Safety and tolerability assessment of intrastriatal neural allografts in five patients with Huntington's disease

This study describes issues related to the safety and tolerability of fetal striatal neural allografts as assessed in five patients with Huntington's disease. Huntington's disease (HD) is characterized by motor, cognitive, and behavioral disturbances. The latter include psychological disturbances and, as a consequence, we took particular care to analyze behavioral changes, in addition to the usual "safety" follow-up. We conducted multidisciplinary follow-up at least 2 years before and 1 year after grafting. Psychological care extended to close relatives. The grafting procedure itself was altogether safe and uneventful, and there were no apparent clinical deleterious effects for 1 year. The immunosuppressive treatment, however, was complicated by various problems (irregular compliance, errors of handling, side effects). Direct psychological consequences of the transplantation procedure were rare and not worrisome, although mood alteration requiring treatment was observed in one patient. Indirectly, however, the procedure required patients and relatives to accept constraints that tended to complicate familial situations already marred by aggressivity and depression. All patients and close relatives expressed major expectations, in spite of our strong and repeated cautioning. It is clearly important to be aware of these particular conditions since they may eventually translate into psychological difficulties in coping with the long-term clinical outcome of the procedure, if not beneficial. Despite an overall good tolerance, therefore, this follow-up calls for caution regarding the involvement of HD patients in experimental surgical protocols.     

Ectopic noradrenergic hyperinnervation does not functionally compensate for neonatal forebrain acetylcholine lesion

Adult rats who have undergone neonatal 192 IgG-saporin induced lesions of forebrain acetylcholine (ACH) neurons are normal on many behavioral tasks. In this study we determined whether ectopic hippocampal ingrowths, a documented consequence of these neonatal cholinergic lesions, functionally compensate for ACH denervation in these rats. Neonatal rats underwent systemic 6-hydroxydopamine (6-OHDA) injections on postnatal days (PND) 1-3 to prevent the ingrowths, and/or intraventricular 192 IgG-saporin injections on PND 7. The 192 IgG-saporin profoundly reduced basal forebrain p75 neurotrophin receptor (p75(NTR)) immunoreactive (IR) neurons. The 6-OHDA treatment abolished hippocampal and cortical dopamine-beta-hydroxylase (DBH) IR terminals, indicating the absence of normal norepinephrine (NE) innervation. Ectopic DBH IR and p75(NTR) IR varicosities which occurred in the hippocampus of 192 IgG-saporin treated rats were also eliminated by 6-OHDA treatment. Behavioral testing in adulthood indicated no effect of the treatments on the Morris water maze. 192 IgG-saporin treatment caused perseveration during delayed spatial alternation (DSA) and increased working but not reference memory errors on the radial arm maze (RAM). The 6-OHDA plus 192 IgG-saporin treated rats did not differ from the 192 IgG-saporin only rats on any task. These results indicate that ectopic hippocampal NE ingrowths do not functionally compensate for neonatal ACH lesions. Neonatal forebrain ACH lesion impairs working memory on the RAM but the absence of an effect on DSA contraindicates a basic dysfunction of short term memory. Despite severe combined neonatal loss of forebrain ACH and NE innervation, behavior is remarkably intact.     

Prognostic variables in male breast cancer

The prognostic role of ploidy status, S phase fraction, estrogen and progesterone receptor status, and the expression of p53 and erbB-2 protein in male breast carcinoma (MBC) remains controversial. The primary objective of this study was to determine which of the common prognostic factors for female breast cancer predict prognosis in MBC. A secondary objective was to assess the impact of comorbid illnesses on survival. A retrospective review of demographic data, surgical treatment, pathological staging, adjuvant treatment and follow-up was completed for 16 patients with MBC (1 intraductal and 15 invasive). Formalin-fixed, paraffin-embedded tissue was processed for ploidy, S phase fraction, and immunohistochemical detection of estrogen and progesterone receptors plus expression of p53 and erbB-2 protein. Six of 15 patients with infiltrating ductal carcinoma are currently alive without evidence of disease and a median survival of 61 months. Nine patients died after a median survival of 52 months, with 6 patients having no evidence of recurrent breast cancer. Two of 3 deaths secondary to advanced breast cancer occurred in patients who initially presented with T4 lesions and were staged IIIB. Two of 15 tumors were erbB-2 positive, whereas only 1 tested weakly positive for p53 protein. We observed that MBCs express erbB-2 and p53 proteins infrequently. Neither ploidy status, S phase fraction, nor erbB-2/p53 status provided any apparent improvement in establishing prognosis beyond routine pathological staging. Advanced TNM stage was associated with diminished survival. The majority of MBCs express estrogen and progesterone receptors. Survivals in MBC were reduced in association with comorbid medical conditions.     

Decreases in dilated pupil size in depressed patients with age may reflect adrenergic changes

Some studies have suggested that noradrenergic activity may decrease with age in depressed patients. Pupil size is regulated by a balance between norepinephrine and acetylcholine. The present study compares pupil size in 10 unmedicated patients with unipolar depression (296. 3) and in 16 normal controls. Pupil size after dilation with tropicamide, a cholinergic antagonist, was inversely related to age in the patients (r=-0.87), but did not diminish with age in controls. The results suggest that pupil size may provide an index of diminished noradrenergic function with age in patients with major depression.     

Lesion-associated accumulation of uPAR/CD87- expressing infiltrating granulocytes, activated microglial cells/macrophages and upregulation by endothelial cells following TBI and FCI in humans

Urokinase-type plasminogen activator receptor (uPAR/CD87) together with its ligand, urokinase-type plasminogen activator (uPA), constitutes a proteolytic system associated with tissue remodelling and leucocyte infiltration. uPAR is a member of the glycosyl phosphatidyl inositol (GPI) anchored protein family. The functional role of uPAR comprises fibrinolysis by conversion of plasminogen to plasmin. In addition, uPAR promotes cell adhesion, migration, proliferation, re-organization of the actin cytoskeleton, and angiogenesis. Furthermore, uPAR is involved in prevention of scar formation and is chemoattractant to macrophages and leucocytes. In order to investigate the pathophysiological role of uPAR following human CNS injury we examined necrotic brain lesions resulting from traumatic brain injury (TBI; n = 28) and focal cerebral infarctions (FCI; n = 17) by immunohistochemistry. Numbers of uPAR+ cells and uPAR+ blood vessels were counted. Following brain damage, uPAR+ cells increased significantly within 12 h, reached a maximum after 3-4 days and remained elevated until later stages. uPAR was expressed by infiltrating granulocytes, activated microglia/macrophages and endothelial cells. Numbers of uPAR+ vessels increased in parallel subsiding earlier following FCI than post TBI. The restricted, lesion-associated accumulation of uPAR+ cells in the brain parenchyma and upregulated expression by endothelial cells suggests a crucial role for the influx of inflammatory cells and blood-brain barrier (BBB) disturbance. Through a failure in BBB function, uPAR participates in formation of brain oedema and thus contributes to secondary brain damage. In conclusion, the study defines the localization, kinetic course and cellular source of uPAR as a potential pharmacological target following human TBI and FCI.     

Breakthrough pain in cancer patients: new therapeutic approaches to an old challenge

Breakthrough pain is a well recognized but ill-defined phenomenon that occurs commonly in the presence of otherwise stable, persistent pain. It is defined now as a "transient pain episode that occurs, or breaks through from the otherwise stable background pain." Breakthrough pain is usually associated with moderate to severe pain and may form a predictor of poor response to treatment with routine pharmacotherapy. Breakthrough pain is also associated with functional impairment and psychological distress. The assessment and treatment should be multidimensional. Although primary therapies such as chemotherapy, radiation treatment, and surgical options are explored, the mainstay of treatment is pharmacotherapy. Nonpharmacologic methods, such as orthotic devices and joint stabilizations along with behavioral methods, should be explored. Anesthetic and neurosurgical procedures are performed on a limited number of patients based on the prognosis, intractable nature of pain, and favorable risk/benefit ratio. Newer oral transmucosal fentanyl offers a favorable pharmacokinetic and pharmacodynamic profile and ease of administration.