Airway hillocks are injury-resistant reservoirs of unique plastic stem cells.

Airway hillocks are stratified epithelial structures of unknown function1. Hillocks persist for months and have a unique population of basal stem cells that express genes associated with barrier function and cell adhesion. Hillock basal stem cells continually replenish overlying squamous barrier cells. They exhibit dramatically higher turnover than the abundant, largely quiescent classic pseudostratified airway epithelium. Hillocks resist a remarkably broad spectrum of injuries, including toxins, infection, acid and physical injury because hillock squamous cells shield underlying hillock basal stem cells from injury. Hillock basal stem cells are capable of massive clonal expansion that is sufficient to resurface denuded airway, and eventually regenerate normal airway epithelium with each of its six component cell types. Hillock basal stem cells preferentially stratify and keratinize in the setting of retinoic acid signalling inhibition, a known cause of squamous metaplasia2,3. Here we show that mouse hillock expansion is the cause of vitamin A deficiency-induced squamous metaplasia. Finally, we identify human hillocks whose basal stem cells generate functional squamous barrier structures in culture. The existence of hillocks reframes our understanding of airway epithelial regeneration. Furthermore, we show that hillocks are one origin of 'squamous metaplasia', which is long thought to be a precursor of lung cancer.

Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic Inflammation.

BACKGROUND & AIMS: Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNA-binding protein that promotes the turnover of numerous proinflammatory and oncogenic messenger RNAs. Here, we assess the role of TTP in regulating gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) development. METHODS: We used a TTP-overexpressing model, the TTPΔadenylate-uridylate rich element mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and SPEM. RESULTS: We found that TTPΔadenylate-uridylate rich element mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing 5 days after ADX showed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Importantly, TTP overexpression did not protect from high-dose-tamoxifen-induced SPEM development, suggesting that protection in the ADX model is achieved primarily by suppressing inflammation. Finally, we show that protection from gastric inflammation was only partially due to the suppression of Tnf, a well-known TTP target. CONCLUSIONS: Our results show that TTP exerts broad anti-inflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of proneoplastic gastric inflammation. Transcript profiling: GSE164349.

British Association of Urological Surgeons (BAUS) and Nurses (BAUN) consensus document: management of the complications of long-term indwelling catheters.

OBJECTIVE: To look at best evidence and expert opinion to provide advice in the form of a consensus statement lead by Female, Neurological and Urodynamic Urology (FNUU) section of the British Association of Urological Surgeons (BAUS) in conjunction with the British Association of Urological Nurses (BAUN). METHODS: Initially a literature search was performed with incorporation of aspects of the existing guidance and further informed by UK best practice by core members of the group. The document then underwent reviews by the FNUU Executive Committee members, the BAUN executive committee, a separate experienced urologist and presented at the BAUS annual meeting 2020 to ensure wider feedback was incorporated in the document. RESULTS: Complications of long-term indwelling catheters include catheter-associated urinary tract infections (CAUTI), purple urine bag syndrome, catheter blockages, bladder spasms (causing pain and urinary leakage), loss of bladder capacity, urethral erosion ("catheter hypospadias")/dilatation of bladder outlet and chronic inflammation (metaplasia and cancer risk). CONCLUSIONS: We have provided a list of recommendations and a troubleshooting table to help with the management of the complications of long term catheters.

DDIT4 Licenses Only Healthy Cells to Proliferate During Injury-induced Metaplasia.

BACKGROUND AND AIMS: In stomach, metaplasia can arise from differentiated chief cells that become mitotic via paligenosis, a stepwise program. In paligenosis, mitosis initiation requires reactivation of the cellular energy hub mTORC1 after initial mTORC1 suppression by DNA damage induced transcript 4 (DDIT4 aka REDD1). Here, we use DDIT4-deficient mice and human cells to study how metaplasia increases tumorigenesis risk. METHODS: A tissue microarray of human gastric tissue specimens was analyzed by immunohistochemistry for DDIT4. C57BL/6 mice were administered combinations of intraperitoneal injections of high-dose tamoxifen (TAM) to induce spasmolytic polypeptide-expressing metaplasia (SPEM) and rapamycin to block mTORC1 activity, and N-methyl-N-nitrosourea (MNU) in drinking water to induce spontaneous gastric tumors. Stomachs were analyzed for proliferation, DNA damage, and tumor formation. CRISPR/Cas9-generated DDIT4-/- and control human gastric cells were analyzed for growth in vitro and in xenografts with and without 5-fluorouracil (5-FU) treatment. RESULTS: DDIT4 was expressed in normal gastric chief cells in mice and humans and decreased as chief cells became metaplastic. Paligenotic Ddit4-/- chief cells maintained constitutively high mTORC1, causing increased mitosis of metaplastic cells despite DNA damage. Lower DDIT4 expression correlated with longer survival of patients with gastric cancer. 5-FU-treated DDIT4-/- human gastric epithelial cells had significantly increased cells entering mitosis despite DNA damage and increased proliferation in vitro and in xenografts. MNU-treated Ddit4-/- mice had increased spontaneous tumorigenesis after multiple rounds of paligenosis induced by TAM. CONCLUSIONS: During injury-induced metaplastic proliferation, failure of licensing mTORC1 reactivation correlates with increased proliferation of cells harboring DNA damage, as well as increased tumor formation and growth in mice and humans.

Development of Pancreatic Acinar Cell Metaplasia During Gastric Repair in a Rat Duodenal Contents Reflux Model.

BACKGROUND: We previously reported the development of pancreatic acinar cell metaplasia (PACM) in the glandular stomach of a duodenal contents reflux model (reflux model). AIMS: We aimed to investigate the characteristics and histogenesis of PACM using a reflux model. METHODS: A reflux model was created using 8-week-old male Wistar rats, which were killed up to 30 weeks postoperatively. Histological examination was performed to analyze the glandular stomach-jejunal anastomosis. Furthermore, electron microscopic images of PACM samples were compared with pancreatic and gastric glands removed from rats that had not undergone surgery. Immunostaining for α-amylase, HIK1083, TFF2, and Ki-67 was performed, and double fluorescent staining was carried out using antibodies against α-amylase and HIK1083, or α-amylase and TFF2. RESULTS: In all reflux model rats, PACM was observed proximal to the glandular stomach-jejunal anastomosis, surrounded by pseudopyloric metaplasia. The number of chief cells was decreased in the deep part of the gland, where PACM occurred. Electron microscopy showed that PACM cells had greater numbers of rough endoplasmic reticulum tubules than chief cells, and exhibited pancreatic acinar cell morphology. Upon immunochemical staining, the regenerative foveolar epithelium and part of the pseudopyloric glands stained strongly positive for TFF2, whereas PACM cells were only weakly positive. Double fluorescent staining identified early lesions of PACM in the neck, which were double positive for α-amylase and TFF2, but negative for HIK1083. CONCLUSIONS: PACM could be induced by duodenal contents reflux. PACM originates from stem cells located in the neck of oxyntic glands during gastric mucosal regeneration.

p63+Krt5+ basal cells are increased in the squamous metaplastic epithelium of patients with radiation-induced chronic Rhinosinusitis.

BACKGROUND: Squamous metaplasia (SM) is an irreversible form of airway epithelial remodeling. Hyperproliferation of basal cells was observed in squamous metaplastic epithelium of chronically inflamed airway. However, the association of such aberrant proliferation of basal cells with SM in the nasal epithelium after radiation damage remains unclear. The aim of this study was to investigate SM and accompanying levels of p63+Krt5+ (basal cell markers) cells in the nasal epithelium of patients with radiation-induced chronic rhinosinusitis (CRSr) and patients with chronic rhinosinusitis without nasal polyps (CRSsNP) compared to healthy controls. METHODS: We assessed the prevalence of SM and the expression of p63+, Krt5+, p63+Krt5+, and Ki67+ cells through immunofluorescence(IF) staining of the inferior turbinate (IT) tissues from patients with CRSr (n = 36), CRSsNP (n = 33) and controls (n = 28). RESULTS: The prevalence of SM and the number of p63+Krt5+ cells were both significantly increased in patients with CRSr compared to patients with CRSsNP and controls. The number of Ki67+ cells were both significantly increased in patients with CRSr and CRSsNP compared to controls, but the ratio of Ki67+ cells to p63+Krt5+ cells was significantly lower in patients with CRSr compared to patients with CRSsNP. In patients with CRSr, an increased number of p63+Krt5+ basal cells was observed in SM epithelium compared to non-SM epithelium. CONCLUSION: SM is increased in the nasal epithelium of patients with CRSr, in which aberrant levels of p63+Krt5+ basal cells serves as an important pathologic feature in the squamous metaplastic epithelium.

Low Levels of Alcohol Consumption and Risk of Intestinal Metaplasia: A Cohort Study.

BACKGROUND: The impact of alcohol drinking on gastric precancerous lesions remains unclear. We investigated the relationship of alcohol intake with risk of atrophic gastritis (AG) and intestinal metaplasia (IM). METHODS: This study included 202,675 Korean adults free from AG and IM on their initial endoscopy who were followed with repeated endoscopic examinations. A parametric proportional hazards model was used to estimate the adjusted HR (aHR) with 95% confidence interval (CI) for incident AG and IM based on endoscopic diagnosis. RESULTS: During a mean follow-up of 4.7 years, 64,853 incident AG cases and 4,536 IM cases were identified. Alcohol consumption including drinking frequency, quantity, and binge drinking were consistently associated with increased risk of both AG and IM in a dose-response manner. After adjustment for confounders, the multivariable aHRs (95% CIs) for incident IM comparing average alcohol intake of <10, 10-<20, 20-<40, and ≥40 g/day with lifetime abstainers were 1.27 (1.02-1.56), 1.34 (1.07-1.66), 1.50 (1.20-1.86), and 1.54 (1.23-1.93), respectively. Former drinkers were also at a higher risk for AG and IM compared with lifetime abstainers. These associations were consistently observed in never smokers and in time-dependent analyses. CONCLUSIONS: In a large cohort of Korean individuals, alcohol intake even at low levels was independently associated with increased risk of developing endoscopic AG and IM, supporting a role of alcohol consumption in the pathogenesis of AG and IM, the precursor lesions of stomach cancer. IMPACT: Alcohol consumption from low-level drinking may contribute to gastric carcinogenesis.

Switches of SOX17 and SOX2 expression in the development of squamous metaplasia and squamous intraepithelial lesions of the uterine cervix.

AIMS: The dynamics and topographical distribution of SOX17 and SOX2 expression was studied in the transformation zone (TZ) of the uterine cervix. This TZ is a dynamic area where switches from glandular into squamous epithelium can be recognized, new squamocolumnar junctions are formed, and premalignant lesions originate. SOX17 and SOX2 show mutually exclusive expression patterns in the normal uterine cervix, with SOX2 being exclusively found in squamous epithelium, while SOX17 is detected in endocervical columnar cells and reserve cells. METHODS AND RESULTS: Normal cervices and squamous intraepithelial lesions (SIL) were studied with immunohistochemistry, methylation of SOX17, human papilloma virus (HPV) genotyping, and in situ hybridization. In the TZ squamous metaplasia originating from these reserve cells can still show SOX17 expression, while also remnants of SOX17-positive immature metaplasia can be recognized in the normal squamous epithelium. SOX17 expression is gradually lost during maturation, resulting in the exclusive expression of SOX2 in the majority of (SIL). This loss of SOX17 expression is independent of methylation of the CpG island in its promotor region. HPV can be detected in SOX17-positive immature metaplastic regions in the immediate vicinity of SOX2-positive SIL, suggesting that switches in SOX17 and 2 expression can occur upon HPV infection. CONCLUSIONS: This switch in expression, and the strong association between the distribution of reserve cells and squamous areas within the columnar epithelium in the TZ, suggests that reserve cell proliferations, next to basal cells in the squamous epithelium, are potential targets for the formation of squamous lesions upon viral infection.

Upregulation of miR-92a contributes to blocking goblet cell metaplasia by targeting MUC5AC in asthma.

As a chronic airway disease, asthma has two characteristics, tissue remodeling and airway inflammation. This research focused on miR-92a to explore how it works in asthma. We revealed that the expressions of miR-92a were decreased in both serum and lung tissues from ovalbumin-induced asthma mouse. Bioinformatics analysis, quantitative polymerase chain reaction (qPCR) and dual luciferase assay revealed that miR-92a targets MUC5AC, which was linked to mucus hypersecretion in the pulmonary tracts. By injecting miR-92a-mimics into the trachea, both the airway hyper-reactivity and airway inflammation can be alleviated in an asthma mouse model which is induced by ovalbumin. Moreover, the goblet cell phenotype of asthmatic mice is significantly reduced by the action of miR-92a. Furthermore, miR-92a blocked interleukin (IL)-13-induced MUC5AC luciferase activity in 16HBE. Together, upregulation of miR-92a expression in asthmatic mice plays a role in blocking goblet cell metaplasia by targeting MUC5AC, and thus in the treatment of chronic airway diseases, miR-92a can prevent epithelial remodeling, which is a reasonable method.

Bilateral Chondroid Metaplasia of Conjunctiva Associated With Monoclonal Gammopathy of Undetermined Significance.

PURPOSE: To describe a case of a patient with bilateral proliferation of chondrocytes of the lower palpebral conjunctiva. METHODS: Observational case report and review of relevant literature. RESULTS: Conjunctival biopsy from an 83-year-old man with bilateral acquired lower conjunctival nodules revealed a benign proliferation of chondrocytes. A general medical evaluation revealed serum monoclonal gammopathy with light-chain proteinuria. CONCLUSIONS: Bilateral-acquired benign chondrocyte tumefactions of the palpebral conjunctiva have not been previously reported. This initiated a search for a biologically plausible explanation. The findings in this report support that these proliferations represent chondroid metaplasia related to light-chain deposition. The diagnosis requires exclusion of other forms of chondrocyte proliferation including well-differentiated chondrosarcoma.

Long-term follow up of serum pepsinogens in patients with gastric cancer or dysplasia after Helicobacter pylori eradication.

BACKGROUND AND AIM: Few studies have evaluated the change in serum pepsinogen (sPG) levels after the eradication of Helicobacter pylori. The aim of this study was to evaluate the effect of H. pylori eradication on sPG levels in patients with gastric cancer/dysplasia in comparison to a control group. METHODS: We prospectively enrolled 368 patients with gastric cancer/dysplasia and 610 control subjects. H. pylori status and sPG levels were measured before and after eradication. The follow-up time points were classified as < 12, 12-23, 24-35, and ≥ 36 months. RESULTS: In 179 H. pylori-eradicated patients with gastric cancer/dysplasia and 168 control group subjects, sPG I significantly decreased, and the sPG I/II ratio significantly increased after eradication compared to baseline, and this improvement in sPG values was maintained during all follow-up time points. Significant differences in sPG I and the sPG I/II ratio were observed between the gastric cancer/dysplasia group and the control group < 24 months after eradication. However, these differences in sPG values disappeared after ≥ 24 months of follow up. Moreover, significant differences in the intestinal metaplasia grade were observed between these two groups before eradication until < 24 months after eradication. However, these differences in the intestinal metaplasia grade disappeared after ≥ 24 months of follow up in the corpus. CONCLUSION: The sPG values and intestinal metaplasia grade (corpus) in the gastric cancer/dysplasia group became similar to those in the control group at long-term follow up after H. pylori eradication. It might be related with the reduction of metachronous gastric neoplasm.

Osseous Metaplasia in a Bladder Diverticulum in a Patient with Mosaic Menkes Disease.

Menkes disease, or Kinky Hair Syndrome, is a rare disorder of copper metabolism that causes fatal neurodegenerative disease in infancy. This X-linked disorder results from mutations in the ATP7A gene. Along with neurological decline, characteristic coarse appearance of the hair is seen. Urological issues are prevalent in this patient population, with bladder diverticula being the most common. Herein, we describe a unique male patient with genetic mosaicism and osseous metaplasia found in a ruptured bladder diverticulum.

Proliferation and Differentiation of Gastric Mucous Neck and Chief Cells During Homeostasis and Injury-induced Metaplasia.

BACKGROUND & AIMS: Adult zymogen-producing (zymogenic) chief cells (ZCs) in the mammalian gastric gland base are believed to arise from descending mucous neck cells, which arise from stem cells. Gastric injury, such as from Helicobacter pylori infection in patients with chronic atrophic gastritis, can cause metaplasia, characterized by gastric cell expression of markers of wound-healing; these cells are called spasmolytic polypeptide-expressing metaplasia (SPEM) cells. We investigated differentiation and proliferation patterns of neck cells, ZCs, and SPEM cells in mice. METHODS: C57BL/6 mice were given intraperitoneal injections of high-dose tamoxifen to induce SPEM or gavaged with H pylori (PMSS1) to induce chronic gastric injury. Mice were then given pulses of 5-bromo-2'-deoxyuridine (BrdU) in their drinking water, followed by chase periods without BrdU, or combined with intraperitoneal injections of 5-ethynyl-2'-deoxyuridine. We collected gastric tissues and performed immunofluorescence and immunohistochemical analyses to study gastric cell proliferation, differentiation, and turnover. RESULTS: After 8 weeks of continuous BrdU administration, fewer than 10% of homeostatic ZCs incorporated BrdU, whereas 88% of neck cells were labeled. In pulse-chase experiments, various chase periods decreased neck cell label but did not increase labeling of ZCs. When mice were given BrdU at the same time as tamoxifen, more than 90% of cells were labeled in all gastric lineages. After 3 months' recovery (no tamoxifen), ZCs became the predominant BrdU-labeled population, whereas other cells, including neck cells, were mostly negative. When we tracked the labeled cells in such mice over time, we observed that the proportion of BrdU-positive ZCs remained greater than 60% up to 11 months. In mice whose ZCs were the principal BrdU-positive population, acute injury by tamoxifen or chronic injury by H pylori infection resulted in SPEM cells becoming the principal BrdU-positive population. After withdrawal of tamoxifen, BrdU-positive ZCs reappeared. CONCLUSIONS: We studied mice in homeostasis or with tamoxifen- or H pylori-induced SPEM. Our findings indicated that mucous neck cells do not contribute substantially to generation of ZCs during homeostasis and that ZCs maintain their own census, likely through infrequent self-replication. After metaplasia-inducing injury, ZCs can become SPEM cells, and then redifferentiate into ZCs on injury resolution.

Change of the duodenal mucosa-associated microbiota is related to intestinal metaplasia.

BACKGROUND: In this study, we aimed to investigate the characteristics of the duodenal mucosal microbiota of patients with intestinal metaplasia (IM) and compare it with those of the gastric mucosal microbiota. METHOD: We collected the duodenal and gastric mucosal samples from 10 adult patients with IM and 10 healthy controls (HC). The V3-V4 region of the bacterial 16S rRNA gene was examined by high throughput sequencing method. RESULTS: The diversity of the HC duodenal microbiota was higher than that of IM patient based on the Shannon and Simpson index while the Chao indices of IM duodenal mucosal microbiota was significantly higher than that of gastric mucosal microbiota of patients with IM. There was a marked difference in the duodenal microbiota structure between patients with IM and HC (ANOSIM, R = 1, P = 0.001). We also found that the Helicobacter pylori infection in gastric mucosa did not influence the structure of duodenal mucosal microbiota. The gastric mucosal microbiota structure significantly differed between patients with IM and HC who were H. pylori-negative (ANOSIM, R = 0.452, P = 0.042) or H. pylori-positive (ANOSIM, R = 0.548, P = 0.003), respectively. For duodenal mucosal microbiota, genera Lactococcus, Flavobacterium, Psychrobacter, Mysroides, Enhydrobacter, Streptococcus, and Leuconostoc were enriched in patients with IM. In contrast, genera Bacillus, Solibacillus, Lysinibacillus, Exiguobacterium, Oceanobacillus, and Paenibacillus were enriched in HC. CONCLUSION: A marked dysbiosis duodenal mucosal microbiota in patients with IM was observed, and this dysbiosis might be responsible for IM pathogenesis.

High-fat-diet-induced modulations of leptin signaling and gastric microbiota drive precancerous lesions in the stomach.

OBJECTIVES: Obesity is a risk factor for malignancy in various tissues, and has been associated with gut microbiota alterations. However, the link between obesity-associated microbiota and gastric pathogenesis has not been clarified. We demonstrated that high-fat-diet (HFD) feeding causes intestinal metaplasia, which are precancerous lesions of the stomach, with augmented gastric leptin signaling. The aim of this study was to investigate the precise role of leptin signaling in the altered microbiota composition and pathogenesis in the stomach during diet-induced obesity. METHODS: Male C57 BL/6 J, leptin receptor (Lepr)-mutated db/db, and gastrointestinal epithelium-specific Lepr conditional knockout (T3 b-Lepr cKO) mice were fed a HFD or control diet. Gastrointestinal microbiota was analyzed by 16 S rRNA gene sequences and quantitative polymerase chain reaction. Transplantation of gastric microbiota of HFD-fed mice was performed to evaluate metaplasia onset in recipient mice. RESULTS: One week of HFD caused severe microbial dysbiosis in the stomach. The microbiota changes were accompanied by increased gastric leptin, leading to the consequent development of intestinal metaplasia. Transplantation of gastric microbiota from HFD-fed mice induced intestinal metaplasia in recipient mice; however, only a limited effect on pathogenesis was noted. HFD-fed db/db mice did not show a decrease in microbial abundance. Moreover, T3 b-Lepr cKO mice failed spontaneous obesity, and suppressed decreased abundance of gastric microbiota and occurrence of intestinal metaplasia during HFD feeding similar to db/db mice. CONCLUSIONS: Gastric leptin signaling modulates the gastric microbiota community and regulates the pathogenesis in the gastric mucosa.

Helicobacter pylori and cytokine gene variants as predictors of premalignant gastric lesions.

Gastric cancer remains the third leading cause of mortality from cancer worldwide and carries a poor prognosis, due largely to late diagnosis. The importance of the interaction between Helicobacter pylori (H. pylori) infection, the main risk factor, and host-related genetic factors has been studied intensively in recent years. The genetic predisposition for non-hereditary gastric cancer is difficult to assess, as neither the real prevalence of premalignant gastric lesions in various populations nor the environmental risk factors for cancer progression are clearly defined. For non-cardiac intestinal-type cancer, identifying the factors that modulate the progression from inflammation toward cancer is crucial in order to develop preventive strategies. The role of cytokines and their gene variants has been questioned in regard to non-self-limiting H. pylori gastritis and its evolution to gastric atrophy and intestinal metaplasia; the literature now includes various and non-conclusive results on this topic. The influence of the majority of cytokine single nucleotide polymorphisms has been investigated for gastric cancer but not for preneoplastic gastric lesions. Among the investigated gene variants onlyIL10T-819C, IL-8-251, IL-18RAP917997, IL-22 rs1179251, IL1-B-511, IL1-B-3954, IL4R-398 and IL1RN were identified as predictors for premalignant gastric lesions risk. One of the most important limiting factors is the inhomogeneity of the studies (e.g., the lack of data on concomitant H. pylori infection, methods used to assess preneoplastic lesions, and source population). Testing the modifying effect of H. pylori infection upon the relationship between cytokine gene variants and premalignant gastric lesions, or even testing the interaction between H. pylori and cytokine gene variants in multivariable models adjusted for potential covariates, could increase generalizability of results.

Histopathological Effects of Bone Cement on Cartilage Tissue.

INTRODUCTION: Glass ionomer bone cement is frequently applied with cartilage grafts in otology, even as a single unit. OBJECTIVE: This experimental study was performed to investigate the histopathological effects of bone cement on cartilage tissue. METHODS: The study was conducted between January 2018 and April 2018 and used 12 New Zealand White rabbits. The right ears of the rabbits constituted the study group, while the left ears were the controls. Ketac Cem Radiopaque (3 M Germany) was used as glass ionomer cement. Tissue samples from the rabbits were subjected to histopathological analysis to compare acute and chronic inflammation, foreign body reaction, angiogenesis, collagenesis, fibrosis, necrosis, cartilage fracture, osseous metaplasia, and loss of chondrocyte nuclei between the groups. RESULTS: The rates of cartilage fracture (P = 0.044), foreign body reaction (P < 0.001), acute inflammation (P = 0.009), chronic inflammation (P = 0.002), and angiogenesis (P = 0.003) were significantly higher in the study group compared with the controls. The study group showed some degree of necrosis; no necrosis was observed in the control group, but the difference was not statistically significant (P = 0.101). There were no significant differences in fibrosis, collagenesis, osseous metaplasia, or loss of chondrocyte nuclei between the groups. CONCLUSIONS: This study showed that application of bone cement can cause acute and chronic inflammation, foreign body reactions, angiogenesis, and cartilage fractures. Further studies are needed to determine the long-term effects of bone cement on cartilage.

Effect of Electronic Cigarettes on the Inner Mucosa of the Craniofacial Region.

OBJECTIVES: The aim of this paper is to investigate electronic cigarettes (e-cigarettes) from the otorhinolaryngologic point of view. METHODS: The authors searched Central Database of Kirikkale University Library, Google, PubMed, and Proquest and Google Scholar. RESULTS: An electronic cigarette or e-cigarette is a battery-powered device that vaporizes a liquid, generally including nicotine. Nowadays, e-cigarettes are used for smoking cessation or to reduce the consumption of conventional tobacco cigarettes. First generation e-cigarette devices were similar to conventional tobacco cigarettes in terms of shape and size and expressed as "cigalikes." Differently from traditional cigarettes in which tobacco is burned to generate smoke, electronic cigarettes contain a tank filled with liquid. It was found that e-cigarette liquids contained different types of chemical compounds which were either previously known carcinogens or probably prove to be carcinogenic to humans in the near future. It seems that the use of electronic cigarette does not harm the oral cells. However, the use of e-cigarette for 4 weeks led to metaplasia and hyperplasia of the laryngeal mucosa in rats. Furthermore, e-ciagarettes produce some adverse effects on the nasal mucosa, supressing the immune system. CONCLUSION: It should not be considered that e-cigarettes are safer unless their effects on the mucosa of the ear, nose, and throat are more precisely clarified.