Human Neural Stem Cells: Isolation, Expansion and Transplantation

Neural stem cells, with the capacity to self renew and produce the major cell types of the brain, exist in the developing and adult rodent central nervous system (CNS). Their exact function and distribution is currently being assessed, but they represent an interesting cell population, which may be used to study factors important for the differentiation of neurons, astrocytes and oligodendrocytes. Recent evidence suggests that neural stem cells may also exist in both the developing and adult human CNS. These cells can be grown in vitro for long periods of time while retaining the potential to differentiate into nervous tissue. Significantly, many neurons can be produced from a limited number of starting cells, raising the possibility of cell replacement therapy for a wide range of neurological disorders. This review summarises this fascinating and growing field of neurobiology, with a particular focus on human tissues.     

A theoretical study of multisensory integration in the superior colliculus by a neural network model

Neurons in the superior colliculus (SC) integrate stimuli of different modalities. In this work, a mathematical model of the integrative response of SC neurons is presented, to gain a deeper insight into the possible mechanisms involved, and on individual differences in integrative abilities. The model includes two unimodal areas (auditory and visual), which communicate via feedforward and feedback synapses with a third multisensory area. Each neuron is represented via a sigmoidal relationship and a first-order dynamic. Neurons in the same area interact via lateral synapses. Simulations show that the model, with a basal parameter set, can mimic various responses described in the literature: (i) multimodal enhancement in response to two cross-modal stimuli within the receptive field, according to the inverse-effectiveness principle; (ii) within-modality suppression and cross-modality suppression by a stimulus (of the same or other modality) placed outside the receptive field. Sensitivity analysis on model parameters demonstrate that different classes of neurons observed in the literature (such as, neurons which exhibit within modality suppression without cross-modality suppression, or neurons with asymmetrical cross-modality suppression) can be reproduced by simply modifying synaptic strengths in the multimodal area. Finally, exempla of the possible role of feedback mechanisms in ambiguous conditions (such as reinforcement of a poor perception by a second cross-modal stimulus, or ventriloquism) are shown and critically discussed. The model may be of value to assess the different mechanisms responsible for multisensory integration in the SC, and, in future, to study neural plasticity in multisensory systems during development or rehabilitation.     

The prevalence and distribution of gingival recession in subjects with a high standard of oral hygiene

Abstract The aim of this study was to evaluate the prevalence and the development/progression of attachment loss and gingival recession at buccal tooth surfaces in a population sample with a high standard of oral hygiene. An additional aim was to study the relationship between attachment loss and gingival recession. The subject sample examined comprised 225 regular denial care attendants at 12 community dental clinics in Sweden. Ail subjects were subjected to a baseline examination in 1977–78 and were re-examined after 5 years and 12 years. The clinical examinations involved assessment of plaque, gingivitis, probing depth, probing attachment loss and gingival recession. A full-mouth set of intra-oral radiographs was obtained at each examination and used for determination of the height of periodontal bone support. The results of the cross-sectional and longitudinal analyses performed showed that in subjects with a high standard of oral hygiene (i) buccal gingival recession was a frequent finding, (ii) the proportion of subjects with recession increased with age. (iii) the prevalence as well as the incidence of recessions within the dentition showed different patterns depending on age, (iv) sites with recession showed susceptibility for additional apical displacement of the gingival margin and (v) loss of approximal periodontal support was associated with gingival recession at the buccal surface.     

Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha

Activation of inflammatory pathways may contribute to the beginning and the progression of both atherosclerosis and type 2 diabetes. Here we report a novel interaction between insulin action and control of inflammation, resulting in glucose intolerance and vascular inflammation and amenable to therapeutic modulation. In insulin receptor heterozygous (Insr+/-) mice, we identified the deficiency of tissue inhibitor of metalloproteinase 3 (Timp3, an inhibitor of both TNF-alpha-converting enzyme [TACE] and MMPs) as a common bond between glucose intolerance and vascular inflammation. Among Insr+/- mice, those that develop diabetes have reduced Timp3 and increased TACE activity. Unchecked TACE activity causes an increase in levels of soluble TNF-alpha, which subsequently promotes diabetes and vascular inflammation. Double heterozygous Insr+/-Timp3+/- mice develop mild hyperglycemia and hyperinsulinemia at 3 months and overt glucose intolerance and hyperinsulinemia at 6 months. A therapeutic role for Timp3/TACE modulation is supported by the observation that pharmacological inhibition of TACE led to marked reduction of hyperglycemia and vascular inflammation in Insr+/- diabetic mice, as well as by the observation of increased insulin sensitivity in Tace+/- mice compared with WT mice. Our results suggest that an interplay between reduced insulin action and unchecked TACE activity promotes diabetes and vascular inflammation.     

Toxicity of mycophenolate mofetil in patients with inflammatory bowel disease

Trials of mycophenolate mofetil (MMF) in inflammatory bowel disease (IBD) suggest that it may be useful in patients intolerant of azathioprine. We examined the safety and efficacy of MMF in IBD patients intolerant of or unresponsive to azathioprine. Twelve patients [seven with Crohn's disease (CD); seven women; mean age 40 years, range 14-76 years] were treated with MMF 500 mg b.i.d. for a mean of 12.5 weeks. Intolerance was defined as the development of side effects that resolved on discontinuing MMF. Improvement was described as symptomatic improvement, decreased steroid use, or disease entering endoscopic remission. Four patients responded with symptomatic improvement and reduced steroids or mesalazine requirement. Three patients developed headache, nausea, or arthralgia. Three patients developed profuse bloody diarrhea, and in two cases with previously quiescent ulcerative colitis (UC), the source was shown to be ulcers in a drug-induced colitis with histologic features similar to those previously reported in four renal transplant patients on MMF. There is no clear evidence of efficacy of MMF in the treatment of IBD, and its use in this condition should be confined to a randomized controlled trial. Moreover, as patients with UC may be unduly prone to colonic injury, MMF may not be a suitable drug for its treatment.     

Abdominal aortic aneurysm in patients affected by intermittent claudication: prevalence and clinical predictors

Background

Abdominal aortic aneurysm (AAA) is a frequent cause of death among elderly. Patients affected by lower extremity peripheral arterial disease (LE-PAD) seem to be particularly at high risk for AAA. We aimed this study at assessing the prevalence and the clinical predictors of the presence of AAA in a homogeneous cohort of LE-PAD patients affected by intermittent claudication.

Methods

We performed an abdominal ultrasound in 213 consecutive patients with documented LE-PAD (ankle/brachial index ≤0.90) attending our outpatient clinic for intermittent claudication. For each patient we registered cardiovascular risk factors and comorbidities, and measured neutrophil count.

Results

The ultrasound was inconclusive in 3 patients (1.4%), thus 210 patients (169 males, 41 females, mean age 65.9 ± 9.8 yr) entered the study. Overall, AAA was present in 19 patients (9.0%), with a not significant higher prevalence in men than in women (10.1% vs 4.9%, p = 0.300). Patients with AAA were older (71.2 ± 7.0 vs 65.4 ± 9.9 years, p = 0.015), were more likely to have hypertension (94.7% vs 71.2%, p = 0.027), and greater neutrophil count (5.5 [4.5 – 6.2] vs 4.1 [3.2 – 5.5] x10³/μL, p = 0.010). Importantly, the c-statistic for neutrophil count (0.73, 95% CI 0.60 – 0.86, p =0.010) was higher than that for age (0.67, CI 0.56–0.78, p = 0.017). The prevalence of AAA in claudicant patients with a neutrophil count ≥ 5.1 x10³/μL (cut-off identified at ROC analysis) was as high as 29.0%.

Conclusions

Prevalence of AAA in claudicant patients is much higher than that reported in the general population. Ultrasound screening should be considered in these patients, especially in those with an elevated neutrophil count.

     

Role of the laboratory in monitoring patients receiving dual antiplatelet therapy

Introduction: The increasing demand for therapeutic monitoring in patients receiving antiplatelet therapy has been paralleled by the development of instruments and tests whose clinical usefulness is still under debate. We devised a laboratory approach to detect patients with antiplatelet resistance at risk to develop thrombotic events. Methods: One hundred and eighty patients, under aspirin and clopidogrel after angioplasty and stent implantation, were studied by PFA100^® with collagen/epinephrine (CoEPI, cutoff 165s) cartridge and by Multiplate^® using arachidonic acid (ASPItest, pos < 862AUC), ADP (ADPtest, pos < 417AUC), and collagen (COLtest, pos < 607AUC). Results: Only 67 of 173 patients with ASPI < 862 displayed a prolonged CoEPI and up to 65 patients had normal CoEPI despite ASPI < 300. Patients with ASPI < 300 had significantly lower COL than patients with ASPI > 300. One hundred and thirty‐eight patients displaying ADP < 417 had significantly lower COL than those with ADP > 417. Association between COL and ADP remained after ASPI stratification: in patients with suboptimal (ASPI 300–892) or maximal (ASPI < 300) response to aspirin, having ADP < 417 (clopidogrel responsive) increased COL positivity, respectively, from 9.5 to 58.8% and from 47.6 to 82.7%. Conclusion: A combination of specific tests may be useful in identifying higher‐risk patients with poor compliance or drug resistance who potentially may benefit from therapy change.