AMPA and metabotropic excitoxicity explain subplate neuron vulnerability

Cerebral hypoxia–ischemia results in unique patterns of injury during development owing to selective vulnerability of specific cell populations including subplate neurons. To evaluate the contribution of glutamate excitotoxicity, we studied enriched cultures of subplate neurons in comparison with cortical neurons, deriving expression profiles for glutamate receptor subunits by microarray and immunoblot. The excitotoxic potency of specific glutamate receptors was tested with selective agonists and antagonists. After 1 week in culture, subplate neurons are more sensitive to oxygen–glucose deprivation than cortical neurons, confirming in vivo observations. Subplate and cortical neurons are equally sensitive to glutamate and insensitive to NMDA. Subplate neurons are more sensitive than cortical neurons to AMPA and express twofold less GluR2. Subplate neurons express significantly more mGluR3, a receptor proposed to be protective. Despite this increased expression, group II mGluR agonists increase subplate neuron death and antagonists lessen glutamate excitotoxicity, suggesting a novel mechanism for subplate vulnerability.     

Time-oriented experimental design method to optimize hydrophilic matrix formulations with gelation kinetics and drug release profiles

A new experimental design methodology was developed by integrating the response surface methodology and the time series modeling. The major purposes were to identify significant factors in determining swelling and release rate from matrix tablets and their relative factor levels for optimizing the experimental responses. Properties of tablet swelling and drug release were assessed with ten factors and two default factors, a hydrophilic model drug (terazosin) and magnesium stearate, and compared with target values. The selected input control factors were arranged in a mixture simplex lattice design with 21 experimental runs. The obtained optimal settings for gelation were PEO, LH-11, Syloid, and Pharmacoat with weight ratios of 215.33 (88.50%), 5.68 (2.33%), 19.27 (7.92%), and 3.04 (1.25%), respectively. The optimal settings for drug release were PEO and citric acid with weight ratios of 191.99 (78.91%) and 51.32 (21.09%), respectively. Based on the results of matrix swelling and drug release, the optimal solutions, target values, and validation experiment results over time were similar and showed consistent patterns with very small biases. The experimental design methodology could be a very promising experimental design method to obtain maximum information with limited time and resources. It could also be very useful in formulation studies by providing a systematic and reliable screening method to characterize significant factors in the sustained release matrix tablet.     

Emerging therapeutic approaches in the management of retinal angiogenesis and edema

Conditions resulting in retinal angiogenesis and edema (exudative age-related macular degeneration, diabetic retinopathy, retinal vein occlusion and retinopathy of prematurity) are major causes of visual impairment, with significant impact on quality of life. There has been increasing clinical usage of anti-vascular endothelial growth factor (anti-VEGF) agents to stop retinal angiogenesis and resolve intraretinal fluid arising from these conditions. However, anti-VEGFs have not been completely successful in curing these conditions, and a range of emerging treatments aimed at supplementing or competing with anti-VEGF agents are being developed. We will discuss the proposed merits these emerging agents bring to the treatment arsenal and how they compare with anti-VEGFs with regards to therapeutic activity, potency, specificity and safety. This review will also highlight recent pre-clinical research findings and suggest where future research might be directed.     

Thyrolipoma and thyrolipomatosis: 5 case reports and historical review of the literature

Because thyrolipoma (adenolipoma of thyroid) and thyrolipomatosis (diffuse lipomatosis of thyroid) are distinctively rare conditions with only few cases reported in the literature, we are reporting 5 additional cases. All the 5 patients were adult females, with ages from 38 to 79 years, who presented with thyroid masses. Four of the patients had normal thyroid function tests and one had mild hypothyroidism. All patients received partial or total thyroidectomy. The thyroid specimens showed either circumscribed yellow-tan masses (cases 1, 2, and 3) or diffuse yellow-brown discoloration (cases 4 and 5). Histologic examination revealed abundant mature fat infiltrating the affected thyroid tissue in 3 distinct patterns: (1) fat infiltration limited to follicular adenomas (thyrolipoma); (2) fat diffusely infiltrating throughout the thyroid gland (thyrolipomatosis); or (3) fat infiltration involving both follicular adenoma and their surrounding thyroid tissue. Because of the rarity of thyroid fat-containing lesions, confusion in differential diagnosis may occasionally occur. It is important to be aware during frozen section that these lesions may present as extrathyroidal nodules, which can be radioactive on intraoperative scan for parathyroid glands. In addition, a papillary thyroid carcinoma was also identified in one case of thyrolipomatosis. All patients recovered well after surgery and there has been no recurrence of the lesions after 1 to 24 years of clinical follow-up. In summary, we are reporting 5 rare cases of thyrolipoma and thyrolipomatosis with distinct histologic patterns. Previously reported cases of thyrolipomatosis were reviewed and analyzed with the current cases.     

Exploratory neuropharmacological evaluation of a conformationally constrained thyrotropin-releasing hormone analogue

A conformationally constrained peptidomimetic derived from the endocrine and neuroactive tripeptide thyrotropin-releasing hormone (pGlu-His-Pro-NH(2)) was synthesized by convenient solid-phase organic chemistry and evaluated as a potential central nervous system agent. While this ethylene-bridged peptide analogue has been reported to lack the hormonal effect of the native peptide, we have shown in animal models that it possesses central nervous system activity characteristic of thyrotropin-releasing hormone. Compared to control, the peptidomimetic showed significant analeptic and antidepressant-like potencies. Moreover, an enhanced selectivity in antidepressant-like effect was measured when compared to that of the native peptide. Immobilized artificial membrane chromatography and in vitro metabolic stability studies also revealed that this constrained peptidomimetic has higher affinity to the blood-brain barrier than the native peptide and is metabolically stable. Consequently, this structure may be used as a template to design centrally selective and metabolically stable thyrotropin-releasing hormone analogues as potential neuropharmaceutical agents.     

Perceptions of patients on Medicare Part D medication therapy management services

ObjectivesTo determine patients’ perceptions and expectations about medication therapy management (MTM) services pertaining to the core elements of an MTM service in the community pharmacy setting, and to develop educational strategies and outreach programs aimed at increasing patients’ knowledge of MTM services and the expanded role of pharmacists in the community pharmacy setting.DesignMulticenter, cross-sectional, anonymous study.SettingFour regional community chain pharmacies in Maryland and Delaware in January and February 2006.Patients81 patients who were 18 years of age or older and able to complete the survey.InterventionSurvey containing 14 questions administered within pharmacies, two of which had patient care centers that were providing clinical services.Main outcome measurePatients’ perceptions and expectations regarding MTM services.Results49 of 81 patients (60%) had never heard of MTM services. A total of 65 patients (80%) had never had or received a medication therapy review, 63 (78%) never had or received a personal medication record, and 70 (86%) never had or received a medication action plan. Some 56% of participants (n = 45) thought that pharmacist provision of medication therapy reviews, personal medication records, medication action plans, recommendations about medications, and referral to other health care providers was very important. At least 70% of participants (n = 57) thought that having one-on-one consultation sessions with pharmacists to improve communication and relationships with their pharmacists and to improve their medication use and overall health was very important. More than 50% of participants indicated that they would like to receive brochures or talk to their pharmacist to learn more about MTM services.ConclusionPatients have very limited knowledge of the core elements of an MTM service in the community pharmacy setting. Patients reported that pharmacist provision of MTM services was important, but they were concerned about privacy and pharmacists’ time. Patients are also supportive of and believe that MTM services can improve communication and relationship with their pharmacist and improve medication use. Patients appear to prefer receiving brochures and talking to pharmacists to learn more about MTM services. This survey identified a key opportunity for pharmacists to inform patients about MTM services.     

The melanocortinergic pathway is rapidly recruited by emotional stress and contributes to stress-induced anorexia and anxiety-like behavior

Neurons producing melanocortin receptor agonist, alpha-MSH derived from proopiomelanocortin, and antagonist, agouti-related protein, are known to be sensitive to metabolic stress such as food deprivation and glucoprivation. However, how these neurons respond to emotional/psychological stress remained to be elucidated. We report here that acute emotional stressors, i.e. restraint and forced swim, evoked mRNA expression of c-fos, a neuronal activation marker, in a high percentage of proopiomelanocortin neurons (up to 53% for restraint stress and 62% for forced swim), with marked variations along the rostro-caudal axis of the arcuate nucleus. In contrast, only a small population of agouti-related protein neurons in this brain region was activated. These neuronal activation patterns were correlated with behavioral reactions. Both stressors suppressed feeding and induced anxiety-like behavior in the elevated plus-maze test, as reflected by a reduction in the percentage of entries and time spent in the open arms. Central pretreatment with SHU9119, a melanocortin receptor antagonist, dose dependently attenuated the anorectic and anxiogenic effects elicited by acute restraint or forced swim. These results indicate that the melancortinergic pathway can be rapidly recruited by acute emotional stress, and that activation of melanocortin signaling is involved in mediating stress-induced anorexia and anxiety.     

Post-hypoxic animal model of myoclonus

Post-hypoxic myoclonus is a form of myoclonus frequently caused by cardiac arrest. Development of an animal model may facilitate understanding of the condition and its treatments. We describe an animal model of post-hypoxic myoclonus developed in our laboratory through cardiac arrest, initially induced by chemical and later by mechanical obstruction of major cardiac vessels. These animals respond to valproate, clonazepam and 5-hydroxytrytophan reminiscent of its human counterpart. We review their behavioral, pharmacological and neuropathological features. Therapy developed for myoclonus in this model may be helpful for myoclonus from other etiologies such as corticobasal degeneration, Lewy-body disorders, Creutzfeld-Jacob disease, Alzheimer's disease.