Faculty Bibliography

A critical comparison of the attributes of several types of stem cells is presented, with particular emphasis on properties that are critical for the application of these cells for therapeutic purposes. The importance of an autologous source of pluripotent stem cells is stressed. It is apparent that two sources currently exist for non-embryonic pluripotent stem cells--very small embryonic-like stem cells (VSELs) and induced pluripotent stem cells (iPS). The impact of the emerging iPS research on therapy is considered.

OBJECTIVE: Young adults with childhood-onset GH deficiency (GHD) have reduced memory and attention, which can be improved by treatment with GH. Little information is available on cognitive function in elderly GHD patients. DESIGN: Single center, double-blind, randomized, placebo-controlled study of 52-week duration. METHODS: Elderly GH therapy naive GHD patients (n=34; age range 60-77 years) were enrolled and randomized to receive placebo or GH therapy which was titrated to achieve a target IGF-I level of +1 to +2 s.d. of the normal mean for age. Cognitive function was assessed at baseline and after 24 and 52 weeks, using a computerized psychometric test package (Neurobehavioral Examination System-2). RESULTS: The mean GH dose was 0.16+/-0.06 mg/day; mean IGF-I increased from 135+/-59 ng/ml at baseline to 213+/-77 ng/ml during active treatment. The GH-treated group had better mean serial digit learning scores compared with placebo group (P<0.05). Assessment of effect sizes showed that improvements in memory occurred with GH after 24 weeks. The overall adverse event rates were similar in the GH and the placebo group. CONCLUSION: This study indicates that GH replacement may be accompanied by improvement in certain measures of cognitive function in elderly patients with GHD.

OBJECTIVE:There is growing evidence in the neuropsychological literature that growth hormone (GH) deficiency is associated with cognitive impairment. There is also evidence that this impairment may be ameliorated with GH replacement therapy. The current study assessed the nature and severity of cognitive impairment associated with growth hormone deficiency, as well as effect of GH replacement on cognitive function by conducting a meta-analysis of the published literature to date. METHOD/METHODS:Thirteen studies met the inclusion criteria and these included: five cross-sectional studies investigating GH deficiency; and, eight (eight prospective, two of which also included cross-sectional comparisons) investigating GH replacement. Effect sizes (Cohen's d) falling into six cognitive domains were computed (separately for GH deficiency and GH replacement). RESULTS:For GH deficiency, each of the cognitive domains assessed (besides language) showed moderate to large impairments when compared to matched controls (Effect sizes -0.46 to -1.46). For GH replacement, even though treated patients still performed moderately to largely below that of controls, when compared to their own baselines (as in prospective analyses), moderate improvements were found in cognitive performance, particularly attention and memory. CONCLUSION/CONCLUSIONS:This meta-analysis clearly demonstrates the link between GH and cognitive performance, where poor performance can be ameliorated with GH treatment.

BACKGROUND: Desloratadine reduces symptoms and maintains nasal airflow in patients with seasonal allergic rhinitis (SAR) during experimental allergen exposure. OBJECTIVE: To compare the effects of desloratadine and placebo on symptom scores, quality of life (QOL), and nasal airway patency in patients with SAR during the allergy season. METHODS: Adults with symptomatic SAR were randomized in a double-blind manner to receive desloratadine, 5 mg, or placebo for 14 days. Patient-rated SAR symptoms were recorded twice daily (morning and evening). On days 1 and 15, SAR symptoms were scored jointly (investigator and patient), nasal airflow was measured using 4-phase rhinomanometry, and QOL and the overall condition of SAR were rated. Overall treatment response was scored on day 15. Adverse events were recorded. RESULTS: At day 15, total symptom (P = .03) and total nasal symptom (P = .02) scores and patient morning-rated individual nasal symptom scores (except nasal stuffiness) (P < or = .04) decreased significantly from baseline with desloratadine vs placebo. Flow in the descending expiratory nasal airflow phase was significantly greater (P = .046) and the percentage increase in total inspiratory nasal airway resistance was less (P = .03) in the desloratadine group vs the placebo group. The overall condition of SAR was less severe (P = .045), the therapeutic response was greater (P = .004), and the nasal symptom domain of the QOL score was significantly better (P = .03) in the desloratadine group. Adverse event rates were similar in both groups. CONCLUSION: Desloratadine treatment for 14 days improved nasal airflow and resistance as well as symptom and QOL scores in patients with symptomatic SAR during the allergy season.

BACKGROUND: Desloratadine is a selective H1-antihistamine used in the treatment of allergic rhinitis and chronic idiopathic urticaria. Desloratadine inhibits the release of allergic inflammatory mediators in vitro. We studied the impact of desloratadine on mast cell degranulation due to activation and re-activation by the secretagogue, compound 48/80. METHODS: Rat peritoneal eluate containing 5-6% mast cells were activated by a low concentration of compound 48/80 in a medium containing the vital fluorescent dye, Sulforhodamine-B (SFRM-B, 200 microg/ml), which is engulfed by activated mast cells. The fluorescent image of activated mast cells was captured digitally and the total fluorescent area was analyzed when desloratadine was applied before or after compound 48/80. RESULTS: Mast cells were not activated by desloratadine (10(-4) M), SFRM-B (200 microg/ml), or diluent alone. A low concentration of compound 48/80 (0.125 microg/ml) induced fluorescence, while mast cells lost fluorescent images due to further degranulation on re-exposure to compound 48/80. Desloratadine (10(-8)-10(-4) M), inhibited compound 48/80-induced mast cell degranulation in a concentration-dependent manner. Desloratadine also reduced the loss of fluorescent images due to re-exposure to compound 48/80. CONCLUSIONS: Desloratadine may have a mast cell stabilizing effect at low concentrations in response to repeated mast cell activation in vitro.

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1 versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic 'overshooting' with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-alpha and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.

The standard intravenous short Synacthen test (SSST) has long been accepted as one of the most reliable diagnostic tests of adrenocortical insufficiency. Intramuscular (i.m.) administration of ACTH obviates the need of venous cannulation and can be used as an alternative to the intravenous test. Nevertheless, reports of correlation between cortisol response to i.m. ACTH1-24 and 24-hr average cortisol concentration are scarce. We studied this relation in 64 nonobese healthy men. Blood samples for serial cortisol measurements were collected hourly over 24 hrs. The following day, blood samples were collected at baseline and at 30 and 60 min after intramuscular (i.m.) administration of 250 microg of ACTH1-24. All healthy men reached 24-hr serum cortisol peak values (Cmax) between 0600 h and 1000 h. Following i.m. ACTH1-24, cortisol levels significantly increased at both 30 (C30ACTH) and 60 (C60ACTH) minutes, when compared to baseline values. C30ACTH and C60ACTH significantly correlated with Cmax and with the 24-hr time-integrated cortisol concentration (AUC0-24). Morning mean cortisol was calculated as the average of serum concentrations measured between 0600 h and 1000 h (C(av)6-10) and correlated very well with AUC0-24. In conclusion, we confirmed that i.m. administration of ACTH1-24, followed by a single blood sampling at 60 min for cortisol measurement represents a valid, convenient and cost- effective screening test of adrenal function.