Impact of treatments on fecal microbiota and fecal metabolome in symptomatic uncomplicated diverticular disease of the colon: a pilot study.

Symptomatic uncomplicated diverticular disease (SUDD) affects 50% of people having diverticulosis. We performed a pilot study assessing the effect of current treatments on fecal microbiota and metabolome in SUDD. Thirteen consecutive females with SUDD were treated with a 2-week therapeutic trial of 30 g/day fiber supplementation (3 patients), 1.6 g/day of mesalazine (3 patients), 900 billion/day of probiotic mixture VivoMixx® (3 patients), or 800 mg/day of rifaximin (4 patients). Stool samples were collected at entry (T0), at the end of the 2-week therapeutic course (T1), and 30 (T2) and 60 days (T3) after the end of the therapeutic course. Real-time PCR quantified targeted microorganisms. Fecal metabolome patterns were studied by high-resolution proton NMR spectroscopy. At cumulative analysis, symptoms significantly decreased at each time point during follow-up (p less than 0.0001), and only left-lower quadrant pain increased again at T3. The overall bacterial quantity was not altered by the treatments. The amount of Akkermansia muciniphila species was significantly reduced at T1 (p=0.017) and at T2 (p=0.026), while at T3 the reduction was not significant in comparison to enrollment (p=0.090). Fecal molecular profile showed significant changes at T1 and T2, while at T3 it became similar to that of T0. Differences were found for 18 of the quantified molecules (tryptophan, phenylalanine, tyrosine, 4-hydroxyphenylacetate, urocanate, X-6.363, X-5.779, uridylate, galactose, X-4.197, threonine, sarcosine, methionine, 2-oxoisocaproate, 5-aminolevulinate, alanine, leucine, valerate). Metabolome and microbiota changed in patients with SUDD under treatment, confirming a possible role of dysbiosis/dysmetabolome in the pathology.

Human neural stem cells derived from fetal human brain communicate with each other and rescue ischemic neuronal cells through tunneling nanotubes.

Pre-clinical trials have demonstrated the neuroprotective effects of transplanted human neural stem cells (hNSCs) during the post-ischemic phase. However, the exact neuroprotective mechanism remains unclear. Tunneling nanotubes (TNTs) are long plasma membrane bridges that physically connect distant cells, enabling the intercellular transfer of mitochondria and contributing to post-ischemic repair processes. Whether hNSCs communicate through TNTs and their role in post-ischemic neuroprotection remains unknown. In this study, non-immortalized hNSC lines derived from fetal human brain tissues were examined to explore these possibilities and assess the post-ischemic neuroprotection potential of these hNSCs. Using Tau-STED super-resolution confocal microscopy, live cell time-lapse fluorescence microscopy, electron microscopy, and direct or non-contact homotypic co-cultures, we demonstrated that hNSCs generate nestin-positive TNTs in both 3D neurospheres and 2D cultures, through which they transfer functional mitochondria. Co-culturing hNSCs with differentiated SH-SY5Y (dSH-SY5Y) revealed heterotypic TNTs allowing mitochondrial transfer from hNSCs to dSH-SY5Y. To investigate the role of heterotypic TNTs in post-ischemic neuroprotection, dSH-SY5Y were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (OGD/R) with or without hNSCs in direct or non-contact co-cultures. Compared to normoxia, OGD/R dSH-SY5Y became apoptotic with impaired electrical activity. When OGD/R dSH-SY5Y were co-cultured in direct contact with hNSCs, heterotypic TNTs enabled the transfer of functional mitochondria from hNSCs to OGD/R dSH-SY5Y, rescuing them from apoptosis and restoring the bioelectrical profile toward normoxic dSH-SY5Y. This complete neuroprotection did not occur in the non-contact co-culture. In summary, our data reveal the presence of a functional TNTs network containing nestin within hNSCs, demonstrate the involvement of TNTs in post-ischemic neuroprotection mediated by hNSCs, and highlight the strong efficacy of our hNSC lines in post-ischemic neuroprotection. Human neural stem cells (hNSCs) communicate with each other and rescue ischemic neurons through nestin-positive tunneling nanotubes (TNTs). A Functional mitochondria are exchanged via TNTs between hNSCs. B hNSCs transfer functional mitochondria to ischemic neurons through TNTs, rescuing neurons from ischemia/reperfusion ROS-dependent apoptosis.

Intercellular crosstalk mediated by tunneling nanotubes between central nervous system cells. What we need to advance.

Long-range intercellular communication between Central Nervous System (CNS) cells is an essential process for preserving CNS homeostasis. Paracrine signaling, extracellular vesicles, neurotransmitters and synapses are well-known mechanisms involved. A new form of intercellular crosstalk mechanism based on Tunneling Nanotubes (TNTs), suggests a new way to understand how neural cells interact with each other in controlling CNS functions. TNTs are long intercellular bridges that allow the intercellular transfer of cargoes and signals from one cell to another contributing to the control of tissue functionality. CNS cells communicate with each other via TNTs, through which ions, organelles and other signals are exchanged. Unfortunately, almost all these results were obtained through 2D in-vitro models, and fundamental mechanisms underlying TNTs-formation still remain elusive. Consequently, many questions remain open, and TNTs role in CNS remains largely unknown. In this review, we briefly discuss the state of the art regarding TNTs identification and function. We highlight the gaps in the knowledge of TNTs and discuss what is needed to accelerate TNTs-research in CNS-physiology. To this end, it is necessary to: 1) Develop an ad-hoc TNTs-imaging and software-assisted processing tool to improve TNTs-identification and quantification, 2) Identify specific molecular pathways involved into TNTs-formation, 3) Use in-vitro 3D-CNS and animal models to investigate TNTs-role in a more physiological context pushing the limit of live-microscopy techniques. Although there are still many steps to be taken, we believe that the study of TNTs is a new and fascinating frontier that could significantly contribute to deciphering CNS physiology.

GFAP serves as a structural element of tunneling nanotubes between glioblastoma cells and could play a role in the intercellular transfer of mitochondria.

Tunneling nanotubes (TNTs) are long F-actin-positive plasma membrane bridges connecting distant cells, allowing the intercellular transfer of cellular cargoes, and are found to be involved in glioblastoma (GBM) intercellular crosstalk. Glial fibrillary acid protein (GFAP) is a key intermediate filament protein of glial cells involved in cytoskeleton remodeling and linked to GBM progression. Whether GFAP plays a role in TNT structure and function in GBM is unknown. Here, analyzing F-actin and GFAP localization by laser-scan confocal microscopy followed by 3D reconstruction (3D-LSCM) and mitochondria dynamic by live-cell time-lapse fluorescence microscopy, we show the presence of GFAP in TNTs containing functional mitochondria connecting distant human GBM cells. Taking advantage of super-resolution 3D-LSCM, we show the presence of GFAP-positive TNT-like structures in resected human GBM as well. Using H2O2 or the pro-apoptotic toxin staurosporine (STS), we show that GFAP-positive TNTs strongly increase during oxidative stress and apoptosis in the GBM cell line. Culturing GBM cells with STS-treated GBM cells, we show that STS triggers the formation of GFAP-positive TNTs between them. Finally, we provide evidence that mitochondria co-localize with GFAP at the tip of close-ended GFAP-positive TNTs and inside receiving STS-GBM cells. Summarizing, here we found that GFAP is a structural component of TNTs generated by GBM cells, that GFAP-positive TNTs are upregulated in response to oxidative stress and pro-apoptotic stress, and that GFAP interacts with mitochondria during the intercellular transfer. These findings contribute to elucidate the molecular structure of TNTs generated by GBM cells, highlighting the structural role of GFAP in TNTs and suggesting a functional role of this intermediate filament component in the intercellular mitochondria transfer between GBM cells in response to pro-apoptotic stimuli.

An overview of the diagnosis and pharmacologic treatment of migraine.

Migraine, an episodic headache disorder, is one of the most common complaints encountered by primary-care physicians and neurologists. Nevertheless, it remains underdiagnosed and undertreated. Rational migraine treatment necessitates an accurate diagnosis, identification and removal of potential triggering factors, and, frequently, pharmacologic intervention. Effective management also includes establishing realistic expectations, patient reassurance, and education. The choice of medication (abortive, symptomatic) for an acute attack depends on such factors as the severity of the attack, presence or absence of vomiting, time of onset to peak pain, rate of bioavailability of the drug, comorbid medical conditions, and side-effect profile. Effective agents for acute attacks include simple or combination analgesics, nonsteroidal anti-inflammatory drugs, ergot derivatives, selective serotonin agonists, and antiemetics. Opioid analgesics are unnecessary for most patients. The choice of preventive (prophylactic, interval) medication depends primarily on comorbid medical conditions and side-effect profile. Useful preventive agents include beta-adrenergic blockers, calcium channel blockers, tricyclic antidepressants, anticonvulsant medications, and serotonin antagonists.

Cold lesion of a vertebral angioma with Tc-99m-labeled monoclonal antibodies against granulocytes.

Antigranulocyte immunoscintigraphy is indicated for diagnostic imaging to determine the location and extent of infection. We present a case of a focal cold lesion in a vertebra of a patient thought to have a septic focal lesion. Whole-body scanning and dorsal spine SPECT revealed no focal increased uptake. CT and MR studies revealed the presence of a vertebral angioma. Conditions associated with a defect of uptake in immunoscintigraphy are discussed.

ACGME competencies in neurology: web-based objective simulated computerized clinical encounters.

OBJECTIVE: The American Headache Society developed an innovative Web-based neurology resident educational program to 1) meet the objectives of the Accreditation Council for Graduate Medical Education Outcomes Project; 2) provide measurable improvement of a neurology resident's understanding of headache and the performance within each core competency; 3) assist residents and program directors in identifying knowledge gaps; and, ultimately, 4) improve the quality of patient care through enhanced educational initiatives. METHODS: Quantitative analysis focused on pretest and post-test results, level attainment on case-based simulations, competency achievement, and interactions between cases. One of four validated global scores was related to each resident response on all competency learning opportunities and was measured, from one case to another, to determine improvement and understanding. The pretest and post-test each consisted of 50 randomized questions that tested baseline and improvement on specific core competencies and understanding of headache. RESULTS: The pretest mean score was 30.08, and the post-test mean score was 34.79. A paired sample t test analysis showed a significant difference from pretest to post-test scores (M = -4.72, SD = 4.88, t[91] = -9.269, p < 0.001). There was significant improvement in the competencies as the residents moved through the cases as well as in each of the competencies from the pretest to the post-test. Results showed that residents increased their knowledge and performance by synthesizing the content. CONCLUSIONS: This outcomes analysis demonstrates the effectiveness of the American Headache Society Neurology Resident's Program in improving the resident's knowledge of headache medicine and Accreditation Council for Graduate Medical Education core competencies.

Chronic migraine and medication-overuse headache through the ages.

We set out to review early descriptions of chronic migraine and medication-overuse headache. The International Headache Society (IHS) recently gave criteria for chronic migraine and medication-overuse headache. Chronic migraine was absent from the 1988 IHS criteria. Peters and Horton described ergotamine-overuse headache in 1951. In the 1980s it was more fully appreciated that overuse of other acute headache medications could increase headache frequency. We reviewed published English-language papers and book chapters. Willis (1672), Oppenheim (1900), Collier (1922), Balyeat (1933), and von Storch (1937) all described chronic migraine. Lennox (1934), O'Sullivan (1936), Silfverskiold (1947), Graham (1955), Friedman (1955), and Lippman (1955) wrote about ergotamine-overuse headache. Graham (1955), Friedman (1955), Lippman (1955), and Horton and Peters (1963) outlined withdrawal protocols. Chronic migraine has been mentioned in the literature for centuries, while medication-overuse headache has been written about for decades. Graham, Friedman, and Lippman deserve credit for separately reporting the first ergotamine withdrawal programmes.

Facial pain as a symptom of nonmetastatic lung cancer.

Patients with nonmetastatic lung cancer may rarely experience facial pain as a presenting symptom, during the course of the disease or upon recurrence of the disease. This study reviews a 10-year experience at Mayo Clinic. The aim of this study was to (1) further characterize the clinical features of facial pain as a symptom of nonmetastatic lung cancer, and (2) assist clinicians in recognizing this association. Ten cases were identified. All patients complained of severe, aching, facial pain typically aural-temporal in location, ipsilateral to the lung cancer. Six of the 10 cases involved the left side. Recent weight loss was present in 7 of 10 patients, with an elevated sedimentation rate in 6. Digital clubbing was documented in three. Neurologic examinations and neuroimaging were normal in all patients. Lumbar puncture, when performed, was normal. Facial pain preceded the diagnosis of lung cancer by 1 to 24 months. In three patients, facial pain was the initial symptom of tumor recurrence. Four of the 10 tumors were adenocarcinoma; radiation with or without chemotherapy appears to be the treatment of choice for the facial pain. The presumed mechanism is local invasion of the vagus nerve. In suspected cases, a chest x-ray and chest CT are indicated.

Hyperthyroidism and periodic paralysis.

The periodic paralyses are a rare group of disorders which may be familial, sporadic, occur in association with hyperthyroidism or as a result of potassium loss. A 46-year-old otherwise healthy Filipino male is described who presented with a second episode of paroxysmal painless weakness. Examination revealed a pattern of weakness consistent with a myopathic process (symmetric/proximal). The neurologic examination was otherwise physiologic. The clinical features are described as well as the differential diagnosis, pathophysiology, and treatment. This case also demonstrates the phenomenon wherein periodic paralysis may precede clinical hyperthyroidism.

Haemorheological evaluation with the Filtrometer MF4 in a group of diabetics.

In this research we evaluated the red blood cell deformability using the Filtrometer MF4. Our study includes a group of 44 diabetics and a group of 20 normal controls. Since we used only paper filters, the reading, made on four channels on the same sample, lasted 83' at the end of which we examined: SL80%, SL60%, SL50%, SL40%, SL20% (values of the trigonometric tangent of the alpha angle, i.e., the angle that the geometric tangent at the curve in predetermined points forms with the t axis); T50 (time employed to filter 50% of the sample); MinT (time employed to reach residual blood volume). Examining the trend of the SL values it is evident that the filtration curve is different between normals and diabetics and not between diabetics subdivided for vascular complications.

Treatment and management of cluster headache.

Cluster headache is an uncommon yet well-defined neurovascular syndrome occurring in both episodic and chronic varieties. The most striking feature of cluster headache is the unmistakable circadian and circannual periodicity. Inheritance may play a role in some families. The attacks are of extreme intensity, of short duration, occur unilaterally, and are accompanied by signs and symptoms of autonomic dysfunction. In contrast to migraine, during an attack the cluster patient prefers to pace about. Attacks frequently occur at night. Although the pathophysiology of cluster headache remains to be fully elucidated, several seminal observations have recently been made. The medical treatment of cluster headache includes both acute therapy aimed at aborting individual attacks and prophylactic therapy aimed at preventing recurrent attacks during the cluster period. Agents used for acute therapy include inhalation of oxygen, sumatriptan, and dihydroergotamine. Transitional prophylaxis involves the short-term use of either corticosteroids or ergotamine derivatives. The cornerstone of maintenance prophylaxis is verapamil, yet methysergide, lithium, and divalproex sodium may also be employed. In some patients, melatonin or topiramate may be useful adjunctive therapies.

Idiopathic intracranial hypertension and seventh nerve palsy.

Patients with idiopathic intracranial hypertension may occasionally present with coexisting lower motor neuron facial weakness. This study reviews a 6-year experience at Mayo Clinic. The aim of this study was to determine the possible association of idiopathic intracranial hypertension and facial paresis. Two cases were identified. Both fulfilled the modified Dandy's diagnostic criteria for idiopathic intracranial hypertension. Treatment consisted of steroids in one, and emergent optic nerve sheath fenestration in the other. The cranial nerve palsies resolved in both cases.

Hypnic headache: another indomethacin-responsive headache syndrome?

Hypnic headache syndrome is a benign, recurrent, late-onset headache disorder that occurs exclusively during sleep. Lithium has been reported to be an effective treatment, but the side effects of this medication are sometimes prohibitive, particularly in the elderly. Other drugs have been reported to be effective in this disorder, including caffeine, flunarizine, and verapamil. Recently, indomethacin has been reported to effectively suppress hypnic headaches. We report the response of seven patients with hypnic headache who were treated with indomethacin. Hypnic headache syndrome appears to represent yet another headache disorder in which there is sometimes an impressive response to indomethacin.

Medication-induced (analgesic rebound) headache: historical aspects and initial descriptions of the North American experience.

A review of the initial descriptions of medication-induced (misuse) headache in the North American literature indicates that this disorder was first identified in the mid-1950s. It was not until the early 1980s that this phenomenon became well established.