Design and Application of Automated Algorithms for Diagnosis and Treatment Optimization in Neurodegenerative Diseases.

Neurodegenerative diseases represent a growing healthcare problem, mainly related to an aging population worldwide and thus their increasing prevalence. In particular, Alzheimer's disease (AD) and Parkinson's disease (PD) are leading neurodegenerative diseases. To aid their diagnosis and optimize treatment, we have developed a classification algorithm for AD to manipulate magnetic resonance images (MRI) stored in a large database of patients, containing 1,200 images. The algorithm can predict whether a patient is healthy, has mild cognitive impairment, or already has AD. We then applied this classification algorithm to therapeutic outcomes in PD after treatment with deep brain stimulation (DBS), to assess which stereotactic variables were the most important to consider when performing surgery in this indication. Here, we describe the stereotactic system used for DBS procedures, and compare different planning methods with the gold standard normally used (i.e., neurophysiological coordinates recorded intraoperatively). We used information collected from database of 72 DBS electrodes implanted in PD patients, and assessed the potentially most beneficial ranges of deviation within planning and neurophysiological coordinates from the operating room, to provide neurosurgeons with additional landmarks that may help to optimize outcomes: we observed that x coordinate deviation within CT scan and gold standard intra-operative neurophysiological coordinates is a robust matric to pre-assess positive therapy outcomes- "good therapy" prediction if deviation is higher than 2.5 mm. When being less than 2.5 mm, adding directly calculated variables deviation (on Y and Z axis) would lead to specific assessment of "very good therapy".

Color LED reflection topography: validation of equivalent keratometry reading for IOL power calculation in eyes with previous corneal myopic refractive surgery.

PURPOSE: To compare the accuracy of the equivalent keratometry reading (EKR) from a color LED corneal topographer (Cassini) with that of other no-history formulas for intraocular lens (IOL) power calculation in eyes with previous myopic excimer laser surgery. SETTING: Centro de Oftalmología Barraquer, Barcelona, Spain. DESIGN: Retrospective case series. METHODS: The refractive outcomes of the Cassini EKR entered into the Haigis formula were compared with those of the Barrett True-K, Haigis-L, and Shammas-PL formulas and the Triple-S method combined with the Haigis formula. Optimized lens constants for virgin eyes were used. The mean prediction error (PE), the median absolute error (MedAE), and the percentage of eyes with a PE within ±0.25 diopter (D), ±0.50 D, ±0.75 D, and ±1.00 D were calculated. RESULTS: The study comprised 37 patients (37 eyes). The Haigis-L, Shammas-PL, and Barrett True-K no-history methods produced a myopic mean PE that was significantly different from zero (P < .001, P < .001 and P = .004, respectively), whereas the mean PEs of Cassini EKR and the Triple-S combined with the Haigis formula were not different from zero (P > .05). Repeated-measures analysis of variance disclosed a significant difference among the PE of all methods (P < .0001). The MedAE of the Cassini EKR, Barrett True-K, Haigis-L, Shammas-PL, and Triple-S was, respectively, 0.34 D, 0.34 D, 0.49 D, 0.48 D, and 0.31 D (P = .0026). CONCLUSIONS: The performance of the combination of standard Haigis formula with Cassini EKR was comparable to other no-history formulas in eyes with previous myopic excimer laser surgery.

Low temperature glass/crystal transition in ionic liquids determined by H-bond vs. coulombic strength.

Self-assembled ionic liquid crystals are anisotropic ionic conductors, with potential applications in areas as important as solar cells, battery electrolytes and catalysis. However, many of these applications are still limited by the lack of precise control over the variety of phases that can be formed (nematic, smectic, or semi/fully crystalline), determined by a complex pattern of different intermolecular interactions. Here we report the results of a systematic study of crystallization of several imidazolium salts in which the relative contribution of isotropic coulombic and directional H-bond interactions is carefully tuned. Our results demonstrate that the relative strength of directional H-bonds with respect to the isotropic Coulomb interaction determines the formation of a crystalline, semi-crystalline or glassy phase at low temperature. The possibility of pinpointing H-bonding directionality in ionic liquids make them model systems to study the crystallization of an ionic solid under a perturbed Coulomb potential.

Dual energy CT in the management of antiplatelet therapy in patients with acute ischemic stroke for carotid obstruction.

BACKGROUND AND PURPOSE: Acute tandem occlusions often require carotid stenting. Combination of mechanical and pharmacologic therapies in addition to antiplatelet drugs administered to prevent acute stent thrombosis might increase the risk of intracerebral hemorrhage. We present a protocol of antiplatelet regimen based on early post-procedural dual-energy CT (DE-CT). MATERIAL AND METHODS: Fifty consecutive stroke patients with tandem occlusions treated with acute carotid stenting after intracranial thrombectomy and TICI 2b/3 were reviewed. All patients received intravenous lysine acetylsalicylate during the procedure. Dual (aspirin+clopidogrel with or without clopidogrel load, groups A and B, respectively) or mono (aspirin) antiplatelet regimen (group C) was administered 12-24 h later according to brain DE-CT findings. Carotid ultrasonography was performed at 24 h and before discharge. We evaluated the rate of subsequent symptomatic intracranial hemorrhage (SICH) and acute stent thrombosis in each group. RESULTS: Between June 2014 and December 2016, 50 patients were included (mean age 66 years, 76% men, baseline NIHSS 16, median time from symptom onset to recanalization 266 min). According to DE-CT, 24 patients were assigned to group A, 19 to group B and 7 to group C (4 of them had SICH at that time). One patient suffered a subsequent SICH (belonging to group B). There was only one stent thrombosis without clinical repercussions in group B. CONCLUSIONS: DE-CT may contribute to select antiplatelet regimen after acute carotid stenting in tandem occlusions.

The role of contextual signal TGF-ß1 inducer of epithelial mesenchymal transition in metastatic lung adenocarcinoma patients with brain metastases: an update on its pathological significance and therapeutic potential.

Lung adenocarcinoma (LA) is the most common cause of cancer-related death worldwide. Despite the advances over last decade in new targeted therapies, cancer genetics, diagnostics, staging, and surgical techniques as well as new chemotherapy and radiotherapy protocols, the death rate from LA remains high. The tumour microenvironment is composed of several cytokines, one of which is transforming growth factor ß1 (TGF-ß1), which modulates and mediates the expression of epithelial-mesenchymal transition (EMT), correlated with invasive growth in LAs, and exhibits its pleiotropic effects through binding to transmembrane receptors TßR-1 (also termed activin receptor-like kinases - ALKs) and TßR-2. Accordingly, there is an urgent need to elucidate the molecular mechanisms associated with the tumoural spreading process and therapeutic resistance of this serious pathology. In this review, we briefly discuss the current role of contextual signal TGF-ß1 inducer of epithelial mesenchymal transition in metastatic lung adenocarcinoma patients with brain metastases, and give an overview of our current mechanistic understanding of the TGF-ß1-related pathways in brain metastases progression, TGF-ß1 pathway inhibitors that could be used for clinical treatment, and examination of models used to study these processes. Finally, we summarise the current progress in the therapeutic approaches targeting TGF-ß1.

Long-Term Results of Deep Brain Stimulation of the Mamillotegmental Fasciculus in Chronic Cluster Headache.

BACKGROUND: Deep brain stimulation (DBS) and the proper target for chronic cluster headache (CCH) are still subjects of controversy. OBJECTIVES: We present our long-term results of analysis of the target and its structural connectivity. METHODS: Fifteen patients with drug-resistant CCH underwent DBS in coordinates 4 mm lateral to the III ventricular wall and 2 mm behind and 5 mm below the intercommissural point. The clinical parameters recorded were the number of weekly attacks, pain intensity, and duration of the headache. Structural connectivity was studied using 3-T MR diffusion tensor imaging (DTI). RESULTS: All of our patients improved from a mean of 39 attacks/week to 2; pain intensity decreased from 9 to 3 out of 10, and the mean cephalalgia duration decreased from 53 to 8 min. The mean stereotactic coordinates of the effective contact location were 6.1 mm lateral to the midcommissural point and 1.2 mm behind and 4.0 mm below the intercommissural point. DTI analysis showed that this target was connected to tracts and nuclei of the posterior mesencephalic tegmentum, specifically the dorsal longitudinal and mamillotegmental fasciculi. CONCLUSIONS: Our data showed DBS to be a safe and useful procedure for the treatment of drug-resistant CCH; the rate of improvement was higher than those found in other series. Although these are promising results, larger series targeting those fasciculi with a longer follow-up are needed.

A novel amyloid designable scaffold and potential inhibitor inspired by GAIIG of amyloid beta and the HIV-1 V3 loop.

The GAIIG sequence, common to the amyloid beta peptide (residues 29-33) and to the HIV-1 gp120 (residues 24-28 in a typical V3 loop), self-assembles into amyloid fibrils, as suggested by theory and the experiments presented here. The longer YATGAIIGNII sequence from the V3 loop also self-assembles into amyloid fibrils, of which the first three and the last two residues are outside the amyloid GAIIG core. We postulate that this sequence, with suitably selected modifications at the flexible positions, can serve as a designable scaffold for novel amyloid-based materials. Moreover, we report the single crystal X-ray structure of the beta-breaker peptide GAIPIG at 1.05 Å resolution. The structural information provided in this study could serve as the basis for structure-based design of potential inhibitors of amyloid formation.

[(CH3)2NH2]7Pb4X15 (X = Cl- and Br-), 2D-Perovskite Related Hybrids with Dielectric Transitions and Broadband Photoluminiscent Emission.

We have prepared two new lead halides with the novel general formula of DMA7Pb4X15 (DMA = [(CH3)2NH2]+ and X = Cl- or Br-) by using an easy route under mild conditions at room temperature. These compounds exhibit an unprecedented crystal structure, are formed by layers of distorted [PbX6] octahedra, which share corners and faces, and contain intercalated DMA cations. Very interestingly, they display dielectric transitions, which are related to a partial order-disorder process of the DMA cations between 160 and 260 K. Additionally, these new layered hybrids exhibit a broadband photoluminiscent emission, which is related to the structural distortions of the [PbX6] octahedra. These findings not only open up large possibilities for future optoelectronic applications of these materials, but they also offer a novel playground for an easy modulation of electrical and optical properties of hybrid organic-inorganic materials. We anticipate that this novel A7Pb4X15 formula can be adequate to tune the family of the hybrid lead halides using other alkylammonium cations, such as methylammonium, formamidinium, or ethylammonium, to improve their photoelectronic properties.

Endovascular treatment in the acute and non-acute phases of carotid dissection: a therapeutic approach.

BACKGROUND: Carotid dissection (CD) may, in certain cases, lead to significant stenosis, occlusion, or pseudoaneurysm formation, causing embolic stroke or hemodynamic failure, despite medical therapy. OBJECTIVE: To evaluate the results of endovascular treatment and clinical outcomes of patients with CD. METHODS: A four-hospital retrospective study of endovascular treatment of extracranial CD in which medical treatment had failed or patients presented with a National Institute of Health Stroke Scale (NIHSS) score ≥8. RESULTS: Thirty-eight patients (mean age 46.6±13.5 years, 78.9% male, 84.2% spontaneous CD, 44.7% left CD and 26.3% bilateral CD) were analyzed. In 24 patients (63.2%) treatment was undertaken in the acute-phase CD (APCD). IV recombinant tissue plasminogen activator was administered in 7 (29.2%) APCD cases. The patients with APCD exhibited a high rate of successful revascularization (Thrombolysis In Cerebral Infarction ≥2b; 19 patients (79.2%)), a low risk of symptomatic intracranial hemorrhage (n=2 (8.3%)), and good global functional outcomes (modified Rankin Scale (mRS) ≤2; n=17 (70.8%)). Good recanalization correlated (p=0.001) with good clinical evolution (mRS ≤2) in the patients with APCD. Of the 14 patients with non-acute phase CD (NAPCD), seven were treated for pseudoaneurysm with multiple stents (six patients) or covered prostheses, with stenosis being treated in the remaining seven patients. CONCLUSIONS: Endovascular treatment of selected cases of patients with CD associated with thromboembolic events and hemodynamic failure after unsuccessful medical therapy is a safe and effective method of restoring vessel lumen integrity, with good short-term clinical evolution.

Analysis of endovascular treatment of ruptured microaneurysms compared with ruptured larger aneurysms.

OBJECTIVE: To retrospectively analyze the complications and outcome of the endovascular treatment of ruptured microaneurysms compared with the treatment of ruptured larger aneurysms. METHODS: 40 ruptured cerebral microaneurysms treated by endovascular techniques were selected retrospectively and compared with 207 larger ruptured cerebral aneurysms treated by endovascular techniques during the same time period. Medical charts and imaging studies were reviewed to analyze baseline clinical and epidemiologic characteristics, procedural complications, and clinical outcomes RESULTS: Cerebral microaneurysms had a higher incidence of intraoperative technical ruptures (13.5% vs 2.9%, p<0.005). The number of thromboembolic complications was not increased. Patient prognosis was similar for the two groups (mean modified Rankin Scale score 1.81 vs 2.09, p>0.1). CONCLUSIONS: Coiling of cerebral microaneurysms has a reasonable safety profile with good clinical outcomes, similar to coiling of larger aneurysms. In our experience, the systematic use of remodeling balloons, operator experience, and the ability to manage complications are the reasons for the satisfactory results.

Structure of the Receptor-Binding Carboxy-Terminal Domain of the Bacteriophage T5 L-Shaped Tail Fibre with and without Its Intra-Molecular Chaperone.

Bacteriophage T5, a Siphovirus belonging to the order Caudovirales, has a flexible, three-fold symmetric tail, to which three L-shaped fibres are attached. These fibres recognize oligo-mannose units on the bacterial cell surface prior to infection and are composed of homotrimers of the pb1 protein. Pb1 has 1396 amino acids, of which the carboxy-terminal 133 residues form a trimeric intra-molecular chaperone that is auto-proteolyzed after correct folding. The structure of a trimer of residues 970-1263 was determined by single anomalous dispersion phasing using incorporated selenomethionine residues and refined at 2.3 Å resolution using crystals grown from native, methionine-containing, protein. The protein inhibits phage infection by competition. The phage-distal receptor-binding domain resembles a bullet, with the walls formed by partially intertwined beta-sheets, conferring stability to the structure. The fold of the domain is novel and the topology unique to the pb1 structure. A site-directed mutant (Ser1264 to Ala), in which auto-proteolysis is impeded, was also produced, crystallized and its 2.5 Å structure solved by molecular replacement. The additional chaperone domain (residues 1263-1396) consists of a central trimeric alpha-helical coiled-coil flanked by a mixed alpha-beta domain. Three long beta-hairpin tentacles, one from each chaperone monomer, extend into long curved grooves of the bullet-shaped domain. The chaperone-containing mutant did not inhibit infection by competition.

A Covalent Organic Helical Cage with Remarkable Chiroptical Amplification.

Purely organic shape-persistent chiral cages are designed through the use of rigid chiral axes. Covalent dimerization of a tripodal fragment bearing chiral allenes forms a molecular twisted prism with loop-like lateral edges presenting 10-fold chiroptical amplification compared to its isolated building blocks. The expected geometry of covalent organic helical cage (M,M)3 -1 was confirmed by X-ray crystal structure analysis. Comparison of the chiroptical responses of this shape-persistent molecular container with more flexible analogues highlights how the control of the conformational freedom of the molecule can be used to obtain molecular cages with strong chiroptical responses. Selective inclusion-complex formation with ferrocenium ions [(P,P)3 -1@Fc(+) ] was confirmed and quantified with HR-ESI-MS and NMR spectroscopy.

Antiphospholipid Syndrome of Late Onset: A Difficult Diagnosis of a Recurrent Embolic Stroke.

A 77-year-old woman with atrial fibrillation (AF) treated with warfarin had a cortical left middle cerebral artery (MCA) stroke (October 2009, international normalized ratio [INR], 1.6) and a cortical left frontal stroke (October 2011, INR, 1.9). Anticoagulation was adjusted. In October 2011, she had a right frontal stroke (INR, 2.3). Acetylsalicylic acid (ASA) was temporally added to the treatment. In June 2013, she had a left occipital stroke (INR, 2.3). Warfarin was changed to rivaroxaban. In August 2013, she had a right occipital stroke. ASA 100 was added to the treatment. On all occasions, repeated neurovascular studies and echocardiography were normal. Diagnoses were cardioembolic stroke. In November 2013, she was admitted because of a left MCA stroke. A complete blood analysis showed the presence of anticardiolipin, anti-b2-glycoprotein antibodies, and lupus anticoagulant. Primary antiphospholipid syndrome (APS) was later confirmed. APS should be considered in young stroke patients, however is not frequent in stroke patients older than 70 years with several cerebrovascular risk factors. The existence of AF in our patient with several embolic strokes made the cardiembolic etiology likely. Uncommon causes of stroke were not considered despite the repetition of the ischemic events. Thus, a wider etiological study should be made in all patients with a recurrent stroke regardless of age, such as a complete blood analysis including immunology study in order to exclude an APS of late onset.

Mucosa nasal: un nuevo tejido para el diagnóstico biópsico de amiloidosis hereditaria relacionada con transtirretina / Nasal mucosa: A new site for tissue biopsy to diagnose hereditary TTR amyloidosis

Background and objective: We report 2 carriers of the TTRV30M mutation and its plasmatic biochemical marker with clinical symptoms compatible with hereditary TTR amyloidosis. Materials and methods: Based on our previously reported casual finding of amyloid TTR in nasal mucosa (2008), we requested biopsy of this tissue to search for amyloid with Congo red staining and TTR immunohistochemical analysis. Results: The histological diagnosis was achieved by retrospective analysis of surgical sinonasal biopsy in the first patient and prospective biopsy of inferior nasal concha in the second. Large interstitial deposits of ATTR were observed in both cases. Conclusions: We suggest nasal mucosa as a suitable site for tissue biopsy in patients with suspected hereditary TTR amyloidosis (AU)

Antecedentes y objetivo: Presentamos 2 portadores de la mutación TTRV30M y su marcador bioquímico plasmático, con síntomas sugestivos de amiloidosis hereditaria TTR. Material y métodos: Basándonos en el hallazgo casual de amiloide TTR en la mucosa nasal previamente publicado (2008), indicamos la biopsia de este tejido para la búsqueda de amiloide TTR con tinción Rojo Congo y análisis inmunohistoquímico de TTR. Resultados: El diagnóstico histológico se logró en el primer enfermo con análisis retrospectivo de la biopsia de material operatorio sinonasal, y en el segundo con biopsia prospectiva del cornete nasal inferior. En ambos casos se observaron grandes depósitos intersticiales de amiloide de amiloidosis hereditaria relacionada con transtirretina. Conclusiones: Consideramos que la biopsia de la mucosa nasal es idónea para el diagnóstico de pacientes con sospecha de amiloidosis hereditaria TTR (AU)

Nasal mucosa: a new site for tissue biopsy to diagnose hereditary TTR amyloidosis.

BACKGROUND AND OBJECTIVE: We report 2 carriers of the TTRV30M mutation and its plasmatic biochemical marker with clinical symptoms compatible with hereditary TTR amyloidosis. MATERIALS AND METHODS: Based on our previously reported casual finding of amyloid TTR in nasal mucosa (2008), we requested biopsy of this tissue to search for amyloid with Congo red staining and TTR immunohistochemical analysis. RESULTS: The histological diagnosis was achieved by retrospective analysis of surgical sinonasal biopsy in the first patient and prospective biopsy of inferior nasal concha in the second. Large interstitial deposits of ATTR were observed in both cases. CONCLUSIONS: We suggest nasal mucosa as a suitable site for tissue biopsy in patients with suspected hereditary TTR amyloidosis.

Preparation and characterization of a halogen-bonded shape-persistent chiral alleno-acetylenic inclusion complex.

A chiral bidentate inclusion complex has been formed by halogen-bond interaction between the pyridyl moieties of a pyridoallenoacetylenic host and octafluorodiiodobutane. X-ray crystallography showed that the guest adopts a chiral conformation inside the molecular channels formed by stacking of the host units. A 10 ppm shielding of the (15)N NMR resonance for the pyridil units provided evidence of the formation of the halogen-bond complex in solution.

Chronic migraine does not increase posterior circulation territory (PCT) infarct-like lesions.

UNLABELLED: Two population-based studies have found an increased prevalence of posterior circulation territory (PCT) infarct-like lesions in migraine, which seemed to increase with attack frequency. OBJECTIVE: To determine whether chronic migraine (CM) patients are at increased risk of PCT infarct-like lesions. METHODS: We prospectively obtained brain MRIs from adult women fulfilling CM criteria. To keep radiologists blinded we also obtained brain MRIs in 15 episodic migraine (EM) patients. MRIs were acquired on a 1.5 T unit. Protocol included whole brain weighted images in sagittal T1 (5 mm slices), axial FLAIR T2 (3 mm) and combined proton density and T2 fast spin echo (3 mm). Two independent neuroradiologists carefully analyzed all the images. RESULTS: One hundred women with CM participated. Their ages ranged from 18 to 68 years (mean 43.7) and the length of CM ranged from 0.5 to 38 years (mean 9.8). Sixty-three patients (63%) had at least one vascular risk factor. Thirty-three met analgesic overuse criteria. Fifty-one had a history of migraine with aura attacks, though aura frequency was below one per month in all patients except one. Eleven were not on preventatives. We found PCT infarct-like lesions in only 6 CM patients aged 42-64 years (mean age 54 years) who had at least two vascular risk factors. CONCLUSIONS: As frequency of PCT infarct-like lesions in our CM patients was in the low range than that found for EM in general population studies, we conclude that frequency of migraine attacks itself is not a factor increasing PCT infarct-like lesion risk.

Mycobacterium tuberculosis shikimate kinase inhibitors: design and simulation studies of the catalytic turnover.

Shikimate kinase (SK) is an essential enzyme in several pathogenic bacteria and does not have any counterpart in human cells, thus making it an attractive target for the development of new antibiotics. The key interactions of the substrate and product binding and the enzyme movements that are essential for catalytic turnover of the Mycobacterium tuberculosis shikimate kinase enzyme (Mt-SK) have been investigated by structural and computational studies. Based on these studies several substrate analogs were designed and assayed. The crystal structure of Mt-SK in complex with ADP and one of the most potent inhibitors has been solved at 2.15 Å. These studies reveal that the fixation of the diaxial conformation of the C4 and C5 hydroxyl groups recognized by the enzyme or the replacement of the C3 hydroxyl group in the natural substrate by an amino group is a promising strategy for inhibition because it causes a dramatic reduction of the flexibility of the LID and shikimic acid binding domains. Molecular dynamics simulation studies showed that the product is expelled from the active site by three arginines (Arg117, Arg136, and Arg58). This finding represents a previously unknown key role of these conserved residues. These studies highlight the key role of the shikimic acid binding domain in the catalysis and provide guidance for future inhibitor designs.