Rare and New Mutations of B-Globin in Azari Population of Iran, a Considerable Diversity.

Background: Thalassemia, as the most common single-gene genetic disorder, is related to a defect in the synthesis of one or more hemoglobin chains. More than 200 mutations have been identified in the ß-globin gene. Globally, every susceptible racial group has its own specific spectrum of the common mutations that are well-known to a particular geographic region. On the other hand, varying numbers of diverse rare mutations may occur. Materials and Methods: The subjects of the study included 2113 heterozygote or homozygote ß-thalassemia cases selected among couples who participated in the Iranian national thalassemia screening program from January 2011 to November 2019. Molecular characterization of the ß-thalassemia mutation was initially carried out by the amplification-refractory mutation system-polymerase chain reaction (ARMS-PCR) technique for common mutations, followed by sequencing, Gap PCR, and Multiple ligation-dependent probe amplification (MLPA) methods - in cases not detected by the ARMS-PCR. Results: The existence of 39 rare and new point mutations and 4 large deletions were described in our cohort. Sicilian (-13,337bp) deletion, CD36/37 (-T), and CD15 TGG>TGA were encountered more often than the others in a decreasing order, in terms of frequency. The least frequent mutations/deletions were deletion from HBD exon 1 to HBB promoter, 619 bp deletion, Deletion from up HBBP1-Exon3 HBBP1 and up HBB-0.5Kb down HBB, CAP+8 C>A, CD37 (G>A), CD6 (-A), IVSI-2 (T>C), IVSII-705 T>G, and IVSII-772 (G>A). Each occurred once. Five mutations/variants were also determined which have not been reported previously in Iran. Conclusion: According to the findings of the study, the Northwestern Iranian population displayed a wide variety of thalassemia allelic distributions. Identification of rare and new mutations in the ß-thalassemia in the national population is beneficial for screening programs, genetic counseling, and prenatal diagnosis.

Hyfrecation and Interference With Implantable Cardiac Devices.

BACKGROUND: Mohs micrographic surgery, excisional surgery, and electrodessication and curettage (ED&C) are common dermatologic procedures that often use electrodessication through hyfrecators to achieve hemostasis. According to in vitro studies, electrodessication is considered safe in patients with implanted cardiac devices. To the authors' knowledge, there are no in vivo data to support this claim. OBJECTIVE: In this study, the authors aim to describe the outcomes of hyfrecation during dermatologic procedures in patients with pacemakers and implantable cardiac devices. METHODS: Retrospective chart review was completed from March 2014 to April 2018 at a single center. Forty-five patients met criteria of having a cardiac device and having undergone an electrosurgery procedure using the Conmed 2000 Hyfrecator (Utica, NY). Adverse perioperative and postoperative outcomes, as well as device malfunction, were evaluated. RESULTS: No adverse perioperative effects were reported. Device reports were examined for inappropriate firing of the defibrillator, loss of capture, temporary inhibition of pacing, battery drainage, pacing at an elevated or erratic rate, failure to deliver antitachycardia, reversion to asynchronous pacing, induction of arrhythmias, or tissue damage at lead tissue, but no such issues were found. CONCLUSION: The lack of complications associated with cardiac devices with hyfrecation is reassuring. However, prospective and larger retrospective studies are warranted.

Motor cortex metabolite alterations in amyotrophic lateral sclerosis assessed in vivo using edited and non-edited magnetic resonance spectroscopy.

Previous MRI and proton spectroscopy (1H-MRS) studies have revealed impaired neuronal integrity and altered neurometabolite concentrations in the motor cortex of patients with amyotrophic lateral sclerosis (ALS). Here, we aim to use MRI with conventional and novel MRS sequences to further investigate neurometabolic changes in the motor cortex of ALS patients and their relation to clinical parameters. We utilized the novel HERMES (Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy) MRS sequence to simultaneously quantify the inhibitory neurotransmitter GABA and antioxidant glutathione in ALS patients (n = 7) and healthy controls (n = 7). In addition, we have also quantified other MRS observable neurometabolites using a conventional point-resolved MR spectroscopy (PRESS) sequence in ALS patients (n = 20) and healthy controls (n = 20). We observed a trend towards decreasing glutathione concentrations in the motor cortex of ALS patients (p = 0.0842). In addition, we detected a 11% decrease in N-acetylaspartate (NAA) (p = 0.025), a 15% increase in glutamate + glutamine (Glx) (p = 0.0084) and a 21% increase in myo-inositol (mIns) (p = 0.0051) concentrations for ALS patients compared to healthy controls. Furthermore, significant positive correlations were found between GABA-NAA (p = 0.0480; Rρ = 0.7875) and NAA-mIns (p = 0.0448; Rρ = -0.4651) levels among the patients. NAA levels in the bulbar-onset patient group were found to be significantly (p = 0.0097) lower compared to the limb-onset group. A strong correlation (p < 0.0001; Rρ = -0,8801) for mIns and a weak correlation (p = 0.0066; Rρ = -0,6673) for Glx was found for the disease progression, measured by declining of the ALS Functional Rating Scale-Revised criteria (ALSFRS-R). Concentrations of mIns and Glx also correlated with disease severity measured by forced vital capacity (FVC). Results suggest that mean neurometabolite concentrations detected in the motor cortex may indicate clinical and pathological changes in ALS.

Psychosocial impact of psoriasis: a review for dermatology residents.

Psoriasis is a chronic inflammatory disease with both a physical and psychosocial burden. To offer strategies for dermatology residents to assess and manage psychosocial aspects of psoriasis, a PubMed search of articles indexed for MEDLINE was performed using the following terms: psoriasis, depression, anxiety, work productivity, sexual functioning, and interpersonal relationships. Selected articles covered the prevalence, assessment, and management of each of the psychosocial domains of psoriasis. Depression is a common comorbidity in psoriasis patients, and the psychosocial burden of psoriasis is immense. Dermatology providers play a vital role in assessing and managing the psychosocial aspects of the disease along with medical management.

Non-invasive assessment of disease progression and neuroprotective effects of dietary coconut oil supplementation in the ALS SOD1G93A mouse model: A 1H-magnetic resonance spectroscopic study.

Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease primarily characterized by progressive degeneration of motor neurons in the motor cortex, brainstem and spinal cord. Due to relatively fast progression of ALS, early diagnosis is essential for possible therapeutic intervention and disease management. To identify potential diagnostic markers, we investigated age-dependent effects of disease onset and progression on regional neurochemistry in the SOD1G93A ALS mouse model using localized in vivo magnetic resonance spectroscopy (MRS). We focused mainly on the brainstem region since brainstem motor nuclei are the primarily affected regions in SOD1G93A mice and ALS patients. In addition, metabolite profiles of the motor cortex were also assessed. In the brainstem, a gradual decrease in creatine levels were detected starting from the pre-symptomatic age of 70 days postpartum. During the early symptomatic phase (day 90), a significant increase in the levels of the inhibitory neurotransmitter γ- aminobutyric acid (GABA) was measured. At later time points, alterations in the form of decreased NAA, glutamate, glutamine and increased myo-inositol were observed. Also, decreased glutamate, NAA and increased taurine levels were seen at late stages in the motor cortex. A proof-of-concept (PoC) study was conducted to assess the effects of coconut oil supplementation in SODG93A mice. The PoC revealed that the coconut oil supplementation together with the regular diet delayed disease symptoms, enhanced motor performance, and prolonged survival in the SOD1G93A mouse model. Furthermore, MRS data showed stable metabolic profile at day 120 in the coconut oil diet group compared to the group receiving a standard diet without coconut oil supplementation. In addition, a positive correlation between survival and the neuronal marker NAA was found. To the best of our knowledge, this is the first study that reports metabolic changes in the brainstem using in vivo MRS and effects of coconut oil supplementation as a prophylactic treatment in SOD1G93A mice.

Nonnegative Canonical Polyadic Decomposition for Tissue-Type Differentiation in Gliomas.

Magnetic resonance spectroscopic imaging (MRSI) reveals chemical information that characterizes different tissue types in brain tumors. Blind source separation techniques are used to extract the tissue-specific profiles and their corresponding distribution from the MRSI data. We focus on automatic detection of the tumor, necrotic and normal brain tissue types by constructing a 3D MRSI tensor from in vivo 2D-MRSI data of individual glioma patients. Nonnegative canonical polyadic decomposition (NCPD) is applied to the MRSI tensor to differentiate various tissue types. An in vivo study shows that NCPD has better performance in identifying tumor and necrotic tissue type in glioma patients compared to previous matrix-based decompositions, such as nonnegative matrix factorization and hierarchical nonnegative matrix factorization.

Comparison of unsupervised classification methods for brain tumor segmentation using multi-parametric MRI.

Tumor segmentation is a particularly challenging task in high-grade gliomas (HGGs), as they are among the most heterogeneous tumors in oncology. An accurate delineation of the lesion and its main subcomponents contributes to optimal treatment planning, prognosis and follow-up. Conventional MRI (cMRI) is the imaging modality of choice for manual segmentation, and is also considered in the vast majority of automated segmentation studies. Advanced MRI modalities such as perfusion-weighted imaging (PWI), diffusion-weighted imaging (DWI) and magnetic resonance spectroscopic imaging (MRSI) have already shown their added value in tumor tissue characterization, hence there have been recent suggestions of combining different MRI modalities into a multi-parametric MRI (MP-MRI) approach for brain tumor segmentation. In this paper, we compare the performance of several unsupervised classification methods for HGG segmentation based on MP-MRI data including cMRI, DWI, MRSI and PWI. Two independent MP-MRI datasets with a different acquisition protocol were available from different hospitals. We demonstrate that a hierarchical non-negative matrix factorization variant which was previously introduced for MP-MRI tumor segmentation gives the best performance in terms of mean Dice-scores for the pathologic tissue classes on both datasets.

Tensor based tumor tissue type differentiation using magnetic resonance spectroscopic imaging.

Magnetic resonance spectroscopic imaging (MRSI) has the potential to characterise different tissue types in brain tumors. Blind source separation techniques are used to extract the specific tissue profiles and their corresponding distribution from the MRSI data. A 3-dimensional MRSI tensor is constructed from in vivo 2D-MRSI data of individual tumor patients. Non-negative canonical polyadic decomposition (NCPD) with common factor in mode-1 and mode-2 and l(1) regularization on mode-3 is applied on the MRSI tensor to differentiate various tissue types. Initial in vivo study shows that NCPD has better performance in identifying tumor and necrotic tissue type in high grade glioma patients compared to previous matrix-based decompositions, such as non-negative matrix factorization and hierarchical non-negative matrix factorization.

Different quantification algorithms may lead to different results: a comparison using proton MRS lipid signals.

Proton magnetic resonance spectroscopy (MRS) is a sensitive method for investigating the biochemical compounds in a tissue. The interpretation of the data relies on the quantification algorithms applied to MR spectra. Each of these algorithms has certain underlying assumptions and may allow one to incorporate prior knowledge, which could influence the quality of the fit. The most commonly considered types of prior knowledge include the line-shape model (Lorentzian, Gaussian, Voigt), knowledge of the resonating frequencies, modeling of the baseline, constraints on the damping factors and phase, etc. In this article, we study whether the statistical outcome of a biological investigation can be influenced by the quantification method used. We chose to study lipid signals because of their emerging role in the investigation of metabolic disorders. Lipid spectra, in particular, are characterized by peaks that are in most cases not Lorentzian, because measurements are often performed in difficult body locations, e.g. in visceral fats close to peristaltic movements in humans or very small areas close to different tissues in animals. This leads to spectra with several peak distortions. Linear combination of Model spectra (LCModel), Advanced Method for Accurate Robust and Efficient Spectral fitting (AMARES), quantitation based on QUantum ESTimation (QUEST), Automated Quantification of Short Echo-time MRS (AQSES)-Lineshape and Integration were applied to simulated spectra, and area under the curve (AUC) values, which are proportional to the quantity of the resonating molecules in the tissue, were compared with true values. A comparison between techniques was also carried out on lipid signals from obese and lean Zucker rats, for which the polyunsaturation value expressed in white adipose tissue should be statistically different, as confirmed by high-resolution NMR measurements (considered the gold standard) on the same animals. LCModel, AQSES-Lineshape, QUEST and Integration gave the best results in at least one of the considered groups of simulated or in vivo lipid signals. These outcomes highlight the fact that quantification methods can influence the final result and its statistical significance.

Ex vivo high resolution magic angle spinning metabolic profiles describe intratumoral histopathological tissue properties in adult human gliomas.

In gliomas one can observe distinct histopathological tissue properties, such as viable tumor cells, necrotic tissue or regions where the tumor infiltrates normal brain. A first screening between the different intratumoral histopathological tissue properties would greatly assist in correctly diagnosing and prognosing gliomas. The potential of ex vivo high resolution magic angle spinning spectroscopy in characterizing these properties is analyzed and the biochemical differences between necrosis, high cellularity and border tumor regions in adult human gliomas are investigated. Statistical studies applied on sets of metabolite concentrations and metabolite ratios extracted from 52 high resolution magic angle spinning recordings coming from patients with different grades of glial tumors show a strong correlation between the histopathological tissue properties and the considered metabolic profiles, regardless of the malignancy grade. The results are in agreement with the pathology obtained by the histopathological examination that succeeded the high resolution magic angle spinning measurements. The metabolite concentration set can better differentiate between the considered histopathological tissue properties compared to the ratios. Representative reference tissue models describing the metabolic behavior are extracted for characterizing the intratumoral tissue properties. The proposed metabolic profiles reflect that the metabolites behavior is interconnected, and typical biochemical patterns emerge for each histopathological tissue property.

Non-negative blind source separation techniques for tumor tissue typing using HR-MAS signals.

Given High Resolution Magic Angle Spinning (HR-MAS) signals from several glioblastoma tumor subjects, the goal is to differentiate between tumor tissue types by separating the different sources that contribute to the profile of each spectrum. Blind source separation techniques are applied for obtaining characteristic profiles for necrosis, high cellular tumor and border tumor tissue, and providing the contribution (abundance) of each tumor tissue to the profile of the spectra. The problem is formulated as a non-negative source separation problem. We illustrate the effectiveness of the proposed methods and we analyze to which extent the dimension of the input space could influence the performance by comparing the results on the full magnitude signals and on dimensionally reduced spaces.

Systematic review and meta-analysis of combination therapy for smoking cessation.

OBJECTIVES: To review published clinical trials on combination therapy for smoking cessation and determine the role of this regimen for treating tobacco dependence. DATA SOURCES: Search terms included in this systematic review were nicotine replacement patch, nicotine replacement therapy, nicotine replacement gum, nicotine replacement inhaler, nicotine replacement nasal spray, nicotine replacement lozenge, bupropion SR (for sustained release), combination therapy, smoking cessation, and varenicline. Trials conducted from 1994 through October 10, 2007, were identified using EBM Reviews: Cochrane Central Register of Controlled Trials and Medline. STUDY SELECTION: Clinical trials of various regimens for smoking cessation were included based on a large sample size (n > or = 200); use of first-line smoking cessation therapies; double-blind, randomized, placebo-controlled design; and study duration of 1 year or more. The primary objective of the included clinical trials was to assess the efficacy of combination therapy. Studies that involved medications other than first-line therapies, adolescents, and post hoc analyses and that were not written in English were excluded. DATA SYNTHESIS: Five clinical trials meeting the inclusion criteria were reviewed. All of the studies included the use of the nicotine replacement patch along with one other agent. A total of 2,204 patients were treated. Combination therapy was significantly better than monotherapy at all pooled comparisons (P < 0.05). The aggregated relative risk of abstinence comparing combination with single treatment groups was 1.42 (95% CI 1.21-1.67), 1.54 (1.19-2.00), and 1.58 (1.25-1.99) at 3, 6, and 12 months, respectively. Adverse effects with combination nicotine replacement therapy were minimal and similar to placebo or monotherapy. CONCLUSION: Current literature indicates that combination therapy is statistically better than monotherapy in smoking cessation treatment as assessed by 3-, 6-, and 12-month abstinence rates. Adverse effects and adherence to combination therapy are similar to monotherapy and placebo.

Model order selection for quantification of a multi-exponential magnetic resonance spectrum.

Magnetic resonance spectroscopic signals analyzed by time-domain models in order to retrieve estimates of the model parameters usually require prior knowledge about the model order. For multi-exponential signals where a superposition of peaks occurs at the same resonance frequency, but with different damping values, model order selection criteria from information theory can be used. In this study, several generalized versions of information criteria are compared using Monte-Carlo simulation signals. The best criterion is further applied for selecting the model order of experimental glycogen signals.

Different familial transmission patterns in bipolar I disorder with onset before and after age 25.

Gene identification in common disorders such as Alzheimer disease and breast cancer has greatly profited from the use of age of onset as criterion to delineate subgroups of disease characterized by different inheritance patterns. In bipolar affective disorder, where the majority of linkage studies have produced conflicting results, studies reporting clinical characteristics and familial occurrence of disease have suggested that age of onset might serve as an indicator for identifying more homogeneous subgroups of disease. Our study was the first to examine this hypothesis by the means of segregation analysis. We investigated a sample of 177 bipolar I probands recruited from consecutive admissions and their first- and second-degree relatives (2,407 subjects). Probands were subdivided into an early-onset (n = 107) and a late-onset group (n = 70) using an age of onset of 25 as a cut-off point. This age was chosen because the observed age of onset distribution was bimodal with a cut-off of 25 years. Morbid risks for affective disorder were found significantly higher (P = 0.01) in relatives of probands with an early onset than in probands with late onset of disease. The segregation analysis showed that the disease is transmitted differently in early- and late-onset groups. In the early-onset group, a non-Mendelian major gene with a polygenic component was favored while the data in the late-onset group were compatible with a multifactorial model. This result may have important implications for future molecular studies aiming at the identification of disease-associated genes.

Antiendothelial cell antibodies in thromboangiitis obliterans.

The occurrence of autoimmune phenomena in 28 patients with thromboangiitis obliterans (Buerger's disease) was determined. The following were sought: antineutrophil cytoplasmic antibodies against proteinase 3 (cANCA) and myeloperoxidase (pANCA), antinuclear antibodies, anti-Ro antibodies, anticardiolipin antibodies, and antiendothelial cell antibodies (AECA). For the last, an enzyme-linked immunosorbent assay was developed which verified the presence of the AECA phenomenon with immunofluorescence and confocal microscopy. Seven patients with active disease had AECA titers of 1,857 +/- 450 arbitrary units (AU) compared with 126 +/- 15 AU in 30 normal control subjects (P < 0.001) and 461 +/- 41 AU in 21 patients in remission (P < 0.01). Antibodies from the sera of patients with active disease reacted not only with surface epitopes but also with sites within the cytoplasm of human endothelial cells. AECA may be useful in following disease activity and may play a role in the pathogenesis of thromboangiitis obliterans.

Anti-endothelial cell antibodies in Takayasu arteritis.

BACKGROUND: Although a specific etiology for Takayasu arteritis has not been found, the bulk of evidence favors an autoimmune mechanism. We examined the sera of 19 patients with Takayasu arteritis for antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), anti-DNA antibodies, antibodies to extractable nuclear antigens (ENA), anti-Ro anti-bodies, anticardiolipin antibodies, circulating immune complexes, and anti-endothelial cell antibodies (AECA). METHODS AND RESULTS: We used enzyme-linked immunoassays, immunofluorescence, counterimmunoelectrophoresis, fluorescent-activated cell sorter (FACS) analysis, and confocal microscopy. We found that although no patient had positive ANCA, ANA, anti-DNA antibodies, ENA antibodies, anti-Ro antibodies, or anticardiolipin antibodies, 18 of the 19 patients had AECA. The AECA titers of the patients were 2561 +/- 1458 compared with 126 +/- 15 arbitrary units in a normal group of control subjects (P < .001). To verify the specificity of AECA, we performed cytofluorimetry on human endothelial cells with the sera from patients and control subjects. Two entirely separate patterns of fluorescence intensity were identified. We next performed immunocytochemistry and confocal microscopy with human endothelial cells subjected to patients' sera and to sera from normal subjects. The cells subjected to sera from patients with Takayasu arteritis demonstrated specific immunofluorescent staining of their plasma membrane and cytosol. CONCLUSIONS: AECA are frequently present in patients with Takayasu arteritis. They may play a role in the pathogenesis. Furthermore, they may be useful as an additional diagnostic tool.

Disease activity and autoantibodies to endothelial cells in patients with Wegener's granulomatosis.

The purpose of this study was to assess the utility of antiendothelial cell antibodies (AECAs) in patients with active and inactive Wegener's granulomatosis. We studied 32 patients with Wegener's disease (clinical criteria and biopsy, as well as titers of antineutrophil cytoplasmic antibodies with a cytoplasmic pattern [cANCA]) over 4 years and compared their AECA values with those of 24 normal subjects similar in age and gender distribution, as well as with those of patients with chronic glomerulonephritis with or without dialysis and of patients with severe arteriosclerosis. We measured AECAs, cANCAs, C-reactive protein, erythrocyte sedimentation rate, proteinuria, and renal function in patients with active disease or in patients reactivating their disease. A time course with repeated AECAs was conducted over 27 months in 24 patients. The AECAs were measured with an enzyme-linked immunosorbent assay. The specificity was verified with immunofluorescent confocal microscopy, which showed the AECA epitopes to be within the cytoplasm of endothelial cells. Elevated AECA titers were found in all patients with active disease, not all of whom had positive cANCAs. Although elevated AECAs were also found in some patients with inactive disease, normal AECA values were seen only in patients with inactive disease. Patients with active disease entering remission showed a decrease in AECA titers, while patients entering a relapse increased their AECA titers. We conclude that AECAs are present in patients with Wegener's granulomatosis. To our knowledge, these are the first serial AECA observations. Our data suggest that AECAs are correlated with disease activity. Antiendothelial cell antibody values in the normal range strongly support remission. These findings may be of clinical utility in distinguishing relapse from concomitant illness.

Invasive metastasing pulmonary aspergillosis under polychemotherapy.

We report on a female patient who received a polychemotherapy because of an extensive pemphigus vulgaris. Under this therapy, the general condition of the patient worsened. Noncharacteristic symptoms, such as dyspnoea and tachycardia occurred. In spite of comprehensive, also invasive diagnostics, pulmonary foci demonstrable by X-ray morphology and computer tomography could not be specified. In the course of treatment, a cerebral compression symptomatology developed. Post mortem, a pulmonary aspergillosis with abscess-formation in the brain was found. The antigen identification completed the diagnosis. The increasing significance of Aspergillus infections is pointed out. The results of clinical examination and the differential diagnosis as well as the possibility of the diagnosis of pulmonary aspergillosis are demonstrated.