Ectopic expression of rhombotin-2 causes selective expansion of CD4-CD8- lymphocytes in the thymus and T-cell tumors in transgenic mice

Although the proto-oncogene rhombotin-2 (RBTN-2) is widely expressed in most tissues, it is not expressed in T cells. We investigated the potential for overexpression of RBTN-2 to cause tumors in T cells and other tissues by constructing transgenic mice that expressed RBTN-2 under control of the metallothionein-1 promoter. Despite overexpression of RBTN-2 in all tissues, transgenic mice developed T-cell tumors only, thus indicating that tumorigenesis caused by RBTN-2 is T-cell-specific. Thymic tumors were found between 37 and 71 weeks and were invariably associated with metastasis to nonlymphoid organs. Thymuses from apparently healthy transgenic mice were also examined. In some mice there was an 10-fold increase in the CD4-CD8- thymocyte subset, yet the total number of thymocytes was the same as that in wild-type mice. Thymic homeostasis was maintained by a compensatory reduction in the CD4+CD8+ subset. The expansion of CD4-CD8- thymocytes was associated with increased expression of RBTN-2 and with increased cell proliferation. No differences were found in the proportion of thymocytes undergoing apoptosis in transgenic mice. Furthermore, RBTN-2- induced expansion of CD4-CD8- cells did not block differentiation of these cells. Thymuses with 30% CD4-CD8- cells were essentially monoclonal, indicating that all thymic immunophenotypes were derived from a single clone. Overall, our data are consistent with the following scenario: (1) RBTN-2 expression in T cells causes selective and polyclonal proliferation of CD4-CD8- thymocytes accompanied by a compensatory decrease in other thymocyte subsets; (2) a clone with growth advantage and differentiation potential is selected and populates the thymus; and (3) this clone eventually breaches homeostasis of the thymus, accompanied or followed by metastasis to other organs.     

Macrolides: A Canadian Infectious Disease Society position paper

Since the introduction of erythromycin in 1965, no new compounds from the macrolide antimicrobial class were licensed in Canada until the 1990s. Clarithromycin and azithromycin, since their introduction, have become important agents for treating a number of common and uncommon infectious diseases. They have become prime agents in the treatment of respiratory tract infections, and have revolutionized the management of both genital chlamydial infections, by the use of single-dose therapy with azithromycin, and nontuberculous mycobacterial infections, by the use of clarithromycin. The improvement of clarithromycin and azithromycin over the gastrointestinal intolerability of erythromycin has led to supplanting the use of the latter for many primary care physicians. Unfortunately, the use of these agents has also increased the likelihood for misuse and has raised concerns about a resultant increase in the rates of macrolide resistance in many important pathogens, such as Streptococcus pneumoniae. This paper reviews the pharmacology and evidence for the current indications for use of these newer agents, and provides recommendations for appropriate use.Key Words: Azithromycin, Clarithromycin, Erythromycin, Macrolides, Review, Therapeutic useErythromycin A is a naturally occurring, microbiologically active compound of the macrolide class of antibiotics. Chemical modification of erythromycin A''s 14-membered lactone ring has led to the formation of semisynthetic derivatives with not only improved bioavailability and tolerability, but also expanded spectrums of microbiological activity and improved pharmacokinetic profiles. Such modifications produced clarithromycin, classified as a macrolide because it retains the central 14-membered lactone ring (1,2), and azithromycin, classified as an azalide due to its 15-membered aglycone ring (1). The latter two compounds are the newest agents in the macrolide class licensed for use in Canada. Roxithromycin and dirithromycin are available in other countries.These compounds are clinically active against Gram-positive and Gram-negative cocci, and Gram-negative bacilli (primarily Haemophilus influenzae, Legionella species, Moraxella catarrhalis, Campylobacter jejuni, Bordatella pertussis and Helicobacter pylori). Azalides such as azithromycin have exhibited superior activity against Gram-negative pathogens and are generally less active against Gram-positive pathogens. Intracellular pathogens such as Chlamydia species, Mycoplasma species, Ureaplasma species, Borrelia species and nontuberculous mycobacteria species show varying susceptibilities. On the basis of their microbial activity, both the macrolides and azalides have been shown to be clinically useful in the treatment of uncomplicated skin and soft tissue infections, upper and lower respiratory tract infections, sexually transmitted Chlamydia trachomatis infection and peptic ulcer disease. Additionally, the improved pharmacokinetic profiles and acid stability exhibited by the newer agents may lead to enhanced patient adherence through less frequent dosing and improved bioavailability in the presence of food.     

Pilot Trial of a Comprehensive Summer Psychosocial Treatment for High-Functioning Young Children with ASD

This study examined the feasibility and preliminary outcomes of a comprehensive summer psychosocial treatment (summerMAX^yc) for high-functioning young children, ages 4–6 years, with ASD (HFASD). The 5-week treatment, conducted 5 days per week, 6 h per day, included skills instruction and therapeutic activities targeting social/social-communication skills, facial-emotion recognition, and interest expansion. A behavioral system was implemented to increase skills acquisition and maintenance and reduce ASD symptoms and problem behaviors. Feasibility was supported in high levels of treatment fidelity and child, parent, and staff clinician satisfaction. Significant post-treatment improvements were found for 9 of 10 outcome measures including parent and staff clinician ratings of targeted social/social-communication skills, ASD symptoms, and broader adaptive social and communication skills, and staff clinician ratings of daily living skills. Results suggested that summerMAX^yc was feasible and may yield positive outcomes for 4–6 year olds with HFASD.     

Role of ambulatory blood pressure monitoring in the assessment and prognosis of patients with borderline hypertension

The role of ambulatory blood pressure (ABP) monitoring in the assessment of mild/borderline hypertension (BHT) is unclear. The aim of this study was to test the hypothesis that measurement of ABP in borderline hypertensives differentiates patients with true mild hypertension from those with isolated clinic hypertension (raised office BP but normal ABP) and that a raised ABP identifies a subgroup who are more likely to progress to and require treatment over 1 year. Consecutive untreated patients with BHT (n = 127, 44 +/- 13 years, 45% male) were divided into two groups according to awake ABP: Group 1 (normal ABP < or = 136/86, n = 48), and Group 2 (abnormal ABP > 136/86, n = 79). Left ventricular mass index (LVMI) was greater (116 +/- 30 vs 101 +/- 25 g/m2, p < 0.01) and the proportion of patients with an increased LVMI was significantly higher (34% vs 17%, p = 0.05) in Group 2. During 1 year of follow-up, significantly more patients in Group 2 (34%) required antihypertensive treatment compared with Group 1 (8%, p = 0.01). ABP monitoring usefully discriminates between patients with true BHT and those with isolated clinic hypertension. An elevated awake ABP on initial assessment is associated with a higher LVMI and a greater likelihood of progression to moderate hypertension requiring pharmacological treatment.     

Hypoglossal motoneuron responses to pulmonary and superior laryngeal afferent inputs

In decerebrate, paralyzed cats ventilated with a cycle-triggered pump, the inspiratory discharges of the hypoglossal (whole nerve or single fibers), phrenic, and recurrent laryngeal nerves were compared, and the effects of pulmonary and superior laryngeal afferent inputs were observed. During lung inflations in phase with neural inspiration, hypoglossal and recurrent laryngeal activities differed from phrenic with respect to (a) burst onset times: both preceded the phrenic; (b) overall pattern: phrenic, augmenting; hypoglossal, decrementing; recurrent laryngeal, plateau-like. When inflation was withheld, the phrenic pattern was not markedly changed, but both hypoglossal and recurrent laryngeal became augmenting; the marked increase of hypoglossal activity (both whole nerve and single fiber) indicated strong inhibition by lung afferents. Superior laryngeal electrical stimulation evoked excitation of the contralateral phrenic (latency 4.1 msec) and the ipsilateral whole hypoglossal (latency 5.3 msec), followed by bilateral inhibitions (durations 20-30 msec); most hypoglossal fibers showed only inhibition. We conclude that, although both hypoglossal and phrenic outputs are driven by the inspiratory pattern generator(s), their promotor systems differ with respect to influences from central and peripheral inputs.     

Oral antifungals as prophylaxis in haematological malignancy

In the standard treatment of patients with haematological malignancy, immunosuppressive therapy produces prolonged periods of neutropenia and mucositis, which increase the risk of systemic fungal infection. In allogeneic bone marrow transplantation, this risk extends well beyond the period of neutropenia when graft-versus-host disease, and its treatment, result in prolonged lymphocytopenia. Various agents are used for antifungal prophylaxis and treatment but all have limitations: amphotericin B is restricted by the need for intravenous infusion and the occurrence of adverse events, fluconazole by its narrow spectrum of activity and the emergence of fluconazole-resistant fungi and itraconazole capsules by erratic absorption. Oral administration of antifungals has clear advantages in prophylaxis and an important current strategy is to maximize the extent and reliability of the oral bioavailability of antifungal agents. Mucositis is the main obstacle for success of strategies based on oral delivery. In this review, the ability of these new oral formulations to deliver sufficient antifungal prophylaxis is evaluated.