Search

The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect. Using identity-by-descent (IBD) networks, we estimate the broad- and fine-scale population ancestry of risk allele carriers and their relatives. Analysis of ancestral migration routes reveals ancestors who inhabited Denmark in the 1700s, migrated to the Northeastern United States in the early 1800s, and traveled across the Midwest to arrive in Utah in the late 1800s. IBD/coalescent-based allele dating analysis reveals a relatively recent origin of the AF risk allele (~5000 years). Thus, our approach broadens the scope of study for disease susceptibility alleles to the context of human migration and ancestral origins., Many rare high-impact variants have been associated with disease, but the origins and functional impact are not always explored. Here, the authors trace the ancestry of a rare high impact atrial fibrillation allele in KCNQ1, and use iPSC-derived cardiomyocytes to characterize the effect of the allele.

BACKGROUND CONTEXT Outcomes of treatment in care of patients with spinal disorders are directly related to patient selection and treatment indications. However, for many disorders, there is absence of consensus for precise indications. With the increasing emphasis on quality and value in spine care, it is essential that treatment recommendations and decisions are optimized. PURPOSE The purpose of the North American Spine Society Appropriate Use Criteria was to determine the appropriate (ie reasonable) multidisciplinary treatment recommendations for patients with degenerative spondylolisthesis across a spectrum of more common clinical scenarios. STUDY DESIGN A Modified Delphi process was used. METHODS The methodology was based on the Appropriate Use Criteria development process established by the Research AND Development Corporation. The topic of degenerative spondylolisthesis was selected by the committee, key modifiers determined, and consensus reached on standard definitions. A literature search and evidence analysis were completed by one work group simultaneously as scenarios were written, reviewed, and finalized by another work group. A separate multidisciplinary rating group was assembled. Based on the literature, provider experience, and group discussion, each scenario was scored on a nine-point scale on two separate occasions, once without discussion and then a second time following discussion based on the initial responses. The median rating for each scenario was then used to determine if indications were rarely appropriate (1 – 3), uncertain (4-6), or appropriate (7-9). Consensus was not mandatory. RESULTS There were 131 discrete scenarios. These addressed questions on bone grafting, imaging, mechanical instability, radiculopathy with or without neurological deficits, obesity, and yellow flags consisting of psychosocial and medical comorbidities. For most of these, appropriateness was established for physical therapy, injections, and various forms of surgical intervention. The diagnosis of spondylolisthesis should be determined by an upright x-ray. Scenarios pertaining to bone grafting suggested that patients should quit smoking prior to surgery, and that use of BMP should be reserved for patients who had risk factors for non-union. Across all clinical scenarios, physical therapy (PT) had an adjusted mean of 7.66, epidural steroid injections 5.76, and surgery 4.52. Physical therapy was appropriate in most scenarios, and most appropriate in patients with back pain and no neurological deficits. Epidural steroid injections were most appropriate in patients with radiculopathy. Surgery was generally more appropriate for patients with neurological deficits, higher disability scores, and dynamic spondylolisthesis. Mechanical back pain and presence of yellow flags tended to be less appropriate, and obesity in general had relatively little influence on decision making. Decompression alone was more strongly considered in the presence of static versus dynamic spondylolisthesis. On average, posterior fusion with or without interbody fusion was similarly appropriate, and generally more appropriate than stand-alone interbody fusion which was in turn more appropriate than interspinous spacers. CONCLUSIONS Multidisciplinary appropriate treatment criteria were generated based on the Research AND Development methodology. While there were consistent and significant differences between surgeons and non-surgeons, these differences were generally very small. This document provides comprehensive evidence-based recommendations for evaluation and treatment of degenerative spondylolisthesis. The document in its entirety will be found on the North American Spine Society website ( https://www.spine.org/Research-Clinical-Care/Quality-Improvement/Appropriate-Use-Criteria) .

High quality evidence is difficult to generate, leaving substantial knowledge gaps in the treatment of spinal conditions. Appropriate use criteria (AUC) are a means of determining appropriate recommendations when high quality evidence is lacking.Define appropriate use criteria (AUC) of cervical fusion for treatment of degenerative conditions of the cervical spine.Appropriate use criteria for cervical fusion were developed using the RAND/UCLA appropriateness methodology. Following development of clinical guidelines and scenario writing, a one-day workshop was held with a multidisciplinary group of 14 raters, all considered thought leaders in their respective fields, to determine final ratings for cervical fusion appropriateness for various clinical situations.Final rating for cervical fusion recommendation as either "Appropriate," "Uncertain" or "Rarely Appropriate" based on the median final rating among the raters.Inclusion criteria for scenarios included patients aged 18 to 80 with degenerative conditions of the cervical spine. Key modifiers were defined and combined to develop a matrix of clinical scenarios. The median score among the raters was used to determine the final rating for each scenario. The final rating was compared between modifier levels. Spearman's rank correlation between each modifier and the final rating was determined. A multivariable ordinal regression model was fit to determine the adjusted odds of an "Appropriate" final rating while adjusting for radiographic diagnosis, number of levels and symptom type. Three decision trees were developed using decision tree classification models and variable importance for each tree was computed.Of the 263 scenarios, 47 (17.9 %) were rated as rarely appropriate, 66 (25%) as uncertain and 150 (57%) were rated as appropriate. Symptom type was the modifier most strongly correlated with the final rating (adjusted ρ2 = 0.58, p.01). A multivariable ordinal regression adjusting for symptom type, diagnosis, and number of levels and showed high discriminative ability (C statistic = 0.90) and the adjusted odds ratio (aOR) of receiving a final rating of "Appropriate" was highest for myelopathy (aOR, 7.1) and radiculopathy (aOR, 4.8). Three decision tree models showed that symptom type and radiographic diagnosis had the highest variable importance.Appropriate use criteria for cervical fusion in the setting of cervical degenerative disorders were developed. Symptom type was most strongly correlated with final rating. Myelopathy or radiculopathy were most strongly associated with an "Appropriate" rating, while axial pain without stenosis was most associated with "Rarely Appropriate."

Analysis of the full genome of an environmentally unique, halotolerant Streptomyces sp. strain GSL-6C, isolated from the Great Salt Lake, revealed a gene cluster encoding the biosynthesis of the salinipeptins, d-amino-acid-containing members of the rare linaridin subfamily of ribosomally synthesized and post-translationally modified peptides (RiPPs). The sequence organization of the unmodified amino acid residues in salinipeptins A-D (1-4) were suggested by genome annotation, and subsequently, their sequence and post-translational modifications were defined using a range of spectroscopic techniques and chemical derivatization approaches. The salinipeptins are unprecedented linaridins bearing nine d-amino acids, which are uncommon in RiPP natural products and are the first reported in the linaridin subfamily. Whole genome mining of GSL-6C did not reveal any homologues of the reported genes responsible for amino acid epimerization in RiPPs, inferring new epimerases may be involved in the conversion of l- to d-amino acids. In addition, the N-oxide and dimethylimidazolidin-4-one moieties in salinipeptins B and C, which are modified from N, N-dimethylalanine, are unknown in bacterial peptides. The three-dimensional structure of salinipeptin A, possessing four loops generated by significant hydrogen bonding, was established on the basis of observed nuclear Overhauser effect (NOE) correlations. This study demonstrates that integration of genomic information early in chemical analysis significantly facilitates the discovery and structure characterization of novel microbial secondary metabolites.

Chemical investigation of a marine actinomycete within the family Streptomycetaceae (our strain CNQ-149) has led to the isolation of the unprecedented alkaloids, actinobenzoquinoline (1) and actinophenanthrolines A-C (2-4). The chemical structures of 1-4 were assigned by interpretation of NMR spectroscopic data, and their absolute configurations were assigned by X-ray analysis. Actinobenzoquinoline possesses a 5-methyloxazolidin-4-one moiety and a dihydrobenzo[h]quinoline core structure, while actinophenanthrolines A-C are composed of hydroxypropanamide-substituted 1,7-phenanthroline core skeletons.

To evaluate the impact of dedicated reader education on accuracy/confidence of peripheral zone index cancer and anterior prostate cancer (PCa) diagnosis with mpMRI; secondary aim was to assess the ability of readers to differentiate low-grade cancer (Gleason 6 or below) from high-grade cancer (Gleason 7+).Five blinded radiology fellows evaluated 31 total prostate mpMRIs in this IRB-approved, HIPAA-compliant, retrospective study for index lesion detection, confidence in lesion diagnosis (1-5 scale), and Gleason grade (Gleason 6 or lower vs. Gleason 7+). Following a dedicated education program, readers reinterpreted cases after a memory extinction period, blinded to initial reads. Reference standard was established combining whole mount histopathology with mpMRI findings by a board-certified radiologist with 5 years of prostate mpMRI experience.Index cancer detection: pre-education accuracy 74.2%; post-education accuracy 87.7% (p = 0.003). Confidence in index lesion diagnosis: pre-education 4.22 ± 1.04; post-education 3.75 ± 1.41 (p = 0.0004). Anterior PCa detection: pre-education accuracy 54.3%; post-education accuracy 94.3% (p = 0.001). Confidence in anterior PCa diagnosis: pre-education 3.22 ± 1.54; post-education 4.29 ± 0.83 (p = 0.0003). Gleason score accuracy: pre-education 54.8%; post-education 73.5% (p = 0.0005).A dedicated reader education program on PCa detection with mpMRI was associated with a statistically significant increase in diagnostic accuracy of index cancer and anterior cancer detection as well as Gleason grade identification as compared to pre-education values. This was also associated with a significant increase in reader diagnostic confidence. This suggests that substantial interobserver variability in mpMRI interpretation can potentially be reduced with a focus on education and that this can occur over a fellowship training year.

The microbial production, isolation, and structure elucidation of four new napyradiomycin congeners (1-4) is reported. The structures of these compounds, which are new additions to the marine-derived meroterpenoids, were defined by comprehensive spectroscopic analysis and by X-ray crystallography. Using fluorescence-activated cell sorting (FACS) analysis, napyradiomycins 1-4 were observed to induce apoptosis in the colon adenocarcinoma cell line HCT-116, indicating the possibility of a specific biochemical target for this class of cytotoxins.

Reported herein is the isolation and structure elucidation of three highly modified peptides, actinoramides A-C (1-3), which are produced by a marine bacterium closely related to the genus Streptomyces. The planar structures of the actinoramides, which are composed of the unusual amino acids 2-amino-4-ureidobutanoic acid and 4-amino-3-hydroxy-2-methyl-5-phenylpentanoic acid, were assigned by chemical transformations and by interpretation of spectroscopic data, while the absolute configuration of these new peptides were defined by application of the advanced Marfey's and Mosher's methods.

Cultivation of actinomycete strain CNQ-418, retrieved from a deep ocean sediment sample off the coast of La Jolla, California, has provided marinopyrroles A–F. Sharing just 98% 16S rRNA gene sequence identity with S. sannurensis, the strain likely represents a new Streptomyces species. The metabolites contain an unusual 1,3′-bipyrrole core decorated with several chlorine and bromine substituents and possess marked antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). The congested N,C-biaryl bond establishes an axis of chirality that, for marinopyrroles A-E, is configurationally stable at room temperature. Moreover, the natural products are fashioned strictly in the M-configuration. The Paal-Knorr condensation was adapted for the synthesis of the 1,3′-bipyrrole core. Halogenation of this material with N-bromosuccinimide cleanly furnished the 4,4′,5,5′-tetrahalogenated core that characterizes this class of marine-derived metabolites.

[structure: see text] Two new cyclic peptides, thalassospiramides A and B (1 and 2), were isolated from a new member of the marine alpha-proteobacterium Thalassospira. The thalassospiramides, the structures of which were assigned by combined spectral and chemical methods, bear unusual gamma-amino acids and show immunosuppressive activity in an interleukin-5 production inhibition assay (IC50 = 5 muM for thalassospiramide B).

Chemical investigation of a marine actinomycete within the family Streptomycetaceae (our strain CNQ-149) has led to the isolation of the unprecedented alkaloids, actinobenzoquinoline (1) and actinophenanthrolines A-C (2-4). The chemical structures of 1-4 were assigned by interpretation of NMR spectroscopic data, and their absolute configurations were assigned by X-ray analysis. Actinobenzoquinoline possesses a 5-methyloxazolidin-4-one moiety and a dihydrobenzo[h]quinoline core structure, while actinophenanthrolines A-C are composed of hydroxypropanamide-substituted 1,7-phenanthroline core skeletons.

SummaryLow-nutrient media and long incubation times facilitated the cultivation of 20 taxonomically diverse Gram-negative marine bacteria within the phyla Bacteroidetes and Proteobacteria. These strains comprise as many as three new families and include members of clades that had only been observed using culture-independent techniques. Chemical studies of the type strains representing two new families within the order Cytophagales led to the isolation of nine new alkaloid secondary metabolites that can be grouped into four distinct structure classes, including azepinones, aziridines, quinolones, and pyrazinones. Several of these compounds possess antibacterial properties and appear, on structural grounds, to be produced by amino acid-based biosynthetic pathways. Our results demonstrate that relatively simple cultivation techniques can lead to the isolation of new bacterial taxa that are capable of the production of alkaloid secondary metabolites with antibacterial activities. These findings support continued investment in cultivation techniques as a method for natural product discovery.

The apparent diffusion coefficient (ADC) values for benign central zone (CZ) of the prostate were compared with ADC values of benign peripheral zone (PZ), benign transition zone (TZ), and prostate cancer, using histopathologic findings from radical prostatectomy as the reference standard.The study included 27 patients with prostate cancer (mean [± SD] age, 60.0 ± 7.6 years) who had 3-T endorectal coil MRI of the prostate performed before undergoing prostatectomy with whole-mount histopathologic assessment. Mean ADC values were recorded from the ROI within the index tumor and within benign CZ, PZ, and TZ, with the use of histopathologic findings as the reference standard. ADC values of the groups were compared using paired t tests and ROC curve analysis.The ADC of benign CZ in the right (1138 ± 123 × 10(-6) mm(2)/s) and left (1166 ± 141 × 10(-6) mm(2)/s) lobes was not significantly different (p = 0.217). However, the ADC of benign CZ (1154 ± 129 × 10(-6) mm(2)/s) was significantly lower (p0.001) than the ADCs of benign PZ (1579 ± 197 × 10(-6) mm(2)/s) and benign TZ (1429 ± 180 × 10(-6) mm(2)/s). Although the ADC of index tumors (1042 ± 134 × 10(-6) mm(2)/s) was significantly lower (p = 0.002) than the ADC of benign CZ there was no significant difference (p = 0.225) between benign CZ and tumors with a Gleason score of 6 (1119 ± 87 × 10(-6) mm(2)/s). In 22.2% of patients (6/27), including five patients who had tumors with a Gleason score greater than 6, the ADC was lower in benign CZ than in the index tumor. The AUC of ADC for the differentiation of benign CZ from index tumors was 72.4% (sensitivity, 70.4%; specificity, 51.9%), and the AUC of ADC for differentiation from tumors with a Gleason score greater than 6 was 76.7% (sensitivity, 75.0%; specificity, 65.0%).The ADC of benign CZ is lower than the ADC of other zones of the prostate and overlaps with the ADC of prostate cancer tissue, including high-grade tumors. Awareness of this potential diagnostic pitfall is important to avoid misinterpreting the normal CZ as suspicious for tumor.

Three potent cancer cell cytotoxins, piperazimycins A-C (1-3), have been isolated from the fermentation broth of a Streptomyces sp., cultivated from marine sediments near the island of Guam. The structures of these cyclic hexadepsipeptides were assigned by a combination of spectral, chemical, and crystallographic methods. The piperazimycins are composed of rare amino acids, including hydroxyacetic acid, alpha-methylserine, gamma-hydroxypiperazic acid, and gamma-chloropiperazic acid. The novel amino acid residues 2-amino-8-methyl-4,6-nonadienoic acid and 2-amino-8-methyl-4,6-decadienoic acid were found as components of piperazimycins A and C, respectively. When screened in the National Cancer Institute's 60 cancer cell line panel, piperazimycin A exhibited potent in vitro cytotoxicity toward multiple tumor cell lines with a mean GI50 of 100 nM.

In the course of our continuing search for new antitumor-antibiotics from marine-derived actinomycete bacteria, four new cytotoxic compounds, designated as daryamides A (1), B (2), and C (3) and (2E,4E)-7-methylocta-2,4-dienoic acid amide (4), were isolated from the culture broth of a marine-derived Streptomyces strain CNQ-085. The structures of these new compounds were assigned by detailed interpretation of spectroscopic data. The relative configuration of 1 was determined by comprehensive NMR analysis, while the absolute configuration of 1 was determined as 4S,5R using the modified Mosher method. The daryamides show weak to moderate cytotoxic activity against the human colon carcinoma cell line HCT-116 and very weak antifungal activities against Candida albicans.

A taxonomic study was carried out to clarify the taxonomy of representatives of a group of marine actinomycetes previously designated MAR 1 and considered to belong to the family Micromonosporaceae. The organisms had phenotypic properties consistent with their assignment to this taxon. The strains formed a distinct taxon in the 16S rRNA Micromonosporaceae gene tree and shared a range of phenotypic properties that distinguished them from members of all of the genera with validly published names classified in this family. The name proposed for this novel taxon is Salinispora gen. nov. The genus contains two species recognized using a range of genotypic and phenotypic criteria, including comparative 16S–23S rRNA gene spacer region and DNA–DNA relatedness data. The names proposed for these taxa are Salinispora arenicola sp. nov., the type species, and Salinispora tropica sp. nov.; the type strains of these novel species have been deposited in service culture collections as strain CNH-643T (=ATCC BAA-917T=DSM 44819T) and strain CNB-440T (=ATCC BAA-916T=DSM 44818T), respectively.

An extensive study of the secondary metabolites produced by the obligate marine actinomycete Salinispora tropica (strain CNB-392), the producing microbe of the potent proteasome inhibitor salinosporamide A (1), has led to the isolation of seven related gamma-lactams. The most important of these compounds were salinosporamide B (3), which is the deschloro-analogue of 1, and salinosporamide C (4), which is a decarboxylated pyrrole analogue. New SAR data for all eight compounds, derived from extensive testing against the human colon carcinoma HCT-116 and the 60-cell-line panel at the NCI, indicate that the chloroethyl moiety plays a major role in the enhanced activity of 1.

[structure: see text] Analysis of the fermentation broth of a strain of the marine actinomycete Salinispora tropica has led to the isolation of two unprecedented macrolides, sporolides A (1) and B (2). The structures and absolute stereochemistries of both metabolites were elucidated using a combination of NMR spectroscopy and X-ray crystallography.

It is now thirty years since Americans finally departed from Saigon in 1975.That this longest war in U.S.history still electrifies the political climate was abundantly evident in the last presidential election. John Kerry opened his campaign with a dramatic rendering of his heroic feats as a swift-boat commander in Vietnam to which members of his crew gave testimony. Anti-Kerry political ads followed, sponsored by the putative Swift-Boat Veterans for Truth, who sought to portray him as utterly unworthy of his wartime honors. Another pro-Republican group depicted Kerry as a national anti-war activist who debased the coinage of traditional patriotism, and thereby disqualified himself from leading the nation in the war in Iraq as well as in the struggle against terrorism. Anti-Bush ads then challenged the integrity of the President's record as a reserve Air Force pilot during the Vietnam War. Within the preceding context, it is clear that any contemporary historian engaged in writing about Vietnam must be aware that the very process itself entails a political act. The war there has affected the deep stories of all those who were, and are, either defenders or opponents of America's involvement in that military action. There is also the inevitable distortion of memory and of bias among those who viewed the war from such varying perspectives as that of the church, of the larger society, as well as of the academy. Yawning generation gaps were current during the "war and still affect our perspectives today. Any historian examining so divisive a conflict must struggle to achieve the necessary scholarly detachment, even when he or she has access to what seem to be voluminous records. In writing about Catholic Relief Services I have the luxury of rich documentation that reveals both sides in a war that polarized the nation. Nevertheless, there is always a danger of interpretive prejudices unwittingly creeping into any narrative of conflict. Introduction: The Context In 1943, during Franklin D. Roosevelt's post-World War II planning to incorporate religious voluntary agencies into relief and recovery efforts, Catholic War Relief Services-NCWC was established by the Catholic bishops' National Catholic Welfare Conference. After 1955 it was renamed Catholic Relief Services-NCWC. As a participant in the National War Fund, CRS was allotted 2.4 million dollars for immediate projects to respond to the needs of Polish refugees in Mexico, Palestine, and other Catholic refugees and prisoners of war. Of course, CRS could not use the funds for ecclesiastical purposes or any kind of religious activity, but all funds were to go for health and general-welfare projects. CRS was almost entirely dependent upon U.S. aid; it also received the funds collected in every diocese on Laetare Sunday that originated in a 1941 collection for overseas aid. Over the years Church World Service (which included the major Protestant denominations and the Orthodox Church) and the United Jewish Appeal collected funds on that same weekend, marking it a special time for reflection on the needs of the human family. Eileen Egan, author of a history of CRS, captured the significance of the appeals by the principal faiths: "By their efficacy in mobilizing their communities to make sacrifices for suffering in far corners of the globe, the faith-related volunteer agencies earned the respect of the U.S. government, of foreign governments . . . and of intergovernmental agencies. ... In the post-war decades, over threefourths of all voluntary aid from the American people was donated by the three great faith-related agencies."1 Of course, this voluntary aid could be used for religious activities. In postwar Europe CRS had the advantage of funneling its U.S. aid for the social welfare and medical needs of people through the Church's extensive networks of institutions, i.e., hospitals, orphanages, and other charities. It was the only agency overseas recognized by many countries, making it the largest relief service. …

The human infectious disease anthrax is caused by the sporeforming, Gram-positive bacterium Bacillus anthracis. The disease, which is most common in those that handle infected farm animals, has also been used as a bioterrorism weapon. In 2001, just a week after the World Trade Center attacks, anthrax was deliberately spread through the US postal system by sending letters with powdered B. anthracis spores. This caused 22 cases of anthrax infection and ultimately claimed five lives. [1] Depending upon the method of exposure (inhalation of spores and direct bacterial contact, among others) B. anthracis infections can require prolonged treatment often for six months with a variety of antibiotics. The pulmonary form of anthrax is considered a medical emergency that may require continuous intravenous therapy with potent antibiotics. In the event of a bioterrorism attack, individuals exposed to B. anthracis will be given antibiotics prior to the onset of the illness. A vaccine has been developed but is not yet available to the general public. [2] Given the severity of this disease, and the fact that it can be spread by aerosol dispersal, the development of effective new antibiotics remains a high priority. As a resource for developing microbial antibiotics, we have focused our efforts on marine microorganisms, particularly those that are in the deep oceans. Examination of a Streptomyces species (our strain CNH365), isolated from near-shore marine sediments found near Santa Barbara, CA, showed that culture extracts possessed significant activity against B. anthracis and methicillin-resistant Staphylococcus aureus in broth dilution assays. Subsequent fractionation of the extract following antibacterial activities yielded a pure

The purpose of this article is to present a survey of important neuropsychiatric issues and recent findings regarding the evaluation and treatment of neuropsychiatric symptoms and syndromes in patients with intellectual disability (ID). The cause of ID, environmental or genetic, can be determined in few patients. Etiology is idiopathic in most patients. ID and psychiatric illness are not mutually exclusive; individuals with ID have increased rates of psychiatric illness. Although recognition of significant axis I psychopathology is important, not all challenging behaviors in persons with ID will have a clear axis I diagnosis. Psychologic, behavioral, and environmental treatments are appropriate measures, but pharmacotherapy often is needed. Our experience has shown us that the more severe, disruptive, and dangerous the behavior, the stronger the indication for empirical drug treatment trials. Community-based models of support with neuropsychiatric intervention can be a potent therapeutic combination in the management of challenging behaviors in individuals with ID.

(PCy3)2Cl2RuCHPh-catalyzed Kharasch additions of trihaloalkanes across olefins provide polyhalogenated adducts, which upon hydrolysis furnish α,β-unsaturated ketones, aldehydes, or γ-hydroxybutenolides. This two-step process represents an overall acylation or carbonylation of an olefin.

Commentary on Yang S, Werner BC, Cancienne JM, Hassanzadeh H, Shimer AL, Shen FH, Singla A. Preoperative epidural injections are associated with increased risk of infection after single-level lumbar decompression. Spine J 2016:16:190–5 ( in this issue ).

A long-recognized association exists between epilepsy and affective disturbance, especially depression. People with complex partial seizures that result from temporal lobe seizure foci are highly vulnerable to psychiatric disorders. Accurate diagnosis of such disorders is an important key to treatment. Interictal depression or dysphoria is the most clinically significant problem of this type. Pharmacotherapeutic treatments that have positive effects in other types of depressive illness are also effective for depression associated with epilepsy. Electroconvulsive therapy is helpful to some patients with depression that is refractory to drug treatment or psychotherapy. Surgical resection of seizure foci may lead to psychiatric improvement for some individuals, but can also have psychiatric complications.

Background: Conventional contrast cineangiography and intravascular ultrasound (IVUS) provide a limited definition of vessel microstructure and are unable to evaluate dissection, tissue prolapse, and stent apposition on a size scale less than 100 μm. Objective: To evaluate the use of intravascular optical coherence tomography (OCT) to assess the coronary arteries in patients undergoing coronary stenting. Methods: OCT was employed in patients having percutaneous coronary interventions. Images were obtained before initial balloon dilatation and following stent deployment, and were evaluated for vessel dissection, tissue prolapse, stent apposition, and stent asymmetry. IVUS images were obtained before OCT, using an automatic pull back device. Results: 42 stents were imaged in 39 patients without complications. Dissection, prolapse, and incomplete stent apposition were observed more often with OCT than with IVUS. Vessel dissection was identified in eight stents by OCT and two by IVUS. Tissue prolapse was identified in 29 stents by OCT and 12 by IVUS; the extent of the prolapse (mean (SD)) was 242 (156) μm by OCT and 400 (100) μm by IVUS. Incomplete stent apposition was observed in seven stents by OCT and three by IVUS. Irregular strut separation was identified in 18 stents by both OCT and IVUS. Conclusions: Intracoronary OCT for monitoring stent deployment is feasible and provides superior contrast and resolution of arterial pathology than IVUS.

This paper provides an outline of a collaborative research project between researchers at the University of California, San Diego, University of Rhode Island, and the Bristol-Myers Squibb Pharmaceutical Research Institute, with participating members from the Developmental Therapeutics Branch of the National Cancer Institute. The program, formally funded by the National Cancer Institute under the National Cooperative Drug Discovery Groups (NCDDG) program, seeks to discover new anticancer drugs from marine organisms, in particular invertebrates such as sponges and ascidians, and marine microalgae, marine bacteria and fungi. In this report, the program and results obtained since its beginning in 2000 will be summarized.

Progress on development of lead-salt thermoelectrically-cooled (TE-cooled) imaging sensors will be presented. The imaging sensor architecture has been integrated into field-ruggedized hardware, and supports the use of lead-salt based detector material, including lead selenide and lead sulfide. Images and video are from a lead selenide focal plane array on silicon ROIC at temperatures approaching room temperature, and at high frame rates. Lead-salt imagers uniquely possess three traits: (1) Sensitive operation at high temperatures above the typical ‘cooled’ sensor maximum (2) Photonic response which enables high frame rates faster than the bolometric, thermal response time (3) Capability to reliably fabricate 2D arrays from solution-deposition directly, i. e. monolithically, on silicon. These lead-salt imagers are less expensive to produce and operate compared to other IR imagers based on II-VI HgCdTe and III-V InGaAsSb, because they do not require UHV epitaxial growth nor hybrid assembly, and no cryo-engine is needed to maintain low thermal noise. Historically, there have been challenges with lead-salt detector-to-detector non-uniformities and detector noise. Staring arrays of lead-salt imagers are promising today because of advances in ROIC technology and fabrication improvements. Non-uniformities have been addressed by on-FPA non-uniformity correction and 1/f noise has been mitigated with adjustable noise filtering without mechanical chopping. Finally, improved deposition process and measurement controls have enabled reliable fabrication of high-performance, lead-salt, large format staring arrays on the surface of large silicon ROIC wafers. The imaging array performance has achieved a Noise Equivalent Temperature Difference (NETD) of 30 mK at 2.5 millisecond integration time with an f/1 lens in the 3-5 μm wavelength band using a two-stage TE cooler to operate the FPA at 230 K. Operability of 99.6% is reproducible on 240 × 320 format arrays.

The isolation and structure elucidation of a new meroterpenoid, actinoranone (1), produced by a marine bacterium closely related to the genus Streptomyces is reported. Actinoranone is composed of an unprecedented dihydronaphthalenone polyketide linked to a bicyclic diterpenoid. The stereochemistry of 1 was defined by application of the advanced Mosher’s method and by interpretation of spectroscopic data. Actinoranone (1) is significantly cytotoxic to HCT-116 human colon cancer cells with an LD50 = 2.0 μg/mL.

Study design A case of synergistic necrotizing gangrenous fasciitis after spinal surgery is reported. Objectives To describe this unusual complication, explain the rationale of treatment, and increase awareness of this serious postoperative complication. Summary of background data Although several cases of postoperative synergistic necrotizing fasciitis have been reported, there are no previously reported cases of this condition after spinal surgery. Methods A rapidly progressive necrotizing spinal wound infection after fusion for degenerative disc disease was treated in a 39-year-old man. Results The infection was successfully treated with serial debridements, appropriate antibiotics, and hyperbaric wound oxygenation. Conclusions The authors suggest adherence to the fundamental principles of treatment including radical surgical debridement and appropriate antibiosis for necrotizing gangrene after spinal surgery. In evaluation of aggressive spinal wound infections, diagnosis of synergistic necrotizing fasciitis should be kept in mind. Although hyperbaric wound oxygenation was implemented as an adjunct and appeared to aid in controlling the infection, its effect on outcome is not clear.

Three new cyclic heptapeptides, cyclomarins A−C (1−3), were isolated from extracts of a cultured marine bacterium collected in the vicinity of San Diego, CA. The major metabolite, cyclomarin A (1), contains three common and four unusual (or unique) amino acids. The structures of the new metabolites were determined using 1D and 2D NMR methods, and the stereochemistry was determined from an X-ray crystal structure of the diacetate derivative of 1. Cyclomarin A (1) displays significant antiinflammatory activity in both in vivo and in vitro assays.

Two new cytotoxic dioxopiperazine dimers, 11,11′-dideoxyverticillin A (1) and 11′-deoxyverticillin A (2), and the previously described verticillin A (3), have been isolated from the mycelium of a marine-derived fungus of the genus Penicillium. an inactive, but new bisdethio-bis(methylthio)-dioxopiperazine, 4, was also obtained by extraction of the culture broth. the structures and absolute stereochemistries of the new compounds were assigned on the basis of NMR and CD experiments. Compounds 1 and 2 exhibit potent in vitro cytotoxicity against HCT-116 human colon carcinoma (IC50= 30ng/ml).

Two isomeric linear peptides, aspergillamides A and B (1, 2), were isolated from the mycelium of a cultured marine fungus of the genus Aspergillus. The producing strain (designated CNC-120), was obtained from a saline lake sediment sample collected from Acklins Island, the Bahamas. The structures of the new peptides were elucidated using comprehensive 2D NMR methods. At 25°C, in both acetone and dimethylsulfoxide, aspergillamide A exists as a 1:1 mixture of trans- and cis-amide rotational isomers (1a and 1b). Under identical conditions, aspergillamide B is predominantly in the cis-amide form. The absolute stereochemistries of the amino acids in aspergillamide A were assigned as L by hydrolysis and comparison with commercial standards. Aspergillamide A showed modest in vitro cytotoxicity [IC50 = 16 μg/ml) toward the human colon carcinoma cell line HCT-116.

Investigation of the culture extracts of a marine-derived Streptomyces sp. led to the isolation of three new bohemamine-type pyrrolizidine alkaloids, bohemamine B (1), bohemamine C (2), and 5-chlorobohemamine C (3). The structures were elucidated using NMR methods, and the relative stereochemistry was determined using double-pulsed-field-gradient spin echo (DPFGSE) NOE studies.

The human infectious disease anthrax is caused by the sporeforming, Gram-positive bacterium Bacillus anthracis. The disease, which is most common in those that handle infected farm animals, has also been used as a bioterrorism weapon. In 2001, just a week after the World Trade Center attacks, anthrax was deliberately spread through the US postal system by sending letters with powdered B. anthracis spores. This caused 22 cases of anthrax infection and ultimately claimed five lives. [1] Depending upon the method of exposure (inhalation of spores and direct bacterial contact, among others) B. anthracis infections can require prolonged treatment often for six months with a variety of antibiotics. The pulmonary form of anthrax is considered a medical emergency that may require continuous intravenous therapy with potent antibiotics. In the event of a bioterrorism attack, individuals exposed to B. anthracis will be given antibiotics prior to the onset of the illness. A vaccine has been developed but is not yet available to the general public. [2] Given the severity of this disease, and the fact that it can be spread by aerosol dispersal, the development of effective new antibiotics remains a high priority. As a resource for developing microbial antibiotics, we have focused our efforts on marine microorganisms, particularly those that are in the deep oceans. Examination of a Streptomyces species (our strain CNH365), isolated from near-shore marine sediments found near Santa Barbara, CA, showed that culture extracts possessed significant activity against B. anthracis and methicillin-resistant Staphylococcus aureus in broth dilution assays. Subsequent fractionation of the extract following antibacterial activities yielded a pure

The isolation and structure elucidation of a new meroterpenoid, actinoranone (1), produced by a marine bacterium closely related to the genus Streptomyces is reported. Actinoranone is composed of an unprecedented dihydronaphthalenone polyketide linked to a bicyclic diterpenoid. The stereochemistry of 1 was defined by application of the advanced Mosher's method and by interpretation of spectroscopic data. Actinoranone (1) is significantly cytotoxic to HCT-116 human colon cancer cells with an LD50 = 2.0 μg/mL.

Compared with earlier prostate MRI techniques that suffered from relatively poor sensitivity and specificity for detecting prostate cancer because of their reliance predominantly on morphology, multiparametric prostate MRI (mpMRI) in 2013 provides a wealth of functional information that has made possible vastly improved detection and characterization of prostate cancer. Our aims in this article are to describe the various imaging sequences that comprise the mpMRI exam, as well as to review current literature on the strengths/weaknesses of these sequences; to delineate strategies for standardizing interpretation and reporting of MRI results; and finally, to expound on the role that prostate MRI currently does and potentially can play in clinical practice.

Cyanosporasides are marine bacterial natural products containing a chlorinated cyclopenta[a]indene core of suspected enediyne polyketide biosynthetic origin. Herein, we report the isolation and characterization of novel cyanosporasides C–F (3–6) from the marine actinomycetes “Salinispora pacifica” CNS-143 and Streptomyces sp. CNT-179, highlighted by the unprecedented C-2' N-acetylcysteamine functionalized hexose group of 6. Cloning, sequencing, and mutagenesis of homologous ~50 kb cyanosporaside biosynthetic gene clusters from both bacteria afforded the first genetic evidence supporting cyanosporaside's enediyne, and thereby p-benzyne biradical, biosynthetic origin and revealed the molecular basis for nitrile and glycosyl functionalization. This study provides new opportunities for bioengineering of enediyne derivatives and expands the structural diversity afforded by enediyne gene clusters.

The culturability of heterotrophic marine bacteria obtained from the surfaces of two species of marine algae (Lobophora variegata andHalimeda copiosa) was assessed by comparing total DAPI-stained cell counts to colony-forming bacterial counts on two agar media. The colony-forming bacterial counts on a low-nutrient medium (LN) consisting of seawater and agar were significantly greater for both algal species than counts obtained on a high-nutrient medium (HN) similar in composition to that typically used for the isolation of heterotrophic marine bacteria. On average, 14 and 58%, respectively, of the total bacteria fromL. variegata andH. copiosa were culturable on LN. These recovery rates far exceed those typically reported for marine bacteria. Of 119 LN strains obtained in pure culture, 55% failed to grow on HN. The yeast extract component of HN (1.5 gl-1) was responsible for the majority of the observed inhibition, suggesting that this nutrient can be highly toxic to marine bacteria. Eighty-nine percent of the strains inhibited by HN were capable of growth when the nutrients in this medium were diluted by a factor of 100 with seawater. Of 66 epiphytic strains, 30 (45%) initially inhibited by HN showed the ability to adapt to this medium after a period of laboratory handling. The initial inability of low-nutrient-adapted bacteria to grow on high-nutrient media may be due to nutrient shock. The results presented here indicate that the culturability of specific populations of marine bacteria can be dramatically improved by the use of low-nutrient media. Further, the importance of developing new medium formulations that eliminate traditional nutrients, some of which are clearly toxic to bacteria, is demonstrated.

Elijopyrones A-D (1–4) were isolated from a cultured marine actinomycete (isolate CNB-880). The producing strain was obtained from a sediment collected from the San Elijo Lagoon, Cardiff, California. The structures of the new compounds were determined by comprehensive spectral analyses.

thus the discovery of a major new group of thesebacteria in marine sediments suggests that the ocean repre-sents an overlooked habitat from which to isolate theseimportant microorganisms. Given thatthe rate of discovery ofnew biologically active compounds from common soil actino-mycetes has been falling

Reported is the structure and biosynthesis of ansalactam A, an ansamycin class polyketide produced by an unusual modification of the polyketide pathway. This new metabolite, produced by a marine sediment-derived bacterium of the genus Streptomyces , possesses a novel spiro γ-lactam moiety and a distinctive isobutyryl polyketide fragment observed for the first time in this class of natural products. The structure of ansalactam A was defined by spectroscopic methods including X-ray crystallographic analysis. Biosynthetic studies with stable isotopes further led to the discovery of a new, branched chain polyketide synthase extender unit derived from (E)-4-methyl-2-pentenoic acid for polyketide assembly observed for the first time in this class of natural products.

The isolation and structure determination of a new chlorinated benzophenone antibiotic, pestalone (1), is described. The new compound was produced by a cultured marine fungus only when a unicellular marine bacterium, strain CNJ-328, was co-cultured in the fungal fermentation. The fungus, isolated from the surface of the brown alga Rosenvingea sp. collected in the Bahamas Islands, was identified as an undescribed member of the genus Pestalotia. The structure of 1, initially assigned with only modest confidence by combined spectral and chemical data, was confirmed by single-crystal X-ray analysis. Pestalone (1) exhibits moderate in vitro cytotoxicity in the National Cancer Institute's 60 human tumor cell line screen (mean GI(50) = 6.0 microM). More importantly, pestalone shows potent antibiotic activity against methicillin-resistant Staphylococcus aureus (MIC = 37 ng/mL) and vancomycin-resistant Enterococcus faecium (MIC = 78 ng/mL), indicating that pestalone should be evaluated in advanced models of infectious disease.