Response to Comment on "Permanent human occupation of the central Tibetan Plateau in the early Holocene".

We show that Zhang and Li's sedimentological model for the Chusang travertine neglects the three-dimensional information from multiple outcrops and that their optically stimulated luminescence (OSL) age of about 20,000 years for the human imprints is untenable. We highlight the robustness of our chronology and explore reasons why Zhang and Li's OSL age is a gross overestimation of the real depositional age of the imprinted travertine.

Permanent human occupation of the central Tibetan Plateau in the early Holocene.

Current models of the peopling of the higher-elevation zones of the Tibetan Plateau postulate that permanent occupation could only have been facilitated by an agricultural lifeway at ~3.6 thousand calibrated carbon-14 years before present. Here we report a reanalysis of the chronology of the Chusang site, located on the central Tibetan Plateau at an elevation of ~4270 meters above sea level. The minimum age of the site is fixed at ~7.4 thousand years (thorium-230/uranium dating), with a maximum age between ~8.20 and 12.67 thousand calibrated carbon-14 years before present (carbon-14 assays). Travel cost modeling and archaeological data suggest that the site was part of an annual, permanent, preagricultural occupation of the central plateau. These findings challenge current models of the occupation of the Tibetan Plateau.

Systemic inflammation in acute intermittent porphyria: a case-control study.

This study aimed to examine whether acute intermittent porphyria (AIP) is associated with systemic inflammation and whether the inflammation correlates with disease activity. A case-control study with 50 AIP cases and age-, sex- and place of residence-matched controls was performed. Plasma cytokines, insulin and C-peptide were analysed after an overnight fast using multiplex assay. Long pentraxin-3 (PTX3) and complement activation products (C3bc and TCC) were analysed using enzyme-linked immunosorbent assay (ELISA). Urine porphobilinogen ratio (U-PBG, µmol/mmol creatinine), haematological and biochemical tests were performed using routine methods. Questionnaires were used to register AIP symptoms, medication and other diseases. All 27 cytokines, chemokines and growth factors investigated were increased significantly in symptomatic AIP cases compared with controls (P < 0·0004). Hierarchical cluster analyses revealed a cluster with high visfatin levels and several highly expressed cytokines including interleukin (IL)-17, suggesting a T helper type 17 (Th17) inflammatory response in a group of AIP cases. C3bc (P = 0·002) and serum immunoglobulin (Ig)G levels (P = 0·03) were increased significantly in cases with AIP. The U-PBG ratio correlated positively with PTX3 (r = 0·38, P = 0·006), and with terminal complement complex (TCC) levels (r = 0·33, P = 0·02). PTX3 was a significant predictor of the biochemical disease activity marker U-PBG in AIP cases after adjustment for potential confounders in multiple linear regression analyses (P = 0·032). Prealbumin, C-peptide, insulin and kidney function were all decreased in the symptomatic AIP cases, but not in the asymptomatic cases. These results indicate that AIP is associated with systemic inflammation. Decreased C-peptide levels in symptomatic AIP cases indicate that reduced insulin release is associated with enhanced disease activity and reduced kidney function.

Metabolic and anthropometric factors related to skeletal muscle UCP3 gene expression in healthy human adults.

This cross-sectional investigation sought to determine the relationship between selected metabolic, endocrine, and anthropometric factors and skeletal muscle UCP3 mRNA in healthy adult humans. Twenty-four healthy adults (13 male and 11 female) across a range of aerobic capacity, age, and body composition were studied. Muscle biopsies were obtained from the vastus lateralis, from which UCP3 mRNA was quantified by Northern blot, and fiber type was determined by use of the myosin ATPase staining procedure. In addition, resting energy expenditure and maximum rate of oxygen consumption were determined by indirect calorimetry, body composition was determined by dual-energy X-ray absorptiometry, and fasting plasma leptin and insulin were determined by ELISA. UCP3 mRNA was correlated positively with the percent type I fibers (r = 0.842, P < 0.001), plasma leptin (r = 0.454, P = 0.026), and plasma insulin (r = 0.615, P < 0.001) and inversely to age (r = -0.411, P = 0.046). Stepwise multiple regression analysis determined that percent type I muscle fibers was the best predictor of vastus lateralis UCP3 mRNA, and no other variable entered the equation (model r(2) = 0.66). This study suggests that of the variables measured, UCP3 mRNA is primarily related to skeletal muscle fiber type in healthy adults. The factors that contribute to fiber-specific differences in UCP3 mRNA expression will need to be examined in future studies.

Effect of the PufQ protein on early steps in the pathway of bacteriochlorophyll biosynthesis in Rhodobacter capsulatus.

The addition in trans of the pufQ gene to a strain of Rhodobacter capsulatus from which the entire puf operon had been deleted, increased its ability to synthesize coproporphyrinogen from both delta-aminolevulinic acid and porphobilinogen. Studies at the enzyme level indicated that the conversion of porphobilinogen to uroporphyrinogen III had about a 2-fold higher level of activity in the anaerobically-grown pufQ-containing strain. This increase in activity over the puf-deletion strain appeared to occur during transitions from aerobic to semiaerobic growth conditions. These results indicated that the PufQ protein may exert a stimulatory effect quite early in the pathway of bacteriochlorophyll biosynthesis.

Perineuronal morphine: a comparison with epidural morphine.

In a double-blind, randomised controlled cross-over study the effects of perineuronal (perifemoral) injections of morphine were compared with epidural injections with the same amount of morphine in patients after knee surgery. Better pain scores were achieved during treatment with epidural morphine. We have not been able to confirm the hypothesis of neuro-axonal transport of morphine from the periphery to the spinal cord.

Effects of a behavioral intervention on epileptic seizure behavior and paroxysmal activity: a systematic replication of three cases of children with intractable epilepsy.

Three children with very frequent refractory epileptic seizures underwent a behavioral intervention consisting of symptom discrimination, countermeasures, contingent relaxation, and positive reinforcement for correct responses in a systematic replication series. The studies involved a 6-h nonintervention base rate, a 6-h treatment phase, and a 6-h nonintervention follow-up under laboratory conditions for each child. Neurophysiologic and behavioral measures of the effects of treatment were made using electroencephalogram (EEG)-video equipment. Effects of treatment were assessed by using a random sample of EEG-video sequences in base rate and follow-up. Results showed that no significant reduction of either seizure behavior or paroxysmal EEG activity was found subsequent to training in discrimination of early paroxysmal activity and/or sensations preceding seizures. Both seizure behavior and paroxysmal activity were significantly reduced in all three cases following intervention with an adapted countermeasure technique. No additional effects could be noted subsequent to the application of either contingent relaxation or positive reinforcement for correct responses. Paroxysmal EEG changes and seizure behavior were highly correlated. Reduction of the clinical manifestation or seizure response by behavioral manipulation was accompanied by a reduction of the total amount of paroxysmal activity as measured by the EEG.