Chemical leukoderma denotes an acquired hypopigmentation caused by repeated exposure to specific chemical compounds simulating clinically idiopathic vitiligo. The ailment has been increasing in developing countries like India in recent years. Etiologically, a lot of chemicals, especially phenolic group, have been identified in various countries including India. The term, “chemical leukoderma syndrome” has been described to encompass all the various manifestations of chemical leukoderma. Clinical diagnostic criteria have been proposed to diagnose chemical leukoderma clinically more confidently. Chemical leukoderma represents an acquired vitiligo-like hypomelanosis induced by repeated exposure to specific chemical compounds. This chemical effect, independent of their sensitizing potential, is distinctly separate from post-inflammatory depigmentation and Koebner in vitiligo.Chemical leukoderma is also designated as contact leukoderma or occupational leukoderma. Chemical leukoderma has been reported from many countries of the world, developing as well as developed, induced probably by “globalization processes.”Chemical leukoderma remains an under-diagnosed common condition often inducing clinical dilemma with idiopathic vitiligo in dermatological practice. This ailment has been increasing rapidly in incidence in recent decades in developing countries like India.p-phenylenediamine, mercurials, arsenics, azelaic acid, corticosteroids, tretinoin, otic preparations such as eserine and thiotepa as well as systemic medications such as chloroquine and fluphenazine (prolixin).3]Tyrosinase-related protein-1 (Tyrp1), by catalytic conversion of chemicals, produces radical oxygen species. This oxidative stress triggers activation of cellular free-radical scavenging pathway to prevent cell death. Genetic inability of melanocytes to tolerate and/or respond to oxidative stress may underlie etiology of chemical leukoderma.Elevated tumor necrosis factor related apoptosis-inducing ligands (TRAIL) death receptor expression and heat shock protein (HSP) play important role in onset of chemical leukoderma and later its generalization by systemic auto-immunity. Melanocyte exposed to 4-tertiary butyl phenol (TBP) induces elevated TRAIL expression. TRAIL expression is strongly positive even in peri-leukoderma skin.Dendritic cells (DC) effector functions also take pivotal role in spreading of leukoderma. Stressed melanocytes mediate DC inactivation by releasing heat shock protein (HSP70). DC function is partially inhibited by antibody to TRAIL .20]FigFig20]FChemical leukoderma should be considered in the differential diagnosis of every case of idiopathic vitiligo or leukomelanoderma. Chemical leukoderma develops not only at the site of chemical contact, but also remotely. The mechanism responsible for this distant spread of the disease could be: (i) sensitization, (ii) autChemical leukoderma, such as vitiligo, lacks definitive diagnostic features. Clinico-histopathologically, no absolute criteria can differentiate chemical leukoderma from vitiligo. However, chemical leukoderma can be diagnosed clinically by a history of repeated exposure to a known or suspected depigmenting agent at the primary site, distribution of macules corresponding to chemical exposure, and the presence of numerous acquired confetti or pea-sized macules.21]21]Chemical leukoderma can be differentiated from post-inflammatory leukoderma by the clinical features of the latter: (1) primary rash always limited to the original area and (2) no confetti or remote macules. SimilarlAll age groups from pediatric to geriatric including neonates may be affected by chemical leukoderma. Although adults have a much higher incidence of chemical leukoderma, a considerable number of children below the age of 12 years may also be affected, which has not been reported much in the western literature. This may indicate that exposure to household objects rather than to industrial chemicals has caused an important role in the pathogenesis of chemical leukoderma in Indian patients. Females suffered more than males probably due to more exposure to offending household objects and more offering of treatment due to the prevalent social stigma regarding vitiligo and any other depigmenting skin diseases in Asian countries.[The presence of numerous acquired confetti or pea-sized macules is characteristic, although not diagnostic, of chemical leukoderma. In an Indian study, a considerable number of patients (88.4%) showed confetti macules, which thus represents an important diagnostic clue for chemical leukoderma.Contact dermatitis is not a prerequisite for the development of chemical leukoderma. However,The face and scalp were the commonest and least affected sites involved, respectively, in chemical leukoderma. Within the face the eyelids were a major area of involvement. This probably originates from greater penetration of the offending toxic chemicals through the thinner skin of the face (eyelids being the thinnest) compared with the thicker skin of the scalp. However, the hands and feet, although composed of much thicker skin, showed a high incidence of chemical leukoderma, probably due to a higher rate of exposure.There prevails some confusion regarding the varying terminology of chemical leukoderma or occupational leukoderma. The term “contact leukoderma” may be confusing as the adjective “contact” may indicate that leukoderma is confined only to the site of contact, which is baseless as shown in the various studies.21 The teSome patients who, despite the omission of all contributory toxic chemicals for more than 1 year, still develop vitiliginous patches in different parts of their body. These cases can be termed as “chemical vitiligo” to represent the vitiliginous process, which was switched on initially by the chemicals and continued even after stopping use of the chemicals.A syndromic classification of chemical leukoderma similar to allergic contact dermatitis syndrome has beenChemical leukoderma has to be excluded with certainty from every case of idiopathic vitiligo. However,As in developing countries like India the patent loads of chemical leukoderma have been increasing in recent years and this skin ailment resembles vitiligo very closely causing psycho-social reaction, the clinico-etiological diagnosis of this skin disorder is very much warranted. Further, clinico-etiological studies can refine the diagnostic pattern as well as pinpoint etiological factors.


Genomic copy number alterations are widely associated with a broad range of human tumors and offer the potential to be used as a diagnostic tool. Especially in the emerging era of personalized medicine medical informatics tools that allow the fast visualization and analysis of genomic alterations of a patient's genomic profile for diagnostic and potential treatment purposes increasingly gain importance.We developed CNAReporter, a software tool that allows users to visualize SNP-specific data obtained from Affymetrix arrays and generate PDF-reports as output. We combined standard algorithms for the analysis of chromosomal alterations, utilizing the widely applied GenePattern framework. As an example, we show genome analyses of two patients with distinctly different CNA profiles using the tool.Glioma subtypes, characterized by different genomic alterations, are often treated differently but can be difficult to differentiate pathologically. CNAReporter offers a user-friendly way to visualize and analyse genomic changes of any given tumor genomic profile, thereby leading to an accurate diagnosis and patient-specific treatment. Genomic copy number alterations are widely associated with a broad range of human diseases . In gene2 ratios of probe intensities in tumor compared to either a reference sample or reference set - the values representing copy numbers; (2) smoothing and segmentation of copy numbers followed by selection of areas of copy number alterations (CNA); (3) if available, analysis of loss-of-heterozygosity (LOH) and (4) visualization of the CNA/LOH profile.Copy number analysis for a single patient usually include several major steps, such as (1) raw data processing with normalization and calculation of logMany tools for the analysis of copy number profiles have been developed by the scientific community and are often freely available and cover all steps of analyses such as Affymetrix CNAT , CNAG 66, dChipSOur goal, therefore, was to create an easy to use tool for non-sophisticated users who would want a "snapshot" of the genomic profile for a particular tumor/tissue sample from the raw microarray data and to obtain that data in an easy to understand printable format suitable for clinical trial study charts or medical records. Based on the widely used GenePattern framework , we deveCNAReporter calls for a matched pair of patient-specific tumor and germline reference CEL and CHP files Figure , which aGenerateAffyCNTfiles calculates copy numbers (CN), provides smoothed CN-profiles and calculates LOH status of genomic locations. All results are stored in standard Affymetrix CNT files. The module was written in Perl as a wrapper for platform corresponding binary executables of the Affymetrix DevNet Tools copy-number pipeline [We designed CNAReporter as a GenePattern 3.0 pipeline , consistpipeline , allowinpipeline .GenerateAlterationReport determines CNA and LOH areas. The final output is a printable PDF-file that provides a table of altered genomic areas and graphic visualizations as a genomic profile and chromosome plot . Using a Gaussian approach, raw SNP profiles are smoothed (>500 kb window by default) and segmented by a Hidden Markov Model approach [Copy numbers are calculated using Affymetrix Copy Number Analysis Tool (CNAT 4), a set of command line programs. We allow filtering out SNPs with large PCR fragment length  to support samples with partially degraded DNA . For staapproach ,19. Raw LOH calls for each SNP are determined by comparing corresponding genomic calls in the tumor and the germline sample, provided that SNPs are heterozygous in the reference sample. Specifically, we use the LOH algorithm as implemented in CNAT 4 . LOH valUtilizing copy numbers and LOHs that characterize the underlying tumor sample by individual SNPs, CNAReporter applies three threshold parameters to define areas of CNAs. Increasing the absolute values of those parameters makes detection more conservative, thereby, decreasing the number of false positive areas but increasing the possibility of missing real changes. In addition, neighboring LOH areas are combined if they are within a certain threshold distance from each other . Lowering this parameter may cause splitting of LOH areas due to errors in genotyping calls. Default thresholds are determined empirically from the analysis of other brain tumor samples.Tissue from fresh frozen tumor specimens and resultant data were collected under an NCI-IRB (FWA # 00005897/IRB# 00000001)-approved protocol (NCI#:02C0140). Informed consent was obtained from each patient and documented in the medical records. Specimens and data were de-identified to comply with patients' privacy rules.Routinely, we analyse genomic profiles of glioma patients with CNAReporter. Specifically, we extract and hybridize DNA from patient tumor samples to the Affymetrix 500K SNP chips  using meWe introduced CNAReporter, a user-friendly, integrated tool that allows the quick analysis and visualization of chromosomal alterations. In particular, CNAReporter provides detailed high-quality reports of genomic alterations in a printable format, allowing our application to be used as a standard tool for clinical diagnostics and decision-making. Specifically, we use CNAReporter routinely for the analysis of genomic alterations of brain tumor tissues, potentially allowing us to make objective tumor subtype diagnoses, stratify patients into biologically more homogeneous tumor subgroups for clinical trials and select patient-specific treatments based on objective genomic data. We designed CNAReporter as a pipeline in GenePattern environment, a well-known open-source web-based framework that supports multiple platforms. Once properly installed on a server, GenePattern does not require additional software to be installed on the user's computer and can be accessed from any site with only a web browser. The GenePattern framework provides security, job management, uniform interface, relative ease of customization and integration with other developers' tools. Currently, GenePattern already has several modules for SNP analysis in its repository, such as the preprocessing SNPFileCreator module  and GISTIC for chromosomal aberrations discovery in multi-sample datasets . We belihttp://gforge.nci.nih.gov/projects/cnareport.CNAReporter with installation and usage instructions as well as all required files can be downloaded from The program is available for Linux/Unix, Mac and Windows operating systems, and requires MATLAB 2007b (or later) with Bioinformatics Toolbox, Perl 5 (including CRAN libraries) and GenePattern 3.0 (or later).CN: (DNA) copy number; CNA: copy number alteration; LOH: loss of heterozygosity; SNP: single nucleotide polymorphism; (M)bp: (Mega) base pairs.YK, JCZ, SW and HF formulated the requirements of the tool. YK designed the pipeline. YK, SB and HC implemented the tool. HF coordinated the study. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1755-8794/3/11/prepub


Intercellular channels called gap junctions enable multicellular organisms to exchangeinformation rapidly between cells. Though gap junctions are held to be ubiquitous in solidtissues, we have only recently found them in the lymphoid organs. Functional direct cell-cellcommunication has now been confirmed by us and other groups in bone marrow, thymus, andin secondary lymphoid tissues. What functions do they serve in the lymphoreticular systemwhere, so far, only cytokines/growth factors and adhesion molecules have been considered asregulators? Here we show evidence for and refer to published work about functional direct cellcellcommunication through gap junctions in germinal center reactions and make proposals fortheir role in the immune response.in situ at the same locationas the protein. On antigen challenge, gap junctions appeared on the FDC as they formedmeshworks in germinal centers. In order to find out which germinal center cells communicatedirectly, we separated FDC-rich, low-density, B-cell fractions from human tonsil. In culture, weinjected single FDC with the low-molecular-weight fluorescent dye, Lucifer Yellow (Mr 457Da), which passed between adjacent FDC and sometimes from FDC to B cells.We found a large amount of the connexin43 (Cx43) gap junctions in the germinal centers ofsecondary lymphoid follicles. Ultrastructurally and immunohistologically, most of the junctionswere detected on the processes of follicular dendritic cells (FDC) enveloping nondividingcentrocytes in the light zone of germinal centers where B-cell selection is thought to take place.Further support for this finding came by revealing the Cx43 mRNA Based on these findings and their assigned functions in other tissues, gap junctions maycontribute to germinal center reactions in the following ways: (1) they may regulate folliclepattern formation by controlling FDC growth, (2) they may be involved in FDC-B-cell signalingcontributing to the final rescue of selected B cells from apoptosis, and (3) they may enable FDCto work as a functional syncytium providing a cellular internet for integrating germinal centerevents. Data supporting these interpretations are briefly discussed.


The approval of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in the treatment of metastatic colorectal cancer (CRC) has expanded the armamentarium against this disease.This paper will review the historical progress and recent clinical developments of anti-EGFR therapies in the treatment of metastatic CRC. Novel strategies of targeting the EGFR pathway to improve efficacy as well as ongoing research in identifying specific molecular predictors of response will be discussed. A decade ago, thesystemic treatment of colorectal cancer (CRC)consisted only of fluoropyrimidine-based chemotherapy administered alone or incombination with either oxaliplatin or irinotecan in an empirical fashion,guided by serial measurements of radiological response. Owing to the remarkableadvances in our understanding of the molecular mechanisms of carcinogenesis,target-based therapies are now commonly used as in the treatment of many typesof cancer, including CRC. Cetuximaband panitumumab are monoclonal antibody against the epidermal growth factorreceptor (EGFR) that has been approved for the treatment of patients with metastatic CRC , 2. The The concept ofmanipulation of EGFR in the treatment of epithelial malignancies such ascolorectal and lung cancers has actually been envisaged since the mid 1960s . It was α (TGF-α), heparin-binding EGF(HB-EGF), and amphiregulin (AR). Ligand binding, dimerization, andphosphorylation of EGFR lead to activation of downstream proteins, leading to acascade mediating cell growth and survival [EGFR is a 170 kD member of the ErbB receptor tyrosinekinase family of signaling proteins, and its ligands include epidermal growthfactor (EGF), transforming growth factor-survival . Two difsurvival , 4.Cetuximab  and panitumumab  are two anti-EGFR monoclonal antibodies currently approved in thetreatment of metastatic CRC. Thestructural difference between the IgG-1-based cetuximab and IgG-2-basedpanitumumab is believed to have implications on their mechanisms of action. Preclinical studies have suggested that the cetuximab molecule is able toinduce antibody-dependent cell-mediated cytotoxicity (ADCC), 5, wherPharmacokineticsstudies have shown that cetuximab's binding affinity for EGFR was shown to beone log higher than its natural ligand and its mechanism of action is thoughtto be competitive inhibition of ligand binding to EGFR. Cetuximab aloneresulted in in vitro and in vivo growth inhibition in multipletumor types, including CRCs , 5. CetuP = .007). Fifty-six patients who wererandomized to cetuximab alone eventually crossed over to the combination arm,while 3.6% and 35.7% of these patients achieved partial response and stabledisease, respectively. This study led to the US Food Drug Administration (FDA)approval of cetuximab in patients with irinotecan-refractory meta static CRC. Subsequently, the NCIC-CO.17 study randomizedpatients who had failed at least 2 lines of prior therapies, to eithersupportive care or cetuximab alone [P < .001).The landmark BOND trial  randomizP = .036) than the chemotherapy alonearm, but there was no difference in overall survival in the initialintention-to-treat analysis. Response rate was also significantly better in thecombination arm , resulting in a larger number ofpatients being down staged enough to undergo resection of liver metastases(9.8% versus 4.5%). The “OPUS”study [Cetuximab has alsobeen investigated in the first-line setting. The “CRYSTAL”  study isP < .0001). The lack of difference in OS  maybe attributed to the cross-overdesign, where 76% of patients in the BSC arm subsequently received panitumumab. As expected with anti-EGFR therapies,skin-related toxicities occurred in 90% of patients in the panitumumab groupbut no patients had grade 3 or 4 infusional reactions.The US FDA approvalof panitumumab was based on a pivotal multinational phase III study that involved over 400 patients . This sAlthough not approved for the treatment of CRC, small molecule inhibitors of the EGFR tyrosinekinase (TKI) have been shown to have meaningful activity in different tumortypes such as lung and pancreatic cancer. In contrast to EGFR monoclonalantibodies, the site of action of these drugs is intracellular at theATP-binding site of the EGFR TK domain. Compared with monoclonal antibodies,TKIs may potentially inhibit multiple targets and tend not to induce receptordownregulation.Gefitinib is alow-molecular-weight competitive inhibitor of ATP-binding pocket of the EGFR TKdomain , which iErlotinib has alsobeen studied in advanced CRC. There have been mixed reports of some clinical activity when used as a singleagent. As with gefitinib, erlotinib produced a higher response rate whencombined with chemotherapy. High incidence of toxicity was noted when given incombination with systemic chemotherapy, especially in two trials whereerlotinib was given in combination with FOLFOX and bevacizumab , 20, witAnti-EGFR monoclonalantibodies and EGFR TKIs are associated with a distinctive skin rash. The rashis characterized histologically as a neutrophilic infiltrate in perifollicularareas within the basal layer of the skin, which is different from that seen intypical acne. Skin toxicity is generally observed within 2 to 3 weeks afterthe start of treatment and gradually resolves in most patients, even when anti-EGFRtreatment is continued. In the BOND study, the most frequently observed adverseevent to cetuximab was the skin rash, and in the panitumumab study, Hecht etal.  reportedThe “EVEREST” study was a phCombinations ofmultiple targeted agents with or without the additional of chemotherapy havealso been investigated. The BOND-2 trial  randomizEGFR as determinedby immunohistochemical (IHC) methods was the first biomarker investigated as apotential predictor of response. It is overexpressed in over 80% of colorectalcancers . HoweverThere has been muchinterest in determining whether EGFR gene mutations may play a role inaffecting response to cetuximab or panitumumab. Previous research in nonsmallcell lung cancer  has showIt has been hypothesized thatDNA is a more stable molecule thana protein and thus EGFR gene copy number maybe more accurate reflection of theEGFR status than IHC expression . In a coP = .016; median survival 16.3 versus6.9 months). An increase in EGFR copy number was also significantly associatedwith objective tumor response.KRAS is a guanosinetriphosphate (GTP)-binding protein that acts as a critical on-off switch incellular growth and survival pathways. It plays a key role in the RAS/MAPK signally pathway located downstream ofmany growth factor receptors, including EGFR, and involved in carcinogenesis. Mutations of KRAS that result in the constitutive activation of MAPK pathwaydownstream occurs in about 40% of colorectal cancers . A retroIt has been hypothesized thatirrespective of the level of EGFR expression, the presence of a KRAS mutationis associated with a constitutive activation of the RAS/MAPKpathway, leading to cell proliferation which cannot be significantly inhibitedby cetuximab. KRAS mutations have also been implicated in resistance againstEGFR TKIs in lung adenocarcinomas .Large scale retrospectivereviews retrieved archived tumor tissue from prior cetuximab and panitumumabtrials. KRAS mutation analysis was performed tested in tumor samples collectedfrom over 1000 participants of the “CRYSTAL” , “OPUS”Throughout the last decade,significant advancement in our understanding of the molecular mechanisms ofmetastatic CRC has been made. Anti-EGFR monoclonal antibodies approved for use in the metastatic setting havebroadened the therapeutic armamentarium in the treatment of metastatic CRC. The most effective sequence and combinationsof anti-EGFR therapy with chemotherapy and, or bevacizumab in order to achievecytotoxic potentiation with limited toxicity need to be addressed. Advancesmade in the identification of predictive biomarkers such as KRAS mutationsallow us to select distinct groups of patients who are most likely to benefitfrom cetuximab therapy.


Rates of preterm birth have been rising over the past several decades. Factors contributing to this trend remain largely unclear, and exposure to environmental contaminants may play a role.We investigated the relationship between phthalate exposure and preterm birth.Within a large Mexican birth cohort study, we compared third-trimester urinary phthalate metabolite concentrations in 30 women who delivered preterm (< 37 weeks of gestation) with those of 30 controls (≥ 37 weeks of gestation).n-butyl phthalate (MBP) concentrations were higher and monobenzyl phthalate (MBzP) concentrations lower. In a crude comparison before correcting for urinary dilution, geometric mean urinary concentrations were higher for the phthalate metabolites MBP, MBzP, mono(3-carboxylpropyl) phthalate, and four metabolites of di(2-ethyl-hexyl) phthalate among women who subsequently delivered preterm. These differences remained, but were somewhat lessened, after correction by specific gravity or creatinine. In multivariate logistic regression analysis adjusted for potential confounders, elevated odds of having phthalate metabolite concentrations above the median level were found.Concentrations of most of the metabolites were similar to those reported among U.S. females, although in the present study mono-We found that phthalate exposure is prevalent among this group of pregnant women in Mexico and that some phthalates may be associated with preterm birth. Approximately 4 million neonatal deaths occur each year globally, of which more than one-quarter are caused by preterm birth . AlthougThere is growing concern for the potential role of environmental pollutants in preterm birth, yet this area remains poorly understood . Only a n-butyl phthalate (DBP)] may include personal care products such as perfumes, lotions, and cosmetics; through their use as solvents; or as coatings on timed-release pharmaceuticals  and monoethyl phthalate (MEP)  .Although previous studies investigated the association between phthalate exposure and gestational age among primarily term births, the relationship with preterm births has not yet been addressed. In the present study we conducted a nested case–control analysis of the association between urinary phthalate metabolites and preterm birth in a Mexico City birth cohort.n = 30) were selected randomly among women who had completed ≥ 37 weeks of gestation at the time of delivery.The present study was nested within a Mexican birth cohort study in which women were recruited during prenatal visits at one of four clinics of the Mexican Institute of Social Security (IMSS) in Mexico City between 2001 and 2003 . The clin-octyl phthalate (DOP)], and monocarboxyisooctyl phthalate (MCOP) and monocarboxyisononyl phthalate (MCNP) .A spot (second morning void) urine sample was collected from each woman during a third-trimester visit to the project’s research center. Phthalate metabolites were measured in urine to avoid potential sample contamination from the parent diester and because the metabolites, as opposed to the parent diesters, seem to be the active toxicants . The folThe analytical approach involved enzymatic deconjugation of the metabolites from their glucuronidated form, solid-phase extraction, separation with high-performance liquid chromatography, and detection by isotope-dilution tandem mass spectrometry . The limPc = P[(1.014 − 1)/SG − 1)], where Pc is the SG-corrected phthalate metabolite concentration (micrograms per liter), P is the observed phthalate metabolite concentration, 1.014 is the median SG value among the present study population, and SG is the specific gravity of the individual urine sample. SG was measured using a handheld digital refractometer . Phthalate metabolite concentrations were also corrected by creatinine , which was measured using a MicroLab AT Plus robotic liquid handler  and Microplate Spectrophotometer . Finally, we calculated (in nanomoles per milliliter) the sum of concentrations of DEHP metabolites that were measured .Urinary phthalate metabolite concentrations were corrected for urine dilution by specific gravity (SG) using the formula t-tests and chi-square tests when appropriate. For phthalate metabolite concentrations below the LOD, we used an imputed value equal to one-half the LOD. In preliminary crude analyses to assess whether women who experienced a preterm birth had higher phthalate metabolite concentrations than controls, we compared geometric mean values between the two groups using t-tests. To take into account potential confounding variables, we used multivariable logistic regression to model the odds of having high (above the median) phthalate metabolite concentrations among the preterm women compared with controls. Variables considered in this analysis included maternal age, prepregnancy body mass index (BMI), parity, education, marital status, the infant’s sex, and gestational age at the time of urine sample collection. Variables that did not differ between cases and controls and did not statistically confound (change in effect estimate of > 10%) in any of the models were not retained. The variables that did appreciably change (> 10%) the effect estimate in at least one of the models were included in all models for consistency.We performed data analysis using SAS version 9.1 . Maternal and pregnancy characteristics were tabulated and compared between cases and controls using Student’s Correlations between phthalate metabolites were moderate to strong. Spearman correlation coefficients between metabolites from different parent diesters ranged from 0.21 (between MEHP and MEP) to 0.68 (between MECPP and MCPP). The Spearman correlation between MEHP and MBP was 0.44. Among the DEHP metabolites, Spearman correlations ranged from 0.80 to 0.84 between MEHP and the oxidized metabolites  and were ≥ 0.91 between the oxidized DEHP metabolites. Among metabolites of DBP, the Spearman correlation between MBP and MCPP was 0.85.p < 0.005). Cases had higher SG (p = 0.07) and Cr (p = 0.06) values than did controls, indicating that the urine samples of women who delivered at term were more diluted than samples from women who delivered preterm. These differences in urine dilution somewhat reduced the observed differences in phthalate metabolite concentrations after correcting by SG and Cr, but concentrations of all metabolites remained higher in cases than in controls.We conducted a nested case–control analysis of Mexican mother–infant pairs and found evidence for the presence of higher third-trimester urinary concentrations of phthalate metabolites among pregnant women who delivered pre-term (< 37 weeks gestation) compared with women who delivered at term (≥ 37 weeks). The differences between cases and controls for DBP metabolites  and MEHP were not sensitive to correction for urinary dilution using SG or Cr or to the adjustment for potential confounding variables. These results provide the first evidence of an association between phthalate exposure during pregnancy and preterm birth.p = 0.03). However, there are uncertainties over the use of cord blood to measure phthalates in the study, because blood measures of phthalate exposure can be compromised because of contamination by phthalate diesters in sampling tubes and lipases in the blood that can convert the diesters to monoesters  among mothers delivering pre-term are consistent with an Italian study of 84 newborns that reported an inverse association between gestational age and DEHP exposure . In thatnoesters .p < 0.001). In contrast, our results are inconsistent with another recent study of third-trimester urines from 404 women in a multiethnic birth cohort from New York City, which reported increased gestational ages in relation to MEHP and the sum of MBP, MEP, and MiBP concentrations ], which served to lessen the differences in phthalate metabolite concentrations after correcting for SG or Cr. Cr clearance increases significantly during pregnancy, in a manner that peaks and then begins to decline several weeks before term  in pre-term birth among a group of Mexican women. Additional research, including larger human studies and experimental studies, are warranted to further investigate the relationship between phthalate exposure and preterm birth.


Autofluorescence imaging is used widely for diagnostic evaluation of various epithelial malignancies. Cancerous lesions display loss of autofluorescence due to malignant changes in epithelium and subepithelial stroma. Carcinoma of unknown primary site presents with lymph node or distant metastasis, for which the site of primary tumour is not detectable. We describe here the use of autofluorescence imaging for detecting a clinically innocuous appearing occult malignancy of the palate which upon pathological examination was consistent with a metastatic squamous cell carcinoma.A submucosal nodule was noted on the right posterior hard palate of a 59-year-old white female during clinical examination. Examination of this lesion using a multispectral oral cancer screening device revealed loss of autofluorescence at 405 nm illumination. An excisional biopsy of this nodule, confirmed the presence of a metastatic squamous cell carcinoma. Four years ago, this patient was diagnosed with metastatic squamous cell carcinoma of the right mid-jugular lymph node of unknown primary. She was treated with external beam irradiation and remained disease free until current presentation.This case illustrates the important role played by autofluorescence tissue imaging in diagnosing a metastatic palatal tumour that appeared clinically innocuous and otherwise would not have been biopsied. Light-induced tissue autofluorescence examination is currently considered as a standard of care for screening and diagnostic evaluation of early neoplastic changes of the skin, cervix, lung, bladder, gastrointestinal tract and oral cavity -11. DyspRecently the U.S. Food and Drug Administration has approved autofluorescence-based oral mucosal screening devises which are marketed as VELscope and Identafi™ 3000 for early detection of potentially malignant oral lesions. Here we report of a case to highlight the value of tissue autofluorescence visualization in diagnosing a squamous cell carcinoma, metastatic to the palate, which clinically presented as an innocuous appearing submucosal nodule.A 59-year-old white female was receiving regular dental treatment at the Special Patient Clinic of the University of Texas Dental Branch at Houston. During her recent clinic visit, we noticed a submucosal nodule on her posterior hard palate during routine oral examination. The patient was unaware of this lesion. This lesion was covered by intact mucosa, was non-fluctuant and had the consistency of an irritation fibroma. This submucosal nodule measured 0.8 cm in greatest diameter and palpation of this nodule elicited no tenderness or blanching.Her medical history is significant for cervical lymph node metastasis of squamous cell carcinoma from unknown primary, hypertension, chronic obstructive pulmonary disease, hypothyroidism and depression. The patient was diagnosed with squamous cell carcinoma of unknown primary, metastatic to the right mid jugular lymph nodes approximately four years ago. Various imaging studies were performed at the time which failed to identify the primary site of this tumour. The patient was treated with a course of external beam radiation therapy to the pharyngeal axis and the neck. Her oral mucosa and teeth were shielded from the direct radiation therapy beams. Patient had no clinical evidence of either primary or metastatic tumour during the last four years. Her current medications include levothyroxine, enalapril malate and fluoxetine. The patient had a 10-pack-year history of smoking and social consumption of alcohol. The patient's family history was unremarkable.Our clinical differential diagnosis for this palatal nodule included traumatic fibroma and epidermoid cyst. However, because of her past medical history of metastatic disease, we examined this nodule using a multispectral oral cancer screening device (Identafi™ 3000). This submucosal nodule revealed decreased autofluorescence at 405 nm illumination Figure . On the ®  and Identafi 3000™  for light-induced fluorescence visualization of oral mucosa. VELscope uses a blue/violet light (400-460 nm) to illuminate oral mucosa and a specific filter allows the clinician to visualize tissue autofluorescence. Identafi 3000 uses multiple illumination settings namely white, amber (560 nm) and violet (405 nm) to visualize the oral mucosal reflectance (white and amber) and fluorescence (violet).Increasing need for additional non-invasive tests to augment conventional white light oral examination has driven the development of various real-time light-induced fluorescence visualization devices for detection and delineation of potentially malignant oral lesions ,13. The Light-induced tissue fluorescence visualization technologies are being used increasingly as non-invasive diagnostic aids to characterize biochemical and structural changes associated with neoplastic transformation ,11,14. TOur patient was diagnosed with carcinoma of unknown primary site (CUP), defined as metastatic carcinoma present in the lymph nodes with no identifiable primary tumour despite thorough clinical and radiographic evaluations . The incWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.NV serve as an investigator in a clinical study evaluating the oral cancer screening devise "Identafi 3000™" which was sponsored by Trimira, Houston, Texas.AG is a co-owner of patents that have been licensed to Remicalm LLC, Houston, Texas, Trimira's parent company and serves as an unpaid scientific advisor to Remicalm LLC.NV, SK and AG participated in the diagnostic evaluation and management of the patient. All authors read and approved the final manuscript


Monitored, acute phlebotomy is safe and cost-effective. It decreases blood volume and viscosity, increases cardiac output and improves exercise tolerance in patients.The increased incidence of ventilator-associated complications in patients with chronic obstructive pulmonary disease (COPD) necessitates rapid weaning and extubation. The presence of secondary polycythemia in this subgroup increases the incidence of stroke and myocardial infarction due to hyperviscosity and tissue hypoxia. We present a 58-year-old male patient of COPD with secondary polycythemia (hematocrit 64%) who had possible hyperviscosity-related complications leading to cardiac arrest after a minor surgical procedure. The patient developed ventilator dependence after recovery. Phlebotomy was done to remove 10% of total blood volume. Symptomatic improvement was dramatic. Improvement in weaning indices like rapid shallow breathing index and PaO Acute episodes of respiratory failure in patients with chronic obstructive pulmonary disease (COPD) caused by infections, heart failure, pulmonary embolism or other causes account for 5-10% of emergency medical admissions to a hospital. particulSecondary polycythemia, a complication of chronic hypoxia in COPD, results in tissue hypoxia, metabolic acidosis, increased thrombogenocity and higher incidence and severity of coronary disease and stroke in these patients.We present a patient with COPD and secondary polycythemia who developed ventilator dependence, post-resuscitation, from complications after a minor surgical procedure. Weaning and extubation were facilitated with phlebotomy removing 10% of his blood volume. To the best of our knowledge this is the only report on the use and benefits of phlebotomy for this indication. We discuss the work done in this area and possible causes of dramatic improvement seen in our patient.1 and PEF of 34, 14 and 17 percent predicted respectively).A 58-year-old male presented in the month of May with scrotal swelling and cellulitis. Patient was a chronic smoker (over 200 pack years) diagnosed as COPD with corpulmonale. He had a ruddy complexion, finger tip cyanosis and injected conjunctiva. He complained of easy fatigability, headaches, daytime somnolence and dyspnoea on exertion (elicited retrospectively) pointing to polycythemia related hyperviscosity. Previous pulmonary function test revealed severe restriction and very severe obstruction  patient started complaining of respiratory distress. Chest auscultation revealed distant respiratory sounds and diffuse rhonchi. Room air saturation was now monitored to be 82%. Patient was shifted to the Intensive Care Unit (ICU), 20 minutes later, for emergency management after oxygen at 10 liters/min via a face mask and salbutamol nebulization failed to improve his condition.2 150 mmHg) after a trial of non-invasive ventilation (NIV) for 45 minutes which failed to improve his blood gas picture [In the ICU invasive ventilation was initiated in view of life threatening acidemia (pH 7.001) and hypercarbia .Over the next few hours his condition stabilized. His blood sample tended to rapid clumping pointing towards hyperviscosity-antiplatelets and antithrombotics were started. His general condition improved after hydration, steroids, antibiotics and physiotherapy. Chest was clear on auscultation. Major criteria for weaning being satisfied, weaning efforts were started with an aim at early separation from ventilator. Patient developed tachypnoea, increased accessory muscle activity, diaphoresis, facial signs of distress, tachycardia, arrhythmias and hypotensio. SaOAssociating signs of dependence to tissue hypoxia due to hyperviscosity phlebotomy was done removing total 10% blood volume in two sittings, four hours apart, on the third day. After the phlebotomy he claimed to be “feeling my fittest in many years”. Extubation after four hours was successful. There was no requirement for non-invasive ventilation after extubation. There was no significant improvement in pulmonary functions tests however. He was discharged with advice of intermittent oxygen therapy and follow-up after seven days.We postulate a combination of factors for the sudden decompensation of our patient. The stress of surgery and imperfect pain relief with local anesthesia may have caused tachypnoea. Increased respiratory rate increased the dead space ventilation and as expiratory time shortened, further muscle loading resulted, causing additional dynamic hyperinflation. Increased pulmonary vascular resistance and reduced venous return was exacerbated further by the supine position, impaired right heart function and decreased cardiac output. Inadequate systemic oxygen delivery aggravated by the hyperviscosity then added a metabolic component to the respiratory acidosis. There is a logarithmic rise in blood viscosity beyond a hematocrit of 55%. Sludging of blood in capillaries causes tissue hypoxia, metabolic acidosis, increased thrombogenocity and higher incidence and severity of coronary disease and stroke in these patients as seen A diagnosis of secondary polycythemia was made in our patient based on well-defined criteria of British Committee for Standards in Hematology. ManagemeAmong the common pathophysiological factors associated with failure to wean are thos2/PAO2 ratio occurred after phlebotomy-other parameters remaining almost same [We recorded remarkable improvement-decrease in respiratory rate and improvement in PaOost same . After ePhlebotomy in patients with secondary polycythemia has been shown to improve cerebral blood flow, speciallet al. Improvement in oxygenation, seen in our patient, may be attributable to a mild congestion not appreciated clinically or radiographically which improved with volume reduction. The decrease in respiratory rate may be explained by a decreased work of breathing due to increased cardiac output and oxygen delivery explaining the marked subjective improvement the patient claimed.Follow-up pulmonary function tests did not show a significant improvement in keeping with the conclusions of Dayton Our experience would highlight the benefits of bedside phlebotomy, which is readily available, cost- effective and safe as a one-time procedure to facilitate early weaning and extubation in difficult-to-wean COPD patients with secondary polycythemia. This may be tried prior to extubation to avoid need for/improve chances of success of NIV ventilation for weaning. We would also like to stress on the possible benefit of monitored anesthesia care even for minor surgical procedures in these patients.


Morphological changes in preterm infants with bronchopulmonary dysplasia (BPD) have functional consequences on lung volume, ventilation inhomogeneity and respiratory mechanics. Although some studies have shown lower lung volumes and increased ventilation inhomogeneity in BPD infants, conflicting results exist possibly due to differences in sedation and measurement techniques.tPTEF/tE) than healthy preterm and term controls. These changes were related to disease severity. No differences were found for ventilation inhomogeneity.We studied 127 infants with BPD, 58 preterm infants without BPD and 239 healthy term-born infants, at a matched post-conceptional age of 44 weeks during quiet natural sleep according to ATS/ERS standards. Lung function parameters measured were functional residual capacity (FRC) and ventilation inhomogeneity by multiple breath washout as well as tidal breathing parameters. Preterm infants with BPD had only marginally lower FRC (21.4 mL/kg) than preterm infants without BPD (23.4 mL/kg) and term-born infants (22.6 mL/kg), though there was no trend with disease severity. They also showed higher respiratory rates and lower ratios of time to peak expiratory flow and expiratory time (Our results suggest that preterm infants with BPD have a high capacity to maintain functional lung volume during natural sleep. The alterations in breathing pattern with disease severity may reflect presence of adaptive mechanisms to cope with the disease process. This leads to disturbed alveolar septation with fewer but larger alveoli and impaired vascular growth in these infants Chronic lung disease of infancy remains one of the major complications in premature infants, with possible impact upon short- and long-term respiratory morbidity These morphological changes in BPD lungs have functional consequences on lung volume, ventilation homogeneity and mechanics of the respiratory system, as reviewed recently To obtain valid information on the natural and dynamic pattern of breathing and overcome factors potentially causing the above mentioned inconsistencies, it is necessary to measure tidal breathing parameters in addition to lung volume and ventilation inhomogeneity in a large sample of unsedated infants, matching preterm infants with contemporarily recruited healthy controls, and using the same appropriate methods for all infants adhering to recently published ATS/ERS standards for infant lung function testing With this in mind, the aim of our study was to compare lung volume, ventilation inhomogeneity and tidal breathing parameters in preterm infants with and without BPD with term-born infants matched for post-conceptional age at study date. In addition, we aimed to assess which clinical factors are associated with the respective lung function parameters in BPD infants.In this cross-sectional observational study, we measured lung function in preterm infants with and without BPD and healthy term-born infants. Subjects were matched for a post-conceptional age of 44 weeks at study date and recruited during 1999–2007 within the region of Bern, Switzerland.The Bernese Cantonal Ethics Committee approved the study protocol and written informed consent was obtained from parents.Preterm infants of less than 37 weeks gestational age hospitalized at the University Children's hospital of Bern, Switzerland, were recruited during initial hospital stay. Detailed prenatal and neonatal history was routinely recorded during the hospital stay into a database. Any missing parameters were supplemented at the time of lung function or by retrospective chart analysis.Based on the ATS definition of BPD, we categorized preterm infants into healthy and mild, moderate and severe BPD, respectively Based on the definition of the clinical risk index for babies  infants were given a CRIB score Term-born healthy infants were antenatally recruited within a prospective birth cohort study since 1999 in the region of Bern, Switzerland Lung function measurements were performed via an infant face mask  during unsedated sleep in supine position with the head midline, according to ATS/ERS standards of infant lung function testing 6 as previously described ao) and lung clearance index (LCI).Lung volume and ventilation inhomogeneity were determined using multiple-breath washout (MBW) technique with 4% SFtPTEF/tE).For analysis, we used the first 100 regular breaths of tidal breathing during non-REM sleep from the total 10-min-recording, and excluded sighs and ten breaths before and after a sigh. From these, mean tidal breathing parameters of flow, volume and flow-volume loop were calculated as per the ERS/ATS standards for infant lung function testing Descriptive statistics and regression analysis were used to compare MBW and tidal breathing parameters between groups. These and subsequent analyses were performed using STATA 10 .To investigate which lung function parameters discriminate best between groups, receiver-operator characteristics (ROC) curves were calculated. First, we grouped healthy term and preterm infants together and compared them with BPD infants; second within the healthy infants we compared term-born with preterm infants.ao, LCI, respiratory rate, tidal volume and tPTEF/tE. We first entered the following clinical variables as explanatory variables into the univariable model: weight and length (both determined at the time of the study), post-conceptional age, gender, prenatal steroids, maternal smoking during pregnancy, maternal chorioamnionitis, days of supplementary oxygen, duration of intubation, duration of continuous positive airway pressure (CPAP), surfactant medication, postnatal weight gain and CRIB score. We then performed multivariable linear regression analysis for each of the outcome parameters and included all explanatory variables that were significantly associated  in the univariable analysis. We then used a backward stepwise exclusion strategy by dropping the variable with the highest p-value until only significantly associated variables were left and built one final model including all the variables that were significantly associated  with any of the outcome parameters. This final model is reported for all the five lung function parameters.We also assessed which clinical variables may determine lung function in preterm infants. We performed univariable linear regression analyses with the following main lung function parameters as outcomes: FRCBetween 1999 and 2007, the study enrolled 185 preterm and 239 term-born infants; anthropometric data are given in There was no clear trend in changes of FRC adjusted for body weight with increasing disease severity , Table 3LCI did not differ systematically between groups , Table 3Tidal volume per body weight was also comparable between groups , respiratPTEF/tE  and neuro-respiratory compensatory mechanisms. The last component is likely to be dominant in influencing short-term variability/adaptability of FRC. To determine this influence, we examined the association between weight (as a surrogate for body size) as the explanatory variable and lung and tidal volumes as outcomes, since weight was the strongest contributor to volume . The R2 2 value of 8% for term-born and of 39% for preterm infants; see 2 value of 5% for term-born and of 27% for preterm infants). 2 tended to increase with disease severity, i.e. the adaptability of FRC given the respective weight (reflected by 1−R2) is decreased, or in other words, with increasing disease severity lung volume is increasingly determined by body size. This could mean that in the BPD infants neuro-respiratory mechanisms are either already activated or mechanical properties limit the activation of these mechanisms. Comparable results were obtained for tidal volume. None of the associations improved by additionally including other variables, such as e.g. length or duration of oxygen.We found a much tighter correlation for preterm compared to term-born infants between weight and tidal volume  may be a proxy for disease severity and thus may also be a consequence of changes in lung development rather than a cause.Studies showing increased respiratory morbidity and decreased lung function in childhood and adolescent survivors of BPD suggest that late pulmonary sequelae of BPD leads to increasing incidence of chronic obstructive pulmonary disease in future years tPTEF/tE values with increasing BPD severity. In addition to its association with dynamic regulation of lung mechanics as discussed above, a decreased tPTEF/tE may have long-term consequences for BPD infants. At the 10-year follow-up of 616 children from a birth cohort, Haland et al. were not only able to demonstrate that tPTEF/tE after birth correlated with mid-expiratory flow rate at 10 years, but they could also show that infants with a tPTEF/tE below the median have a 2.1-fold risk of having current asthma at 10 years We found decreasing In conclusion, parameters describing the shape of the tidal breathing flow-volume loop seem to be simple surrogate markers of breathing alterations in infants with BPD, which are easy to obtain and thus seem to be useful in the clinical setting. Our findings are more representative of the normal state of breathing in these infants, but consistent with findings of reduced forced flows in sedated infants. Normal end-expiratory lung volumes during natural sleep in BPD infants suggests that they have a high capacity to compensate by dynamically adapting their breathing pattern, which they are able to do when neither sedated nor clinically stressed. These findings are in agreement with the clinical picture, and have important implications for understanding the pathophysiology and management of the more recent form of BPD.


Diffuse alveolar opacities (DAO) due to pulmonary tuberculosis are usually described in immunocompromised patients. In adult patients residing in high endemic areas such as India, alveolar opacities are not reported frequently in non-immunocompromised pulmonary tuberculosis patients. We describe a twenty-five-year-old woman who presented with bilateral diffuse alveolar opacities and initial diagnostic work up was directed to non-tuberculosis etiologies. Her sputum was not suggestive of tuberculous or any other infective etiology. However, histopathological examination of specimen from fine needle aspiration cytology through percutaneous route suggested chronic granulomatous disease with detection of mycobacterium. Polymerase chain reaction test in BAL and FNAC specimen confirmed tubercular etiology. Though not frequent, pulmonary tuberculous etiology is worth considering in the differential diagnosis of DAO as not only tuberculosis is fully treatable but also early detection shall help to avoid unnecessary invasive tests and cut down transmission to contacts. Alveolar opacities often present a diagnostic enigma to radiologists and pulmonologists alike. The classical alveolar opacities are characterized by 1) fluffy and ill-defined margins except where they abut upon a pleural surface, 2) coalescence of individual lesions with the adjacent one as the intervening alveoli become involved, (3) butterfly or bat’s wing distribution, and (4) presence of air-bronchogram manifested when the air filled bronchi are surrounded by infiltrates in alveoli.[ fluffy a coalesceair-bronchogram within alveolar opacities and presence of right pleural effusion. Thoracentesis and the evaluation of pleural fluid showed exudative effusion but leading to no further differentiation. The various differential diagnoses considered [3R3Z3E3/4H3R3). She had a favorable response with anti-tubercular chemotherapy.A twenty-five-year-old woman presented at our Institute with three months history of cough with scanty expectoration, progressive dyspnoea and chest pain. She migrated from Nepal to India along with her husband and was working as a part-time domestic helper. There was no history of diabetes, hypertension, or any other significant disease. She had weight loss by 4 kg over the last three months, presently weighing 40 kg. She had dyspnoea at rest, respiratory rate 28/min, and pulse rate 120/min. She had wide spread crackles over bilateral lung fields. No significant cardiovascular system or ECG finding was observed. No cause of chronic alveolar edema could be elicited. There was no clinical evidence of any gynecological involvement. No BCG scar was seen and she could not recall any BCG vaccination. Her complete blood count, routine biochemical tests including blood sugar and urinalysis were within normal limits. Her serum was non-reactive for HIV-antigens on two different occasions. Chest radiograph revealed bilateral diffuse alveolar opacities having irregular fluffy margins with a pattern of coalescence and presenting in butterfly distribution. The blunting of right CP angle was also seen . The tubnsidered  were indnsidered  and the nsidered  confirmiacute alveolar pattern is usually seen in pulmonary edema, pneumonia, hyaline membrane disease, aspiration pneumonia, pulmonary hemorrhagic disorders, etc. Chronic pattern may be seen in sarcoidosis, alveolar proteinosis, lymphomas, alveolar cell carcinoma, desquamative pneumonitis, mineral oil aspiration, alveolar microlithiasis, and also in chronic infections such as tuberculosis or fungal infections. The radiological manifestations of alveolar cell carcinoma are highly variable and are often indistinguishable from other lesions with similar appearance. The alveolar form of lymphoma may present as primary lesion of the lung or as a part of disseminated disease.[As mentioned earlier, alveolar pattern may be encountered in a wide variety of unrelated diseases.4 The wor disease.3 The per disease. Alveolar disease. In sarco disease. In tuber disease.–10In the present case report, the patient had symptoms for three months and her lung opacities did not respond to antibiotic therapy administered by the general physician before she was referred to our institute. There were certain points during initial work-up that not favoring the diagnosis of the tuberculosis: the patient had no fever and had no known immunocompromised state. It has been documented that approximately 10% of patients who are subsequently proved to have tuberculosis had a pulmonary infiltrate that was thought not to be the characteristic of tuberculosis on radiographs.The CT-guided transthoracic needle aspiration of the pulmonary lesions suggested the tuberculous etiology that was supported by confirmation using PCR test. The presence of exudative pleural effusion with lymhocytic predominance was compatible with the diagnosis of tuberculosis. The present patient may serve a message that tuberculous etiology should be kept in the differential diagnosis of diffuse alveolar opacities even in high endemic regions and should be ruled out at an early stage as tuberculosis is fully treatable and the initiation of early antitubercular chemotherapy shall interrupt the chain of transmission to the contact persons and children. If missed during initial work-up; endless time-consuming, costly and invasive procedures shall be undertaken without leading to fruitful outcome and that will elevate the patient’s apprehension and decrease the faith in diagnostic methodology.


The simultaneous occurrence of pulmonary carcinoid tumor and tuberculosis is very rare. A case of pulmonary carcinoid tumor is described in a 35-year-old male patient who had concomitant ipsilateral pulmonary tuberculosis. The importance of dual pathological diagnosis in clinical practice is also emphasized. Pulmonary carcinoid is an uncommon tumor that constitutes only 0.5% to 2.5% of all pulmonary neoplasms. It is a low-grade malignant neoplasm believed to be derived from surface or glandular epithelium of the conducting or transitional airways. Most of The simultaneous occurrence of pulmonary carcinoid tumor and tuberculosis is very unusual. Although all histological types of lung cancer can coexist with pulmonary tuberculosis, only few4A 35-year-old man presented with history of right-sided pleuritic chest pain and low-grade fever for last one month. There were no other complaints. He also had history of hemoptysis and cough five months back for which he was investigated and found to have some pulmonary abnormality on chest X-ray. Although sputum status for acid-fast bacilli was not available in previous records, the tuberculin reaction was strongly positive (18-mm induration with blister formation). He received daily antituberculosis therapy with streptomycin, isoniazid, rifampicin and ethambutol for two months before presenting to us. He was a graduate and denied any history of addiction.On examination patient had normal body mass index and no significant findings on routine physical examination. Respiratory system examination revealed altered percussion note and diminished intensity of breath sounds over the right infrascapular area. Other systemic examination was unremarkable.1] 62%, forced vital capacity [FVC] 65% of predicted and FEV1/FVC ratio 80.7%). Ultrasonography of abdomen was reported to be normal. On CT scan of thorax, there was a well-defined soft-tissue density lesion in relation with the right lower lobe bronchus, having few areas of calcification and narrowing the lumen. A linear soft-tissue density band was extending from the lesion to the pleura, suggesting a collapse segment. A small tissue-density lesion was also evident in the right upper lobe [Figures The patient's investigations revealed normal hemoglobin, blood counts, bleeding profile and other organ functions. Chest X-ray showed a homogenous opacity without airbronchogram in the right lower zone. His sputum was negative for acid-fast bacilli. Spirometry revealed moderate restrictive pattern  right lower lobe tumor: Carcinoid tumor ; (ii) riThe postoperative period was uneventful and he received 5-flourouracil 750 mg intravenously every 15 days for 3 months along with antituberculosis treatment for 1 year (2 HRZE/10 HR). One year later, his chest X-ray showed right opaque hemithorax with normal left lung fields. On bronchoscopy, the right bronchial stump was well healed. The CT scan thorax revealed no evidence of tumor recurrence, lymphadenopathy or focal pulmonary parenchymal lesions. The abdominal CT scan also ruled out any hepatic lesion, retroperitoneal lymphadenopathy or ascites. The patient did well in the following six years and then was lost to follow-up.Carcinoid tumors are neuroendocrine tumors arising from kultchitzsky cells. They can be central or peripheral, and on the basis of histological and cytological features, can be divided in two fairly distinct clinicopathologic types, that is, typical and atypical. Both varThe radiological findings in central tumors are pneumonitis, atelectasis and bronchiectasis. Nonobstructing central and peripheral tumor may appear as solitary pulmonary nodule. Computed tomographic scanning is useful in identifying endobronchial lesion as well as lymph node enlargement. The CT sThe coexistence of lung cancer and pulmonary tuberculosis is well known; however, the coexistence of bronchial carcinoid and pulmonary tuberculosis has been rarely reported in the English literature, possibly because the pulmonary carcinoid tumors are rare tumors. Agaev reportedThe pulmonary tumorlet are localized, minute lesions resembling carcinoid tumor caused by nodular proliferation of neuroendocrine cells of the respiratory tract extending beyond the epithelium into the adjacent wall or lung parenchyma. These are small usually microscopic, tumor-like lesions mostly found in damaged lung tissue, for example, bronchiectasis, chronic abscess, tuberculosis and sometime even carcinoid tumor itself. It is inThe coexistence of pulmonary carcinoid tumor and pulmonary tuberculosis is very rare. When two diseases are located in the same lung, the diagnosis may be difficult at times until surgical intervention as one lesion can mask the other. The clinicians must be fully aware that two different pathological processes may coexist in the same patient, and therefore in nonresponding tuberculosis cases, dual pathology or alternative diagnosis must be considered apart from other causes such as drug resistance or paradoxical response and should be thoroughly investigated accordingly.


An 18-year-old girl presented with a painless, dusky, raised lesion covered with hairs, over the left shin since two years of her age. The lesion had been slowly growing from the time of appearance and there was history of increased sweating over the lesion. No aggravating or relieving factors for the increased sweating over the lesion could be noted. There was history of frequent trivial trauma to the lesion (due to its location over the anterior shin) associated with serosanguinous discharge and later scab formation.Her general physical and systemic examinations were normal. Cutaneous examination revealed bluish grey, firm, hairy nodule, 2 × 3 cm, in size having an ulcerated surface with scabs at foci over the anterior aspect of the left lower limb Figures  and 2. IExamination of hair, nails and mucous membranes was unremarkable. The lesion was excised and submitted for histopathology Figures  and 4.Histopathology showed thickened epidermis and an increased number of small and medium-sized blood vessels  with thiThe patient was followed up for two years after excision and there was no recurrence of lesion.et al., described an entity called ‘sweating angiomatous hamartoma’ in 1963.[3Eccrine angiomatous hamartoma (EAH) is a rare, benign cutaneous tumor usually present at birth or during early infancy and childhood. It has been reported under different names in the literature. Vilanova  in 1963.–4 The hyin 1963.3 EAH presHistopathologically, EAH is characterized by a dermal proliferation of well-differentiated eccrine secretory and ductal elements closely associated with thin-walled angiomatous channels.–4On histopathology, EAH is characterized by a dermal proliferation of well-differentiated eccrine secretory and ductal elements closely associated with thin-walled angiomatous channels. Unusual histopathologic variants have been reported and include the infiltration of adipose tissue, increased dermal mucin, and the presence of apocrine glands or pilar structures.8In 1971, Zeller and Goldman first described an eccrine pilar angiomatous nevus in a 37-year-old patient[The differential diagnoses of EAH include an eccrine nevus, tufted angioma, macular telangiectatic mastocytosis, nevus flammeus, glomus tumor, and smooth muscle hamartoma. These entities can be readily differentiated by histopathology.5 The nat


Diffusion-weighted magnetic resonance imaging is a very sensitive tool for the early diagnosis of acute ischemic stroke. This is employed in some stroke centers as the primary screening tool to select patients eligible for thrombolysis.We present the case of a 49-years old Chinese man whose diffusion-weighted magnetic resonance imaging performed 12 hours of symptom onset was negative.Although the initial diffusion-weighted magnetic resonance imaging was negative, the imaging repeated after 4 days despite static neurological symptoms and signs, could demonstrate an acute medullary infarction.Diffusion-weighted imaging may not be100% sensitive in very early stages, especially in posterior circulation strokes. Our case serves as a reminder that clinical assessment still retains priority until a diagnostic modality offering 100% sensitivity and specificity is discovered. Diffusion-weighted magnetic resonance imaging (DWI-MRI) is considered to be a very sensitive tool for the early diagnosis of acute ischemic stroke. This is employed in some stroke centers as the primary screening tool to select patients eligible for thrombolysis. However DWI may not be100% sensitive in very early stages, especially in posterior circulation strokes. We present a patient in which DWI-MRI was negative even after 12 hours of symptom onset and only the imaging repeated after 4 days could demonstrate an acute infarction.A 49-year old Chinese man, office clerk by occupation was admitted with sudden vertigo and unsteady gait. The vertigo was unremitting with eye closure and not posturally related. There was no trauma, neck pain or illness. There was no significant medical illness in past and accordingly, he was not on regular medication and did not smoke. Clinical examination revealed right lateral gaze-evoked nystagmus, right upper limb dysmetria and ataxic gait. Sensation to pain and temperature was intact and there was no evidence of a Horner's syndrome.An emergent computerized tomography (CT) of the brain was unremarkable. An MRI of the brain including diffusion-weighted imaging (DWI) 24 hours after admission did not reveal an acute lesion. However, an absent right vertebral artery flow void on axial T2-weighted images was observed Figure . CervicaOur patient demonstrates that DWI-MRI performed early may fail to demonstrate an acute infarct especially if it is small and located in territory supplied by posterior circulation. This may have an impact on the clinical decision making process in centres using DWI-MRI as a tool to guide aggressive therapy in patients with acute stroke . Our casIn acute cell death, failure of sodium-potassium ATPase pumps result in the shift of water from extracellular to intracellular compartments, reflected as a hyperintense lesion on DWI . DWI proabsence of a DWI-lesion does not completely rule out an ischemic state.Technical reasons have been postulated for the occasional failure of DWI-MRI to demonstrate an acute infarction including poor spatial resolution, high signal-to-noise ratio and magnetic susceptibility artefacts around the brain stem . AnotherThis may be argued that the first MRI could have missed the particular section of the brain that underwent the ischemic infarct. This possibility, although very unlikely, can not be completely excluded. Another explanation for DWI-negative MRI could be an interval infarction between the two MRI scans performed in our case. However, our patient did not develop any new symptoms or signs suggestive of a new neurological injury.In conclusion, if there is a high index of suspicion for an acute cerebrovascular event especially involving the posterior circulation with an unremarkable initial MRI-DWI, a repeat study after 24 hours of a fixed neurological deficit may be more demonstrative. Our case serves as a reminder that clinical assessment still retains priority until a diagnostic modality offering 100% sensitivity and specificity is discovered.DWI: Diffusion-weighted imaging; MRI: Magnetic resonance imaging; CT: Computerized tomography.The authors declare that they have no competing interests.RR Patient management, initial draft of the manuscript, VKS Patient management, draft and review of manscript, conceptualization and final approval, BPLC Patient management, conceptualization, final approval.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


Sir,A two-and-a-half-month-old infant born out of non-consanguinous marriage by normal vaginal delivery presented with a pigmented patch involving the trunk and whole right leg  since bisatellite nevi are commonly associated. The surface of the nevus is usually rugose or warty and nodular with large terminal hairs, which become more prominent as the infant grows toward puberty. These have an increased malignant potential. Various associated abnormalities are reported with it, the most common being leptomeningeal melanocytosis. Other common associated abnormalities are spina bifida, meningocoele and club foot and hypertrophy or atrophy of a limb involved by the nevus.[Congenital bathing trunk nevus is a congenital melanocytic nevus, also known as garment nevus or giant hairy nevus. The incidence is rare around 1 in 500,000 newborns.[he nevus. Hamartomhe nevus. Other ashe nevus.Complete androgen insensitivity syndrome has been described as a X-linked recessive disorder. The chilWe report this case of congenital bathing trunk nevus associated with multiple smaller satellite nevi, atrophy of the right leg involved by the nevus, and a rare coincidental finding of ambiguous genitalia, which has never been reported earlier.


The serpin (serine protease inhibitor) superfamily constitutes a class of functionally highly diverse proteins usually encompassing several dozens of paralogs in mammals. Though phylogenetic classification of vertebrate serpins into six groups based on gene organisation is well established, the evolutionary roots beyond the fish/tetrapod split are unresolved. The aim of this study was to elucidate the phylogenetic relationships of serpins involved in surveying the secretory pathway routes against uncontrolled proteolytic activity.serpin genes, exist in early diverging deuterostomes and probably also in cnidarians, indicating that the origin of a mammalian serpin can be traced back far in the history of eumetazoans. A C-terminal address code assigning association with secretory pathway organelles is present in all neuroserpin orthologs, suggesting that supervision of cellular export/import routes by antiproteolytic serpins is an ancient trait, though subtle functional and compartmental specialisations have developed during their evolution. The results also suggest that massive changes in the exon-intron organisation of serpin genes have occurred along the lineage leading to vertebrate neuroserpin, in contrast with the immediately adjacent PDCD10 gene that is linked to its neighbour at least since divergence of echinoderms. The intron distribution pattern of closely adjacent and co-regulated genes thus may experience quite different fates during evolution of metazoans.Here, rare genomic characters are used to show that orthologs of neuroserpin, a prominent representative of vertebrate group 3 neuroserpin gene orthologs has undergone substantial rearrangements during metazoan evolution.This study demonstrates that the analysis of microsynteny and other rare characters can provide insight into the intricate family history of metazoan serpins. Serpins with the capacity to defend the main cellular export/import routes against uncontrolled endogenous and/or foreign proteolytic activity represent an ancient trait in eukaryotes that has been maintained continuously in metazoans though subtle changes affecting function and subcellular location have evolved. It is shown that the intron distribution pattern of  Most serpins inhibit proteases from one or several different clans of peptidases; some superfamily members, however, exert disparate roles, such as assisting in protein folding or transportation of hormones . This fudementia , while wdementia . Neurosedementia ,9. Nativdementia ,11, suggnogaster -15, demoSerpin genes represent a substantial fraction of metazoan genomes, often amounting to several dozens of members in mammals. In various vertebrate lineages multiple expansions of serpin genes have occurred [serpin genes may be obscured further by a propensity for reciprocal or non-reciprocal exchange of cassette exons coding for the hypervariable reactive site loop region (RSL) [The elucidation of phylogenetic relationships among animal serpins poses a notorious problem . Serpin occurred ,18 resulon (RSL) . The seqon (RSL) .serpin genes display highly variant exon-intron patterns that, however, may be strongly conserved within some taxons. Gene architecture and other rare genetic characters constitute a robust basis to group vertebrate serpins [serpin genes with equivalent gene structures often tend to be organised in clusters [serpin gene groups arose. Here, data are presented that reveal a deeply rooting, continuous lineage of secretory pathway-associated serpins in metazoans that provide a surveillance and controlling function against proteolytic activity within the major cellular export/import routes.In metazoans,  serpins -22. Grouclusters ; howeverclusters . None ofclusters . Howeverserpin genes contains five members  that share a highly conserved group-specific exon-intron pattern characterised by the presence of six introns at equivalent positions. Another probably homologous intron mapping to the N-terminal region cannot be positioned unambiguously due to alignment problems [http://www.ncbi.nlm.nih.gov/projects/mapview/map_search.cgi?taxid=9606. Between these two serpin genes and immediately adjacent to the neuroserpin gene, but in inverse orientation, the PDCD10 (programmed cell death 10) gene is found , a syndrome associated with seizures and neurological deficits due to focal haemorrhages [neuroserpin gene and in inverse orientation, the GOLPH4 marker is found that codes for a transmembrane protein (GPP130) involved in endosome-to-Golgi traffic of proteins [Group 3 of mammalian problems . In the elopment ; howeverelopment . Mutatioorrhages . Downstrproteins -29.PDCD10-neuroserpin-GOLPH4 triad is maintained in the genomes of chicken, the clawed frog , and the zebrafish (Danio rerio). Current genome sequence releases also revealed synteny of the pancpin gene with these three genes in the genome of the clawed frog , and conservation of the close head-to-head association of the neuroserpin/GOLPH4 gene pair in the Japanese pufferfish (Fugu rubripes)  Figure  and in TBranchiostoma floridae) and sea urchins (Strongylocentrotus purpuratus) showed that a serpin gene is present in either of these species in close vicinity to the PDCD10 gene  that was recently shown to inhibit proprotein convertases [PDCD10/Spn-1 gene pair includes a closely related paralog (Bfl-Spn-2) of B. floridae Spn-1 .Extension of microsynteny analysis to lancelets  within a 20 kb DNA segment. Apart from synteny of its gene with PDCD10, Spu-Spn-1 shares a signal peptide, a conserved RSL region including the dibasic KR motif preceding the inhibitor's putative scissile bond (P5-P1': TMTKR ↓ S), and a variant (HEEL) of the canonical KDEL signal with the corresponding lancelet serpin  displays features suggesting shared ancestry with neuroserpin orthologs. These features include a dibasic amino acid sequence motif preceding the putative scissile bond, and a C-terminal extension ending with the tetrapeptide sequence SDEL, a functional variant of the canonical ER retention/retrieval signal [Inspection of genomes from deeper rooting metazoans revealed s Figure , depictiectensis , one of l signal . This seStrongylocentrotus purpuratus, and Spn-1 from Branchiostoma, their genes depict quite different patterns of intron distribution  intron resides in the sequence coding for the signal peptide (accession number: NW_001288761). The Spn-1 gene from lancelets harbours introns at positions 75c and 174a (α1-antitrypsin numbering). This intron-poor gene architecture contrasts with the mammalian neuroserpin gene that depicts the characteristic group 3 exon-intron structure with introns at positions 167a, 230a, 290b, 323a, 352a, and 380a . Strikingly, none of these intron positions is conserved among neuroserpin orthologs from lancelets, sea urchins or vertebrates. There is also no congruence of the introns at positions 75c and 174a in the lancelet Spn-1 gene with any of the other vertebrate serpin genes  seem to have been lost in the sea urchin, since they are present in the earlier diverging cnidarian, Nematostella vectensis. The sea anemone PDCD10 gene contains eight introns, six of which are found at equivalent positions in the human homolog. Nematostella vectensis genes were recently demonstrated to share the majority of intron positions with their mammalian counterparts [PDCD10 introns of C. elegans superimposes on an intron found in the orthologs from humans, the sea urchin, or the sea anemone.Contrasting with the s Figure . The PDCterparts . None ofPDCD10 and neuroserpin orthologs during diversification of deuterostomes. Apparently, expression of the head-to-head arranged genes is controlled by a bi-directional, asymmetrically acting promoter region inserted within the ~0.9 kb intergenic region separating the transcription units coding for PDCD10 and neuroserpin [The findings here reveal a clear history of neuroserpin, a prominent group 3 vertebrate serpin. Features derived from the genomic, gene and protein level provide ample discriminatory data to enable drawing of a reliable kinship history of its previously unknown origin. Microsynteny analysis proved to be especially illuminating, demonstrating that rare genomic characters can provide very useful information for decoding of bonds in protein families with intricate evolutionary history. Recent investigations provide a plausible explanation for the strongly conserved syntenic association of roserpin . Dependeroserpin , to enabStrongylocentrotus or Branchiostoma, contain classical ER retention signals (KDEL or HEEL) at their C-terminal ends, and the Nematostella Spn-1 sequence terminates with SDEL, which functions as an autonomous ER retention/retrieval signal in HeLa cells, when hooked to a reporter protein [Xenopus is HDFEEL  in the RSL region . In lancDrosophila [Anopheles [Spn4 gene is prone to recombination events, especially in the regions coding for the RSL region [Spn4 gene from fruit flies and neuroserpin orthologs from deuterostomes requires further investigation.Though the data clearly indicate that the roots of mammalian neuroserpin may be traced back far in the history of animals, unequivocal support for a neuroserpin ortholog in arthropods is still lacking. Several labs have provided evidence for a serpin (Spn4) with furin inhibiting activity and containing a canonical ER targeting signal in osophila -15, and nopheles . HoweverL region . Unravelneuroserpin/PDCD10 gene pair reveals some remarkable insights into the evolution of the exon-intron structure of metazoan genes. Even closely adjacent genes that are physically linked at least since divergence of echinoderms and chordates may be subject to quite different trends affecting the intron distribution patterns. Comparably few changes in the exon-intron architecture have happened in PDCD10 orthologs since divergence of lineages leading to sea anemones and vertebrates  of the currently known three Nematostella vectensis serpin genes maps to residue 42c . Looking up at deuterostomes, the sea urchin neuroserpin ortholog Spu-Spn-1 is also devoid of introns within the region coding for the serpin core. In contrast, the Spn-1 genes from Branchiostoma floridae  is due to massive intron loss, in contrast to most other introns that have survived hundreds of millions of years in these creatures. Intron gain is possibly not as rare as sometimes believed [The history of the s Figure . In PDCDnt times ,38; for ceolatum  each depin genes . Therefobelieved , howeverbelieved , for as Bilateria. The continuous presence of neuroserpin orthologs equipped with C-terminal signal sequences assigning residence within the secretory pathway documents that serpins functioning as guards of the cellular export/import routes represent an ancient trait. This surveillance role has been subject to subtle functional and local variances during evolution as evidenced by changes within the RSL and the subcellular address signal. In contrast to many other, even closely linked genes, in which the majority of intron positions has been conserved for hundreds of millions of years, the intron distribution pattern of neuroserpin gene orthologs has experienced massive changes, perhaps dominated by intron gain.In this study, we analysed and resolved the evolutionary roots of neuroserpin, a secretory-pathway associated mammalian serpin. Insight into the intricate history of the multi-membered serpin superfamily beyond the fish/tetrapod split was obtained by showing that orthologs of neuroserpin exist at least since the emergence of deuterostomes and probably already since divergence of eumetazoans and 1-antitrypsin sequence for searching. Chromosomal microsynteny analysis was performed using the NCBI Map Viewer [Tetraodon genome browser [Strongylocentrotus purpuratus genome database [Serpin protein and DNA sequences of various genomes were extracted from publicly accessible databases (see Additional file p Viewer , the ENSp Viewer , the JGIp Viewer , the Tet browser , the UCS browser , and insdatabase .1-antitrypsin was used as reference for mapping of positions and phasing of introns in serpin genes [Alignments of protein sequences were performed with CLUSTAL X  and refiin genes .AK carried out analyses. HR conceived and supervised the project and wrote the paper. Both authors have read and approved the final manuscript.PDCD10 orthologs in D. melanogaster and C. elegansGenes flanking . Genes flanking PDCD10 orthologs in D. melanogaster and C. elegans. Neighbouring genes of PDCD10Click here for fileSources of data for genomes investigated in this study. Sources of data for genomes investigated in this study. Web adresses of genomesClick here for file


We propose to explore these observations in vivo at the human PHOX2B locus, and also evaluate the potential evidence for genome-wide applicability of these observations through a novel analysis of extant data.Transcriptional regulatory elements are central to development and interspecific phenotypic variation. Current regulatory element prediction tools rely heavily upon conservation for prediction of putative elements. Recent PHOX2B in zebrafish recapitulates the observations at the zebrafish phox2b locus of both conserved and non-conserved regulatory elements. Analysis of human sequences conserved with previously identified zebrafish phox2b regulatory elements demonstrates that the orthologous sequences exhibit overlapping regulatory control. Additionally, analysis of non-conserved sequences scattered over 135 kb 5' to PHOX2B, provides evidence of non-conserved regulatory elements positively biased with close proximity to the gene. Furthermore, we provide a novel analysis of data from the ENCODE project, finding a non-uniform distribution of regulatory elements consistent with our in vivo observations at PHOX2B. These observations remain largely unchanged when one accounts for the sequence repeat content of the assayed intervals, when the intervals are sub-classified by biological role , or by gene density (gene desert versus non-gene desert).Transposon-based transgenic analysis utilizing a tiling path proximal to human In vivo observations at the PHOX2B locus, supported by our analyses of in vitro data from the ENCODE project, suggest that the risk of excluding non-conserved sequences in a search for regulatory elements may decrease as distance from the gene increases. Our data combined with the ENCODE data suggests that this may represent a genome wide trend.While regulatory elements frequently display evidence of evolutionary conservation, a fraction appears to be undetected by current metrics of conservation.  Transcriptional regulatory elements play a critical role in disease -3, develphox2b locus and demonstrated that, at least at that locus, a significant fraction of regulatory sequences displayed no evidence of functional constraint )8 for theTo examine the effects of repeats on pTRR density, we calculated the amount of repeat DNA in each ENCODE sub-region. The hg17 repeat masker track for the UCSC defined ENCODE regions was downloaded in a custom track. To remove any overlap from repeat elements, the Galaxy Database Merge tool was used to concatenate overlapping repeat regions into single intervals. The merged repeats were then partitioned into ENCODE sub-regions using the Galaxy Database Gencode Partition tool. The total repeat base pairs were calculated for each sub-region using the merged partitioned repeats. To confirm that no repeats were lost in the Merge program, the Galaxy Database Base Coverage tool was used to confirm that the repeat masker and merged repeat intervals covered the same total genomic region , with tASM conceived this study. DMM and ZES performed analysis and imaging of zebrafish embryos. DMM, RMV and JH performed injections of zebrafish. DMM and ZES performed amplification and cloning of sequences. ZES performed analysis of ENCODE data. DMM, ZES, and ASM drafted manuscripts with revisions from JH and RMV. All authors read and approved by the final manuscript.Supplementary tables S1-S5Click here for file


A case of primary squamous cell carcinoma in a pre-existing hepatic cyst is presented. A review of theliterature suggests that this rare type of liver tumor tends to arise from solitary, nonparasitic cysts, linedwith squamous epithelium. Effective therapy is not available, the prognosis is grave.


The paradigm that human malignancies are monoclonal has been questioned during recent years by the finding of unrelated, cytogenetically aberrant clones in short-term cultures from certain tumour types, notably carcinomas of the breast, skin and upper aerodigestive tract. In order to analyse whether cytogenetically unrelated clones are also unrelated at the molecular level, we analysed the X-chromosome inactivation status in cell cultures from a cytogenetically highly polyclonal acinic cell carcinoma of the parotid gland. By using cell cultures dominated by a single abnormal clone, obtained through in vitro culturing for 3-5 passages, we showed that the different clones must indeed have originated from different cells.


Different therapeutic options are being used for chronic coronary artery disease (CAD). We report about a 51-year-old female with CAD and refractory angina pectoris despite maximally tolerated medical therapy and after both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). The patient received cardiac shock wave therapy (CSWT) over a period of 6 month. There was no arrhythmia during or after treatment; enzyme levels were normal at all times. PET imaging showed a substantial improvement of myocardial stress perfusion. Since the patient reported that she now was fully capable to deal with her everyday life, further treatment options were postponed. Our case report suggests that ultrasound-guided CSWT is able to improve symptoms and perfusion in ischemic myocardium. Different therapeutic options are being used for chronic coronary artery disease (CAD), including medical treatment, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG). However, a growing number of patients exists who suffer from disabling angina despite, or after having undergone, all these modalities. For this challenging subset of patients with so-called chronic refractory angina, several alternative therapies such as neurostimulator implantation, laser revascularisation, or angiogenesis by gene or cell therapy  may be eA 51-year-old female with CAD, arterial hypertension, and diabetes mellitus presented with disabling angina (CCS class III-IV) despite maximally tolerated medical therapy, and after both PCI and CABG. Three years earlier, triple-vessel CAD had been diagnosed after a non-ST-elevation anterior myocardial infarction. Subsequently, the patient underwent CABG surgery with venous grafts to the left anterior descendent artery (LAD), to a marginal branch (Rm), and to the posterior descendent branch (PDA) from the right coronary artery (RCA). During the current evaluation, echocardiography showed a preserved global left ventricular function with an ejection fraction of 55%, and without significant regional hypokinesia. A bicycle stress test was terminated at 75 watts because of dyspnoea with ST segment depression in leads V5 and V6. A repeat coronary angiography documented occlusion of the LAD, the Rm, and the RCA. The venous grafts to LAD and Rm were fully functional, the RCA bypass was occluded. There was no possibility for a repeat revascularization. Myocardial viability and perfusion at rest and stress (under adenosine induced vasodilation) were assessed by positron emission tomography (PET) imaging, with F-18-FDG and N-13-ammonia, respectively. Areas of decreased stress perfusion were found predominantly in the apex and the anterior and inferior septal wall Figures , while vAs an alternative to neurostimulator implantation the patient was offered cardiac shock wave therapy, and received 18 sessions of CSWT over a period of 6 months focused by 2D echocardiographic guidance to the most ischemic myocardial segments. Serum concentrations of cardiac enzymes  were measured after each shock wave application. There was no arrhythmia during or after treatment; enzyme levels were normal at all times.After the complete treatment course, the patient reported significant improvement of angina (CCS II), supported by an improvement in bicycle exercise capacity to 100 watt. On 2D echocardiography, no significant changes could be observed. Repeated PET imaging showed a substantial improvement of myocardial stress perfusion predominantly in the septum and the adjacent posterior wall Figures . Since tThe medical use of electrohydraulic shock waves includes lithotripsy in urology and gastroenterology, or treatment of specific orthopaedic conditions. As compared to these applications, cardiac shock wave therapy uses shock waves emitted with a nondestructive energy level reduced by a factor of >10. In cultured endothelial cells, it was demonstrated that angiogenic factors are upregulated when exposed to these energy levels . In an aIn this patient, a significant improvement of angina and a moderate improvement of objective exercise tolerance could be achieved by 18 sessions of CSWT over a period of 6 months completely noninvasively, and without any adverse effect. Particularly impressive was the improvement of stress perfusion in the targeted regions as shown by PET imaging. Our case report suggests that ultrasound-guided CSWT is able to improve symptoms and perfusion in ischemic myocardium which is beyond mechanical revascularization. However, a controlled trial is needed to define the role of CSWT in the armamentarium for these challenging patients.