Age-associated systemic factors change central and peripheral immunity in adult male mice.

Aging coincides with major changes in brain immunity that aid in a decline in neuronal function. Here, we postulate that systemic, pro-aging factors contribute to immunological changes that occur within the brain during aging. To investigate this hypothesis, we comprehensively characterized the central and peripheral immune landscape of 20-month-old male mice using cytometry by time-of-flight (CyTOF) and investigated the role of age-associated circulating factors. We found that CD8+ T cells expressing programmed cell death protein 1 (PD1) and tissue-resident memory CD8+ T cells accumulated in the aged brain while levels of memory T cells rose in the periphery. Injections of plasma derived from 20-month-old mice into 5-month-old receiving mice decreased the frequency of splenic and circulating naïve T cells, increased memory CD8+ T cells, and non-classical, patrolling monocytes in the spleen, and elevated levels of regulatory T cells and non-classical monocytes in the blood. Notably, CD8+ T cells accumulated within white matter areas of plasma-treated mice, which coincided with the expression of vascular cell adhesion molecule 1 (VCAM-1), a mediator of immune cell trafficking, on the brain vasculature. Taken together, we here describe age-related immune cell changes in the mouse brain and circulation and show that age-associated systemic factors induce the expansion of CD8+ T cells in the aged brain.

Torpor induces reversible tau hyperphosphorylation and accumulation in mice expressing human tau.

Tau protein hyperphosphorylation and aggregation are key pathological events in neurodegenerative tauopathies such as Alzheimer's disease. Interestingly, seasonal hibernators show extensive tau hyperphosphorylation during torpor, i.e., the hypothermic and hypometabolic state of hibernation, which is completely reversed during arousal. Torpor-associated mechanisms that reverse tau hyperphosphorylation may be of therapeutic relevance, however, it is currently not known to what extent they apply to human tau. Here we addressed this issue using daily torpor in wildtype mice that express mouse tau (mtau) and in mice that lack mtau expression and instead express human tau (htau). AT8, AT100 and Ser396 immunoblotting and immunohistochemistry were used to assess tau (hyper)phosphorylation at clinically relevant phosphorylation sites. We found that torpor robustly and reversibly increases the levels of phosphorylated tau in both mtau and htau mice. Immunohistochemistry revealed four brain areas that show prominent tau phosphorylation: the hippocampus, posterior parietal cortex, piriform cortex and cortical amygdala. Whereas wildtype mice primarily showed increased levels of diffusely organized hyperphosphorylated tau during torpor, htau mice contained clear somato-dendritic accumulations of AT8 reactivity resembling tau pre-tangles as observed in the Alzheimer brain. Interestingly, AT8-positive accumulations disappeared upon arousal, and tau phosphorylation levels at 24 h after arousal were lower than observed at baseline, suggesting a beneficial effect of torpor-arousal cycles on preexisting hyperphosphorylated tau. In conclusion, daily torpor in mice offers a quick and standardized method to study tau phosphorylation, accumulation and clearance in mouse models relevant for neurodegeneration, as well as opportunities to discover new targets for the treatment of human tauopathies.

The role of mitochondria in axonal degeneration and tissue repair in MS.

Axonal injury is a key feature of multiple sclerosis (MS) pathology and is currently seen as the main correlate for permanent clinical disability. Although little is known about the pathogenetic mechanisms that drive axonal damage and loss, there is accumulating evidence highlighting the central role of mitochondrial dysfunction in axonal degeneration and associated neurodegeneration. The aim of this topical review is to provide a concise overview on the involvement of mitochondrial dysfunction in axonal damage and destruction in MS. Hereto, we will discuss putative pathological mechanisms leading to mitochondrial dysfunction and recent imaging studies performed in vivo in patients with MS. Moreover, we will focus on molecular mechanisms and novel imaging studies that address the role of mitochondrial metabolism in tissue repair. Finally, we will briefly review therapeutic strategies aimed at improving mitochondrial metabolism and function under neuroinflammatory conditions.

Fissurectomy combined with botulinum toxin A injection for medically resistant chronic anal fissures.

INTRODUCTION: Chemical sphincterotomy, the use of pharmacological agents to reduce anal sphincter resting pressure, has become more and more popular in the treatment of chronic anal fissures (CAFs). It offers the possibility to avoid a lateral internal sphincterotomy and its associated risk of incontinence. In our hospital, patient with a chronic anal fissure are consecutively treated with isosorbide dinitrate 1% ointment, applied 6 times a day for 8 weeks, followed by diltiazem 2% ointment, applied 2 times a day for 8 weeks and Botulin Toxin A injections (Dysport; Ipsen, Hoofddorp, the Netherlands) in the internal anal sphincter. In a previous study (1), we describe high healing rates with this regime. Objective The objective of this study is to evaluate the effect of the combination of fissurectomy and Botulin Toxin A in the treatment of CAFs. METHODS: Twenty-one patients (10 male patients, median age 48 years) with persistent symptoms of chronic anal fissures after following the above mentioned treatment, were enrolled in this study. Fissurectomy was combined with Botulinum Toxin A (80 U of Dysport) under regional anaesthesia in day care. Results After 12 weeks 19/21 CAFs (90%) had healed. Median follow-up was 16 (9-30) months. No recurrences were seen. CONCLUSION: Fissurectomy in combination with Botulinum Toxin A injection in the internal anal sphincter is an effective treatment for medically resistant CAFs.

Abundant extracellular myelin in the meninges of patients with multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS) myelin debris has been observed within MS lesions, in cerebrospinal fluid and cervical lymph nodes, but the route of myelin transport out of the brain is unknown. Drainage of interstitial fluid from the brain parenchyma involves the perivascular spaces and leptomeninges, but the presence of myelin debris in these compartments has not been described. AIMS: To determine whether myelin products are present in the meninges and perivascular spaces of MS patients. METHODS: Formalin-fixed brain tissue containing meninges from 29 MS patients, 9 non-neurological controls, 6 Alzheimer's disease, 5 stroke, 5 meningitis and 7 leucodystrophy patients was investigated, and immunohistochemically stained for several myelin proteins [proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase)]. On brain material from MS patients and (non)neurological controls, PLP immunostaining was used to systematically investigate the presence of myelin debris in the meninges, using a semiquantitative scale. RESULTS: Extensive extracellular presence of myelin particles, positive for PLP, MBP, MOG and CNPase in the leptomeninges of MS patients, was observed. Myelin particles were also observed in perivascular spaces of MS patients. Immunohistochemical double-labelling for macrophage and dendritic cell markers and PLP confirmed that the vast majority of myelin particles were located extracellularly. Extracellular myelin particles were virtually absent in meningeal tissue of non-neurological controls, Alzheimer's disease, stroke, meningitis and leucodystrophy cases. CONCLUSIONS: In MS leptomeninges and perivascular spaces, abundant extracellular myelin can be found, whereas this is not the case for controls and other neurological disease. This may be relevant for understanding sustained immunogenicity or, alternatively, tolerogenicity in MS.

Fibrin glue treatment for simple and complex anal fistulas.

BACKGROUND/AIMS: Surgical management of anal fistulas is associated with considerable morbidity, mainly related to anal sphincter injury. However, treatment with fibrin glue is a safe and simple method associated with less discomfort and complications. A prospective trial was conducted at our institute to evaluate the use of fibrin glue (Tissucol, Baxter, The Netherlands) for simple and complex anal fistulas. METHODOLOGY: From November 2001 until March 2004, 34 patients (22 male, 12 female, median age 40 years) were treated with Tissucol. Twenty-three (67%) fistulas were classified as simple (subcutaneous, intersphincteric and transsphincteric) and 11 (33%) as complex (suprasphincteric, extrasphincteric and/or associated with Crohn's disease, ulcerative colitis or HIV). RESULTS: Twenty-six patients were treated once, 5 patients were treated twice, 2 patients were treated 3 times and 1 patient underwent 4 Tissucol treatments. After a median follow-up of 7 months, 13 of 23 simple fistulas (56%) and 6 out of 11 complex fistulas (54%) healed, accounting for an overall closure rate of 55%. Complications occurred in two patients, who both developed a perineal abscess after glue instillation. CONCLUSIONS: Fibrin glue treatment is safe and effective in 55% of the patients with anal fistulas. It is a good alternative to conventional surgery.

[Favourable results with local injections of botulinum-A toxin in patients with chronic isosorbide dinitrate ointment-resistant anal fissures]. / Gunstige resultaten van lokale injectie met botuline A toxine bij patiënten met chronische anale fissuren die niet reageren op behandeling met isosorbidedinitraatzalf.

OBJECTIVE: To determine the effectiveness of injection of botulinum-A toxin in the internal anal sphincter as a treatment for chronic therapy-resistant anal fissures. DESIGN: Prospective. METHODS: In the period October 2002-February 2005, 32 consecutive patients (15 men and 17 women), with a median age of 44 years (range: 23-78 years) and suffering from chronic isosorbide dinitrate ointment-resistant anal fissures, were treated with an injection of 40 IU botulinum-A toxin (Dysport, Ipsen, The Netherlands) in the ventral side of the internal anal sphincter. The injection was given as an outpatient procedure under general or spinal anaesthesia. RESULTS: After a median follow-up of 14 months (range: 2-28 months), the chronic anal fissures were cured in 24 ofthe 32 patients (75%). Twenty-two patients were given a second or a third injection. A fissure recurred in one of the cured patients (4%), and one patient suffered from temporary flatus incontinence. CONCLUSION: Botulinum-A toxin injections were effective in 75% of patients with isosorbide dinitrate ointment-resistant chronic anal fissures. This is a simple technique with fewer side effects than local application of NO donors and fewer complications and less morbidity than surgical sphincterotomy.

[Distinguishing nodal naevus from melanoma metastases in the sentinel node in patients with melanoma]. / Een nodale naevus in de schildwachtklier bij patiënten met melanoom: onderscheid met melanoommetastase.

OBJECTIVE: Establishing the frequency of nodal naevi in lymph-node dissections from patients with a melanoma who have undergone a sentinel-node procedure and/or regional node dissection and distinguishing naevi from melanoma metastases. DESIGN: Retrospective and descriptive. METHODS: Patients with a nodal naevus in the sentinel node were selected from a database containing clinical and pathological data on all 65 patients who underwent a sentinel-node procedure for melanoma at our hospital between 1998 and 2001. Also data from the pathology department on the case frequency and the nodal frequency of nodal naevi in the total number of patients with melanoma in whom a sentinel-node procedure and/or therapeutic node dissection had been carried out during the same period, were examined. RESULTS: In 5 patients a nodal naevus was found in the sentinel node. The case frequency was 6.2% and the nodal frequency 0.65%. Distinction from melanoma metastases was made by the use of H&E colouring, localization, architectural and morphological features of the melanocyte cell clusters in the lymph node and sometimes after consultation with the National Melanoma Panel. Immunohistochemical markers provided supplementary information only. CONCLUSION: Nodal naevi in lymph nodes were not uncommon in people with melanoma and can be distinguished from the micrometastases from melanoma.

Brain abscess after transanal hemorrhoidal dearterialization: a case report.

A relatively new therapy in the treatment of hemorrhoids is transanal hemorrhoidal dearterialization (THD). We report a case of brain abscess caused by Streptococcus milleri following THD. Although a brain abscess after drainage of a perianal abscess has been described in the literature, no report exists of a brain abscess following treatment of hemorrhoids. A healthy 51-year-old man with hemorrhoids underwent THD. Two weeks later he presented with a headache, bradyphrenia, flattened behavior and a left hemiplegia. No perianal complaint and/or perianal abscess was present. A contrast CT scan of the cerebrum showed a right temporoparieto-occipital abscess, with edema and compression of the surrounding tissue and lateral ventricles. MRI showed an abscess with leakage in the right lateral ventricle. Treatment with dexamethasone and intravenous antibiotics was started. Because of progression of symptoms, 3 weeks later ventriculoscopy was performed and the abscess was drained. Culture of the punctuate showed S. milleri. Because of developing hydrocephalus 3 days after ventriculoscopy, first an external ventricle drain and later a ventriculoperitoneal drain was placed. Hereafter the hemiplegia and cognitive disorders improved. This case report describes a severe complication following treatment of hemorrhoids with THD which until now, to our knowledge, has never been described in the literature.

Botulinum toxin A injection in ISDN ointment-resistant chronic anal fissures.

BACKGROUND: In the treatment of chronic anal fissures (CAFs), surgical sphincterotomy is more commonly being replaced by chemical sphincterotomy. After the good results of our pilot study including 32 patients, we now describe the effect of botulinum toxin A (BT-A) in a consecutive series of 100 patients with isosorbide dinitrate (ISDN) ointment-resistant CAFs. METHODS: From October 2002 until August 2005, 100 patients (52 males, 48 females) with a median age of 45 (20-79) years were treated with an injection of 40-100 IU BT-A (Dysport, Ipsen, The Netherlands) in the internal anal sphincter. RESULTS: After a median follow-up of 10 (4-38) months, 77 of the 100 CAFs (77%) were cured. 20 patients were given a second injection, 1 a third and 1 a fourth injection. In 11 patients a fissure recurred (14%). In 1 patient (1%) there was temporary incontinence due to flatus. CONCLUSION: With an early response rate of 77% and an overall success rate of 66%, BT-A injections appear to be effective in patients with ISDN ointment-resistant CAFs if initial non-responders are retreated. These results are in concordance with the results of our pilot study. It is a simple technique with little or no side effects, that does not compromise future treatments. Its place in the first-line treatment of CAFs should be investigated further.