Modeling of relationships between pharmacokinetics and blockade of agonist-induced elevation of intraurethral pressure and mean arterial pressure in conscious dogs treated with alpha(1)-adrenoceptor antagonists.

Fiduxosin is a new alpha(1)-adrenoceptor antagonist targeted for the treatment of symptomatic benign prostatic hyperplasia. The purpose of this study was to determine and compare the potencies of the alpha(1)-adrenoceptor antagonists terazosin, doxazosin, tamsulosin, and fiduxosin, based on relationships between plasma drug concentrations and blockade of phenylephrine (PE)-induced intraurethral (IUP) and mean arterial pressure (MAP) responses after single oral dosing in conscious male beagle dogs. Magnitude of blockade and plasma concentrations were evaluated at selected time points over 24 h. All drugs produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against drug plasma concentrations, direct relationships were observed that were well described by the sigmoidal maximal effect model. IUP IC(50) values for terazosin, doxazosin, tamsulosin, and fiduxosin were 48.6, 48.7, 0.42, and 261 ng/ml, respectively. MAP IC(50) values were 12.2, 13.8, 1.07, and 1904 ng/ml, respectively. Uroselectivity index values, defined as MAP IC(50)/IUP IC(50), were 0.25, 0.28, 2.6, and 7.3, respectively. These results extend previous observations with terazosin in this model, showing that doxazosin exhibits a uroselectivity index comparable to terazosin, consistent with the lack of alpha(1)-adrenoceptor subtype selectivity or uroselectivity of these drugs. Tamsulosin, an alpha(1a)-/alpha(1d)-subtype selective agent, had an index value approximately 10-fold greater than the nonselective drugs. Based on its pharmacokinetic profile and a relative uroselectivity 29-fold greater than the nonselective drugs, fiduxosin is expected to exhibit greater selectivity for urethral compared with vascular alpha(1)-adrenoceptors in human and should be a novel, long-acting, uroselective alpha(1)-adrenoceptor antagonist.     

Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke.

Bone marrow stromal cells (MSCs) increase vascular endothelial growth factor (VEGF) expression and promote angiogenesis after stroke. Angiopoietin-1 (Ang1) and its receptor Tie2 mediate vascular integrity and angiogenesis as does VEGF and its receptors. In this study, we tested whether MSC treatment of stroke increases Ang1/Tie2 expression, and whether Ang1/Tie2 with VEGF/ vascular endothelial growth factor receptor 2 (VEGFR2) (Flk1), in combination, induced by MSCs enhances angiogenesis and vascular integrity. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAo) and treated with or without MSCs. Marrow stromal cell treatment significantly decreased blood-brain barrier (BBB) leakage and increased Ang1, Tie2, and occludin (a tight junction protein) expression in the ischemic border compared with MCAo control. To further test the mechanisms of MSC-induced angiogenesis and vascular stabilization, cocultures of MSCs with mouse brain endothelial cells (MBECs) or astrocytes were performed. Supernatant derived from MSCs cocultured with MBECs significantly increased MBEC expression of Ang1/Tie2 and Flk1 compared with MBEC alone. Marrow stromal cells cocultured with astrocytes also significantly increased astrocyte VEGF and Ang1/Tie2 expression compared with astrocyte culture alone. Conditioned media from MSCs alone, and media from cocultures of MSCs with astrocytes or MBECs, all significantly increased capillary tube-like formation of MBEC compared with control Dulbecco's modified Eagle's medium media. Inhibition of Flk1 and/or Ang1 significantly decreased MSC-induced MBEC tube formation. Knockdown of Tie2 expression in MBECs significantly inhibited MSC-induced tube formation. Our data indicate MSC treatment of stroke promotes angiogenesis and vascular stabilization, which is at least partially mediated by VEGF/Flk1 and Ang1/Tie2.     

Psychiatric aspects of epilepsy.

Patients who have epilepsy face many challenges resulting from their illness and have frequent psychiatric comorbidities. Recognition of these disorders is increasing and is having a positive impact on patients' quality of life. Recent recommendations about a new classification system for psychiatric disorders related specifically to epilepsy and based on the relationship of symptoms to seizures, antiepileptic medications, and EEG changes should further research and treatment. Especially insofar psychiatric syndromes specific to epilepsy can be identified, correlation of clinical phenomena with relatively well-understood pathophysiology in epilepsy will allow advances in the understanding of psychiatric illness. This progress should move the treatment of patients who have epilepsy toward a comprehensive biopsychosocial model that focuses on the whole person rather than simply on the disease process.     

Cutaneous Metastasis From Adenoid Cystic Carcinoma of the Parotid Gland

BACKGROUND: Cutaneous metastasis from adenoid cystic carcinoma of the salivary gland is very rare. OBJECTIVE: To present an unusual case of cutaneous metastasis from adenoid cystic carcinoma of the right parotid gland. METHODS: A 63-year-old woman with multiple subcutaneous nodules on the abdomen and a gradually enlarged mass over the right parotid area was examined. A skin biopsy was taken from one of the abdominal nodules. RESULT: Skin biopsy demonstrated the characteristic histopathologic features of metastatic adenoid cystic carcinoma. A subsequent computerized tomography of the head and neck revealed a huge soft tissue mass involving the right parotid gland. Computerized tomography of the chest revealed extensive nodular pleural thickening, and pleural biopsy also showed typical histopathologic features of metastatic adenoid cystic carcinoma. All of these results are consistent with the diagnosis of an adenoid cystic carcinoma of the right parotid gland with disseminated metastases. CONCLUSION: We report a rare case of cutaneous metastasis from adenoid cystic carcinoma of the right parotid gland. The presentation of cutaneous metastasis is often nonspecific and may mimic benign lesions. Subcutaneous nodules that are rapidly developing or eruptive, are rapidly growing and have stony hardness in nature, have pain or tenderness, and have nonhealing ulceration remind us of the possibility of cutaneous metastases. Dermatologists and dermatologic surgeons should keep the diagnosis of cutaneous metastasis in mind and always perform skin biopsy when encountering these lesions.     

Non-HIV-Related Progressive Multifocal Leukoencephalopathy (PML): A Tertiary Cancer Center Experience

In the course of 1 year at a tertiary cancer center, 3 patients (2 men; 1 woman; age 51-75 years) were seen in neurological consultation (1.5% of all consultations). Clinical course in all patients was of a progressive neurologic disorder not consistent with either a primary or secondary malignancy. Magnetic resonance (MR) imaging was most informative with respect to diagnosis and subsequent management. Brain biopsy was performed in all patients to assist in both diagnosis and prognostication. All patients were determined to have progressive multifocal leukoencephalopathy (PML) by brain biopsy.     

Glomerular filtration rate and N-terminal pro-brain natriuretic peptide as predictors of cardiovascular mortality in vascular patients.

OBJECTIVES: The purpose of this work was to assess the prognostic role of glomerular filtration rate (GFR) and NT-terminal pro-B-type natriuretic peptide (NT-proBNP) for mortality end points in the vascular population. BACKGROUND: The GFR and NT-proBNP have been shown to predict mortality end points in free-living and limited vascular populations, independent of traditional risk factors. However, their prognostic power in an unrestricted vascular population is poorly understood. METHODS: A total of 412 subjects from a vascular cohort with a history of either peripheral arterial disease (PAD) and/or other cardiovascular disease (CVD) were included in this prospective cohort analysis and followed for an average of 6.7 years. Outcome variables were all-cause mortality, ischemic heart disease (IHD) mortality, and any cardiovascular mortality. The prognostic roles of GFR and NT-proBNP levels were determined using multivariate survival analysis. RESULTS: Higher GFR (per 10 ml/min/1.73 m2) was significantly protective for all-cause mortality (hazard ratio [HR] 0.81, p < 0.001), IHD mortality (HR 0.82, p = 0.008), and CVD mortality (HR 0.84, p = 0.005). Conversely, NT-proBNP was not a significant predictor of any mortality end point. The GFR showed the strongest association in subjects with a history of other CVD. Although NT-proBNP did not demonstrate a significant prognostic role in any of the subgroups, the data were suggestive for patients with PAD alone. CONCLUSIONS: Glomerular filtration rate was a robust predictor of all-cause, IHD, and cardiovascular mortality in the vascular population, particularly in those with a history of other CVD, while NT-proBNP showed a suggestive association limited to the group with PAD only. These findings suggest that these markers must be selectively applied in the vascular population for greatest clinical utility.     

The changing face of paediatric hydrocephalus: a decade's experience.

All 253 children receiving neurosurgical intervention for hydrocephalus (HCP) at a single British Neurosurgical Unit over a decade were investigated by retrospective case note review. Referral rates and mean age at presentation remained stable throughout, as did proportions of children presenting due to myelomeningocoele or meningitis. Comparing the first and second halves of the decade, the predominant aetiologies (intraventricular haemorrhage [IVH] at <1 year and brain tumour at 1-16 years) reduced from comprising half (70/129) of all cases to just over one-third (43/124). Other significant changes included a 45% reduction in neonatal IVH and a 179% increase in rare miscellaneous disorders. Outcome after 4 years of follow-up for all patients showed 44.4% without deficit, 11.9% with non-cognitive neurological deficits only, 11.5% with cognitive impairment only, 13.5% with both cognitive and neurological impairments, and 15.5% mortality.