Epithelial stem cells in the mammary gland: casting light into dark corners

The epithelial structures of the human breast or the mouse mammary gland are derived from a relatively small number of multipotent, tissue-specific stem cells, of which we are surprisingly ignorant. We do not know how many are required to produce a complete mammary gland, how many times they divide during the process, where they are situated in the gland, or even what they look like. We want to know the answers to these questions, not just to satisfy intellectual curiosity, but also because the answers may shed light on the evolution of breast cancer. Now, studies carried out by Kordon and Smith at the National Cancer Institute have pointed the way toward a new understanding of mammary stem cells and their progeny.     

Physicochemical factors governing the performance of nedocromil sodium as a dry powder aerosol

Previous investigations have found that the in vitro aerosol performance of nedocromil sodium is poor. A study has been undertaken to gain a better understanding of the physicochemical properties of the drug particles together with the factors governing the aerosol performance of inhalation systems containing this drug. Material previously passed through a hammer mill only and particles subsequently passed through a micronizer were characterized, and the information gathered was correlated with the in vitro aerosol performance of the pure drug systems. Optimization of particle sizing procedures revealed that both sets of materials were ultrafine powders with a volume median diameter of approximately 1 microm. It is concluded that the processing stages, employed in the manufacture of these batches of fine particle nedocromil sodium trihydrate, may not in fact be primary particle size reduction stages but instead deaggregation stages and that these govern the aerosol performance. The in vitro aerosol performance of samples of the "micronized" nedocromil sodium stored over a range of relative humidities (RHs) was characterized. Storage RHs in the range 12-76% (where nedocromil sodium is stable as the trihydrate) did not have a dramatic effect on the in vitro aerosol performance of the drug. However, conversion to the heptahemihydrate (following storage of the drug at 86% RH) significantly decreased the deaggregation performance in an in vitro model.     

Effects of nicotine and chlorisondamine on cerebral glucose utilization in immobilized and freely-moving rats

Chlorisondamine blocks central nicotinic receptors for many weeks via an unknown mechanism. Intracerebroventricular administration of [(3)H]-chlorisondamine in rats results in an anatomically restricted and persistent intracellular accumulation of radioactivity. The initial aim of the present study was to test whether nicotinic receptor antagonism by chlorisondamine is also anatomically restricted. Male adult rats were pretreated several times with nicotine to avoid the disruptive effects of the drug seen in drug-na?ve animals. They then received chlorisondamine (10 microg i. c.v.) or saline, and local cerebral glucose utilization (LCGU) was measured 4 weeks later after acute nicotine (0.4 mg kg(-1) s.c.) or saline administration. During testing, rats were partially immobilized. Nicotine significantly increased LCGU in the anteroventral thalamus and in superior colliculus. Chlorisondamine completely blocked the first of these effects. Chlorisondamine significantly reduced LCGU in the lateral habenula, substantia nigra pars compacta, ventral tegmental area, and cerebellar granular layer. The second experiment was of similar design, but the rats were not pre-exposed to nicotine, and were tested whilst freely-moving. Acute nicotine significantly increased LCGU in anteroventral thalamus, superior colliculus, medial habenula and dorsal lateral geniculate. Overall, however, nicotine significantly decreased LCGU. Most or all of the central effects of nicotine on LCGU were reversed by chlorisondamine given 4 weeks beforehand. These findings suggest that chlorisondamine blocks nicotinic effects widely within the brain. They also indicate that in freely-moving rats, nicotine can reduce or stimulate cerebral glucose utilization, depending on the brain area. British Journal of Pharmacology (2000) 129, 147 - 155     

Sulfasalazine metabolite pharmacokinetics in pediatric patients with inflammatory bowel disease: effects of disease activity, acetylator phenotype, and age

The pharmacokinetics and protein binding of sulfapyridine (SP) and its major metabolite, acetylsulfapyridine (ACSP) were examined in 17 prepubertal children and 4 postpubertal adolescents receiving sulfasalazine (SASP) for treatment of inflammatory bowel disease (IBD). Five patients were studied in both active disease and remission. Comparisons were made with a group of 24 outpatients (9-62 years) with IBD controlled on SASP and in remission. Acetylator phenotype was calculated from plasma metabolite ratios. Slow acetylators had increased plasma concentrations of SP and ACSP + SP (P less than 0.05). Apparent SP clearance (clearance/availability) was increased in active disease (P less than 0.05) and AUCSP + ACSP and AUCSP were decreased (P less than 0.05). There were no age-related alterations in apparent SP clearance. Side effects were frequent but were unrelated to SASP dose, SP concentrations, or acetylator phenotype. Disease activity did not significantly alter the serum protein binding of SP or ACSP. The decreased SP and ACSP concentrations seen in active disease may be due to a combination of disease related alterations in either cleavage of SASP or absorption and clearance of SP.     

Longitudinal ABR in the NICU infant

To assess the reliability of ABR testing of NICU infants, longitudinal ABR testing was accomplished on 50 NICU infants while hospitalized and subsequently at 4 and at 20–24 months of age. The results indicate that ABR testing in the NICU may be a poor predictor of subsequent permanent hearing loss. The implications of these findings are discussed with the recommendation that ABR testing in the NICU be used in concert with follow-up testing.     

Effects of a selective 5-HT(1B/1D) receptor agonist on spinal and trigeminal reflexes in the anaesthetized rabbit

The effects of the 5-HT(1B/1D) receptor agonist L-741,604 on a trigeminally-mediated (jaw depressor) reflex and a spinally-mediated (flexion withdrawal) reflex have been compared between spinalized and intact, anaesthetized rabbits. L-741,604 depressed the jaw depressor reflex dose-dependently in all animals, to a median of 5% (inter-quartile range, IQR, 3 - 28%, n=18) of pre-drug levels after a cumulative dose of 3.1 micromol kg(-1) i.v. This effect was reversed by the 5-HT(1B/1D) antagonist GR 127,935 (1 - 2 micromol kg(-1) i.v.). The flexion withdrawal reflex was depressed by L-741, 604 in non-spinalized animals, to a median of 22% (IQR 10 - 36%, n=10) of pre-drug levels after the highest dose, an action that was reversed by GR 127,935. In spinalized rabbits, L-741,604 up to 0.3 micromol kg(-1) i.v. cumulative increased the flexion reflex to a median of 189% (IQR 169 - 198%, n=8) of pre-drug controls. With higher doses the reflex decreased, so that after 3.1 micromol kg(-1) it was 75% (IQR 55 - 96%) of pre-drug levels. Subsequent GR 127,935 increased reflexes to a median of 180% (IQR 136 - 219%) of controls. L-741,604 increased arterial blood pressure and decreased heart rate in both preparations, effects that were reversed by GR 127,935. Thus, when the spinal cord was intact L-741,604 inhibited spinal and trigeminal reflexes in the same way. Although spinalization enabled a non-5-HT(1B/1D)-mediated excitatory effect of L-741,604 on spinal reflexes, there was a clear inhibitory effect of the drug at high doses. These data suggest that L-741,604 inhibits spinal reflexes by increasing descending inhibition and by a direct action in the cord. The same processes could apply to inhibition of trigeminally-mediated events.     

Augmentative and alternative communication for children with cerebral palsy

Children with cerebral palsy (CP) can experience a range of significant speech, language and communication difficulties. Those children with little or no intelligible speech can benefit from the provision of augmentative and alternative communication (AAC) systems. AAC approaches include training in the use of manual signs and/or symbol systems, as part of a ‘total communication’ approach, whereby all possible communicative modalities are considered as potentially useful. For children with severe motor impairment where the potential for signing is limited, intervention typically focuses on supporting symbol use organized on high-tech and low-tech communication aids. This review describes the categories of AAC systems available to children with CP, and outlines AAC assessment and intervention principles, drawing on the World Health Organisation's International Classification of Function, Disability and Health for Children and Youth (ICF-CY). Given the complex health, motor, sensory, learning and communication needs of children with CP, AAC related assessment and intervention requires a multi-disciplinary perspective.     

Severe thrombocytopenia and patterns of bleeding in neonates: results from a prospective observational study and implications for use of platelet transfusions

OBJECTIVE: To describe patterns of clinical bleeding in neonates with severe thrombocytopenia (ST and platelet count <60 × 10(9) L(-1) ), and to investigate the factors related to bleeding. STUDY DESIGN: Seven tertiary-level neonatal units enrolled neonates (n?=?169) with ST. Data were collected prospectively on all clinically apparent haemorrhages. Relationships between bleeding, platelet count and baseline characteristics were explored through regression analysis. RESULTS: Bleeding was recorded in most neonates with ST (138/169; 82%), including 123 neonates with minor bleeding and 15 neonates with major bleeding. The most common sites of minor bleeding were from the renal tract (haematuria 40%), endotracheal tube (21%), nasogastric tube (10%) and skin (15%). Gestational age <34?weeks, development of ST within 10?days of birth and necrotizing enterocolitis were the strongest predictors for an increased number of bleeding events. For neonates with ST, a lower platelet count was not a strong predictor of increased bleeding. CONCLUSIONS: The majority of neonates with ST bleed, although most episodes are minor. These findings establish the importance of clinical factors for bleeding risk, rather than minimum platelet count. Further studies should assess the clinical significance of different types of minor bleed for neonatal outcomes, the predictive value of minor bleeding for major bleeding and the role of platelet transfusions in preventing bleeding.     

Colour in digital pathology: a review

Colour is central to the practice of pathology because of the use of coloured histochemical and immunohistochemical stains to visualize tissue features. Our reliance upon histochemical stains and light microscopy has evolved alongside a wide variation in slide colour, with little investigation into the implications of colour variation. However, the introduction of the digital microscope and whole‐slide imaging has highlighted the need for further understanding and control of colour. This is because the digitization process itself introduces further colour variation which may affect diagnosis, and image analysis algorithms often use colour or intensity measures to detect or measure tissue features. The US Food and Drug Administration have released recent guidance stating the need to develop a method of controlling colour reproduction throughout the digitization process in whole‐slide imaging for primary diagnostic use. This comprehensive review introduces applied basic colour physics and colour interpretation by the human visual system, before discussing the importance of colour in pathology. The process of colour calibration and its application to pathology are also included, as well as a summary of the current guidelines and recommendations regarding colour in digital pathology.