity difference (PID), and up to 3 hours regarding pain relief (PAR). The combination scored better than all other treatments on the summary analgesic efficacy measures sum PI (SUMPI), sum PID (SPID), and total PAR (TOTPAR). The combination was statistically superior to APAP 1000 mg on SUMPI, TOTPAR and maximum PAR (MAXPAR). Acetaminophen 2000 mg showed marginal numerical superiority over 1000 mg for SUMPI, but was not statistically superior for any summary efficacy measure. The 2000-mg dose was numerically inferior to APAPCOD for every summary efficacy measure and statistically inferior regarding SPID and MAXPAR. We concluded that codeine 60 mg added to acetaminophen 1000 mg offers analgesic advantages, and acetaminophen reaches an analgesic ceiling effect at 1000 mg using the dental pain model.

CBF and transcranial Doppler sonography during vasodilatory stress tests in patients with common carotid artery occlusion.

Cerebral blood flow (CBF) and the cerebral vasoreactivity was measured in patients with cerebrovascular disease and longstanding occlusion of the common carotid artery (CCA). In addition, regional CBF was correlated with transcranial doppler (TCD) measurements at baseline and during 6% CO2 inhalation and after intravenous administration of 1 g of acetazolamide. Twelve patients with a mean age of 62 years (range 45 to 71 years) were included, and the data compared to age-matched healthy controls. CBF was measured by intravenous injection of xenon-133 and SPECT (Tomomatic 564). TCD of the middle cerebral artery (MCA) was done by EME TC-64B. A very low global CBF value of 28 +/- 5 (SD) ml 100 g-1 min-1 was found at baseline as compared to 55 +/- 5 ml 100 g-1 min-1 in the normal controls. During 6% CO2-inhalation and after acetazolamide administration, CBF increased by 58 +/- 24% and 51 +/- 21%, respectively, indicating substantial collateral supply. Correlative analysis of CBF in the MCA territory and TCD in the MCA showed statistical significance only for the pooled data, i.e. compiling the data obtained during baseline and the two vasodilatory tests, and then only for the mean and peak TCD velocity (e.g. r = 0.59, p less than 0.002, n = 35, mean velocity, right side). We conclude that TCD measurements do not predict regional CBF in patients with CCA occlusion. The study emphasizes that these two methods yield supplementary information, with TCD measurements providing information of the circle of Willis and CBF studies of the flow distribution.

Side-effects and patient acceptance of 0.2% versus 0.1% chlorhexidine used as post-operative prophylactic mouthwash.

In a double-blind parallel group study including 30 patients, the side-effects and patient acceptance of chlorhexidine mouthwash 0.2% and 0.1% were studied. Side-effects such as loss of taste, burning sensation of the oral mucosa, subjective dryness of the oral cavity and discoloration of teeth and tongue were encountered. There was no statistically significant difference between the chlorhexidine groups with respect to the frequency of the reported side-effects. However, the taste of chlorhexidine 0.1% was significantly better accepted than chlorhexidine 0.2%. 4 patients discontinued the use of chlorhexidine 0.2% before the end of the trial. The quality of the experienced side-effects was stated by the patients as the reason for the discontinuation of chlorhexidine 0.2%. The present work concludes with the recommendation of chlorhexidine 0.1% compared to chlorhexidine 0.2% as a prophylactic mouthwash after oral surgical interventions.

The anti-oedematous efficacy of oxindanac equals that of paracetamol in acute postoperative inflammation; are weak cyclooxygenase inhibitors more effective than strong inhibitors?

In a double-blind crossover study, the clinical anti-oedematous efficacy was compared of a weak cyclooxygenase inhibitor oxindanac 200 mg thrice daily in a controlled clinical trial procedure with paracetamol 1 g thrice daily as a positive control involving objective measurement of acute soft tissue oedema. Paracetamol is a weak cyclooxygenase inhibitor which reduces acute postoperative tissue oedema by 30% compared to a placebo. There was no significant (p = 0.81) difference between oxindanac and paracetamol with respect to anti-oedematous activity. The present finding is discussed in view of previous results obtained in controlled trials with several other anti-inflammatory drugs, using similar objective methodology as the present one. It is proposed that non-steroidal anti-inflammatory drugs acting solely by strong inhibition of cyclooxygenase need not be optimal anti-oedematous drugs. Reasons for this proposal are discussed.

Comparison of 1% and 2% lidocaine hydrochloride used as single local anesthetic: effect on postoperative pain course after oral soft tissue surgery.

It is known that some local anesthetics may cause pain when the initial local anesthetic effect disappears. The aim of this trial was to compare the postoperative pain intensities after infiltration of plain lidocaine 1% and 2% used in gingivectomies. The trial was done as a controlled, randomized, double-blind, parallel group study involving 117 patients with mean age 48 years (range 29-71 years) allocated to two treatment groups. There was no statistically significant difference between the mean postoperative pain courses of lidocaine 1% and 2% after gingivectomies during an 11-h observation period. A numerical difference was seen from 7 to 11 h in favor of lidocaine 1%. There were more patients experiencing no pain, but more patients reporting higher pain scores in the lidocaine 2% group than in the lidocaine 1% group. These differences were not statistically significant. It can be concluded that there is apparently no difference between lidocaine 1% and 2% with respect to postoperative pain experience when using gingivectomy as a pain model.

Comparison of present pain intensity assessments on horizontally and vertically oriented visual analogue scales.

Contrary results have been reported from studies comparing horizontal and vertical orientations of the visual analogue scale (VAS) in non-dental pain states. The vertical orientation of the VAS has been used in our department for several years while the horizontal orientation is the most commonly used in other acute pain models. The present study investigated whether a horizontally oriented VAS is as sensitive as a vertically oriented VAS in the assessment of present pain after oral surgery. Seventy-four patients recorded their pain intensity hourly and half-hourly 15 times during 11 hours after surgery on a horizontal and on a vertical 100 mm VAS. Slightly lower mean and median values were observed at 2/3 of the observation time points for the vertical VAS compared to the horizontal VAS. The results from the two scales were compared with analysis of variance for repeated measures. No significant differences between the horizontal and the vertical VAS-values were found (p = 0.099). Distributions (Kolmogorov-Smirnov test) and dispersions of data were also similar with the two orientations of the VAS. This study shows that a vertically oriented VAS is equally sensitive as a horizontally oriented VAS in assessing present pain intensity after oral surgery.

Reproducibility of postoperative courses after surgical removal of symmetrically impacted wisdom teeth.

The acute postoperative courses after bilateral ¿identical¿ surgical removals of symmetrically impacted third molars on two separate occasions were investigated in a study containing two separate trials. Both trials were conducted as open interpatient crossover trials. Codeine phosphate (50 mg), with assumed analgesic effect but with no known clinical antiinflammatory effect, was given 4 times daily for 3 days starting 2 h after surgery in one trial using 20 patients (mean age 22.7 years, 12 females/8 males) and starting 3 h after surgery in the other trial using 20 patients (mean age 23.0 years, 11 females/9 males). Identical surgical procedures were carried out by the same surgeon in the same patient. The study shows the mean postoperative time courses of pain intensity, sum pain intensity, and swelling to be similar after bilateral operations. Pain intensity difference scores as measures of analgesia suggested the influence of carryover effects with respect to the second operation, irrespective of drug starting time. Mouth opening ability was not similar on each occasion after bilateral surgery. It can be concluded that the carryover design in bilateral surgery is valid and useful with respect to testing drug effects on swelling. The bilateral third molar model also offers the ability to test clinically relevant multiple dose regimens in phase 3 trials. It should, however, be recognized that the bilateral third molar model is highly dependent on the skill of the surgeon and may thus be more difficult to complete than parallel group trials.

A new version of the ischemic tourniquet pain test.

A new method of producing ischemic tourniquet pain is presented. The present test model showed a sex difference in the pain recordings. Sum pain intensity (SPI) for a 5 min trial period of ischemic pain was lower for males than for females (p less than 0.0001). The observed variability between male test subjects was greater than between female subjects, while the variation in pain scores within subjects was lower for males compared to females. The differences between sexes as a group with respect to variability of pain recordings were not statistically significant. Due to the observed sex differences in pain recording it is recommended to use test subjects of the same sex when restricting the test procedure to a limited number of subjects. The present version of the tourniquet pain test, used according to the recommended criteria, allows discriminating between i.v. administered placebo, opioid analgesics (pethidine) and ketamine.

Increase in volume of lignocaine/adrenaline-containing local anaesthetic solution causes increase in acute postoperative pain after gingivectomy.

A randomized, single-blind, within-patient, crossover study was done in 44 patients (27 women and 17 men mean age 47 years, range 29-63) who had bilateral 'identical' gingivectomies. On one occasion a standard volume of local anaesthetic containing lignocaine 2% and adrenaline (1/80 000) was infiltrated into the mucosal tissue before operation. On the other occasion double the standard volume was infiltrated. The intensity of pain postoperatively was recorded by the patients on 100 mm visual analogue scale every hour for an 11-hour observation period. The intensity of pain when double volume had been given was significantly higher than that after the standard volume from 2 to 8 hours postoperatively (P < 0.04), the median (range) being 52.0 mm (0.0-434.0) compared with 30.5 mm (0.0-359.0) after the standard volume (P < 0.005). Doubling the volume of local anaesthetic containing adrenaline that was infiltrated increased the intensity of acute pain after gingivectomy.