Primary carcinoma of the bronchus, with an investigation into its early x -ray diagnosis

#1. Carcinoma of the bronchus - by which is meant a bronchus of dimensions visible to the bronchoscopist - has a distinct clinical entity of its own, distinct from true lung tumors, with which it has previously been grouped. #2. Lung and bronchial tumors are moderately rare but are becoming more frequently diagnosed, and may be much more common than at present realized, owing to the frequency with which they are treated as tuberculosis. #3. A male preponderance and a right-sided maximum incidence seem to indicate a relationship to chronic irritation as an etiological but in the group of cases presented no ship could be established to tuberculosis, influenza, occupational diseases or over -smoking. #4. The clinical syndrome of the primary bronchial tumor is an absolutely persistent cough with either hemoptysis or scant but blood- stained sputum and the lesion is visible on bronchoscopy. The syndrome of primary parenchymal tumor, a much more latent lesion, is severe, otherwise unexplained, weight loss, associated with vague but constant chest pain, or dyspnoea, or the cough - blood combination of the bronchial group. #5. The two groups do not separate pathologically in the same manner. The gross pathology of parenchymal includes nodular, lobar and infiltrative forms, while the bronchial are all infiltrative. Microscopically we get all forms of adeno- carcinoma but also some squamous- celled carcinoma, and of the primary bronchial group reported six out of seven cases were of the latter type. This probably represents a metaplasia to an embryonic cell type latent in the development of the trachea and bronchi from the oesophageal bud. The growth tends to be of a highly malignant type. #6. The radiological literature describes a relatively late case. It groups the appearances as hilar or lober of which the hilar is the more frequent, but at the stage at which the lesion has been previously recognized secondary effects, stenosis, infection, pleural effusion or metastasis, usually complicate the picture. #7. The early diagnostic picture must be recognized in the routine films of the chest, and therefore a special technique is not called for, although stereoscopic films are of great assistance. #8. There are three characteristic factors suggestive of bronchial malignancy: (a) A hilar density, unilateral, occupying the whole hilus, usually just perceptibly separate from the mediastinum, rami- fying out into the parenchyma in irregular strand -like processes and unassociated with any other mediastinal deformity, occurs in the majority of cases. This -may be alone or be associated with one or other of the next two factors. (b) Atelectasis of a 1.hole or part of a lung without discoverable causal history, is very frequent. (c) A pseudo -bronchiectasis , an appearance radiologically identical with true bronchiectasis but caused by blood- filled bronchi. #9. Contrasting with this the parenchymal tumor is less dense, either roughly circular or lobar in shape, rather less infiltrative, and is seldom even apparently hilar in location. #10. This radiological picture of the early bronchial carcinoma must be distinguished from the following groups of lesions: (a) OTHER HILAR DENSITIES such as bronchitis, pneumonia, venous engorgement, will give a more diffuse infiltration and will always be bilateral. (b) APPARENT HILAR DENSITIES such as carcinoma of esophagus, aneurism, and such like, will show a certain definition of edge separating the lesion from the lung, even where there is apparent root infiltration. (c) TUBERCULOSIS will mostly give the features peculiar to that disease - an apical tendency, an irregular mottling rather than strand -like infiltration and an absence of hilar centering. (d) OTHER GLAND LESIONS have a definite edge and a crescentic shape rather than the projecting shape of the malignancy, and even if unilateral tend to show a general widening of the media - stinum. (e) INFLAMMATORY LESIONS are the most difficult as they are so protean in form but they have a general mottled nature, a tendency to multiplicity, an absence of hilar centering and a narrower limitation of the width of the infiltrating edge but never the smooth finished uninfiltrating edge of an stelectasis. #11. Although there are isolated reported cases of successful lobectomy for parenchymal carcinoma, nothing has yet been done for bronchial: but radium in the bronchus is suggested by the author

O Tratamento do Câncer: Organização dos Serviços de Radioterapia

Muitos problemas se apresentam à medicina atual. Um dêles é demonstrar que o tratamento do câncer pelo radium ou pelos raios X, é não só eficiente, mas também seguro. A radioterapia, usada de modo correto, já demonstrou ser agente valioso, capaz de curar muitos tipos de câncer. Hoje, porém, o tratamento pelas irradiações constitue uma ciência que se expande rápidamente, devido às grandes oportunidades que se apresentam ao radium e aos outros isótopos radioativos, e ao grande aumento de poder dos raios X, no campo dos mega-volts e do milhão de volts. É evidente que, para seu desenvolvimento e contrôle apropriados, seja necessária uma organização particularmente cuidadosa. Pensamos, portanto, que vos poderá ser útil conhecer alguma coisa sôbre a organização atual da radioterapia na Grã-Bretanha

Catalyst-Controlled Stereoselective Olefin Metathesis as a Principal Strategy in Multistep Synthesis Design: A Concise Route to (+)-Neopeltolide

Molybdenum-, tungsten-, and ruthenium-based complexes that control the stereochemical outcome of olefin metathesis reactions have been recently introduced. However, the complementary nature of these systems through their combined use in multistep complex molecule synthesis has not been illustrated. A concise diastereo- and enantioselective route that furnishes the anti-proliferative natural product neopeltolide is now disclosed. Catalytic transformations are employed to address every stereochemical issue. Among the featured processes are an enantioselective ring-opening/cross-metathesis promoted by a Mo monoaryloxide pyrrolide (MAP) complex and a macrocyclic ring-closing metathesis that affords a trisubstituted alkene and is catalyzed by a Mo bis(aryloxide) species. Furthermore, Z-selective cross-metathesis reactions, facilitated by Mo and Ru complexes, have been employed in the stereoselective synthesis of the acyclic dienyl moiety of the target molecule.National Institutes of Health (U.S.) (NIH grant GM-59426)National Institutes of Health (U.S.) (NIH grant GM-57212)AstraZeneca (Firm) (Graduate Fellowship)National Science Foundation (U.S.) (NSF award CHE-1362763

The Scottish Early Rheumatoid Arthritis (SERA) Study:an inception cohort and biobank

Background: The Scottish Early Rheumatoid Arthritis (SERA) study is an inception cohort of rheumatoid (RA) and undifferentiated arthritis (UA) patients that aims to provide a contemporary description of phenotype and outcome and facilitate discovery of phenotypic and prognostic biomarkers Methods: Demographic and clinical outcome data are collected from newly diagnosed RA/UA patients every 6 months from around Scotland. Health service utilization data is acquired from Information Services Division, NHS National Services Scotland. Plain radiographs of hands and feet are collected at baseline and 12 months. Additional samples of whole blood, plasma, serum and filtered urine are collected at baseline, 6 and 12 months Results: Results are available for 1073 patients; at baseline, 76 % were classified as RA and 24 % as UA. Median time from onset to first review was 163 days (IQR97-323). Methotrexate was first-line DMARD for 75 % patients. Disease activity, functional ability and health-related quality of life improved significantly between baseline and 24 months, however the proportion in any employment fell (51 to 38 %, p = 0.0005). 24 % patients reported symptoms of anxiety and/or depression at baseline. 35/391 (9 %) patients exhibited rapid radiographic progression after 12 months. The SERA Biobank has accrued 60,612 samples Conclusions: In routine care, newly diagnosed RA/UA patients experience significant improvements in disease activity, functional ability and health-related quality of life but have high rates of psychiatric symptoms and declining employment rates. The co-existence of a multi-domain description of phenotype and a comprehensive biobank will facilitate multi-platform translational research to identify predictive markers of phenotype and prognosis

Change of Gene Structure and Function by Non-Homologous End-Joining, Homologous Recombination, and Transposition of DNA

An important objective in genome research is to relate genome structure to gene function. Sequence comparisons among orthologous and paralogous genes and their allelic variants can reveal sequences of functional significance. Here, we describe a 379-kb region on chromosome 1 of maize that enables us to reconstruct chromosome breakage, transposition, non-homologous end-joining, and homologous recombination events. Such a high-density composition of various mechanisms in a small chromosomal interval exemplifies the evolution of gene regulation and allelic diversity in general. It also illustrates the evolutionary pace of changes in plants, where many of the above mechanisms are of somatic origin. In contrast to animals, somatic alterations can easily be transmitted through meiosis because the germline in plants is contiguous to somatic tissue, permitting the recovery of such chromosomal rearrangements. The analyzed region contains the P1-wr allele, a variant of the genetically well-defined p1 gene, which encodes a Myb-like transcriptional activator in maize. The P1-wr allele consists of eleven nearly perfect P1-wr 12-kb repeats that are arranged in a tandem head-to-tail array. Although a technical challenge to sequence such a structure by shotgun sequencing, we overcame this problem by subcloning each repeat and ordering them based on nucleotide variations. These polymorphisms were also critical for recombination and expression analysis in presence and absence of the trans-acting epigenetic factor Ufo1. Interestingly, chimeras of the p1 and p2 genes, p2/p1 and p1/p2, are framing the P1-wr cluster. Reconstruction of sequence amplification steps at the p locus showed the evolution from a single Myb-homolog to the multi-gene P1-wr cluster. It also demonstrates how non-homologous end-joining can create novel gene fusions. Comparisons to orthologous regions in sorghum and rice also indicate a greater instability of the maize genome, probably due to diploidization following allotetraploidization

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570