Tropisetron: optimal dosage for children in prevention of chemotherapy-induced vomiting

The antiemetic efficacy and tolerability of Tropisetron (Navoban, Novartis Pharma Switzerland AG, Bern), a selective 5-hydroxytriptamine receptor antagonist, has been assessed in the prevention of acute vomiting in children receiving chemotherapy for solid tumors. Tropisetron iv was given 30 min before administration of chemotherapy at a dose of 5 mg in children <20 kg body weight and at a dose of 10 mg in those >20 kg. A total of 50 children were studied in 189 courses of chemotherapy. Control of emesis was defined as total in absence of acute vomiting, as major if 1 or 2 events of acute vomiting occurred, and as not controlled if >2 events of acute vomiting occurred. Response was studied, taking into account Tropisetron dosage, degree of emetogenicity of the chemotherapeutic agents in pretreated and non-pretreated patients, and according to age groups. Tropisetron, administered in a single daily dose of 8-12 mg/m(2), was found to be very effective in completely controlling acute emesis in 92% of the courses of moderately and highly emetogenic chemotherapy administered to pediatric patients with solid tumors. Moreover, Tropisetron, at this dosage, did not lead to any adverse effects.     

Glial transcytosis of a photoreceptor-secreted signaling protein, retinoschisin

In vitro studies have clearly shown that signaling/guidance proteins can diffuse to their targets. However, it is unclear whether they can travel by diffusion in vivo, or if they are distributed in the tissue by an active mechanism. Retinoschisin, a signaling molecule related to neuropilins, is synthesized and secreted by photoreceptor cells in the outer retina; then it interacts with inner retinal cells contributing to synaptic organization and optic nerve fiber integrity. We developed an assay to examine how retinoschisin, which is secreted a distance away, reaches its inner retinal targets. We found that retinoschisin is preferentially taken up and carried into the inner retina from the retinal outer border (the photoreceptor side) by Müller cells (the main glial cells of the vertebrate retina). This transcytosis is disrupted by DL-alpha-aminoadipic acid, a Müller cell/glia-specific toxin. Our results suggest that glial uptake/transcytosis can provide an effective and precise alternative for distributing signaling molecules in the nervous system.     

Inhibition and superactivation of the calcium-stimulated isoforms of adenylyl cyclase

It was shown previously that chronic exposure to opiate agonists increases adenylyl cyclase (AC) activity, a phenomenon termed AC superactivation (or supersensitization). More recently, we showed that acute Gi/o- coupled receptor activation inhibits the activity of several AC isozymes, including Ca2+/calmodulin-stimulated AC-I and -VIII, whereas chronic receptor activation induces their superactivation. Here, we report that both acute Mu-opioid receptor-induced inhibition and chronic induced superactivation of AC-I and -VIII are pertussis toxin sensitive. In addition, we show that proteins that interfere with the activity of Gbetagamma subunits (Gbetagamma scavengers) strongly attenuate the acute inhibition of AC-I and -VIII and the superactivation of AC-I, and abolish the superactivation of AC-VIII. Based on these results, we suggest that Gbetagamma is involved in the acute inhibition and chronic agonist-induced superactivation of AC types I and VIII.     

eNOS genotype is without effect on circulating nitrite/nitrate level in healthy male population

INTRODUCTION: Nitric oxide (NO) plays an important role in the regulation of the cardiovascular system. It is produced by endothelial nitric oxide synthase (eNOS), which exhibits genetic polymorphisms. Although the clinically relevant polymorphism T(+IhI-786)C reduces eNOS-promoter activity, it is not clear whether circulating nitrite/nitrate (NOx) are affected by this polymorphism. MATERIALS AND METHODS: We addressed this issue by studying a homogeneous group of 200 healthy subjects (males, Caucasians, nonsmokers, 18+IBM-56 years of age, and not taking any medication). Genotypes were determined by restriction fragment length polymorphism and circulating NOx were determined by chemiluminescence. RESULTS: We found nonsignificant effects of the T(+IhI-786)C polymorphism on circulating NOx (mean+ALE-S.D.=52.2+ALE-21.4, 49.0+ALE-17.8, and 45.9+ALE-16.8 +A7w-mol/L for genotypes +IBw-TT,+IB0 +IBw-TC,+IB0 and +IBw-CC,+IB0 respectively) and on total plasma cholesterol concentrations (both P>.05). No correlation was found between circulating NOx and total plasma cholesterol concentrations (P>.05). CONCLUSIONS: Our study provides strong evidence that the T(+IhI-786)C polymorphism does not affect plasma NOx concentrations, which are believed to reflect endogenous production of NO. Therefore, our results suggest that this polymorphism does not affect endogenous NO production.     

Susceptibility to form-deprivation myopia in chicks is not altered by an early experience of axial myopia.

PURPOSE: Studies in humans and primates suggest that early visual experience may influence eye growth and refractive development later in life. In this study, we asked whether experimentally-induced myopia in 1-week-old chicks influences the responsiveness to form deprivation at a later age (4 weeks old). METHODS: A group of White Leghorn chicks ("twice deprived," N = 12) were monocularly deprived of form vision with white translucent diffusers at 3 days of age for 4 days. The diffusers were then removed, and the chicks were allowed 3 weeks of normal vision to age 27 days before being deprived again for 4 days. Another group of chicks ("once deprived," N = 9) were monocularly deprived of form vision at age 27 days for 4 days. Refractive errors, corneal curvatures, and axial ocular dimensions were measured by retinoscopy, infrared videokeratometry, and A-scan ultrasonography, respectively. Measurements were performed daily during the periods of deprivation and at approximately 3-day intervals in between treatments and after the final treatment period. RESULTS: The magnitude of the form-deprivation myopia induced by 4 days of deprivation at 27 days of age was significantly smaller than that induced by the same treatment at 3 days of age (-4.1 vs. -9.8 D; paired t-test, p < 0.01). This difference in induced myopia reflects optical scaling with increasing eye size because the deprivation-induced changes in vitreous chamber depth were not significantly different for the two deprivation periods (0.37 vs. 0.35 mm, paired t-test, p = 0.65). The induction of myopia at the younger age did not affect the susceptibility to form-deprivation myopia at the older age; there was no difference in the response to form deprivation at the older age between the once-deprived and twice-deprived groups (-3.5 vs. -4.1 D; unpaired t-test, p = 0.50). There was also a significant correlation between the amount of axial elongation induced in individual eyes during the first and second periods of deprivation (r = 0.631, p < 0.05). CONCLUSIONS: The induction of form-deprivation myopia at a young age does not affect the response to form deprivation at a later age. The significant correlation between the axial elongation induced in individual eyes over the two successive periods of deprivation suggests individual differences, possibly genetic in origin, in the susceptibility to form-deprivation myopia in chicks.     

The utility of p16INK4a and Ki-67 staining on cell blocks prepared from residual thin-layer cervicovaginal material

BACKGROUND: Cell blocks can be prepared from residual thin-layer cervicovaginal (ThinPrep) material and can be used in immunohistochemical staining assays for p16INK4a and Ki-67, which are surrogate markers related to human papillomavirus infection and cell proliferation, respectively. The objectives of the current study were 1) to investigate the feasibility and the role of cell block preparations in identifying significant neoplastic and preneoplastic lesions of the uterine cervix and 2) to assess the feasibility of using p16INK4a and Ki-67 immunohistochemical staining patterns on cell blocks to identify significant preneoplastic cervical lesions. METHODS: Cervicovaginal cytology specimens from 85 patients were analyzed. Cytologic diagnoses based on ThinPrep Papanicolaou test results were as follows: squamous cell carcinoma was diagnosed in 3 specimens, high-grade squamous intraepithelial lesions (HSIL) were diagnosed in 27 specimens, low-grade squamous intraepithelial lesions (LSIL) were diagnosed in 20 specimens, and atypical squamous cells of uncertain significance (ASCUS) were diagnosed in 11 specimens. Diagnoses of negativity for intraepithelial lesions or malignancy (NILM) were made in 24 specimens. Cell block sections were stained with hematoxylin and eosin and were immunostained with antibodies against p16INK4a protein and Ki-67 antigen. RESULTS: The cytomorphologic diagnoses made using cell block preparations were as follows: SCC in 2 specimens, HSIL in 20 specimens, LSIL in 30 specimens, NILM in 32 specimens, and no diagnosis in 1 specimen. In 62 cases (73%), the diagnoses made using cell block preparations were in agreement with the ThinPrep diagnoses. Immunostaining of cell blocks for p16INK4a and Ki-67 exhibited a statistically significant association (P < 0.05) with the presence of significant lesions on either cell block or ThinPrep analysis. CONCLUSIONS: To the authors' knowledge, p16INK4a has not been analyzed previously in ThinPrep cell blocks, and the correlation between Ki-67 expression and cell block diagnoses also has not been reported previously. The current results indicate that cell blocks prepared from residual ThinPrep material represent an additional reliable diagnostic tool in the evaluation of cervical samples. Furthermore, immunohistochemical studies may be helpful in differentiating significant preneoplastic changes from other cervical lesions, such as atrophy.     

Nasu-Hakola disease: a rare entity in Italy. Critical review of the literature

Nasu-Hakola disease (NHD, polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL) is a recessively inherited disorder characterized by systemic bone cysts and progressive presenile dementia associated with sclerosing encephalopathy. The disease has a worldwide distribution, but most patients have been reported in Finland and in Japan; in Italy there are anecdotal reports. The combination of neuropsychiatric symptoms and bone cysts is unique to this disease, which we believe to be underestimated in Italy. The molecular defect has been identified in loss-of-function mutations in the TYROBP gene in Finnish and in Japanese patients, and in the TREM2 gene in other families of different ethnic origins. We reviewed the international literature to define better the diagnostic steps and to draw the attention of neurologists and orthopaedic specialists to the disease. The identification of new cases followed by appropriate genetic counselling, genetic analysis, and study of the territorial distribution of affected patients could be a good strategy to follow in order to improve understanding of the disease.     

Relationship between maternal methadone dosage and neonatal withdrawal

OBJECTIVE: To determine whether maternal methadone dosage affects duration and degree of neonatal narcotic withdrawal. METHODS: This was a retrospective cohort study of pregnant women with opioid addiction who delivered live-born singletons between April 1990 and April 2001. Inpatient detoxification or outpatient methadone maintenance therapy was offered. Women who had a positive drug screen or whose neonate tested positive for opioids were considered to be supplementing. We evaluated indices of neonatal withdrawal according to the maximum daily methadone dosage in the last week of pregnancy. RESULTS: Seventy women with opioid addiction were followed. Median methadone dosage was 20 mg (range 0-150 mg), and 32 infants (46%) were treated for narcotic withdrawal. Among women who received less than 20 mg per day, 20-39 mg per day, and at least 40 mg per day of methadone, treatment for withdrawal occurred in 12%, 44%, and 90% of infants, respectively (P < 0.02). Methadone dosage was also correlated with both duration of neonatal hospitalization and neonatal abstinence score (r(s) =.70 and.73 respectively, both P <.001). Neonates were more likely to experience withdrawal if their mothers were supplementing with heroin, 68% versus 35% (P =.01). Regardless of supplementation, there was a significant relationship between methadone dosage and neonatal withdrawal (P <.05). CONCLUSION: Maternal methadone dosage was associated with duration of neonatal hospitalization, neonatal abstinence score, and treatment for withdrawal. Heroin supplementation did not alter this dose-response relationship. In selected pregnancies, lowering the maternal methadone dosage was associated with both decreased incidence and severity of neonatal withdrawal.     

A phased consent policy for cord blood donation

This article focuses on ethical and policy questions concerning when consent may be sought for the collection and donation of cord blood. It reviews the advantages and disadvantages of alternative times for securing consent, challenges common objections to seeking consent during labor or after collection, and describes a phased consent process--a process that permits consent during early labor to the ex utero collection of cord blood followed by after-consent collection to donation. The phased consent policy attends to the unique characteristics of cord blood collection and donation, respects donors and their families, maximizes the number and diversity of cord blood units collected, preserves the relationship between providers and patients, and preserves public trust in cord blood and other types of tissue banking.