Advancing Parkinson's Disease Diagnostics: The Potential of Arylpyrazolethiazole Derivatives for Imaging α-Synuclein Aggregates.

The development of positron emission tomography (PET) tracers capable of detecting α-synuclein (α-syn) aggregates in vivo would represent a breakthrough for advancing the understanding and enabling the early diagnosis of Parkinson's disease and related disorders. It also holds the potential to assess the efficacy of therapeutic interventions. However, this remains challenging due to different structures of α-syn aggregates, the need for selectivity over other structurally similar amyloid proteins, like amyloid-ß (Aß), which frequently coexist with α-syn pathology, and the low abundance of the target in the brain that requires the development of a high-affinity ligand. To develop a successful PET tracer for the central nervous system (CNS), stringent criteria in terms of polarity and molecular size must also be considered, as the tracer must penetrate the blood-brain barrier and have low nonspecific binding to brain tissue. Here, we report a series of arylpyrazolethiazole (APT) derivatives, rationally designed from a structure-activity relationship study centered on existing ligands for α-syn fibrils, with a particular focus on the selectivity toward α-syn fibrils and control of physicochemical properties suitable for a CNS PET tracer. In vitro competition binding assays performed against [3H]MODAG-001 using recombinant α-syn and Aß1-42 fibrils revealed APT-13 with an inhibition constant of 27.8 ± 9.7 nM and a selectivity of more than 3.3 fold over Aß. Radiolabeled [11C]APT-13 demonstrated excellent brain penetration in healthy mice with a peak standardized uptake value of 1.94 ± 0.29 and fast washout from the brain (t 1/2 = 9 ± 1 min). This study highlights the potential of APT-13 as a lead compound for developing PET tracers to detect α-syn aggregates in vivo.

Eosin, blue LEDs and DIPEA are employed in a simple synthesis of (poly)cyclic O,O- and N,O-acetals.

A simple procedure for the synthesis of (poly)cyclic O,O- and N,O-acetals from various enol ethers, N-acyl enamines or Boc-protected enamines has been developed. The key step is a photocatalytic Stork-Ueno-type cylization using the very simple metal-free conditions of catalytic eosin, diisopropylamine in the green solvent ethanol with blue LED irradition.

Diospyrobezoar Formation in Patient With Sleeve Gastrectomy.

The ingestion of Asian persimmons, Diospyros kaki, is a known cause of gastric bezoars. Patients with a history of gastric operations are at high risk for formation. Different forms of bariatric surgery have been implicated, but literature for bezoar following a sleeve gastrectomy is scarce. This case report describes the pathogenesis, clinical course, and definitive management of gastric diospyrobezoar following a sleeve gastrectomy. With the rising incidence of bariatric procedures being performed, providers should include bezoar in the differential diagnosis in patients with suspected gastric outlet obstruction and should be aware of treatment options for this patient population.

Assessing the effectiveness of public health interventions for Covid-19 in Greece and Cyprus.

In this article, we statistically examine the effectiveness of non-pharmaceutical interventions (NPIs) implemented by the national governments of Greece and Cyprus during 2020 to (a) limit the spread of the SARS-CoV-2 virus, and (b) mitigate the economic fallout brought about by the Covid-19 pandemic. Applying a modified health belief model, we hypothesize that behavioral outcomes at the policy level are a function of NPIs, perceived severity, and social context. We employ a Prais-Winsten estimation in 2-week averages and report panel-corrected standard errors to find that NPIs have clear, yet differential, effects on public health and the economy in terms of statistical significance and time lags. The study provides a critical framework to inform future interventions during emerging pandemics.

En este artículo, examinamos estadísticamente la efectividad de las intervenciones no farmacéuticas (NPI) implementadas por los gobiernos nacionales de Grecia y Chipre durante 2020 para (a) limitar la propagación del virus SARS­CoV­2 y (b) mitigar las consecuencias económicas provocadas por la pandemia de Covid­19. Al aplicar un modelo de creencias de salud modificado, planteamos la hipótesis de que los resultados de comportamiento a nivel de política son una función de las NPI, la gravedad percibida y el contexto social. Empleamos una estimación de Prais­Winsten en promedios de dos semanas e informamos los errores estándar corregidos del panel para encontrar que las NPI tienen efectos claros, aunque diferenciales, en la salud pública y la economía en términos de importancia estadística y retrasos. El estudio proporciona un marco crítico para informar futuras intervenciones durante las pandemias emergentes.

Restoration of localised erosive wear using a combination of dental materials: a conservative approach.

Objectives To present the treatment approach for the restoration of localised anterior erosive wear using a combination of dental materials.Clinical considerations A patient presented in a private dental practice concerned about the aesthetics of his anterior teeth. The patient's history and clinical examination revealed erosive wear on the labial and palatal aspects of his maxillary central incisors and right lateral incisor. The formulated treatment plan was to restore the teeth in a conservative way. A diagnostic wax-up was performed and confirmed with the patient with chairside mock-up. The treatment provided included direct composite restorations, replacement of a porcelain-fused-to-metal crown on his left lateral incisor with a porcelain-fused-to-zirconia crown, and lithium disilicate ceramic veneers on the worn labial surfaces of the central incisors and the right lateral incisor. The preparations for the ceramic veneers were carried out with the aid of the diagnostic mock-up, thus minimising the need for tooth removal of the worn teeth.Conclusions Pre-operative planning for tooth surface loss cases can help to ensure that little or no remaining tooth structure is removed during the restorative procedures. A strict bonding protocol is crucial to ensure longevity of the restorations.

Rare Presentation of a Metastatic Pancreatic Neuroendocrine Neoplasm Presenting with Atrial Flutter.

Pancreatic neuroendocrine neoplasms (PanNENs) rarely secrete serotonin, which is the main cause of carcinoid syndrome. One of its unusual manifestations is carcinoid heart disease or Hedinger's syndrome which is seldom accompanied by cardiac arrhythmias. We report the case of an 88-year-old woman who presented with recently experienced episodes of palpitations and a newly developed atrial flutter with a ventricular rate of 130 beats per minute. Echocardiography revealed thickened and tethered tricuspid and pulmonary valve leaflets causing severe valvular regurgitation and right ventricular dilatation. Episodes of intermittent diarrhoea over the previous 2 years were mentioned, making carcinoid syndrome our working diagnosis. The 5-hydroxyindoleacetic acid (5-HIAA) levels in a 24-hour urine collection specimen were elevated. Conventional imaging studies and a Ga-68 dodecane tetraacetic acid tyrosine-3-octreotate (DOTATATE) positron emission tomography/computer tomography (PET/CT) scan revealed the presence of a metastatic PanNEN arising from the pancreatic tail. The patient was managed with lanreotide and telotristat with remarkable improvement of her symptoms. To our knowledge, this is the first reported case of carcinoid syndrome presenting with atrial flutter as the initial symptom. LEARNING POINTS: Ultrasonography findings can indicate or lead to the diagnosis of carcinoid heart disease or Hedinger's syndrome.Clinicians should investigate rarer causes of atrial flutter when common ones are excluded.Even in advanced metastatic disease, complete remission of symptoms may be achieved with somatostatin analogues along with telotristat ethyl.

Dynamic conjugate F-SHARP microscopy.

Optical microscopy is an indispensable tool in biomedical sciences, but its reach in deep tissues is limited due to aberrations and scattering. This problem can be overcome by wavefront-shaping techniques, albeit at limited fields of view (FOVs). Inspired by astronomical imaging, conjugate wavefront shaping can lead to an increased field of view in microscopy, but this correction is limited to a set depth and cannot be dynamically adapted. Here, we present a conjugate wavefront-shaping scheme based on focus scanning holographic aberration probing (F-SHARP). We combine it with a compact implementation that can be readily adapted to a variety of commercial and home-built two-photon microscopes. We demonstrate the power of the method by imaging with high resolution over extended FOV (>80 µm) deeper than 400 µm inside a mouse brain through a thinned skull.

Sex hormone levels in drug-naïve, first-episode patients with psychosis.

Aim: Sex differences have long been reported in schizophrenia leading to the hypothesis that sex hormones may be implicated in the pathophysiology of the disorder. We assessed gonadal hormones during the fasted state in drug-naïve patients with psychosis.Method: Fasting serum concentrations of follicular-stimulating hormone (FSH) and luteinizing hormone (LH), testosterone, free-testosterone, Sex Hormone Binding Globulin (SHBG) and oestradiol (E2) were compared between a group of 55 newly diagnosed, drug-naïve, first-episode men with psychosis and a group of 55 healthy controls, matched for age, smoking status and BMI. Testosterone, free-testosterone and SHBG were compared between a group of 32 drug-naïve, first-episode females with psychosis and a group of 32 healthy controls matched for age, smoking status and BMI.Results: Testosterone and free-testosterone levels were significantly lower in the patients' group and SHBG levels significantly higher in the patients' group compared to those in healthy controls. The two female groups had similar values in the hormones which were measured.Conclusion: Our findings provide evidence of lower testosterone and free-testosterone levels and increased SHBG levels in drug-naïve, first-episode males with psychosis.KEY POINTSReduced testosterone and free-testosterone levels in drug-naive, first-episode males with psychosis.Increased SHBG levels in drug-naive first-episode males with psychosis.No difference in FSH, LH and E2 levels between drug-naive first episode males with psychosis and controls.No difference in testosterone, free-testosterone and SHBG levels between drug-naive, first-episode women with psychosis and controls.

Comparative Analysis and Predictors of 10-year Tumor Necrosis Factor Inhibitors Drug Survival in Patients with Spondyloarthritis: First-year Response Predicts Longterm Drug Persistence.

OBJECTIVE: To evaluate the 10-year drug survival of the first tumor necrosis factor inhibitor (TNFi) administered to patients with spondyloarthritis (SpA) overall and comparatively between SpA subsets, and to identify predictors of drug retention. METHODS: Patients with SpA in the Hellenic Registry of Biologic Therapies, a prospective multicenter observational cohort, starting their first TNFi between 2004-2014 were analyzed. Kaplan-Meier curves and Cox regression models were used. RESULTS: Overall, 404 out of 1077 patients (37.5%) discontinued treatment (followup: 4288 patient-yrs). Ten-year drug survival was 49%. In the unadjusted analyses, higher TNFi survival was observed in patients with ankylosing spondylitis (AS) compared to undifferentiated SpA and psoriatic arthritis [PsA; significant beyond the first 2.5 (p = 0.003) years and 7 years (p < 0.001), respectively], and in patients treated for isolated axial versus peripheral arthritis (p = 0.001). In all multivariable analyses, male sex was a predictor for longer TNFi survival. Use of methotrexate (MTX) was a predictor in PsA and in patients with peripheral arthritis. Absence of peripheral arthritis and use of a monoclonal antibody (as opposed to non-antibody TNFi) independently predicted longer TNFi survival in axial disease because of lower rates of inefficacy. Achievement of major responses during the first year in either axial or peripheral arthritis was the strongest predictor of longer therapy retention (HR 0.33, 95% CI 0.26-0.41 for Ankylosing Spondylitis Disease Activity Score inactive disease, and HR 0.35, 95% CI 0.24-0.50 for 28-joint Disease Activity Score remission). CONCLUSION: The longterm retention of the first TNFi administered to patients with SpA is high, especially for males with axial disease. The strongest predictor of longterm TNFi survival is a major response within the first year of treatment.

Kilohertz binary phase modulator for pulsed laser sources using a digital micromirror device.

The controlled modulation of an optical wavefront is required for aberration correction, digital phase conjugation, or patterned photostimulation. For most of these applications, it is desirable to control the wavefront modulation at the highest rates possible. The digital micromirror device (DMD) presents a cost-effective solution to achieve high-speed modulation and often exceeds the speed of the more conventional liquid crystal spatial light modulator but is inherently an amplitude modulator. Furthermore, spatial dispersion caused by DMD diffraction complicates its use with pulsed laser sources, such as those used in nonlinear microscopy. Here we introduce a DMD-based optical design that overcomes these limitations and achieves dispersion-free high-speed binary phase modulation. We show that this phase modulation can be used to switch through binary phase patterns at the rate of 20 kHz in two-photon excitation fluorescence applications.

Evaluation of diffusion weighted imaging in the context of multi-parametric MRI of the prostate in the assessment of suspected low volume prostatic carcinoma.

Data from a multi-parametric MRI study of patients with possible early-stage prostate cancer was assessed with a view to creating a more efficient clinical protocol. Based on a correlation analysis suggesting that diffusion-weighted imaging (DWI) scores are more strongly correlated with overall PIRADS scores than other modalities such as dynamic contrast enhanced imaging or spectroscopy, we investigate the combination of T2-weighted imaging (T2w) and DWI as a potential diagnostic tool for prostate cancer detection, staging and guided biopsies. Quantification of the noise floor in the DWI images and careful fitting of the data suggests that the mono-exponential model provides a very good fit to the data and there is no evidence of non-Gaussian diffusion for b-values up to 1000s/mm2. This precludes the use of kurtosis or other non-Gaussian measures as a biomarker for prostate cancer in our case. However, the ADC scores for healthy and probably malignant regions are significantly lower for the latter in all 20 but one patient. The results suggest that a simplified mp-MRI protocol combining T2w and DWI may be a good compromise for a cost and time efficient, early-stage prostate cancer diagnostic programme, combining robust MR biomarkers for prostate cancer that can be reliably quantified and appear well-suited for general clinical practice.

Changes in the cytokine profile in first-episode, drug-naïve patients with psychosis after short-term antipsychotic treatment.

An increasing body of evidence suggests that antipsychotic medication can cause immunological changes that could be attributed to the amelioration of psychotic symptoms or the metabolic side effects of the drugs. So far, the results of the studies remain controversial. Our aim was to compare the levels of interleukin (IL) IL-2, IL-6 and transforming growth factor-ß2 (TGF-ß2) in drug-naïve, first-episode patients with psychosis before and after six weeks of antipsychotic medication. Thirty-nine first-episode patients with psychosis were enrolled in the study. Serum levels of IL-2, IL-6 and TGF-ß2 were measured by enzyme linked immunosorbent assay (ELISA) before and six weeks after the initiation of antipsychotics. In addition, clinical psychopathology was assessed using Positive and Negative Syndrome Scale (PANSS) before and after treatment. Serum levels of IL-2 were significantly increased six weeks after the initiation of antipsychotic treatment (p <0.001) while TGF-ß2 levels were decreased (p <0.001). IL-6 levels were overall increased (p <0.004), but this occurred in a non-linear way. These findings, although preliminary, provide further evidence that antipsychotic treatment in patients with psychosis may be correlated with immunological changes but further research is needed.

Treatment with the first TNF inhibitor in rheumatoid arthritis patients in the Hellenic Registry of Biologic Therapies improves quality of life especially in young patients with better baseline functional status.

OBJECTIVES: To assess in daily practice in patients with rheumatoid arthritis (RA) the effect of treatment with first tumour necrosis factor-α inhibitor (TNFi) in quality of life (Qol), disease activity and depict possible baseline predictors for gains in Qol. METHODS: Patients followed prospectively by the Hellenic Registry of Biologic Therapies were analysed. Demographics were recorded at baseline, while RA-related characteristics at baseline and every 6 months. Paired t-tests were used to detect divergences between patient-reported (Health Assessment Questionnaire (HAQ), EuroQol (EQ-5D)) and clinical tools (Disease Activity Score-28 joints (DAS28)). Clinical versus self-reported outcomes were examined via cross-tabulation analysis. Multiple regression analysis was performed for identifying baseline predictors of improvements in QALYs. RESULTS: We analysed 255 patients (age (mean±SD) 57.1±13.0, disease duration 9.2±9.1 years, prior non-biologic disease-modifying anti-rheumatic drugs 2.3±1.2). Baseline EQ-5D, HAQ and DAS28 were 0.36 (0.28), 1.01 (0.72) and 5.9 (1.3), respectively, and were all significantly improved after 12 months (0.77 (0.35), 0.50 (0.66), 3.9 (1.5), respectively, p<0.05 for all). 90% of patients who improved from high to a lower DAS28 status (low-remission or moderate) had clinically important improvement in Qol (phi-coefficient=0.531,p<0.05). Independent predictors of gains in Qol were lower baseline HAQ, VAS global and younger age (adjusted R2=0.27). CONCLUSIONS: In daily practice TNFi improve both disease activity and Qol for the first 12 months of therapy. 90% of patients who improved from high to a lower DAS28 status had clinically important improvement in Qol. Younger patients starting with lower HAQ and VAS global are more likely to benefit.

Aerobic, resistance and combined training and detraining on body composition, muscle strength, lipid profile and inflammation in coronary artery disease patients.

Fifty-six elderly individuals diagnosed with coronary artery disease participated in the study and were divided into four groups: an aerobic exercise group, a resistance exercise group, a combined (aerobic + resistance) exercise group and a control group. The three exercise groups participated in 8 months of exercise training. Before, at 4 and at 8 months of the training period as well as at 1, 2 and 3 months after training cessation, muscle strength was measured and blood samples were collected. The resistance exercise caused significant increases mainly in muscle strength whereas aerobic exercise caused favourable effects mostly on lipid and apolipoprotein profiles. On the other hand, combined exercise caused significant favourable effects on both physiological (i.e. muscle strength) and biochemical (i.e. lipid and apolipoprotein profile and inflammation status) parameters, while the return to baseline values during the detraining period was slower compared to the other exercise modalities.

Towards new applications using capillary waveguides.

In this paper we demonstrate the enhancement of the sensing capabilities of glass capillaries. We exploit their properties as optical and acoustic waveguides to transform them potentially into high resolution minimally invasive endoscopic devices. We show two possible applications of silica capillary waveguides demonstrating fluorescence and optical-resolution photoacoustic imaging using a single 330 µm-thick silica capillary. A nanosecond pulsed laser is focused and scanned in front of a capillary by digital phase conjugation through the silica annular ring of the capillary, used as an optical waveguide. We demonstrate optical-resolution photoacoustic images of a 30 µm-thick nylon thread using the water-filled core of the same capillary as an acoustic waveguide, resulting in a fully passive endoscopic device. Moreover, fluorescence images of 1.5 µm beads are obtained collecting the fluorescence signal through the optical waveguide. This kind of silica-capillary waveguide together with wavefront shaping techniques such as digital phase conjugation, paves the way to minimally invasive multi-modal endoscopy.

Isotropic inverse-problem approach for two-dimensional phase unwrapping.

We propose a new technique for two-dimensional phase unwrapping. The unwrapped phase is found as the solution of an inverse problem that consists in the minimization of an energy functional. The latter includes a weighted data fidelity term that favors sparsity in the error between the true and wrapped phase differences, as well as a regularizer based on higher-order total variation. One desirable feature of our method is its rotation invariance, which allows it to unwrap a much larger class of images compared to the state of the art. We demonstrate the effectiveness of our method through several experiments on simulated and real data obtained through the tomographic phase microscope. The proposed method can enhance the applicability and outreach of techniques that rely on quantitative phase evaluation.

Digital confocal microscopy through a multimode fiber.

Acquiring high-contrast optical images deep inside biological tissues is still a challenging problem. Confocal microscopy is an important tool for biomedical imaging since it improves image quality by rejecting background signals. However, it suffers from low sensitivity in deep tissues due to light scattering. Recently, multimode fibers have provided a new paradigm for minimally invasive endoscopic imaging by controlling light propagation through them. Here we introduce a combined imaging technique where confocal images are acquired through a multimode fiber. We achieve this by digitally engineering the excitation wavefront and then applying a virtual digital pinhole on the collected signal. In this way, we are able to acquire images through the fiber with significantly increased contrast. With a fiber of numerical aperture 0.22, we achieve a lateral resolution of 1.5µm, and an axial resolution of 12.7µm. The point-scanning rate is currently limited by our spatial light modulator (20Hz).

Parameters of glucose and lipid metabolism at the fasted state in drug-naïve first-episode patients with psychosis: Evidence for insulin resistance.

Diabetes and dyslipidemia are common in patients with psychosis; this association may be partly related to adverse metabolic effects of antipsychotic medications. We assessed glucose and lipid metabolism during the fasted state in drug-naïve patients with psychosis. Fasting serum concentrations of total cholesterol, triglycerides, high density lipoprotein (HDL), glucose, insulin, connecting peptide (C-peptide), homeostatic model assessment index (HOMA-IR), glycated hemoglobin (HbA1C) and serum cortisol were compared between a group of 40 newly diagnosed drug-naïve, first-episode patients with psychosis and a group of 40 healthy controls, matched for age, sex and BMI. Total cholesterol, triglycerides and fasting glucose levels were similar, whereas insulin and C-peptide levels were higher and HDL marginally lower in the patients' group compared to those in healthy controls. Drug-naïve patients with psychosis were more insulin resistant (as assessed by the HOMA-R index) compared to healthy controls. Serum cortisol did not differ between the two groups. There is evidence that drug-naïve, first-episode patients with psychosis are more insulin resistant compared to healthy controls.

Delivery of focused short pulses through a multimode fiber.

Light propagation through multimode fibers suffers from spatial distortions that lead to a scrambled intensity profile. In previous work, the correction of such distortions using various wavefront control methods has been demonstrated in the continuous wave case. However, in the ultra-fast pulse regime, modal dispersion temporally broadens a pulse after propagation. Here, we present a method that compensates for spatial distortions and mitigates temporal broadening due to modal dispersion by a selective phase conjugation process in which only modes of similar group velocities are excited. The selectively excited modes are forced to follow certain paths through the multimode fiber and interfere constructively at the distal tip to form a focused spot with minimal temporal broadening. We demonstrate the delivery of focused 500 fs pulses through a 30 cm long step-index multimode fiber. The achieved pulse duration corresponds to approximately 1/30th of the duration obtained if modal dispersion was not controlled. Moreover, we measured a detailed two-dimensional map of the pulse duration at the output of the fiber and confirmed that the focused spot produces a two-photon absorption effect. This work opens new possibilities for ultra-thin multiphoton imaging through multimode fibers.