Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study.

BACKGROUND: Existing evidence suggests that proinflammatory cytokines play an intermediary role in postchemotherapy cognitive impairment. This is one of the largest multicentered, cohort studies conducted in Singapore to evaluate the prevalence and proinflammatory biomarkers associated with cognitive impairment in breast cancer patients. PATIENTS AND METHODS: Chemotherapy-receiving breast cancer patients (stages I-III) were recruited. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, interferon-γ and tumor necrosis factor-α] were evaluated at 3 time points (before chemotherapy, 6 and 12 weeks after chemotherapy initiation). The FACT-Cog (version 3) was utilized to evaluate patients' self-perceived cognitive disturbances and a computerized neuropsychological assessment (Headminder) was administered to evaluate patients' memory, attention, response speed and processing speed. Changes of cognition throughout chemotherapy treatment were compared against the baseline. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations on self-perceived cognitive disturbances and each objective cognitive domain. RESULTS: Ninety-nine patients were included (age 50.5 ± 8.4 years; 81.8% Chinese; mean duration of education = 10.8 ± 3.3 years). Higher plasma IL-1ß was associated with poorer response speed performance (estimate: -0.78; 95% confidence interval (CI) -1.34 to -0.03; P = 0.023), and a higher concentration of IL-4 was associated with better response speed performance (P = 0.022). Higher concentrations of IL-1ß and IL-6 were associated with more severe self-perceived cognitive disturbances (P = 0.018 and 0.001, respectively). Patients with higher concentrations of IL-4 also reported less severe cognitive disturbances (P = 0.022). CONCLUSIONS: While elevated concentrations of IL-6 and IL-1ß were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment. This study is important because cytokines would potentially be mechanistic mediators of chemotherapy-associated cognitive changes.

Anorexia nervosa and body dysmorphic disorder are associated with abnormalities in processing visual information.

BACKGROUND: Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are characterized by distorted body image and are frequently co-morbid with each other, although their relationship remains little studied. While there is evidence of abnormalities in visual and visuospatial processing in both disorders, no study has directly compared the two. We used two complementary modalities--event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI)--to test for abnormal activity associated with early visual signaling. METHOD: We acquired fMRI and ERP data in separate sessions from 15 unmedicated individuals in each of three groups (weight-restored AN, BDD, and healthy controls) while they viewed images of faces and houses of different spatial frequencies. We used joint independent component analyses to compare activity in visual systems. RESULTS: AN and BDD groups demonstrated similar hypoactivity in early secondary visual processing regions and the dorsal visual stream when viewing low spatial frequency faces, linked to the N170 component, as well as in early secondary visual processing regions when viewing low spatial frequency houses, linked to the P100 component. Additionally, the BDD group exhibited hyperactivity in fusiform cortex when viewing high spatial frequency houses, linked to the N170 component. Greater activity in this component was associated with lower attractiveness ratings of faces. CONCLUSIONS: Results provide preliminary evidence of similar abnormal spatiotemporal activation in AN and BDD for configural/holistic information for appearance- and non-appearance-related stimuli. This suggests a common phenotype of abnormal early visual system functioning, which may contribute to perceptual distortions.

Genome-wide scan of reading ability in affected sibling pairs with attention-deficit/hyperactivity disorder: unique and shared genetic effects.

Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are common highly heritable disorders of childhood, which frequently co-occur. Data from twin and family studies suggest that this overlap is, in part, due to shared genetic underpinnings. Here, we report the first genome-wide linkage analysis of measures of reading ability in children with ADHD, using a sample of 233 affected sibling pairs who previously participated in a genome-wide scan for susceptibility loci in ADHD. Quantitative trait locus (QTL) analysis of a composite reading factor defined from three highly correlated reading measures identified suggestive linkage (multipoint maximum lod score, MLS>2.2) in four chromosomal regions. Two regions (16p, 17q) overlap those implicated by our previous genome-wide scan for ADHD in the same sample: one region (2p) provides replication for an RD susceptibility locus, and one region (10q) falls approximately 35 cM from a modestly highlighted region in an independent genome-wide scan of siblings with ADHD. Investigation of an individual reading measure of Reading Recognition supported linkage to putative RD susceptibility regions on chromosome 8p (MLS=2.4) and 15q (MLS=1.38). Thus, the data support the existence of genetic factors that have pleiotropic effects on ADHD and reading ability--as suggested by shared linkages on 16p, 17q and possibly 10q--but also those that appear to be unique to reading--as indicated by linkages on 2p, 8p and 15q that coincide with those previously found in studies of RD. Our study also suggests that reading measures may represent useful phenotypes in ADHD research. The eventual identification of genes underlying these unique and shared linkages may increase our understanding of ADHD, RD and the relationship between the two.

EEG correlates of methylphenidate response among children with ADHD: a preliminary report.

BACKGROUND: Recent electrophysiologic studies have found fairly consistent differences between children with attention-deficit/hyperactivity disorder (ADHD) and age-matched control subjects. The present study examined electroencephalogram (EEG) changes associated with a double blind, placebo-controlled administration of methylphenidate among children with ADHD. METHODS: Subjects were 10 children, ages 8 to 13, with a primary diagnosis of ADHD. Brain electrical activity was recorded with 7 electrodes in the frontal, central, and midline areas during baseline and cognitive activation conditions. RESULTS: Repeated-measures ANOVAs indicate that children exhibiting a positive medication response had reductions of theta and alpha as well as increased beta in the frontal regions, while nonresponders showed the opposite pattern (p < .05). Significant correlations between improvement on a vigilance task and changes in beta activity in the frontal electrodes emerged as well. CONCLUSIONS: These preliminary findings indicate that there are different electrophysiologic correlates to methylphenidate among ADHD children who are medication responders and nonresponders.

Ethnic variations in children's problem behaviors: a cross-sectional, developmental study of Hawaii school children.

Variations in children's problem behaviors associated with ethnicity and other demographic variables were examined in 6-18-year-old children (N = 804) residing in a multicultural environment. The Child Behavior Checklist-Teacher's Report Form was used to compare the frequency of behavior problems among clinic-referred and nonreferred children of Hawaiian, Asian, and Caucasian ethnicities. Children who were male, clinic-referred, or of Caucasian or Hawaiian ancestry experienced greater levels of behavioral problems. Explanations concerning ethnic variations in children's problem behaviors include: teacher's perceptual bias, differences in teacher threshold to report problem behaviors, and/or true variations in children's behavior.

Learning in honeybees (Apis mellifera) as a function of sucrose concentration.

Foraging honeybees (Apis mellifera) were trained with 2 successively presented targets differing in color or odor, one of which always contained a 5-microliters drop of 50% sucrose solution and the other, a 5-microliters drop of 20% sucrose solution. Latency of response to each target was measured during the training, and at the conclusion, preference was measured in an unrewarded choice test. Analysis of the latencies showed both a prospective effect (faster response to the 50% target than to the 20% target) and a nonassociative retrospective effect (faster response after leaving the 20% target than after leaving the 50% target) reminiscent of the frustration effect in rats. The results both for prospective latency and for choice can be understood on the simple theory that the attractiveness of a target depends on the strength of its association with sucrose and that the effect of concentration is on asymptotic strength.

Innervation of hairs in the facial skin of marsupial mammals.

The innervation of pelage, guard hairs and vibrissae hairs was studied in five species of marsupial mammals by means of electron microscopy for the first time. This study showed that members of different superfamilies in marsupial mammals displayed the same pattern of hair innervation. This also resembled the pattern seen in the placental mammals. All types of hairs had both longitudinal and transverse lanceolate nerve terminals. Pelage hairs did not have any Merkel cells. Guard hairs were very richly innervated and had free nerve endings, lanceolate nerve endings, many Merkel cells with their associated nerve endings and pilo-Ruffini nerve endings. Vibrissae hairs had free nerve endings, Merkel nerve endings and lamellated corpuscles, but pilo-Ruffini nerve endings were not seen in this investigation. Because of the profusion and variety of innervation in guard hairs of the marsupial mammals, these hairs may have a similar function to vibrissae hairs in placental mammals.

Cholinesterase activity in sensory-nerve endings, capillaries and motor end plates of the facial skin of the brush-tailed possum (Trichosurus vulpecula).

The facial skin of two adult and one 50-day-old pouch animal of the marsupial mammal Trichosurus vulpecula was removed after the animals has been suitably anesthetized and perfused for electron microscopy. Small blocks of tissue (1 x 0.5 mm) were cut and incubated in acetylthiocholine iodide substrate for cholinesterase studies. The blocks were then subsequently postfixed in osmium tetroxide. Thin sections were cut and stained with lead acetate. Specific cholinesterase was found within the nerves of both the adult and the 50-day-old pouch animal, and in the motor end plates. Nonspecific cholinesterase was present in pinocytotic vesicles and interlamellar spaces of terminal Schwann cells associated with nerve end organs in the adult, and in the same areas in Schwann cells of nonmyelinated nerves in the pouch animal. It was also present in the pinocytotic vesicles of the capillary endothelium.

Topography and ultrastructure of sensory nerve endings in the joint capsules of the Kowari (Dasyuroides byrnei), an Australian marsupial.

The present investigation in concerned with the topography and ultrastructure of sensory nerve endings in the joint capsules of the Kowari (Dasyuroides byrnei), an Australian marsupial. Material for light and electron microscopy was obtained from shoulder, elbow and knee joint capsules. On the basis of differences in the organization of the connective tissue belonging to the fibrous layer, 3 variants of capsule structure have been distinguished: a rigid, a flaccid and an intermediate type. Whilst the rigid type is characterized by dense connective tissue in the clearly demarcated fibrous layer, the flaccid type shows loose, irregularly arranged connective tissue in the fibrous layer which merges into the synovial layer of the joint capsule. The morphology of the intermediate type corresponds to an intermediate stage between the former two types. In the fibrous layer of the joint capsules three different types of sensory nerve endings were observed: free nerve endings, Ruffini corpuscles and lamellated corpuscles. The free nerve endings are supplied by myelinated afferent axons (1-2 microns in diameter); the terminal thickenings of which are incompletely surrounded by a terminal Schwann cell. Ruffini corpuscles are present in three different varieties: small corpuscles without a perineural capsule predominantly within the flaccid part of the capsule; slightly larger corpuscles with an incomplete perineural capsule and large corpuscles resembling Golgi tendon organs which predominantly occur in the rigid parts of the capsule. The afferent myelinated axons measure 2-4 microns in diameter. The lamellated corpuscles show two variants: small corpuscles with a 2 to 4-layered perineural capsule in the rigid parts of the joint capsules and large corpuscles with two longitudinal clefts of the inner core in the flaccid parts. Both types are supplied by myelinated axons of 3-5 microns in diameter. Thus, in the fibrous layer of the rigid type of joint capsules large Ruffini and small lamellated corpuscles predominate, whereas the fibrous layer of the flaccid type coincides with small Ruffini and large lamellated corpuscles. The present data, therefore, corroborate the concept that the morphology of mechanoreceptors depends upon the texture of the surrounding connective tissue.

The sensory innervation of the nasal glabrous skin in the short-nosed bandicoot (Isoodon macrourus) and the opossum (Didelphis virginiana).

The glabrous skin at the anterior end of the snout of the short-nosed bandicoot and the American opossum was investigated by electron microscopy. In both species of animals, this region was lined by skin with broad epidermal pegs, innervated by three types of intraepidermal nerves. These were intraepidermal nerves which penetrated the epidermis up to the level of the stratum spinosum or the stratum granulosum, intraepidermal nerves in the basal layer of the epidermis partially surrounded by Schwann cell lamellae and intraepidermal nerves associated with Merkel cells. There were two types of free nerve endings in the dermis. The first type was derived from the deep dermal nerve plexus and had the typical characteristics of nerve terminals such as mitochondria, vesicles, irregularly arranged neurotubules and neurofilaments, and glycogen granules. There was a one-to-one relationship between Schwann cell lamellae and these nerve terminals. The second type of nerve ending was brush-like and the ends of the 'brushes' were enclosed in groups by a single Schwann cell lamella. Encapsulated nerve endings in the two types of animals differed in their structure. In the bandicoot, they consisted of a nerve terminal which had one to three branches. These terminals were rounded in profile and were surrounded by Schwann cell lamellae in a stack-like arrangement. An unusual finding was that the terminal sometimes left the corpuscle and made contact with the basal lamina of the epidermis before passing into its basal layer. These corpuscles did not have a perineural capsule. In the opossum, however, simple corpuscles with inner cores completely surrounded by a perineural capsule were seen. The glabrous skin of both types of animals was innervated with Eimer's organs consisting of intraepidermal nerves, Merkel cell nerve endings and encapsulated end-organs, as well as two types of dermal nerve endings.

Endothelial cells in the oral mucosa of Bufo marinus.

The oral mucosa of the cane toad (Bufo marinus) is lined by a pseudostratified columnar ciliated epithelium containing an intraepithelial network of capillaries, which penetrates it to the bases of the distal layer of cells. The capillaries are lined by fenestrated endothelium lying on a complete basal lamina. A connective tissue sheath, approximately 1 micrometer thick, surrounds the capillaries and separates them from the surrounding epithelial cells. Endothelial cells resemble those in lymphatic capillaries in that they show microvillus-like processes or folds projecting into the lumen and also have extremely attenuated and fenestrated cytoplasm except in the nuclear region. Numerous pinocytotic vesicles, bundles of filaments and many electrondense granules occur in the cytoplasm. These granules are oval or round in shape and approximately 250-400 micrometer in diameter. Histochemical tests on the endothelial cells show that the granules do not contain pigment, as both the Schmorl and argentaffin reactions are negative. Both the Sudan black B and Luxol fast blue reactions are also negative showing the lack of stainable lipids. The formaldehyde-induced fluorescence, the argentaffin reactions and lead haematoxylin reactions are negative, indicating that they do not have the characteristics of endocrine cells. The acid phosphatase reaction gives a positive result, localized to the site of the granules by electron microscopy and suggesting that these granules in amphibian capillaries may have a lysosomal function.

Epithelial mucins of the gastro-intestinal tract of Egernia cunninghami.

Epithelial mucins of the gastro-intestinal tract of Egerina cunninghami, an Australian lizard, were investigated by several histochemical stains. The results obtained showed that the gastro-intestinal tract of this reptile has several types of mucus-secreting cells. Mucins secreted by the oesophagus, intestines and cloaca were predominantly acid-sulphated mucins, while the mucus neck cells of the gastric glands produced neutral mucins and the epithelial cells lining the gastric surface secreted a mixture of both neutral and acid mucins.

Fine structure of the olfactory epithelium in some primates.

Electron microscopy of the olfactory epithelium of two prosimian primates, the trees shrew and slow loris, and two simian primates, the macaque and gibbon, has shown that this epithelium consists of three cell types, receptor cells, supporting cells and basal cells, as in other mammals. Receptor cells were ciliated in all the animals investigated except the tree shrew, where, in addition to ciliated receptors, nonciliated receptors bearing only microvilli were occasionally present. Developing receptor cells containing numerous centrioles between nucleus and cell surface were occasionally observed and these cells had poorly developed olfactory knobs and few mitochondria. The olfactory epithelium was similar in morphology in all four species, except that supporting cells showed progressively more numerous, more slender and longer microvilli on their distal surface from tree shrew to slow loris to macaque to gibbon. This may imply a more discriminatory surface in the higher primates in view of the close relationship of these microvilli to the receptor cell surface.

Fine structure of lymphoid cells in the nasal skin of primates.

Electron microscopy of the nasal skin of primates shows that lymphoid cells are normally present in this region. No degeneration or mitosis of these cells or their transformation into other cell types was seen. These intraepidermal lymphocytes contained cytoplasmic fibrils. There was no evidence that they were phagocytic in the epidermis. The present study suggests that these lymphoid cells migrate into the lamina propria but not into the epidermis.

Extrinsic nerve supply of the naked rhinarium in the tree shrew.

The extrinsic nerve supply of the median strip of skin in the naked rhinarium of the tree shrews (Tupaia glis) was studied by means of nerve section. Experiments were designed, where the external nasal nerves, infraorbital nerves or a combination of both were sectioned. The cholinesterase and silver impregnation techniques were employed to demonstrate intraepithelial nerves, mammalian end-organs, and the dermal nerve plexus before and after denervation. These experiments have given results contrary to what was expected, as the skin in this region, which develops from the frontonasal process, was found to be supplied by the infraorbital nerves (branches of the maxillary division of the fifth cranial nerve, which is the nerve of the maxillary process) and not the external nasal nerves (branches of the ophthalmic division of the fifth cranial nerve, the nerve of the frontonasal process).

Histochemical observations on the mucins of the gastrointestinal tract in the toad (Bufo melanostictus).

The pattern of mucin secretion of the gastrointestinal tract of the toad (B. melanostictus) was investigated by histochemical methods. The goblet cells of the oesophagus secreted mainly acid mucins which were sialomucins, while the cells lining the surface of the stomach produced neutral mucins only. Goblet cells of the small intestine and cloaca secreted acid mucins, which were predominently sulphated mucins.