Recombinant adeno-associated viral vector (rAAV) delivery of GDNF provides protection against 6-OHDA lesion in the common marmoset monkey (Callithrix jacchus)

Glial cell line-derived neurotrophic factor (GDNF) has shown potential as a treatment for Parkinson's disease. Recombinant adeno-associated viral vectors expressing the GDNF protein (rAAV-GDNF) have been used in rodent models of Parkinson's disease to promote functional regeneration after 6-OHDA lesions of the nigrostriatal system. The goal of the present study was to assess the anatomical and functional efficacy of rAAV-GDNF in the common marmoset monkey (Callithrix jacchus). rAAV-GDNF was injected into the striatum and substantia nigra 4 weeks prior to a unilateral 6-OHDA lesion of the nigrostriatal bundle. Forty percent of the dopamine cells in the lesioned substantia nigra of the rAAV-GDNF-treated monkeys survived, compared with 21% in the untreated monkeys. Fine dopaminergic fibres were observed microscopically in the injected striatum of some rAAV-GDNF-treated monkeys, suggesting that rAAV-GDNF treatment may have prevented, at least in part, the loss of dopaminergic innervation of the striatum. Protection of dopamine cells and striatal fibre innervation was associated with amelioration of the lesion-induced behavioural deficits. rAAV-GDNF-treated monkeys showed partial or complete protection not only in the amphetamine and apomorphine rotation but also in head position and the parkinsonian disability rating scale. Therefore, our study provides evidence for the behavioural and anatomical efficacy of GDNF delivered via an rAAV vector as a possible treatment for Parkinson's disease.     

Mpi recombinase globally modulates the surface architecture of a human commensal bacterium

The mammalian gut represents a complex and diverse ecosystem, consisting of unique interactions between the host and microbial residents. Bacterial surfaces serve as an interface that promotes and responds to this dynamic exchange, a process essential to the biology of both symbionts. The human intestinal microorganism, Bacteroides fragilis, is able to extensively modulate its surface. Analysis of the B. fragilis genomic sequence, together with genetic conservation analyses, cross-species cloning experiments, and mutational studies, revealed that this organism utilizes an endogenous DNA inversion factor to globally modulate the expression of its surface structures. This DNA invertase is necessary for the inversion of at least 13 regions located throughout the genome, including the promoter regions for seven of the capsular polysaccharide biosynthesis loci, an accessory polysaccharide biosynthesis locus, and five other regions containing consensus promoter sequences. Bacterial DNA invertases of the serine site-specific recombinase family are typically encoded by imported elements such as phage and plasmids, and act locally on a single region of the imported element. In contrast, the conservation and unique global regulatory nature of the process in B. fragilis suggest an evolutionarily ancient mechanism for surface adaptation to the changing intestinal milieu during commensalism.     

Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin

Cerebrospinal fluid (CSF) from healthy individuals contains between 1,000 and 3,000 leukocytes per ml. Little is known about trafficking patterns of leukocytes between the systemic circulation and the noninflamed CNS. In the current study, we characterized the surface phenotype of CSF cells and defined the expression of selected adhesion molecules on vasculature in the choroid plexus, the subarachnoid space surrounding the cerebral cortex, and the cerebral parenchyma. Using multicolor flow cytometry, we found that CSF cells predominantly consisted of CD4+/CD45RA-/CD27+/CD69+-activated central memory T cells expressing high levels of CCR7 and L-selectin. CD3+ T cells were present in the choroid plexus stroma in autopsy CNS tissue sections from individuals who died without known neurological disorders. P- and E-selectin immunoreactivity was detected in large venules in the choroid plexus and subarachnoid space, but not in parenchymal microvessels. CD4+ T cells in the CSF expressed high levels of P-selectin glycoprotein ligand 1, and a subpopulation of circulating CD4+ T cells displayed P-selectin binding activity. Intercellular adhesion molecule 1, but not vascular cell adhesion molecule 1 or mucosal addressin cell adhesion molecule 1, was expressed in choroid plexus and subarachnoid space vessels. Based on these findings, we propose that T cells are recruited to the CSF through interactions between P-selectin/P-selectin ligands and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 in choroid plexus and subarachnoid space venules. These results support the overall hypothesis that activated memory T cells enter CSF directly from the systemic circulation and monitor the subarachnoid space, retaining the capacity to either initiate local immune reactions or return to secondary lymphoid organs.     

Impact of cardiac surgery using cardiopulmonary bypass on course of chronic lymphatic leukemia: a case-control study

BACKGROUND: Chronic lymphatic leukemia (CLL) is a common disease among elderly individuals. The number of older patients undergoing operations with cardiopulmonary bypass (CPB) is increasing. The aim of the present study was to evaluate the impact of cardiac surgery using CPB on the long-term course of CLL. METHODS: From 1992 to 2000, a total of 28 patients with CLL underwent heart surgery using CPB at our institution (group I). These patients were compared with 25 patients from the CLL register who were retrospectively matched with regard to preoperative administration of chemotherapy, Binet classification, age, and sex (group II). A time-point was selected for each patient in group II so that the variables for the two groups corresponded in relation to the time of operation of the patients in group I. Midterm follow-up data in both groups were analyzed. RESULTS: There were no differences between groups regarding matched variables. The mean follow-up time was similar in both groups (2.6 +/- 2.2 vs 2.3 +/- 1.3 years, p > 0.5). The 30-day mortality in group I was 14.3%. The mean stay in the intensive care unit was 4.2 +/- 7.5 days; the median number of units of packed red blood cells transfused was three (range 0 to 17). Compared with group II, in group I significantly fewer patients (11 vs 17, p = 0.049) required chemotherapy significantly later (1.98 +/- 2.06 vs 0.84 +/- 1.18 years, p = 0.018). During follow-up, no difference was found between groups regarding severe infections (10 vs 14, p = 0.14). Despite postoperative mortality in group I, the long-term mortality was similar in both groups (p = 0.3). CONCLUSIONS: Cardiac surgery using CPB did not have a negative impact on the natural course of CLL. Moreover, this procedure seems to be associated with a decrease in the number of postoperative chemotherapy administrations and with an increase of chemotherapy-free survival time. Although CLL may be a risk factor in the early postoperative period, it is not a contraindication for cardiac surgery using CPB.     

High dietary iron concentrations enhance the formation of cholesterol oxidation products in the liver of adult rats fed salmon oil with minimal effects on antioxidant status

The aim of this study was to investigate the effect of high dietary iron concentrations on the antioxidant status of rats fed two different types of fat. Four groups of male adult Sprague-Dawley rats were fed diets with adequate (50 mg iron supplemented per kg diet) or high (500 mg iron supplemented per kg diet) iron concentrations with either lard or salmon oil as dietary fat at 100 g/kg for 12 wk. The antioxidant status of the rats was profoundly influenced by the type of fat. Rats fed salmon oil diets had higher concentrations of thiobarbituric acid-reactive substances (TBARS) (P < 0.001), various cholesterol oxidation products (COP) (P < 0.001), total and oxidized glutathione (P < 0.05) and a lower concentration of alpha-tocopherol (P < 0.05) in liver and plasma than rats fed lard diets. The iron concentration of the diet did not influence the concentrations of TBARS, the activities of superoxide dismutase and glutathione peroxidase or the concentration of alpha-tocopherol in plasma or liver. The activity of catalase (P < 0.01) and the concentrations of total, oxidized and reduced glutathione (P < 0.05) in liver were slightly but significantly higher in rats fed high iron diets than in rats fed adequate iron diets, irrespective of the dietary fat. Rats fed the high iron diets with salmon oil, moreover, had higher concentrations of various COP in the liver (P < 0.001) than rats fed adequate iron diets with salmon oil. These results suggest that feeding a high iron diet does not generally affect the antioxidant status of rats but enhances the formation of COP, particularly if the diet is rich in polyunsaturated fatty acids.     

Carcinoma in situ in a lateral cervical cyst

BACKGROUND: The development of an invasive squamous cell carcinoma within a lateral cervical cyst as a result of malignant transformation of the epithelium is considered a rare circumstance. The existence of this entity is a source of controversy in light of the differential diagnosis, which includes a cervical metastasis from an unknown primary carcinoma (CUP-syndrome). Apart from site, histologic findings, and follow-up, the principal diagnostic criterion for lateral cervical cyst carcinoma is the histomorphologic demonstration of transition of the benign epithelium into invasive squamous cell carcinoma. Although numerous case reports of this entity exist, carcinoma in situ in a lateral cervical cyst has been reported in only five cases thus far. METHOD: In this context, we present the case of a 44-year-old patient with a 7-month history of cervical swelling. RESULTS: After diagnostic extirpation of the tumor, histologic findings were consistent with a lateral branchial cyst with high-grade dysplasia and carcinoma in situ of the squamous epithelial lining. CONCLUSION: This case of a premalignant lesion within a lateral branchial cyst (ie, carcinoma in situ) supplies the "missing link" and adds credibility to the concept of primary branchiogenic carcinoma.     

Determinants for receiving acupuncture for LBP and associated treatments: a prospective cohort study

Background  

Acupuncture is a frequently used but controversial adjunct to the treatment of chronic low back pain (LBP). Acupuncture is now considered to be effective for chronic LBP and health care systems are pressured to make a decision whether or not acupuncture should be covered. It has been suggested that providing such services might reduce the use of other health care services. Therefore, we explored factors associated with acupuncture treatment for LBP and the relation of acupuncture with other health care services.