Ultrastructural and ultrahistochemical studies on ventricular endocardial cells in teleosts (Pisces)

The ultrastructure of the ventricular endocardial cells in 17 bony-fish species representing eight families, is described. In species of Characidae, Cobitidae, Cyprinidae, and Gyrinocheilidae these cells are flat (1–2 µm at nucleus) and contain numerous ribosomes, some few bristle-coated vesicles (BCV) and small (0.243 pm) electron dense inclusion bodies. However, in species of Cichlidae, Gadidae, and Poeciliidae most endocardial cells appear relatively thicker (2–5 µm at nucleus) and contain numerous BCV, tubules of agranular endoplasmic reticulum, and large (0.5-1.5 µm) moderately electron dense bodies (MDB). In the MDB occur a number of small (20–150 nm) electron dense granules. Within the family Anabantidae, most endocardial cells seem to be of the first type in Colisa laliu and Trichogaster leeri. whereas in Helosioma iemmincki there are numerous cells of the second type. When glutaraldehyde/tannic acid fixed heart tissue of Pollachius virens is treated with ferrous chloride, ferric chloride, or osmium tetroxide, and grid stained by uranyl and lead solutions, damaged endocardial cells appear highly electron dense, whereas undamaged ones are electron lucent. Further, when glutaraldehyde fixed tissue is treated with osmium tetroxide/potassium ferrocyanide the subendocardial space is filled by a highly electron dense material. The methods described in this study make it possible to distinguish between those endocardial vacuoles having structural contact with the cell membrane, and those lacking such contact, and also to determine whether the lumen of the former is continuous with the subendocardial space, or with the intertrabecular lumen.     

Role of inflammation in gastrointestinal tract in aetiology and pathogenesis of idiopathic parkinsonism

Idiopathic parkinsonism (IP) is a common disorder, conventionally regarded as neurodegenerative. Its cardinal features, poverty and slowness of movement, muscle rigidity, postural abnormality and a characteristic tremor, are associated with loss of dopaminergic neurones in the substantia nigra of the brain. Genetic factors explain only a minority of cases, and a common toxic environmental insult remains elusive. We propose that IP is a systemic disorder resulting from a ubiquitous peripheral infection, and that only the tip of the iceberg comes to diagnosis. There is evidence for inflammatory/immune activation peripherally and in the brain. We have used statistical modelling to explore links with non-specific and specific systemic markers of inflammation/infection in IP probands, and explore whether their partners and siblings have a frank or pre-presentation parkinsonian state. Critical to this approach is continuous objective measures of the facets of IP. Hypotheses on causality and mechanism are based on the statistical models. There is pathological and clinical evidence for direct involvement of the gastrointestinal tract in IP. The candidacy of Helicobacter pylori infection as a trigger event or driving infection is relatively high. We have found that eliminating infection in late parkinsonism with cachexia, a stage usually considered intractable, can result in a U-turn. However, eradication therapy may not provide a complete solution. Persistence of antibody against cytotoxin-associated antigen (CagA), increases the predicted probability of being labelled as having parkinsonism. Evidence for autoimmunity and immunocompromise is used to build schemes for the natural history. We conclude that current classifications of neuropsychiatric disease may not prove the best with respect to defining sub-clinical disease, prophylaxis or halting progression.     

"Anxiebo", placebo, and postoperative pain

Background

Surgical treatment and its consequences expose patients to stress, and here we investigated the importance of the psychological component of postoperative pain based on reports in the clinical literature.

Discussion

Postoperative pain remains a significant clinical problem. Increased pain intensity with increased demand for opioid medication, and/or a relative unresponsiveness to pain treatment was reported both when the analgesia was administered by means of conventional nurse injection regimes and patient-controlled analgesia (PCA). Both the quality of the analgesia, and the sensitivity of postoperative models for assessing analgesic efficacy could be significantly influenced. The findings could be explained by increased penetration of an algesic anxiety-related nocebo influence (which we chose to call "anxiebo") relative to its analgesic placebo counterpart. To counteract this influence, the importance of psychological effects must be acknowledged, and doctors and attending nurses should focus on maintaining trustful therapist-patient relationships throughout the treatment period. The physical mechanism of anxiebo should be further explored, and those at risk for anxiebo better characterized. In addition, future systemic analgesic therapies should be directed towards being prophylactic and continuous to eliminate surgical pain as it appears in order to prevent the anxiebo effect. Addressing anxiebo is the key to developing reproducible models for measuring pain in the postoperative setting, and to improving the accuracy of measurements of the minimum effective analgesic concentration.

Summary

Anxiebo and placebo act as counterparts postoperatively. The anxiebo state may impair clinical analgesia and reduce the sensitivity of analgesic trials. Ways to minimize anxiebo are discussed.     

Serotonin-1A Receptor Polymorphism (rs6295) Associated with Thermal Pain Perception

Background

Serotonin (5-HT) is highly involved in pain regulation and serotonin-1A (5-HT1A) receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A) may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP) rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities.

Methods

Fourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C–49°C). Nociceptive-flexion reflex (NFR) thresholds were also assessed.

Results

Volunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged.

Conclusion/Significance

To the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a ‘hypo- to hyperalgesic’ response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain pathologies. Further investigations are therefore warranted.     

Language Lateralization in Children Aged 10 to 11 Years: A Combined fMRI and Dichotic Listening Study

Objective

The aims of this study were to develop and assess a method to map language networks in children with two auditory fMRI protocols in combination with a dichotic listening task (DL). The method is intended for pediatric patients prior to epilepsy surgery. To evaluate the potential clinical usefulness of the method we first wanted to assess data from a group of healthy children.

Methods

In a first step language test materials were developed, intended for subsequent implementation in fMRI protocols. An evaluation of this material was done in 30 children with typical development, 10 from the 1^st, 4^th and the 7^th grade, respectively. The language test material was then adapted and implemented in two fMRI protocols intended to target frontal and posterior language networks. In a second step language lateralization was assessed in 17 typical 10–11 year olds with fMRI and DL. To reach a conclusion about language lateralization, firstly, quantitative analyses of the index data from the two fMRI tasks and the index data from the DL task were done separately. In a second step a set of criteria were applied to these results to reach a conclusion about language lateralization. The steps of these analyses are described in detail.

Results

The behavioral assessment of the language test material showed that it was well suited for typical children. The results of the language lateralization assessments, based on fMRI data and DL data, showed that for 15 of the 17 subjects (88%) a conclusion could be reached about hemispheric language dominance. In 2 cases (12%) DL provided critical data.

Conclusions

The employment of DL combined with language mapping using fMRI for assessing hemispheric language dominance is novel and it was deemed valuable since it provided additional information compared to the results gained from each method individually.     

Purification,localization, and expression of human intestinal alkaline sphingomyelinase

Sphingomyelin (SM) metabolism in the gut may have an impact on colon cancer development. In this study, we purified alkaline sphingomyelinase (alk-SMase) from human intestinal content, and studied its location in the mucosa, expression in colon cancer, and function on colon cancer cells. The enzyme was purified by a series of chromatographies. The molecular mass of the enzyme is 60 kDa, optimal pH is 8.5, and isoelectric point is 6.6. Under optimal conditions, 1 mg of the enzyme hydrolyzed 11 mM SM per hour. The properties of the enzyme are similar to those of rat intestinal alk-SMase but not to those of bacterial neutral SMase. Immunogold electronmicroscopy identified the enzyme on the microvillar membrane in endosome-like structures and in the Golgi complexes of human enterocytes. The expression and the activity of the enzyme were decreased in parallel in human colon cancer tissues compared with the adjacent normal tissue. The enzyme inhibited DNA biosynthesis and cell proliferation dose dependently and caused a reduction of SM in HT29 cells. Intestinal alk-SMase is localized in the enterocytes, down-regulated in human colon cancer, and may have antiproliferative effects on colon cancer cells.     

The UTCI-clothing model

The Universal Thermal Climate Index (UTCI) was conceived as a thermal index covering the whole climate range from heat to cold. This would be impossible without considering clothing as the interface between the person (here, the physiological model of thermoregulation) and the environment. It was decided to develop a clothing model for this application in which the following three factors were considered: (1) typical dressing behaviour in different temperatures, as observed in the field, resulting in a model of the distribution of clothing over the different body segments in relation to the ambient temperature, (2) the changes in clothing insulation and vapour resistance caused by wind and body movement, and (3) the change in wind speed in relation to the height above ground. The outcome was a clothing model that defines in detail the effective clothing insulation and vapour resistance for each of the thermo-physiological model’s body segments over a wide range of climatic conditions. This paper details this model’s conception and documents its definitions.     

Effects of metabolic rate on thermal responses at different air velocities in −10°C

The effects of exercise intensity on thermoregulatory responses in cold (−10°C) in a 0.2 (still air, NoWi), 1.0 (Wi1), and 5.0 (Wi5) m s⁻¹ wind were studied. Eight young and healthy men, preconditioned in thermoneutral (+20°C) environment for 60 min, walked for 60 min on the treadmill at 2.8 km/h with different combinations of wind and exercise intensity. Exercise level was adjusted by changing the inclination of the treadmill between 0° (lower exercise intensity, metabolic rate 124 W m⁻², LE) and 6° (higher exercise intensity, metabolic rate 195 W m⁻², HE). Due to exercise increased heat production and circulatory adjustments, the rectal temperature (T_re), mean skin temperature (T_sk) and mean body temperature (T_b) were significantly higher at the end of HE in comparison to LE in NoWi and Wi1, and T_re and T_b also in Wi5. T_sk and T_b were significantly decreased by 5.0 m s⁻¹ wind in comparison to NoWi and Wi1. The higher exercise intensity was intense enough to diminish peripheral vasoconstriction and consequently the finger skin temperature was significantly higher at the end of HE in comparison to LE in NoWi and Wi1. Mean heat flux from the skin was unaffected by the exercise intensity. At LE oxygen consumption (V ₂) was significantly higher in Wi5 than NoWi and Wi1. Heart rate was unaffected by the wind speed. The results suggest that, with studied exercise intensities, produced without changes in walking speed, the metabolic rate is not so important that it should be taken into consideration in the calculation of wind chill index.     

Bronchial mucosal and kidney cortex affinity of 4- and 4,4′-substituted sulphur-containing derivatives of 2,2′-5,5′-tetrachlorobiphenyl in mice

In order to evaluate further the structural requirements previously proposed for accumulation of polychlorinated biphenyls (PCB) and their sulphur-containing metabolites in the respiratory tract of mice, 4-methylthio-, 4-methylsulphonyl and 4,4′-bis(methylthio)-2,2′,5,5′-[¹⁴C]tetrachlorobiphenyl were studied by whole body autoradiography. All the compounds gave rise to a strong accumulation of radioactivity in the mucosa of the bronchi, trachea and larynx. The first two substances were also concentrated in the mucosa of the nasal cavities. At the longer post-injection times all the compounds studied were localized in distinct sites of the kidney cortex. However, while the uptake of the monosubstituted sulphur-containing tetrachlorobiphenyl metabolites there was comparatively weak, the bis(methylthio) derivative showed a remarkable accumulation and retention in the kidney cortex. The study makes it possible to formulate the structural requirements for bronchial accumulation on the basis of the structure of the compounds that are accumulated rather than on the structure of the unmetabolized polychlorobiphenyls. Also with regard to the uptake in the kidney cortex a specific structure-dependency seems to exist.