Expression of the axon growth-related neural adhesion molecule TAG-1/axonin-1 in the adult mouse brain

 TAG-1/axonin-1 is a neuronal cell adhesion molecule of the immunoglobulin superfamily. It is predominantly expressed during neural development and has been reported to be involved in axonal growth and pathfinding. Here, the expression of TAG-1/axonin-1 was investigated anatomically in the adult mouse brain by in situ hybridization using digoxigenin-labeled cRNA probes. Low levels of TAG-1/axonin-1 could be detected in cerebellar granule cells, in tufted and mitral cells of the olfactory bulb, and in pyramidal cells of area CA1 and CA3 of the hippocampus. We suspect that the expression of TAG-1/axonin-1 in these structures of the adult brain may serve neural plasticity. Accepted: 8 September 1997     

Left-hemispheric superiority for visuospatial orientation in homing pigeons

To test for lateralisation of visuospatial orientation during homing, pigeons who had binocularly learned the homeward route from remote release sites were tested monocularly on either their left or their right eye for homing performance. In two experiments with three different release sites, birds using their right eye showed considerably better homing performance. If sun compass information was available, there was no difference in the direction of vanishing. Without this information, a difference between pigeons using their left or right eye emerged. Results show that visuospatial orientation in birds can be lateralised in favour of the left brain hemisphere and lend further support to the view that vision is important for pigeons homing on a familiar route. Cognitive mechanisms which might account for the observed pattern of lateralisation are discussed.     

Managing drug shortages: seven years' experience at one health system.

A health system's experience in monitoring drug shortages since 1996 within the organization and since 2001 on a national level is described. Since January 1996, the Drug Information Service (DIS) at the University of Utah Hospitals and Clinics (UUHSC) has systematically prepared written bulletins to affected practitioners when drug shortages occurred. The DIS began providing information on a national level to the American Society of Health-System Pharmacists in January 2001. A total of 224 drug shortages were tracked from January 1996 to June 2002. All shortages at UUHSC were also national shortages, but only about two thirds of national shortages also affected UUHSC. The most common reasons for shortages were manufacturing problems (28%) and product discontinuation (20%). The most frequently represented pharmacologic-therapeutic categories were central nervous system agents (24%) and serums, toxoids, and vaccines (17%). Of the 119 shortages in 2001, 70 (59%) were still ongoing as of the end of June 2002. The most common potential safety problems were that clinicians might be unfamiliar with the alternative agent (54%) and that the alternative's dosage requirement was different (50%). Over half of the shortages were cost neutral, but the assessment did not include substantial potential indirect costs. Detailed information on drug shortages collected by a health system's drug information service since 1996 indicated a trend toward more frequent shortages.     

Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor.

PURPOSE: To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics. PATIENTS AND METHODS: Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained. RESULTS: The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor. CONCLUSION: Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.     

Chemopreventive effects of alpha-santalol on skin tumor development in CD-1 and SENCAR mice.

Studies from our laboratory have indicated skin cancer chemopreventive effectsof sandalwood oil in CD-1 mice. The purpose of this investigation was to study the skin cancer chemopreventive effects of alpha-santalol, a principal component of sandalwood oil in CD-1 and SENCAR mice. alpha-Santalol was isolated from sandalwood oil by distillation under vacuum and characterized by nuclear magnetic resonance and gas chromatography-mass spectrometry. Chemopreventive effects of alpha-santalol were determined during initiation and promotion phase in female CD-1 and SENCAR mice. Carcinogenesis was initiated with 7,12-dimethylbenz(a)anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). The effects of alpha-santalol treatment on TPA-induced epidermal ornithine decarboxylase (ODC) activity and (3)H-thymidine incorporation in epidermal DNA of CD-1 and SENCAR mice were also investigated. alpha-Santalol treatment during promotion phase delayed the papilloma development by 2 weeks in both CD-1 and SENCAR strains of mice. alpha-Santalol treatment during promotion phase significantly (P < 0.05) decreased the papilloma incidence and multiplicity when compared with control and treatment during initiation phase during 20 weeks of promotion in both CD-1 and SENCAR strains of mice. alpha-Santalol treatment resulted in a significant (P < 0.05) inhibition in TPA-induced ODC activity and incorporation of (3)H-thymidine in DNA in the epidermis of both strains of mice. alpha-Santalol significantly prevents papilloma development during promotion phase of 7,12-dimethylbenz(a)anthracene-TPA carcinogenesis protocol in both CD-1 and SENCAR mice, possibly by inhibiting TPA-induced ODC activity and DNA synthesis. alpha-Santalol could be an effective chemopreventive agent for skin cancer. Additional experimental and clinical studies are needed to investigate the chemopreventive effect of alpha-santalol in skin cancer.     

Th-2 type cytokine receptors in allergic rhinitis and in response to topical steroids

Objectives: Th-2 type cytokine production (inter-leukin-4 [IL-4] and interleukin-5 [IL-5]) has been demonstrated to play a significant role in the pathophysiology of allergic rhinitis (AR), and the treatment of AR with topical corticosteroids has been shown to reduce the expression of Th-2 type cytokines in vivo. However, the contribution and expression of Th-2 type cytokine receptors in AR and their response to corticosteroid treatment remain to be clarified. Objectives of the current study are 1. To examine the expression of the cytokine IL-4 and IL-5 receptors (IL-4R and IL-5R) in a nasal allergen challenge model and to contrast this with the expression of the receptor for the Th-1 type cytokine, interferon-gamma receptor (IFN-γR), and 2. to examine the effects of pretreatment with topical corticosteroid before allergen challenge on the expression of these same receptors. Study Design: Randomized prospective study involving 14 ragweed-allergic subjects evenly divided between placebo and corticosteroid pretreatment. Methods: Immunocytochemistry (alkaline phosphatase-antial-kaline phosphatase labeling [APAAP] technique) was used to stain nasal biopsy specimens before and after allergen challenge. Antibodies used included anti-CD3, CD4, CD8, MBP, IL-4R, IL-5R, and IFN-γR. Results: Following allergen challenge, we observed a significant increase in the Th-2 type cytokine receptors (IL-4R and IL-5R; P < .05), as well as a significant decrease in the expression of the Th-1 type cytokine receptor (IFN-γR; P < .05). Pretreatment with topical corticosteroids before nasal allergen challenge resulted in decreased expression of IL-4R (P < .05) and IL-5R (P < .05) and increased expression of IFN-γR (P < .05). Further, IL-4R and IL-5R expression correlated with eosinophil infiltration in the tissues. Conclusions: We have demonstrated that in AR, cytokine receptors for IL-4, IL-5, and IFN-γ follow a similar pattern to their ligands. In addition, pretreatment with topical corticosteroids was shown to alter the cytokine receptor expression pattern from a Th-2 profile more toward a Th-1 profile. Laryngoscope, 108:1528–1533,1998     

The epidemiology of rotavirus diarrhea in Latin America. Anticipating rotavirus vaccines.

OBJECTIVE: To assess the disease burden and characterize the epidemiology of rotavirus diarrhea in Latin America. METHODS: We conducted a literature review of studies of children < 5 years of age who were hospitalized or seen as outpatients for diarrhea and for whom rotavirus was sought as the etiologic agent of the diarrhea. This review included inpatient and outpatient studies published since 1998 that included at least 100 children and reported surveillance activities lasting at least 12 consecutive months. RESULTS: A total of 18 inpatient and 10 outpatient studies met the criteria for inclusion in this review. Rotavirus was detected in a median of 31% of inpatients (range, 16%-52%) and 30.5% of outpatients (range, 4%-42%). The median detection rate was higher in studies that used an enzyme-linked immunosorbent assay (ELISA) (inpatients 38%, outpatients 33%) versus less sensitive methods of detection. The age distribution of rotavirus disease varied among countries, with 65%-85% of children hospitalized in the first year of life. Most countries had rotavirus admissions year round, and rotavirus generally exhibited a winter seasonal peak in both temperate and tropical climates. CONCLUSIONS: The heavy burden of disease attributable to rotavirus in Latin America suggests that vaccines currently being tested could have considerable impact in preventing hospitalizations, clinic visits, and deaths. The findings of the young age distribution of patients highlight the importance of early immunization for the success of a vaccine program. The data suggest that future surveillance for rotavirus diarrhea in Latin America should use a standardized surveillance protocol with an ELISA for detection. Data from surveillance studies will be critical to monitor the impact of the future introduction of vaccines.