Hydroxyisohexyl 3-cyclohexene carboxaldehyde allergy: relationship between patch test and repeated open application test thresholds

Background  Hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) is a synthetic fragrance ingredient. Case reports of allergy to HICC appeared in the 1980s, and HICC has recently been included in the European baseline series. Human elicitation dose–response studies performed with different allergens have shown a significant relationship between the patch-test threshold and the repeated open application test (ROAT) threshold, which mimics some real-life exposure situations. Fragrance ingredients are special as significant amounts of allergen may evaporate from the skin.
Objectives  The study aimed to investigate the relationship between elicitation threshold doses at the patch test and the ROAT, using HICC as the allergen. The expected evaporation rate was calculated.
Materials and methods  Seventeen HICC-allergic persons were tested with a dilution series of HICC in a patch test and a ROAT (duration up to 21 days). Seventeen persons with no HICC allergy were included as control group for the ROAT.
Results  The response frequency to the ROAT (in μg HICC cm⁻² per application) was significantly higher than the response frequency to the patch test at one of the tested doses. Furthermore the response rate to the accumulated ROAT dose was significantly lower at half of the doses compared with the patch test. The evaporation rate of HICC was calculated to be 72% over a 24-h period.
Conclusions  The ROAT threshold in dose per area per application is lower than the patch test threshold; furthermore the accumulated ROAT threshold is higher than the patch test threshold, which can probably be explained by the evaporation of HICC from the skin in the open test.     

Lipid extract from completely sporoderm‐broken germinating Ganoderma sinensis spores elicits potent antitumor immune responses in human macrophages

Ganoderma sinensis has been used widely in Oriental countries for the prevention and treatment of various diseases including cancer. Previous studies have shown that the lipid extract from Ganoderma exhibits direct cytotoxicity against tumor cells. Here, it is reported that the lipid extract from germinating G. sinensis spores, at lower concentrations that have no direct tumoricidal activity, induce potent antitumor immune responses in human monocytes/macrophages. Upon stimulation with the lipid extract, monocytes/macrophages exhibited markedly increased production of proinflammatory cytokines and surface expression of costimulatory molecules. Conditioned medium from stimulated cells effectively suppressed the growth of tumor cells. Apparently, the lipid extract triggered macrophage activation via a mechanism different from that associated with LPS. Moreover, it was observed that the lipid extract could partially re‐establish the antitumor activity of the immunosuppressive tumor‐associated macrophages. These results indicated that in addition to its direct tumoricidal activity, the lipid extract from G. sinensis spores could exert antitumor activity by stimulating the activation of human monocytes/macrophages. Copyright © 2008 John Wiley & Sons, Ltd.     

Psychiatric patients and their response to experimental stress

Serum levels of Epinephrine (E), norepinephrine (NE), heart rate (HR), skin conductance reaction (SCR) and skin conductance level (SCL) were measured in schizophrenic, endogenous depressed and anxiety patients as well as in normal controls. Conditions were rest, noise and a mental arithmetic (MA) task. Schizophrenic and depressed patients had an attenuated HR response to MA. Moreover, Schizophrenic patients also had higher NE base level and the highest NE secretion during noise. Anxiety and depressed patients showed significantly lower phasic electrodermal activity (SCR) throughout the whole trial, exclusively anxiety patients had significantly higher tonic electrodermal activity (SCL). These findings indicate that autonomous reactions discriminate between patient groups and controls as well as between each other.     

Calcium absorption following small bowel resection in man. Evidence for an adaptive response

Seventeen patients who had undergone extensive small bowel resection were studied for calcium absorption (FACa) and plasma vitamin D metabolites. FACa was measured by a double radio-tracer technique and expressed as percentage of total oral dose. FACa was decreased compared with controls (34%, range: 3-46 v 65%, range: 57-73, P less than 0.01). A positive correlation (r = 0.49, P = 0.05) was found between FACa and the remaining length of small bowel (SBL). As wide variations in both SBL and duration after surgery were observed among the seventeen investigated patients, we were led to individualize less heterogeneous subgroups of patients. Better correlations were found when the patients were divided into two subgroups according to whether the time interval between the resection and the investigation was shorter (r = 0.75, n = 11, P less than 0.02) or longer (r = 0.89, n = 6, P = 0.05) than 2 years. In thirteen patients who had a SBL shorter than 100 cm, a positive correlation was observed between FACa and the time interval after surgery (months): r = 0.65, P less than 0.05. Plasma 1,25 (OH)2D was markedly reduced in the whole group (31 pmol l-1, range: 8-108) compared with controls (103 pmol-1, range: 59-134, P less than 0.01). The present study shows that in extensively small bowel resected patients, calcium absorption is reduced, the alteration being dependent both on the length of the remnant small bowel and on the time after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

评估控制性卵巢刺激中预测卵巢反应性的指标

在辅助生育技术的实施中,控制性卵巢刺激(COS)方案是根据患者情况确定的,在用药剂量和启动时间的掌握上非常重要。由于卵巢本身反应性或基础状态的不同,不同年龄及不同病因的患者有着极大的差异,用量适当可避免因启动剂量过大造成卵巢过度剌激(OHSS),或剂量过少造成低反应,卵泡     

Simultaneous versus sequential optimal design for pharmacokinetic-pharmacodynamic models with FO and FOCE considerations

We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional nature of such models, differences in predicted responses are a consequence of different assumptions about how the models interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques have been explored in the literature where it was found that the sequential and FO approaches can produce biased results. It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature. We consider design for situations where all responses are continuous and extend this methodology to the case where a response may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such responses will offer little information about all parameters and hence a sequential optimization, in the form of product design optimality, may yield near optimal designs.     

Mathematical modelling of the spatio-temporal response of cytotoxic T-lymphocytes to a solid tumour.

In this paper a mathematical model describing the growth of a solid tumour in the presence of an immune system response is presented. In particular, attention is focused upon the attack of tumour cells by so-called tumour-infiltrating cytotoxic lymphocytes (TICLs), in a small, multicellular tumour, without necrosis and at some stage prior to (tumour-induced) angiogenesis. At this stage the immune cells and the tumour cells are considered to be in a state of dynamic equilibrium--cancer dormancy--a phenomenon which has been observed in primary tumours, micrometastases and residual disease after ablation of the primary tumour. Nonetheless, the precise biochemical and cellular mechanisms by which TICLs control cancer dormancy are still poorly understood from a biological and immunological point of view. Therefore we focus on the analysis of the spatio-temporal dynamics of tumour cells, immune cells and chemokines in an immunogenic tumour. The lymphocytes are assumed to migrate into the growing solid tumour and interact with the tumour cells in such a way that lymphocyte-tumour cell complexes are formed. These complexes result in either the death of the tumour cells (the normal situation) or the inactivation (sometimes even the death) of the lymphocytes. The migration of the TICLs is determined by a combination of random motility and chemotaxis in response to the presence of chemokines. The resulting system of four nonlinear partial differential equations (TICLs, tumour cells, complexes and chemokines) is analysed and numerical simulations are presented. We consider two different tumour geometries--multi-layered cell growth and multi-cellular spheroid growth. The numerical simulations demonstrate the existence of cell distributions that are quasi-stationary in time and heterogeneous in space. A linear stability analysis of the underlying (spatially homogeneous) ordinary differential equation (ODE) kinetics coupled with a numerical investigation of the ODE system reveals the existence of a stable limit cycle. This is verified further when a subsequent bifurcation analysis is undertaken using a numerical continuation package. These results then explain the complex heterogeneous spatio-temporal dynamics observed in the partial differential equation (PDE) system. Our approach may lead to a deeper understanding of the phenomenon of cancer dormancy and may be helpful in the future development of more effective anti-cancer vaccines.     

兔肢体爆炸伤合并海水浸泡后在不同复温速率及维持浅低体温下机体炎症反应的特征

Objective To investigate effects of different rewarming rates and maintenance of light hypothermia on inflammatory response in rabbits after limb blast injury, coupled with seawater immersion. Methods First, the model of limb blast injury coupled with seawater immersion was reproduced [the animals were immersed to low body temperature of (31.0±0.5℃)]. Then, 24 adult rabbits were randomly divided into group Ⅰ [the rapid rewarming group, n=6, rewarmed to (38±0.5)℃ at a rate of (8.94±0.93)℃/h], group Ⅱ [the slow rewarming group, n=6, rewarmed to (38±0.5)℃ at a rate of (3.88±0.22)℃/h], group Ⅲ [another slow rewarming group, n=6, rewarmed to (38±0.5)℃ at a rate of (2.18±0.12)℃/h], and the H group [the hypothermia group, n =6, rewarmed to (34 - 35)℃ at a rate of (4.49±0.66)℃/h and kept at that temperature till termination of the experiment]. Regulation of ambient temperature and warm transfusion were used to restore body temperature to target levels and maintained there for 6 hours. Blood samples were taken at 5 different times, I.e. Pre-injury time(T0), post-immersion time (T1), the time when rewarming started (T2), 3 h after rewarming (T3), and 6 h after rewarming (T4). Tissue samples from heart, liver, intestinum, lung and kidney were also collected. Levels of TNF-α (tumor necrosis factor-α), IL-1β (interleukin-1β) and IL-6 (interleukin-6) in plasma and MPO (myeloperoxidase) in homogenate were detected. Results Following rewarming, TNF-α, IL-1β, IL-6 concentrations in the plasma of the animals in group Ⅰ and group H were significantly higher when compared with those of the animals in group Ⅱ and group Ⅲ (P<0.05, P<0.01), and MPO activity in homogenate was significantly higher when compared with that of the animals in group Ⅱ and group Ⅲ(P<0.01, P<0.05), and no statistical difference could be seen between group Ⅱ and Ⅲ (P>0.05). Conclusions Rapid rewarming and maintenance of light hypothermia could obviously elevate TNF-α, IL-1β, IL-6 concentrations in plasma and MPO activity in homogenate, following limb blast injury coupled with hypothermia induced by seawater immersion, while slow rewarming (with a rewarming rate of 2-4℃/h) could significantly inhibit TNF-α, IL-1β, IL-6 levels and PMN activity.     

Characteristics of antibody responses in tick-borne encephalitis vaccination breakthroughs

Tick-borne encephalitis (TBE) virus is an important human pathogenic flavivirus that is endemic in Europe and Asia. The disease can be effectively prevented by inactivated vaccines and vaccination breakthroughs (VBTs) are rare. We investigated the characteristics of antibody responses in such VBTs in comparison to those in unvaccinated TBE patients. In contrast to the unvaccinated controls, most of the VBTs displayed a delayed IgM antibody response and had high avidity and strongly neutralizing antibodies already in the first sample taken upon hospitalization. The antibody profile of these patients therefore had the characteristics of an anamnestic immune response. In the VBTs analyzed, immunological priming and memory were apparently not sufficient or fast enough to prevent the disease.