Human frequency-following response: representation of tonal sweeps

Auditory nerve single-unit population studies have demonstrated that phase locking plays a dominant role in the neural encoding of steady-state speech sounds. Recently, we have reported that the phase-locked activity underlying the human frequency-following response (FFR) could also encode the first two formants of several tonal approximations of steady-state vowels. Since auditory nerve single-unit population studies have also demonstrated that phase locking is used to represent time-varying speech-like sounds, it was reasoned that the phase-locked neural activity underlying the human FFR, likewise, is dynamic enough to represent time-varying sounds. FFRs to a rising and a falling tone were obtained from 8 normal-hearing adults at 95, 85, 75 and 65 dB nHL. Results clearly demonstrated that the human FFR does indeed follow the trajectory of the rising and falling tones. Also, amplitude changes in the FFR supported the view that neural phase locking decreases with increasing frequency. Finally, the relatively smaller FFR amplitude for the falling tone compared to its rising counterpart lends further support to the notion that rising tones produce greater neural synchrony than falling tones. These results indicate that the human FFR may be used to evaluate encoding of time-varying speech sounds like diphthongs and certain consonant-vowel syllables.     

The lecithin/sphingomyelin (L/S) ratio in twin pregnancies.

The lecithin/sphingomyelin (L/S) ratio has been estimated in the amniotic fluid from 20 patients with a twin pregnancy. The values in each pair of amniotic fluids were closely related. If amniotic fluid from one sac only is available, it is suggested that a ratio of 2-5:1 is taken as the lower limit to predict the functional lung maturity of both twins.     

Bubble clicking in pharyngeal aspirate compared with lecithin/sphingomyelin ratio

Tracheal fluid flows into the pharynx, so surfactant can be measured in pharyngeal aspirate. The walls of bubbles in air-free water show rhythmic movements (bubble clicking) if they contain surfactant. Babies with respiratory distress syndrome (RDS) have very little lung surfactant which can be shown by a low lecithin/sphingomyelin (L/S) ratio. To investigate surfactant in newborn babies we analysed 125 pharyngeal aspirates for the L/S ratio and bubble clicking. Both tests became more positive towards term and were related to the incidence of RDS. Babies with birth asphyxia or mild respiratory difficulties had lower L/S ratios and less clicking than normal babies. Both investigations could be used to chart the course of RDS. The L/S ratio is a chemical measurement of surfactant. Bubble clicking, which takes only a few minutes, demonstrates surface tension effects.     

Recurrent urinary tract infection in girls. Group with lower tract findings and a benign course

A group of girls is described with recurrent urinary tract infections characterized by predominantly lower tract symptoms. Clinical, laboratory, and radiography findings during the period of follow-up are presented. Infection persisted in most patients over several years. Response to medical and surgical treatment was unsatisfactory. The mean interval between the initial and most recent radiological study was 6 1/2 years. No case of renal parenchymal scarring was seen.     

Amitriptyline enhances extracellular tissue levels of adenosine in the rat hindpaw and inhibits adenosine uptake

Local administration of amitriptyline into the rat hindpaw produces peripheral antinociception; this is reduced by adenosine receptor antagonists and appears to involve endogenous adenosine. The present study used peripheral microdialysis: (a) to determine whether amitriptyline could enhance extracellular tissue levels of endogenous adenosine in the rat hindpaw and (b) to examine mechanisms by which such an increase could occur. Local injection of amitriptyline into the plantar hindpaw, at doses that produce peripheral antinociception (100-300 nmol), produced an increase in local extracellular levels of adenosine. When injected in combination with formalin, which also enhances such levels of adenosine, an additive increase was observed. This adenosine originated partly as nucleotide, as inhibition of ecto-5'-nucleotidase reduced the amount of adenosine detected in the probe following administration of amitriptyline. When administered in combination with exogenous adenosine, amitriptyline augmented recovery of adenosine in the probe. Pretreatment of rats with capsaicin augmented the ability of amitriptyline to increase adenosine levels detected in the dialysis probe; it also enhanced tissue recovery of exogenously administered adenosine. In uptake studies using cultured rat C6 glioma cells, amitriptyline inhibited adenosine uptake by an adenosine transporter (IC50 0.37 +/- 0.12 mM). In enzyme assays, amitriptyline had no effect on adenosine kinase or adenosine deaminase activity. These results demonstrate that amitriptyline: (a) enhances extracellular tissue levels of adenosine in the rat hindpaw following local administration in vivo and (b) inhibits adenosine uptake but has no effect on metabolism in vitro. Therefore, increased extracellular adenosine levels in vivo appear to result partially from extracellular conversion of nucleotide and partially from inhibition of uptake.     

Pramipexole and levodopa in early Parkinson's disease: dynamic changes in cost effectiveness

BACKGROUND AND OBJECTIVE: In chronic disease, treatment effects and costs accumulate over time; hence, the choice of time horizon in cost-effectiveness analysis can be particularly important. In this article we analyse the dynamic changes in cumulative costs, effects and incremental cost effectiveness of two competing drug strategies in patients with early Parkinson's disease (PD). METHODS: Three hundred and one subjects with PD were randomised to initial pramipexole or levodopa and followed every 3 months over a 4-year period. Healthcare resource use was recorded in patient diaries and valued using a variety of sources at year 2002 US dollar values. Health-related quality of life (HRQoL) was measured using the EuroQoL EQ-5D. The study was conducted from a US societal perspective. Missing data were imputed using a multivariate fixed-effects model. Additional quality adjusted life years (QALY) gained by using pramipexole compared with levodopa were estimated as the area between the normalised treatment HRQoL profiles. The QALYs and costs for each treatment arm were calculated for various study horizons.The incremental cost-effectiveness ratio (ICER) and the net monetary benefit (NB) [using 50,000 US dollars, 100,000 US dollars and 150,000 US dollars as the value of a QALY] were estimated, and were bootstrapped to calculate the standard errors. Cost-effectiveness acceptability curves (CEAC) were built to estimate the probability that pramipexole was cost effective given different societal values of QALY, for various study horizons.We conducted sensitivity analyses on the ICER and the NB to test their robustness to various assumptions about missing data, for various subpopulations and under changes in the drug prices. RESULTS: Under the base-case assumptions, the ICER for pramipexole was 42,989 US dollars per QALY. Using the CEAC approach, the probability that pramipexole was cost effective relative to levodopa over the first 4 years was 0.57, 0.77 and 0.82 when a QALY was valued at 50,000 US dollars, 100,000 US dollars, and 150,000 US dollars, respectively. Over time, the ICER for pramipexole improved and uncertainty around the ICER decreased. If, after treatment withdrawal, HRQoL improved in pramipexole subjects and declined in levodopa subjects (best-case scenario for pramipexole), the probability of pramipexole being cost effective increased to 0.88, 0.96 and 0.98, respectively. Factors that improved the ICER of pramipexole were a decrease in the relative price of pramipexole and having low HRQoL or depression at baseline. CONCLUSIONS: The cost effectiveness of pramipexole compared with levodopa in the treatment of early PD increased as the time horizon of the clinical trial extended from 2 to 4 years. Our results suggest that pramipexole is more cost effective for patients with depression and low baseline HRQoL than in other patient subgroups.     

Effects of vitamin A and/or thyroidectomy on liver microsomal enzymes and their induction in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats

Vitamin A and thyroid hormone status have been shown previously to alter the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. In the present study, we have examined the effects of a vitamin A-excess and a vitamin A-deficient diet on thyroid hormone levels, on selected drug-metabolizing enzymes in liver microsomes, and on their inducibility by TCDD in male Sprague-Dawley rats. Except for a slight increase in serum T3 levels, none of these end points was affected by feeding rats the vitamin A-deficient diet. In contrast, excess dietary vitamin A caused a decrease in serum thyroxine (T4) and triiodothyronine (T3) levels, although the levels of T3 remained in the euthyroid range (60-80 ng/dl). The concentration of liver microsomal cytochromes P-450 and b5 and the basal activity of benzo[a]pyrene hydroxylase and 7-ethoxyresorufin O-de-ethylase were unaffected by excess dietary vitamin A. This result is consistent with our previous observation that the basal activity of these enzymes is dependent more on T3 than on T4 levels. Vitamin A excess markedly suppressed the activity of liver microsomal UDP-glucuronosyl transferase toward 1-naphthol. However, no such enzyme suppression was observed in thyroidectomized rats. This suggests that the suppressive effect of vitamin A on UDP-glucuronosyl transferase activity may be dependent on T3. Neither vitamin A nor thyroid status had any major effect on the inducibility of UDP-glucuronosyl transferase and cytochrome P-450-dependent enzyme activities by TCDD. However, vitamin A and TCDD had a nearly additive effect on suppression of serum T4. It is concluded that liver microsomal enzyme induction is not associated with the modulatory effect of vitamin A and thyroid hormones on the toxicity of TCDD.