Assessment of small airway dysfunction by impulse oscillometry (IOS) in COPD and IPF patients.

OBJECTIVE: Small airway dysfunction is a pathological component of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), and impulse oscillometry is an easy-to-administer, effort-independent non-invasive test reflecting small airway dysfunction. We aimed to compare the impulse oscillometry (IOS) measurements between COPD and IPF patients and investigate their correlation with severity of both diseases and other conventional parameters. PATIENTS AND METHODS: This was a prospective, longitudinal study. We longitudinally evaluated the baseline demographic characteristics, COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) dyspnea scale, Pulmonary Function Test (PFT), Carbon Monoxide Diffusing Capacity (DLCO), Hemogram and Impulse Oscillometry measurements of the patients diagnosed with COPD and IPF. RESULTS: The study included 60 IPF patients and 48 COPD patients. The CAT and mMRC scores were higher in COPD patients. The majority of COPD patients were classified into Category B (46%), while 68% of IPF patients had Stage 1 GAP. The mean FEF 25-75%, which is typically considered to reflect small airway disease, was 93% in IPF patients, while it was significantly lower in COPD patients (29%). Impulse oscillometry measurements were consistent with spirometry parameters. IOS resistance and reactance values were significantly higher in COPD patients than in IPF patients. CONCLUSIONS: IOS is advantageous in COPD and IPF patients who cannot exhale due to severe dyspnea, as it is easy to administer and reflects small airway resistance better. Diagnosis of small airway dysfunction may be beneficial in the management of patients with IPF and COPD.

Biallelic KITLG variants lead to a distinct spectrum of hypomelanosis and sensorineural hearing loss.

BACKGROUND: Pathogenic variants in KITLG, a crucial protein involved in pigmentation and neural crest cell migration, cause non-syndromic hearing loss, Waardenburg syndrome type 2, familial progressive hyperpigmentation and familial progressive hyper- and hypopigmentation, all of which are inherited in an autosomal dominant manner. OBJECTIVES: To describe the genotypic and clinical spectrum of biallelic KITLG-variants. METHODS: We used a genotype-first approach through the GeneMatcher data sharing platform to collect individuals with biallelic KITLG variants and reviewed the literature for overlapping reports. RESULTS: We describe the first case series with biallelic KITLG variants; we expand the known hypomelanosis spectrum to include a 'sock-and-glove-like', symmetric distribution, progressive repigmentation and generalized hypomelanosis. We speculate that KITLG biallelic loss-of-function variants cause generalized hypomelanosis, whilst variants with residual function lead to a variable auditory-pigmentary disorder mostly reminiscent of Waardenburg syndrome type 2 or piebaldism. CONCLUSIONS: We provide consolidating evidence that biallelic KITLG variants cause a distinct auditory-pigmentary disorder. We evidence a significant clinical variability, similar to the one previously observed in KIT-related piebaldism.

The expression profiles of apoptosis-related genes induced usnic acid in SK-BR-3 breast cancer cell.

This study aims to determine whether usnic acid (UA) could induce the expression of apoptosis-related genes in apoptosis pathway. The current study has enabled us to better understand the target of UA in the treatment of breast cancer. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Based on the previous study and the results of this study, UA had the most antiproliferative effect on SK-BR-3 breast cancer cell line. We examined differential expression of 88 apoptosis-related genes by quantitative real-time polymerase chain reaction using the apoptosis primary library panel in SK-BR-3 breast cancer cell. We observed a difference in the significant differential expression of 74 apoptosis-related genes in breast cancer after SK-BR-3 cells applied to UA (7.21 µM) for 48 h. The expression level of 56 of these 74 differentiated apoptosis-related genes increased (p < 0.05), but the expression level of the other 18 related genes decreased (p < 0.05). In order to evaluate the mechanism of apoptosis of UA, Western blot analysis was performed with Bcl-2, Bax, Caspase-3, and Caspase-9 antibodies. According to the Western blot analysis, we obtained similar results with gene-expression data. These results suggest that UA showed a cytotoxic effect in SK-BR-3 cells through activation of the mitochondrial apoptotic pathway. The obtained results from gene expression revealed that the effect of UA on apoptosis pathway is critical for clinical research.

Zigzag longitudinal melanonychia: a peculiar dermoscopic pattern.

BACKGROUND: Longitudinal melanonychia (LM) can present a diagnostic challenge and dermoscopy is of utmost importance for its evaluation and differential diagnosis of LM. OBJECTIVE: This report aimed to describe an unusual dermoscopic pattern in a group of patients that presented with LM. METHODS: The clinical course and features of five LM patients that presented with an unusual 'zigzag' dermoscopic pattern were analyzed retrospectively. RESULTS: In all, four of the five patients were children (age range: 10-13years). In all five patients, the thumb nail was affected. A nail matrix biopsy was available for only one patient and was reported as lentigo. In two (one child and one adult) out of the five patients, spontaneous total regression of the LM was observed. CONCLUSIONS: The peculiar 'zigzag' dermoscopic pattern of LM described herein seems to occur primarily in children. Although this pattern is a benign in nature, it is not clear if it is related to trauma. Further investigation is warranted to clarify the association between the histopathological findings and the zigzag pattern observed via dermoscopy.

Variants in CIB2 cause DFNB48 and not USH1J.

The genetic, mutational and phenotypic spectrum of deafness-causing genes shows great diversity and pleiotropy. The best examples are the group of genes, which when mutated can either cause non-syndromic hearing loss (NSHL) or the most common dual sensory impairment, Usher syndrome (USH). Variants in the CIB2 gene have been previously reported to cause hearing loss at the DFNB48 locus and deaf-blindness at the USH1J locus. In this study, we characterize the phenotypic spectrum in a multiethnic cohort with autosomal recessive non-syndromic hearing loss (ARNSHL) due to variants in the CIB2 gene. Of the 6 families we ascertained, 3 segregated novel loss-of-function (LOF) variants, 2 families segregated missense variants (1 novel) and 1 family segregated a previously reported pathogenic variant in trans with a frameshift variant. This report is the first to show that biallelic LOF variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients. Here, we provide evidence disqualifying CIB2 as an USH-causing gene.

Variations in Multiple Syndromic Deafness Genes Mimic Non-syndromic Hearing Loss.

The genetics of both syndromic (SHL) and non-syndromic hearing loss (NSHL) is characterized by a high degree of genetic heterogeneity. We analyzed whole exome sequencing data of 102 unrelated probands with apparently NSHL without a causative variant in known NSHL genes. We detected five causative variants in different SHL genes (SOX10, MITF, PTPN11, CHD7, and KMT2D) in five (4.9%) probands. Clinical re-evaluation of these probands shows that some of them have subtle syndromic findings, while none of them meets clinical criteria for the diagnosis of the associated syndrome (Waardenburg (SOX10 and MITF), Kallmann (CHD7 and SOX10), Noonan/LEOPARD (PTPN11), CHARGE (CHD7), or Kabuki (KMT2D). This study demonstrates that individuals who are evaluated for NSHL can have pathogenic variants in SHL genes that are not usually considered for etiologic studies.

What is the neutrophil/lymphocyte ratio in sarcoidosis?

AIM: Information regarding the Neutrophil/Lymphocyte ratio (NLR) in sarcoidosis and the data from studies recommending its use as an indicator of inflammation and in the differential diagnosis and prognosis, are limited. With this study, it was aimed to obtain data regarding the NLR level in the patients at the time of presentation to the hospital and to determine the characteristics of patients in whom the NLR value was > 2. RESULTS: During the study period, of the 3434 patients with the sub-diagnosis of D86, 1300 cases whose complete blood count values had been recorded at the time of presentation were included in the study. Of the cases, 40 % were pulmonary sarcoidosis, 7 % were pulmonary sarcoidosis with sarcoidosis of the lymph nodes, 8 % were lymph node sarcoidosis, 1 % were sarcoidosis, of other combined areas, and 40 % of the cases were sarcoidosis that were unspecified. The F/M of the cases were 947/353, and the average age of the cases was 44. When the sarcoidosis groups were grouped into NLR < 2 (Group 1) and NLR ≥ 2 (Gorup 2), 27 % were Group 1, 73 % were Group 2, and a significant correlation was found between the two groups. When the inflammatory indicators were compared with NLR, the PLT/MPV was found to be statistically insignificant, and the ACE, ESR and CRP were found to be statistically significant. CONCLUSION: The Neutrophil/Lymphocyte ratio in the complete blood count, which is an easy and cheap test, can be used as an indicator of inflammation in Sarcoidosis. In clinical practice, wide-based studies comprising the activity and the staging in the prognosis of sarcoidosis are required (Tab. 2, Fig. 2, Ref. 26).

Survival in patients with hypoechoic muscularis propria lesions suggestive of gastrointestinal stromal tumors in gastric wall.

BACKGROUND: Subepithelial lesions (SEL) on upper gastrointestinal endoscopy are frequently encountered and referred to endoscopic ultrasound (EUS). Management of small gastric hypoechoic SELs of muscularis propria (MP) is controversial since EUS-assisted fine needle aspiration may be inconclusive, and surgical excision may be too invasive. We aimed to analyze our gastric MP-SELs in terms of survival and confounding factors. METHODS: Data from gastric hypoechoic MP-SELs suggestive of gastrointestinal stromal tumor (GIST) by EUS were retrospectively reviewed. Surgically resected GISTs were stratified according to the current pathological risk criteria. RESULTS: Sixty-one patients were identified. The mean age was 55.5 ± 13.2 years and 45.6% were male. Mean follow-up duration was 53.4 ± 26.7 (12-110) months. Twenty-eight (45.9%) patients were managed conservatively (diameter 15.3 ± 10.1 mm). There were no metastasis- or tumor-related deaths and no significant size changes (≥ 5 mm) in this group during follow-up. Thirty-three (54.1%) patients underwent complete resection (diameter 34.2 ± 14.1 mm) among which 25 (75.8%) had the final diagnosis of GIST; 2 (8.0%), 14 (56%) and 6 (24%) patients were classified in no-risk, very-low-risk, low-risk categories respectively, while 2 (8.0%) were in moderate-risk and only 1 (4.0%) was in high-risk category. CONCLUSIONS: The excellent survival of patients with small hypoechoic gastric MP-SELs with conservative management represents indolent course of those lesions. We suggest re- consideration of the recommendations in the current guidelines towards extending the follow-up intervals for small MP-SELs.

Application of molecular markers to detect DNA damage caused by environmental pollutants in lichen species.

Pseudevernia furfuracea L. (Zopf), Peltigera praetextata (Flörke ex Sommerf.) Zopf, Lobaria pulmonaria (L.) Hoffm., and Usnea longissima Ach. lichen species were used as bioindicators to assess the genotoxicity of air pollutants. In the present study, we examined significant environmetal pollutants and investigate how changes may lead to damage in DNA structure using RAPD markers. In the study area (Erzurum, Turkey), poor-quality lignite, which generates a large amount of sulfur dioxide, nitrogen oxides, and particle matter, is used for domestic heating, and vehicles also contribute to air pollution. Control lichen samples were collected far from large urban and industrial settlements and transplanted to four polluted sites for 4, 8, or 12 months. The total soluble protein content of the examined four lichen species did not significantly change with exposure time (P < 0.05). The four lichen samples exposed to the pollutants for 8 months had the highest ratio of DNA changes. The ratio of band differences in P. praetextata was higher than that in the other three lichen species, possibly because it has broad leaves that accumulated more pollutants. The average incidences of polymorphism were 64.14, 54.58, 65.76, and 43.06% for P. furfuracea, P. praetextata, L. pulmonaria, and U. longissima, respectively. The genomic template stability (GTS) significantly decreased following exposure to pollutants. GTS ratios revealed that the highest value (98.36%) belonged to U. longissima samples from Site 1 (10 m) after 4 months of exposure, and the lowest values belonged to P. praetextata (73.58%) from Site 3 (100 m) after 8 months of exposure. Based on our findings, we recommend the use of P. praetextata as an indicator of genotoxicity.

Staging of esophageal and gastric cancer in 2014.

Cancers of the upper gastrointestinal (GI) tract; esophageal and gastric carcinomas are highly lethal malignancies that have been ranked among the top 10 most frequent cancers and leading causes of cancer-related mortality. Universally, the tumor-node-metastasis (TNM) staging systems provided by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) are used for esophageal and gastric cancers. Accurate locoregional staging has become critical for the application of appropriate stage-specific treatment options in the multimodality treatment era in order to achieve better patient outcomes. Endoscopic ultrasound (EUS) represents a valuable minimally invasive real-time imaging modality for the assessment of upper GI tract tumors providing evidence for tumor invasion depth and regional nodal involvement corresponding to the T and N status of the TNM staging system, but a clear understanding of its diagnostic performance, limits and complementary role to other imaging modalities is required. This review will focus on the literature about the role and value of EUS in the TNM staging of esophageal and gastric carcinoma. In addition, an overview of the description of the current 7th editions of TNM staging and the revisions of the last editions compared to previous editions are presented.

Branchio-oculo-facial syndrome in a newborn caused by a novel TFAP2A mutation.

We present an 18-day old boy with bilateral cervical cutaneous defect in the retroauricular region, low-set and posteriorly rotated ears, bilateral microphtalmia and bilateral pseudocleft of the upper lip. Histopathological evaluation of cervical cutaneous defect showed ulceration on the surface and ectopic thymus tissue in the deep dermis with cortex, medulla and Hassal's corpuscles. Clinical findings led to the diagnosis of Branchio-oculo-facial syndrome, characterized by branchial defects (erythematous cutaneous defects in cervical region), ocular anomalies (microphthalmia, anophthalmia, lacrimal duct obstruction, coloboma, cataract, ptosis) and facial defects (cleft lip and/or palate, pseudocleft or abnormal philtrum). DNA sequencing showed a novel heterozygous mutation, c.731T>C (p.L244P), in TFAP2A gene confirming the diagnosis of this rare autosomal dominant developmental disorder with variable clinical findings.

Multiple coronary cameral fistulae: a rare anomaly and cause of ischaemia.

An 82-year-old hypertensive, diabetic woman was admitted to our department for pre-operative cardiac evaluation. A myocardial perfusion scan revealed apicoseptal and inferior segment hypoperfusion. Coronary angiography exhibited extensive multiple coronary cameral fistulae draining into the left ventricle in a homogeneous and circular way.

A truncating mutation in GPSM2 is associated with recessive non-syndromic hearing loss.

Hereditary deafness is a genetically heterogeneous phenotype for which more than 100 genomic loci have been identified thus far. By analysis of a consanguineous Palestinian family, GPSM2 was recently discovered to be the cause of autosomal recessive non-syndromic hearing loss DFNB82. Here, we report a second truncating mutation, GPSM2 p.Q562X, identified via autozygosity mapping in a consanguineous Turkish family. This report provides evidence for allelic heterogeneity of GPSM2 and confirms its causative role for non-syndromic deafness.

Evaluation of genotoxicity of Pseudevernia furfuracea (L.) Zopf by RAPD analysis.

We investigated the suitability and applicability of Pseudevernia furfuracea (L.) Zopf for environmental genotoxicity assessment. P. furfuracea lichen specimens were collected from 10 different Pinus species, in every 5 km, starting from around an iron-steel factory located in the central area of Karabük Province up to Yenice Forest. The impact of the pollution sources such as iron-steel factory, roads and railroads, industry, heavy traffic, and waste treatment plants on the heavy metal accumulation in lichens is known. DNA changes in P. furfuracea samples exposed naturally to various polluted sites were analyzed by RAPD to know the influence of the environmental pollution on the hereditary material of the organisms. Twenty-five different primers were tested and 10 yielded clear and reproducible bands. The present study shows the suitability of the lichen samples for the detection of genotoxicity and also provides information about the level of potential genotoxic agents around a steel mill.

Cardiomyopathy with alopecia and palmoplantar keratoderma (CAPK) is caused by a JUP mutation.

Inherited desmosomal cardiocutaneous syndromes are characterized by the quartet of woolly hair, palmoplantar keratoderma (PPK), skin fragility and cardiac abnormalities, which are caused by mutations in genes coding for desmosomal proteins. We describe a previously unrecognized autosomal recessive syndrome in a family with arrhythmogenic right ventricular cardiomyopathy associated with alopecia and PPK (named CAPK). Genetic investigation of the family led us to find a homozygous disease-causing mutation, p.R265H, in JUP which encodes plakoglobin, a well-described member of the desmosome complex. This study expands the clinical spectrum of disorders associated with germline mutations affecting desmosomal proteins by describing a novel phenotype.

A halo in the heart during coronary angiography: calcified left ventricular aneurysm with thrombus formation.

A 74-year-old man presented with chest pain and dyspnoea at the cardiology outpatient clinic. His past medical history included an anterior myocardial infarction in 2008. In the coronary angiogram, a 'halo image' was seen right after the injection of the contrast agent, and it corresponded with the location of the left ventricular aneurysm. A calcified left ventricular aneurysm with mural thrombus was confirmed with cardiac MRI and a CT scan.

Aorto-enteric fistula: a dilemma for the endoscopist as a rare cause of gastro-intestinal bleeding.

A 78-year-old man with a history of aorta-femoral graft operation was admitted to the hospital with symptoms of syncope, melena and haematemesis. He reported several episodes of melena during the previous year for which he underwent repeated gastro-intestinal endoscopic examinations, which were unable to show the site of the gastro-intestinal bleeding. The third upper gastro-intestinal endoscopic examination disclosed a yellowish ulcerative lesion with irregular borders in the third part of the duodenum, which was considered to be a fistula, between the aorta and the duodenum. The patient underwent an explorative operation that revealed an intact aortic graft, firmly adherent to the duodenal wall, and the duodenum that was eroded in the third portion. The duodenum was transected and a duodenoduodenostomy was performed. Although re-bleeding did not occur, the patient died of sepsis eight days after the operation. Aorto-enteric fistulae can be missed due to the common practice of limiting the endoscopic examination to the second part of the duodenum and not considering them in the differential diagnosis of gastro-intestinal bleeding because of their rarity. Possibly, a number of prior endoscopic examinations may be inconclusive until a correct diagnosis is reached in most of the cases.

A founder TMIE mutation is a frequent cause of hearing loss in southeastern Anatolia.

Using Affymetrix 10K arrays, we searched for regions of homozygosity in 51 Turkish families including at least three members with either congenital or prelingual autosomal recessive non-syndromic sensorineural hearing loss (ARNSSNHL), and identified four families whose deafness mapped to the DFNB6 locus on 3p21 containing the TMIE gene. Mutation analysis revealed the p.R84W mutation in all four families. Screening of this mutation in 254 families with ARNSSNHL, without GJB2 mutations, revealed four additional affected families. A novel mutation was found in a non-complementary marriage between a deaf couple who were homozygous for p.R84W and p.W57X, respectively with two affected children who were compound heterozygotes. Six of the TMIE families originated from southeastern Anatolia, making p.R84W a common cause of hearing loss in that region with a relative frequency of 10.3% (95% CI is 2.5-18.1%). The overall prevalence of the p.R84W mutation in ARNSSNHL in Turkey is 2.4% (95% CI is 0.7-4.0%). Genotyping of single-nucleotide polymorphisms flanking the TMIE gene revealed a conserved haplotype, suggesting a single origin for p.R84W from a common ancestor 1250 years ago (95% CI is 650-2500 years). We conclude that p.R84W could be a common mutation in other Middle Eastern populations and should be included in mutation screening offered to individuals with ARNSSNHL.

Evaluation of drug resistance in pulmonary tuberculosis patients at Sureyyapasa Chest Diseases Hospital, Istanbul, Turkey.

SETTING: Sureyyapasa Chest Diseases and Thoracic Surgery Training Hospital, Istanbul, Turkey. OBJECTIVE: To determine levels of Mycobacterium tuberculosis resistance to first-line drugs in patients with pulmonary tuberculosis (PTB). DESIGN: Between 1 January and 31 December 2005, all hospitalised PTB patients with culture-positive M. tuberculosis specimens and corresponding drug susceptibility tests (DST) for isoniazid (INH), rifampicin (RMP), streptomycin (SM) and ethambutol, routinely performed for every tuberculosis (TB) case at our centre, were included. RESULTS: Of a total of 1513 cases, 1277 (84.4%) were new and 236 (15.6%) were previously treated cases. Of the 1513 isolates, 290 (19%) isolates were resistant to at least one of the drugs tested. Resistance among new and previously treated cases was respectively 16.3% (209 of 1277) and 34.3% (81/236). Any SM resistance and any INH resistance were the most common drug resistance in new cases, while any RMP resistance was the most common drug resistance in previously treated cases. Multidrug resistance was detected in 3.2% (n = 41) of new cases and in 13.5% (n = 32) of previously treated cases. CONCLUSION: Planning for TB control requires an assessment of the number and distribution of drug-resistant cases, with laboratories providing accurate and reliable results.

Homozygous FGF3 mutations result in congenital deafness with inner ear agenesis, microtia, and microdontia.

Homozygous mutations in the fibroblast growth factor 3 (FGF3) gene have recently been discovered in an autosomal recessive form of syndromic deafness characterized by complete labyrinthine aplasia (Michel aplasia), microtia, and microdontia (OMIM 610706 - LAMM). In order to better characterize the phenotypic spectrum associated with FGF3 mutations, we sequenced the FGF3 gene in 10 unrelated families in which probands had congenital deafness associated with various inner ear anomalies, including Michel aplasia, with or without tooth or external ear anomalies. FGF3 sequence changes were not found in eight unrelated probands with isolated inner ear anomalies or with a cochlear malformation along with auricle and tooth anomalies. We identified two new homozygous FGF3 mutations, p.Leu6Pro (c.17T>C) and p. Ile85MetfsX15 (c.254delT), in four subjects from two unrelated families with LAMM. The p.Leu6Pro mutation occurred within the signal site of FGF3 and is predicted to impair its secretion. The c.254delT mutation results in truncation of FGF3. Both mutations completely co-segregated with the phenotype, and heterozygotes did not have any of the phenotypic findings of LAMM. Some affected children had large skin tags on the upper side of the auricles, which is a distinctive clinical component of the syndrome. Enlarged collateral emissary veins associated with stenosis of the jugular foramen were noted on computerized tomographies of most affected subjects with FGF3 mutations. However, similar venous anomalies were also detected in persons with non-syndromic Michel aplasia, suggesting that a direct causative role of impaired FGF3 signaling is unlikely.