Allergic contact dermatitis from topical ophthalmic medications: keep an eye on it! Liesbeth Gilissen Lana Dedecker Toon Hulshagen An Goossens First published: 10 January 2019 https://doi.org/10.1111/cod.13209 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cod.13209. PDFTOOLS SHARE Abstract Background Allergic contact dermatitis (ACD) from topical ophthalmic medications is often overlooked.
Objectives To study the demographic characteristics, lesion locations, and associated medical conditions of the patients with ACD from ophthalmic drugs, and to identify the most common allergenic culprits, as well as trends in frequencies over the years.
Methods From January 1990 until December 2016, 16 065 patients were investigated in our clinic; all patients with a positive patch‐test reaction to eye medication or its ingredient(s) having caused ACD were studied. For each allergen identified, the number of positive test results compared with the total number of those in the total population, as well as trends across three periods, namely 1990‐1998, 1999‐2007, and 2008‐2016 were studied.
Results 118 patients (0.7%) presented with positive patch‐test results to ingredients of, and/or topical ophthalmic medications. Aminoglycoside antibiotics, followed by corticosteroids, as pharmacologically active ingredients, as well as wool alcohols, thiomersal and benzalkonium chloride, as excipients were the most frequent culprits. Particularly chloramphenicol showed a decreasing trend in positive reactions over time, whereas reactions tobramycin were increasing.
Conclusion ACD from eye medication is mainly due to active principles, but other excipient ingredients, beside the products "as is", should be tested as well. https://onlinelibrary.wiley.com/doi/10.1111/cod.13209
Diagnosing lanolin contact allergy with lanolin alcohol and Amerchol L101 Jannet Knijp Derk P. Bruynzeel Thomas Rustemeyer First published: 09 January 2019 https://doi.org/10.1111/cod.13210 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cod.13210. PDFTOOLS SHARE Summary Background The prevalence of lanolin contact allergy in dermatitis patients varies from 1.2% to 6.9%. Different lanolin derivatives are used in patch testing.
Objectives To determine which combination of lanolin derivatives is most effective in patch testing for diagnosing lanolin contact allergy.
Methods A retrospective analysis of patients patch tested between 2016 and 2017 was performed. Patients were eligible if tested with lanolin alcohol 30% pet., Amerchol L101 50% pet. and a supplementary series containing other lanolin derivatives. Lanolin alcohol and Amerchol L101 were tested in duplicate.
Results Out of 594 patients, 28.6% (95% confidence interval [CI]: 25.1%‐32.3%) had a positive patch test reaction to at least one lanolin derivative. Reactions were common to lanolin alcohol (14.7%, 95% CI: 11.3%‐18.2%) and Amerchol L101 (15.0%, 95% CI: 11.5%‐18.5%) in the routinely tested series. Reactions to other test preparations were significantly less frequent (P < 0.05). The addition of Amerchol L101 to lanolin alcohol significantly increased the number of positive cases (odds ratio 1.79, P < 0.001).
Conclusions The combination of lanolin alcohol and Amerchol L101 is effective in patch testing for diagnosing lanolin contact allergy. Routinely testing with other lanolin derivatives may not be worthwhile as it detects only few additional patients. https://onlinelibrary.wiley.com/doi/10.1111/cod.13210
Impaired antimicrobial response and mucosal protection induced by ibuprofen in the immature human intestine Emanuela Ferretti, Eric Tremblay, Marie-Pierre Thibault, Sepideh Fallah, David Grynspan, Karolina M. Burghardt, Marcos Bettolli, Corentin Babakissa, Emile Levy & Jean-François Beaulieu Pediatric Researchvolume 84, pages813–820 (2018) | Download Citation
Abstract Background The use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin (INDO) and ibuprofen (IBU) has been shown to be an effective therapy for the closure of patent ductus arteriosus (PDA). However, this treatment has been associated with an increased risk of developing enteropathies in neonates. Whether the use of IBU is safer than INDO for the immature intestine remains to be elucidated.
Methods The direct impact of IBU on the human immature intestinal transcriptome was investigated using serum-free organ culture. Differentially expressed genes were analyzed with Ingenuity Pathway Analysis software and compared with those previously reported with INDO. Validation of differentially expressed genes was confirmed by qPCR.
Results We identified several biological processes that were significantly modulated by IBU at similar levels to what had previously been observed with INDO, while the expression of genes involved in "antimicrobial response" and "mucus production" was significantly decreased exclusively by IBU in the immature intestine.
Conclusions Our findings indicate that IBU has a harmful influence on the immature intestine. In addition to exerting many of the INDO observed deleterious effects, IBU alters pathways regulating microbial colonization and intestinal epithelial defense. https://www.nature.com/articles/s41390-018-0201-y
Clinicopathologic traits and prognostic factors associated with pediatric sinonasal rhabdomyosarcoma Sana H. Siddiqui BA Emaad Siddiqui BS Rich D. Bavier BA Nirali M. Patel BA Suat Kiliç MD Soly Baredes MD, FACS Wayne D. Hsueh MD Jean Anderson Eloy MD, FACS, FARS First published: 10 January 2019 https://doi.org/10.1002/alr.22267 Potential conflict of interest: None provided. Presented orally at the 64th Annual Meeting of the American Rhinologic Society, Atlanta, GA, October 5‐6, 2018. Read the full text PDFTOOLS SHARE Abstract Background Pediatric sinonasal rhabdomyosarcoma (RMS) is an aggressive and rare malignancy. This is the first multi‐institutional study on the prognostic factors associated with outcomes in this population.
Methods The National Cancer Database was queried for the period from 2004 to 2013 for all cases of malignant sinonasal RMS in the pediatric population. The impact of patients' demographics, tumor characteristics, and Intergroup Rhabdomyosarcoma Study Group (IRSG) staging on survival was assessed using chi‐square test, Fisher's exact test, Kaplan‐Meier test, and Cox regression analyses.
Results A total of 157 cases of pediatric sinonasal RMS were identified. Mean age at diagnosis was 9.38 years and male patients comprised 48.4% of the cohort. The nasal cavity (31.8%) and maxillary sinus (30.6%) were the most common primary sites. Alveolar was the most common histology (49.7%), followed by embryonal type (32.5%). The majority of patients received solely chemoradiation (52.9%), followed by surgery with adjuvant chemoradiation (30.6%). Five‐year overall survival (OS) was 55.2% (±4.5%). Metastatic disease was associated with a poorer 5‐year OS rate (24.4% vs 61.5%; p = 0.010). Maxillary sinus site was associated with an improved survival (71.8% vs 47.6%; p = 0.009). On multivariate analysis, chemoradiation with or without surgery was an additional prognostic factor. Although IRSG clinical stages did not correlate with survival, high‐risk patients in the IRSG clinical risk groups were associated with poorer survival on multivariate analysis (hazard ratio [HR], 2.005; 95% confidence interval, 1.007‐3.993; p = 0.048).
Conclusion To date, this is the largest study on pediatric sinonasal RMS. IRSG clinical risk groups may be useful in stratifying high‐risk patients with poor prognosis. https://onlinelibrary.wiley.com/doi/10.1002/alr.22267
Formation of papillary mucosa folds and enhancement of epithelial barrier in odontogenic sinusitis Yuan Zhang MD, PhD Feng Lan MD, PhD Ying Li BS Chengshuo Wang MD, PhD Luo Zhang MD, PhD First published: 08 January 2019 https://doi.org/10.1002/alr.22277 Funding sources for the study: National Key R&D Program of China (2016YFC20160905200); the National Natural Science Foundation of China (81570895, 81420108009, 81400444, 81470678, and 81630023); Changjiang Scholars and Innovative Research Team (IRT13082); Special Fund of Capital Health Development (2011‐1017‐06, 2011‐1017‐02); Special Fund of Sanitation Elite Reconstruction of Beijing (2009‐2‐007); Beijing Health Bureau Program for High Level Talents (2011‐3‐043); Beijing Municipal Administration of Hospitals' Mission Plan (SML20150203); Capital Citizenry Health Program (z161100000116062). Potential conflict of interest: None provided. Read the full text PDFTOOLS SHARE Abstract Background Odontogenic sinusitis (OS) presents more satisfactory therapeutic effect after endoscopic surgery compared with chronic rhinosinusitis (CRS) of other origin. The aim of the present study was to investigate the clinical characteristics, morphological features, and epithelial barrier function of sinus mucosa of OS and discuss the possible relationship with good prognosis.
Methods A total of 25 subjects with OS, 7 CRS without nasal polyps (CRSsNP), 10 CRS with nasal polyps (CRSwNP), and 9 control subjects were recruited. The biopsy specimens were stained with hematoxylin and eosin for general observation of cytomorphologic features. Epithelial tight junctions (TJs) protein claudin‐4 expression was determined to evaluate the epithelial barrier integrity by using immunofluorescence and Image‐Pro Plus software analysis. The representative cytokine profiles regarding T helper 1 (Th1) (interferon [IFN]‐γ), Th2 (interleukin [IL]‐5), and Th17 (IL‐17) were examined by reverse transcription–polymerase chain reaction (RT‐PCR).
Results Extensively small papillary protrusions could be seen in the maxillary sinus mucosa of OS patients under nasal endoscopy, similar to the morphological behavior, which also presented as papillary folds in the surface of the epithelium. The epithelium in OS kept an increased claudin‐4 expression compared with that seen in CRSsNP, CRSwNP, and control subjects. The inflammatory pattern analysis demonstrated that OS belonged to the lymphocyte and plasma cell‐dominant cellular phenotypes, whereas IL‐17 was dominant compared with IFN‐γ as well as IL‐5.
Conclusion The odontogenic infections might induce the formation of papillary mucosa folds and enhance the epithelial TJ barrier function. OS exhibited as lymphocyte and plasma cell–dominant cellular phenotypes and Th17 cytokine profiles. https://onlinelibrary.wiley.com/doi/10.1002/alr.22277
Broncho‐Vaxom® (OM‐85 BV) soluble components stimulate sinonasal innate immunity Vasiliki Triantafillou BS Alan D. Workman MD Neil N. Patel BA, BS Ivy W. Maina BA Charles C. L. Tong MD Edward C. Kuan MD, MBA David W. Kennedy MD … See all authors First published: 07 January 2019 https://doi.org/10.1002/alr.22276 Funding sources for the study: National Institutes of Health (National Institute on Deafness and Other Communication Disorders [NIDCD] R01DC013588 to N.A.C.); Veterans Affairs Merit Review (CX001617 to N.A.C.). Potential conflict of interest: None provided. Presented orally at the ARS Meeting at the annual Combined Otolaryngology Spring Meetings (COSM) on April 18‐22, 2018, National Harbor, MD. Read the full text PDFTOOLS SHARE Abstract Background Broncho‐Vaxom® (OM‐85 BV) is an extract of infectious respiratory bacteria that is used as an immunostimulant outside of the United States for the prevention and treatment of bronchitis and rhinosinusitis. Prior studies have shown that use of OM‐85 BV is associated with reduction in frequency of respiratory infection and decreased duration of antibiotic usage. However, the effects of OM‐85 BV on respiratory mucosal innate immunity are unknown.
Methods Human sinonasal epithelial cells were grown at an air‐liquid interface (ALI). Ciliary beat frequency (CBF) and nitric oxide (NO) production in response to stimulation with OM‐85 BV was measured in vitro. Pharmacologic inhibitors of bitter taste receptor (T2R) signaling were used to determine if this pathway was taste‐receptor–mediated.
Results Apical application of OM‐85 BV resulted in an NO‐mediated increase in CBF (p < 0.05) and increased NO production (p < 0.0001) when compared to saline‐stimulated control cultures. ALI pretreatment with taste receptor pathway inhibitors blocked OM‐85 BV–induced increases in NO.
Conclusion OM‐85 BV has ciliostimulatory and immunogenic properties that may be partially responsible for its observed efficacy as a respiratory therapeutic. These responses were NO‐dependent and consistent with T2R activation. Further work is necessary to elucidate specific component‐receptor signaling relationships. https://onlinelibrary.wiley.com/doi/10.1002/alr.22276
Antineoplastic drugs (AD) have been increasingly used, but the disposal of their wastes in the environment via hospital effluent and domestic sewage has emerged as an environmental issue. The current risks posed to these animals and effects of pollutants on the reptiles' population level remain unknown due to lack of studies on the topic. The aim of the present study was to evaluate the mutagenicity of neonate Podocnemis expansa exposed to environmental concentrations (EC) of cyclophosphamide (Cyc). The adopted doses were EC-I 0.2 μg/L and EC-II 0.5 μg/L Cyc. These doses correspond to 1/10 and ¼ of concentrations previously identified in hospital effluents. Turtles exposed to the CyC recorded larger total number of erythrocyte nuclear abnormalities than the ones in the control group after 48-h exposure. The total number of abnormalities for both groups (EC-I and EC-II) 96 h after the experiment had started was statistically similar to that of animals exposed to high Cyc concentration (positive control 5 × 104 μg/L). This outcome confirms the mutagenic potential of Cyc, even at low concentrations. On the other hand, when the animals were taken to a pollutant-free environment, their mutagenic damages disappeared after 240 h. After such period, their total of abnormalities matched the basal levels recorded for the control group. Therefore, our study is the first evidence of AD mutagenicity in reptiles, even at EC and short-term exposure, as well as of turtles' recovery capability after the exposure to Cyc.
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Faced with the increasing threat from seawater intrusion, it is of great importance to explore the effect of the increase of water and salt on the coastal wetland soil quality. A simulation experiment was designed in this study to identify the impact of water and salt on soil quality in the coastal wetland of Jiaozhou Bay, China.
Materials and methods
Three soil quality indices were applied to investigate the influence of different water and salt conditions on soil quality. Every index was computed by applying the total data set (TDS) and minimum data set (MDS) methods. The TDS included nine soil quality properties determined in 96 samples including pH, bulk density (BD), total organic matter (TOM), ammonium nitrogen (NH4+-N), available phosphorus (AP), available potassium (AK), sucrase activity (SA), urease activity (UA), and alkaline phosphatase activity (APA). Principal component analysis (PCA) was applied to selected indicators for MDS.
Results and discussion
Soil quality decreased with the increase of salt content, and it increased first and then decreased with the increased water content. The soil samples with 60% water content had the lowest quality. Meanwhile, the nutrient indicators and enzyme activity in these soil samples were also lower than those in the other water gradients. The results of soil quality classification showed that the soil quality was mostly reckoned as moderate quality (grade III) and below and only a fraction of these samples was grade I based on all indices.
Conclusions
The results showed that too much water and salt in soil can decrease soil quality, and the effect of water was more obvious than salt. The results of match and kappa statistical analyses indicated that soil quality estimated by the weighted additive soil quality index was more accurate than those estimated by the additive soil quality index and Nemoro soil quality index. Besides, the agreement values of TDS were higher than those of MDS.
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A Case of Stage IV Chromophobe Renal Cell Carcinoma Treated with the Oncolytic ECHO-7 Virus, Rigvir®.
Am J Case Rep. 2019 Jan 12;20:48-52
Authors: Ismailov Z, Rasa A, Bandere K, Brokāne L, Tilgase A, Olmane E, Nazarovs J, Alberts P
Abstract BACKGROUND Renal cell carcinoma is the most commonly diagnosed primary malignant tumor of the kidney in adults, and includes the variant of chromophobe renal cell carcinoma. Despite new targeted therapies that improve progression-free survival (PFS) and overall survival (OS) for early-stage renal cell carcinoma, the 5-year survival for patients with stage IV renal cell carcinoma remains below 10%, and the 50% OS is less than one year. Metastatic renal cell carcinoma can be resistant to cytotoxic chemotherapy. This report is of a case of stage IV chromophobe renal cell carcinoma that responded well to treatment with the oncolytic ECHO-7 virus, Rigvir®. CASE REPORT In December 2015, a 59-year-old man presented with a right-sided chromophobe renal cell carcinoma stage IV (pT₁N₀M₁) with adrenal gland metastasis. He underwent right nephro-adrenalectomy followed by treatments with Rigvir® (≥10⁶ TCID₅₀/ml) by intramuscular (i.m.) injection on three consecutive days. Treatment with Rigvir® continued once per week for three months, and from March 2016, once per month, with continued treatment until computed tomography (CT) scans confirmed that the tumor metastases had stabilized. CONCLUSIONS This case report has demonstrated that the oncolytic ECHO-7 virus, Rigvir® should be evaluated further as a potential treatment for advanced renal carcinoma.
PMID: 30635548 [PubMed - in process]
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Synthesis and biological evaluation of quinoxaline derivatives as tubulin polymerization inhibitors that elevate intracellular ROS and triggers apoptosis via mitochondrial pathway.
Chem Biol Drug Des. 2019 Jan 11;:
Authors: Qi J, Huang J, Zhou X, Luo W, Xie J, Niu L, Yan Z, Luo Y, Men Y, Chen Y, Zhang Y, Wang J
Abstract A series of novel quinoxaline derivatives were synthesized and evaluated for their antiproliferative activity in three human cancer cell lines. Compound 12 exhibited the most potent antiproliferative activity with IC50 in the range of 0.19-0.51 μM. The compound inhibited tubulin polymerization and disrupted the microtubule network, leading to G2/M phase arrest. Furthermore, compound 12 induced ROS production and malfunction of mitochondrial membrane potential. Compound 12 led to cancer cells apoptosis in a dose-dependent manner. Western blot analysis showed that compound 12 induced up-regulation of p21 and affected the expression of cell cycle-related proteins. The binding mode was also probed by molecular docking.
PMID: 30635972 [PubMed - as supplied by publisher]
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Modeling Long ncRNA-Mediated Regulation in the Mammalian Cell Cycle.
Methods Mol Biol. 2019;1912:427-445
Authors: Rabajante JF, Del Rosario RCH
Abstract Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. They have recently gained widespread attention due to the finding that tens of thousands of lncRNAs reside in the human genome, and due to an increasing number of lncRNAs that are found to be associated with disease. Some lncRNAs, including disease-associated ones, play different roles in regulating the cell cycle. Mathematical models of the cell cycle have been useful in better understanding this biological system, such as how it could be robust to some perturbations and how the cell cycle checkpoints could act as a switch. Here, we discuss mathematical modeling techniques for studying lncRNA regulation of the mammalian cell cycle. We present examples on how modeling via network analysis and differential equations can provide novel predictions toward understanding cell cycle regulation in response to perturbations such as DNA damage.
PMID: 30635904 [PubMed - in process]
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Chk1-mediated Cdc25A degradation as a critical mechanism for normal cell-cycle progression.
J Cell Sci. 2019 Jan 11;:
Authors: Goto H, Natsume T, Kanemaki MT, Kaito A, Wang S, Gabazza EC, Inagaki M, Mizoguchi A
Abstract Chk1 is an evolutionally conserved protein kinase that transduces checkpoint signals from ATR to Cdc25A during DNA damage response (DDR). In mammals, Chk1 also controls cellular proliferation even in the absence of exogenous DNA damage. However, little is known about how Chk1 regulates unperturbed cell-cycle progression, and how this effect under physiological conditions differs from its regulatory role in DDR. Here, we have established near-diploid HCT116 cell lines containing endogenous Chk1 protein tagged with a minimum auxin-inducible degron (mAID) using a CRISPR/Cas9-based gene editing. Establishment of these cells enabled us to induce specific and rapid depletion of the endogenous Chk1 protein, which resulted in aberrant accumulation of DNA damage factors that induced cell-cycle arrest at S or G2 phase. Cdc25A stabilized upon Chk1 depletion before the accumulation of DNA damage factors. Simultaneous depletion of Chk1 and Cdc25A partially suppressed the defects caused by Chk1 single depletion. These results indicate that, similar to its function in DDR, Chk1 controls normal cell-cycle progression mainly by inducing Cdc25A degradation.
PMID: 30635443 [PubMed - as supplied by publisher]
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ΔNp63α modulates phosphorylation of p38 MAP kinase in regulation of cell cycle progression and cell growth.
Biochem Biophys Res Commun. 2019 Jan 08;:
Authors: Wang L, Xia W, Chen H, Xiao ZX
Abstract p53-related p63 plays a critical role in regulation of cell proliferation, survival and cell differentiation. Dysregulation of p63 functions results in a disruption of a variety of normal biological processes, including stem cell biology, embryonic development, aging and tumorigenesis. ΔNp63α, a predominantly expressed p63 protein isoform in epithelial cells, plays a crucial role in regulation of cell cycle progression and cell growth. p38 MAP kinases (p38MAPK) are the members of mitogen-activated protein kinases family and are critical in regulation of cell survival in response to stress signals. In this study, we show that ectopic expression of ΔNp63α inhibited phosphorylation of p38MAPK. Acute knockdown of p63 led to a significant upregulation of p38MAPK phosphorylation, resulting in increased p21cip1/waf1 expression, reduced phosphorylation of retinoblastoma protein (RB), cell cycle G1 arrest and cell growth retardation. Restoration of ΔNp63α expression reversed cell cycle arrest and growth inhibition induced by p63 ablation. Pharmacological inhibition of p38MAPK significantly suppressed ΔNp63α ablation-induced cell cycle G1/S arrest. In addition, MAP Kinase Phosphatase 3 (MKP3) was responsible for ΔNp63α-mediated regulation of p38MAPK phosphorylation. Together, these results suggest that ΔNp63α-MPK3-p38MAPK signaling pathway plays an important role in cell cycle progression and cell growth.
PMID: 30635119 [PubMed - as supplied by publisher]
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New Oxidovanadium(IV) Coordination Complex Containing 2-Methylnitrilotriacetate Ligands Induces Cell Cycle Arrest and Autophagy in Human Pancreatic Ductal Adenocarcinoma Cell Lines.
Int J Mol Sci. 2019 Jan 10;20(2):
Authors: Kowalski S, Wyrzykowski D, Hac S, Rychlowski M, Radomski MW, Inkielewicz-Stepniak I
Abstract Pancreatic cancer is characterized by one of the lowest five-year survival rates. In search for new treatments, some studies explored several metal complexes as potential anticancer drugs. Therefore, we investigated three newly synthesized oxidovanadium(IV) complexes with 2-methylnitrilotriacetate (bcma3-), N-(2-carbamoylethyl)iminodiacetate (ceida3-) and N-(phosphonomethyl)-iminodiacetate (pmida4-) ligands as potential anticancer compounds using pancreatic cancer cell lines. We measured: Cytotoxicity using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), neutral red (NR) and lactate dehydrogenase (LDH) assay; antiproliferative activity by bromodeoxyuridine BrdU assay; reactive oxygen species (ROS) generation and cell cycle analysis by flow cytometry; protein level by Western blot and cellular morphology by confocal laser scanning microscopy. The results showed that these oxidovanadium(IV) complexes were cytotoxic on pancreatic cancer cells (PANC-1 and MIA PaCa2), but not on non-tumor human immortalized pancreas duct epithelial cells (hTERT-HPNE) over the concentration range of 10⁻25 μM, following 48 h incubation. Furthermore, molecular mechanisms of cytotoxicity of [4-NH₂-2-Me(Q)H][VO(bcma)(H₂O)]2H₂O (T1) were dependent on antiproliterative activity, increased ROS generation, cell cycle arrest in G2/M phase with simultaneous triggering of the p53/p21 pathway, binucleation, and induction of autophagy. Our study indicates that oxidovanadium(IV) coordination complexes containing 2-methylnitrilotriacetate ligand are good candidates for preclinical development of novel anticancer drugs targeting pancreatic cancer.
PMID: 30634697 [PubMed - in process]
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Abstract Senescence is a stable cell cycle arrest that is either tumor suppressive or tumor promoting depending on context. Epigenetic changes such as histone methylation are known to affect both the induction and suppression of senescence by altering expression of genes that regulate the cell cycle and the senescence-associated secretory phenotype. A conserved group of proteins containing a Jumonji C (JmjC) domain alter chromatin state, and therefore gene expression, by demethylating histones. Here, we will discuss what is currently known about JmjC demethylases in the induction of senescence, and how these enzymes suppress senescence to contribute to tumorigenesis.
PMID: 30634491 [PubMed]
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Current Treatment Options in Gastroenteropancreatic Neuroendocrine Carcinoma.
Oncologist. 2019 Jan 11;:
Authors: Thomas KEH, Voros BA, Boudreaux JP, Thiagarajan R, Woltering EA, Ramirez RA
Abstract Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEPNECs) are a rare neoplasm with a bleak prognosis. Currently there are little prospective data available for optimal treatment. This review discusses the current available regimens and the future direction for the treatment of GEPNECs. Treatment plans for GEPNECs are often adapted from those devised for small cell lung cancer; however, differences in these malignancies exist, and GEPNECs require their own treatment paradigms. As such, current first-line treatment for GEPNECs is platinum-based chemotherapy with etoposide. Studies show that response rate and overall survival remain comparable between cisplatin and carboplatin versus etoposide and irinotecan; however, prognosis remains poor, and more efficacious therapy is needed to treat this malignancy. Additional first-line and second-line treatment options beyond platinum-based chemotherapy have also been investigated and may offer further treatment options, but again with suboptimal outcomes. Recent U.S. Food and Drug Administration approval of peptide receptor radionuclide therapy in low- and intermediate-grade neuroendocrine tumors may open the door for further research in its usefulness in GEPNECs. Additionally, the availability of checkpoint inhibitors lends promise to the treatment of GEPNECs. This review highlights the lack of large, prospective studies that focus on the treatment of GEPNECs. There is a need for randomized control trials to elucidate optimal treatment regimens specific to this malignancy. IMPLICATIONS FOR PRACTICE: There are limited data available for the treatment of poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEPNECs) because of the rarity of this malignancy. Much of the treatment regimens used in practice today come from research in small cell lung cancer. Given the poor prognosis of GEPNECs, it is necessary to have treatment paradigms specific to this malignancy. The aim of this literature review is to summarize the available first- and second-line GEPNEC therapy, outline future treatments, and highlight the vast gap in the literature.
PMID: 30635447 [PubMed - as supplied by publisher]
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Autophagy inhibition to augment mTOR inhibition: A phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma.
Clin Cancer Res. 2019 Jan 11;:
Authors: Haas NB, Appleman LJ, Stein M, Redlinger M, Wilks M, Xu X, Onorati A, Kalavacharla A, Kim T, Zhen CJ, Kadri S, Segal JP, Gimotty PA, Davis LE, Amaravadi RK
Abstract Purpose Everolimus inhibits the mechanistic target of rapamycin (mTOR), activating cytoprotective autophagy. Hydroxychloroquine (HCQ) inhibits autophagy. Based on preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and HCQ, to determine its safety and activity in patients with clear cell renal carcinoma (ccRCC). Experimental Design Three centers conducted a phase I/II trial of everolimus 10 mg daily and HCQ in patients with advanced ccRCC. The objectives were to determine the maximum tolerated dose of HCQ with daily everolimus, and to estimate the rate of 6 month progression-free survival (PFS) in ccRCC patients receiving everolimus/HCQ after 1-3 prior treatment regimens. Correlative studies to identify patient subpopulations that achieved the most benefit included population pharmacokinetics, measurement of autophagosomes by electron microscopy and next generation tumor sequencing. Results No DLT was observed in the phase I trial. The recommended phase II dose of HCQ 600 mg bid with everolimus was identified. Disease control (Stable disease (SD) + partial response (PR)) occurred in 22/33 (67%) evaluable patients. Partial response was observed in 2/33 patients (6%). PFS ≥6 months was achieved in 15/33 (45%) of patients who achieved disease control. Conclusion Combined HCQ 600mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6 month PFS rate was met. HCQ is a tolerable autophagy inhibitor in future RCC or other trials.
PMID: 30635337 [PubMed - as supplied by publisher]
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Second re-irradiation: A delicate balance between safety and efficacy.
Phys Med. 2019 Jan 08;:
Authors: Nieder C
Abstract Except for straightforward palliative indications such as painful bone metastases, re-irradiation is often characterized by a narrow therapeutic window and the potential for decreased efficacy and increased toxicity, especially if the cumulative total dose from both courses is high. Second re-irradiations tend to pose even bigger challenges and are thus offered in a restrictive manner to highly selected patients on a case-by-case basis. Normal tissue dose constraints are still an area of active investigation. Nevertheless, examples of potentially useful indications have been published. The present review briefly summarizes areas of uncertainty and opportunities for future research. If evidence-based concepts with acceptable side effect profiles can be developed, an increasing number of patients may benefit from additional radiotherapy to previously exposed target volumes.
PMID: 30635148 [PubMed - as supplied by publisher]
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Statin use and breast cancer survival - a Swedish nationwide study.
BMC Cancer. 2019 Jan 11;19(1):54
Authors: Borgquist S, Broberg P, Tojjar J, Olsson H
Abstract BACKGROUND: A sizeable body of evidence suggests that statins can cease breast cancer progression and prevent breast cancer recurrence. The latest studies have, however, not been supportive of such clinically beneficial effects. These discrepancies may be explained by insufficient power. This considerably sized study investigates the association between both pre- and post-diagnostic statin use and breast cancer outcome. METHODS: A Swedish nation-wide retrospective cohort study of 20,559 Swedish women diagnosed with breast cancer (July 1st, 2005 through 2008). Dispensed statin medication was identified through the Swedish Prescription Registry. Breast cancer related death information was obtained from the national cause-of-death registry until December 31st, 2012. Cox regression models yielded hazard ratios (HR) and 95% confidence intervals (CI) regarding associations between statin use and breast cancer-specific and overall mortality. RESULTS: During a median follow-up time of 61.6 months, a total of 4678 patients died, of which 2669 were considered breast cancer related deaths. Compared to non- or irregular use, regular pre-diagnostic statin use was associated with lower risk of breast cancer related deaths (HR = 0.77; 95% CI 0.63-0.95, P = 0.014). Similarly, post-diagnostic statin use compared to non-use was associated with lower risk of breast cancer related deaths (HR = 0.83; 95% CI 0.75-0.93, P = 0.001). CONCLUSION: This study supports the notion that statin use is protective regarding breast cancer related mortality in agreement with previous Scandinavian studies, although less so with studies in other populations. These disparities should be further investigated to pave the way for future randomized clinical trials investigating the role of statins in breast cancer.
PMID: 30634941 [PubMed - in process]
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Paroxetine Induces Apoptosis of Human Breast Cancer MCF-7 Cells through Ca2+-and p38 MAP Kinase-Dependent ROS Generation.
Cancers (Basel). 2019 Jan 09;11(1):
Authors: Cho YW, Kim EJ, Nyiramana MM, Shin EJ, Jin H, Ryu JH, Kang KR, Lee GW, Kim HJ, Han J, Kang D
Abstract Depression is more common in women with breast cancer than the general population. Selective serotonin reuptake inhibitors (SSRIs), a group of antidepressants, are widely used for the treatment of patients with depression and a range of anxiety-related disorders. The association between the use of antidepressant medication and breast cancer is controversial. In this study, we investigated whether and how SSRIs induce the death of human breast cancer MCF-7 cells. Of the antidepressants tested in this study (amitriptyline, bupropion, fluoxetine, paroxetine, and tianeptine), paroxetine most reduced the viability of MCF-7 cells in a time-and dose-dependent manner. The exposure of MCF-7 cells to paroxetine resulted in mitochondrion-mediated apoptosis, which is assessed by increase in the number of cells with sub-G1 DNA content, caspase-8/9 activation, poly (ADP-ribose) polymerase cleavage, and Bax/Bcl-2 ratio and a reduction in the mitochondrial membrane potential. Paroxetine increased a generation of reactive oxygen species (ROS), intracellular Ca2+ levels, and p38 MAPK activation. The paroxetine-induced apoptotic events were reduced by ROS scavengers and p38 MAPK inhibitor, and the paroxetine's effect was dependent on extracellular Ca2+ level. Paroxetine also showed a synergistic effect on cell death induced by chemotherapeutic drugs in MCF-7 and MDA-MB-231 cells. Our results showed that paroxetine induced apoptosis of human breast cancer MCF-7 cells through extracellular Ca2+-and p38 MAPK-dependent ROS generation. These results suggest that paroxetine may serve as an anticancer adjuvant to current cancer therapies for breast cancer patients with or without depression.
PMID: 30634506 [PubMed]
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Abstract Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been made to try and overcome this hypoxia. These approaches involve improving oxygen availability, radio-sensitizing or killing the hypoxic cells, or utilizing high LET (linear energy transfer) radiation leading to a lower OER (oxygen enhancement ratio). Interestingly, hyperthermia (heat treatments of 39⁻45 °C) induces many of these effects. Specifically, it increases blood flow thereby improving tissue oxygenation, radio-sensitizes via DNA repair inhibition, and can kill cells either directly or indirectly by causing vascular damage. Combining hyperthermia with low LET radiation can even result in anti-tumor effects equivalent to those seen with high LET. The various mechanisms depend on the time and sequence between radiation and hyperthermia, the heating temperature, and the time of heating. We will discuss the role these factors play in influencing the interaction between hyperthermia and radiation, and summarize the randomized clinical trials showing a benefit of such a combination as well as suggest the potential future clinical application of this combination.
PMID: 30634444 [PubMed]
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On the Choice of the Extracellular Vesicles for Therapeutic Purposes.
Int J Mol Sci. 2019 Jan 09;20(2):
Authors: Campanella C, Caruso Bavisotto C, Logozzi M, Marino Gammazza A, Mizzoni D, Cappello F, Fais S
Abstract Extracellular vesicles (EVs) are lipid membrane vesicles released by all human cells and are widely recognized to be involved in many cellular processes, both in physiological and pathological conditions. They are mediators of cell-cell communication, at both paracrine and systemic levels, and therefore they are active players in cell differentiation, tissue homeostasis, and organ remodeling. Due to their ability to serve as a cargo for proteins, lipids, and nucleic acids, which often reflects the cellular source, they should be considered the future of the natural nanodelivery of bio-compounds. To date, natural nanovesicles, such as exosomes, have been shown to represent a source of disease biomarkers and have high potential benefits in regenerative medicine. Indeed, they deliver both chemical and bio-molecules in a way that within exosomes drugs are more effective that in their exosome-free form. Thus, to date, we know that exosomes are shuttle disease biomarkers and probably the most effective way to deliver therapeutic molecules within target cells. However, we do not know exactly which exosomes may be used in therapy in avoiding side effects as well. In regenerative medicine, it will be ideal to use autologous exosomes, but it seems not ideal to use plasma-derived exosomes, as they may contain potentially dangerous molecules. Here, we want to present and discuss a contradictory relatively unmet issue that is the lack of a general agreement on the choice for the source of extracellular vesicles for therapeutic use.
PMID: 30634425 [PubMed - in process]
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Population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy.
J Clin Pharm Ther. 2019 Jan 12;:
Authors: Chen CY, Zhou Y, Cui YM, Yang T, Zhao X, Wu Y
Abstract WHAT IS KNOWN AND OBJECTIVES: Oxcarbazepine (OXC) is a widely used antiepileptic drug whose effect mainly depends on its active metabolite 10-hydroxycarbazepine (MHD). This study established a population pharmacokinetic (PPK) model of MHD in Chinese children with epilepsy and conducted a dosage simulation in order to provide support for individualized OXC treatment. METHODS: Ninety-one plasma sampling points from 88 paediatric patients were retrospective collected. MHD concentrations were detected, and patients' clinical data were recorded. PPK analysis was performed using a non-linear, mixed-effect modelling approach. The goodness-of-fit (GOF) plots, bootstrap method, prediction-corrected visual predictive check (pcVPC) and normalized prediction distribution errors (NPDE) were performed to evaluate the final model. External model validations by an independent group of paediatric patients (10 patients, 10 blood samples) were conducted. The steady-state trough concentrations of MHD were determined by Monte Carlo simulations for doses ranging from 8 to 60 mg/kg/day. RESULTS: A one-compartment model with first-order elimination successfully described the data. The typical values for MHD clearance (CL/F), distribution volume (V/F) and absorption rate constant (Ka) were 3.25 L/h/70 kg, 151.41 L/70 kg and 0.598 h-1 , respectively. The CL/F and V/F of MHD were related to body weight (WT) via an empirical allometric model. Internal and external validations demonstrated a good predictability of the final model. Monte Carlo simulations revealed that for most paediatric patients, a dosing regimen of 20-30 mg/kg/d bid maybe sufficient to reach MHD therapeutic range. WHAT IS NEW AND CONCLUSION: A PPK model of MHD in Chinese paediatric patients was successfully established. A priori dosing guideline was proposed considering WT and MHD plasma concentrations, providing a basis for OXC dosage calculations and adjustments in Chinese epileptic children.
PMID: 30636182 [PubMed - as supplied by publisher]
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Prevalence of sleep-disordered breathing after stroke and TIA: A meta-analysis.
Neurology. 2019 Jan 11;:
Authors: Seiler A, Camilo M, Korostovtseva L, Haynes AG, Brill AK, Horvath T, Egger M, Bassetti CL
Abstract OBJECTIVE: To perform a systematic review and meta-analysis on the prevalence of sleep-disordered breathing (SDB) after stroke. METHODS: We searched PubMed, Embase (Ovid), the Cochrane Library, and CINAHL (from their commencements to April 7, 2017) for clinical studies reporting prevalence and/or severity of SDB after stroke or TIA. Only sleep apnea tests performed with full polysomnography and diagnostic devices of the American Academy of Sleep Medicine categories I-IV were included. We conducted random-effects meta-analysis. PROSPERO registration number: CRD42017072339. RESULTS: The initial search identified 5,211 publications. Eighty-nine studies (including 7,096 patients) met inclusion criteria. Fifty-four studies were performed in the acute phase after stroke (after less than 1 month), 23 studies in the subacute phase (after 1-3 months), and 12 studies in the chronic phase (after more than 3 months). Mean apnea-hypopnea index was 26.0/h (SD 21.7-31.2). Prevalence of SDB with apnea-hypopnea index greater than 5/h and greater than 30/h was found in 71% (95% confidence interval 66.6%-74.8%) and 30% (95% confidence interval 24.4%-35.5%) of patients, respectively. Severity and prevalence of SDB were similar in all examined phases after stroke, irrespective of the type of sleep apnea test performed. Heterogeneity between studies (I 2) was mostly high. CONCLUSION: The high prevalence of SDB after stroke and TIA, which persists over time, is important in light of recent studies reporting the (1) feasibility and (2) efficacy of SDB treatment in this clinical setting.
PMID: 30635478 [PubMed - as supplied by publisher]
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To investigate the growth of primary human gingival epithelial (HGE) cells on polymer‐infiltrated ceramic network (PICN) material (Vita Enamic) with different surface roughnesses.
Materials and Methods
PICN material specimens were polished with either silica carbide paper (grit‐polished) or the manufacturer's polishing wheels (wheel‐polished), and the surface roughness (Ra) measured. HGE cells were seeded and grown for 1, 3, or 6 days. Growth on tissue culture plastic was used as a control. Non‐linear regression analysis was used to examine the effect of surface roughness on cell growth.
Results
HGE cell growth on tissue culture plastic fitted an exponential growth model over the 6‐day experimental period (R2 = 0.966). Through day 6, cell density on PICN decreased with increasing surface roughness, with a fit to an exponential decay model (R2 = 0.666). A threshold Ra value of 0.254 μm (95% CI 0.177‐0.332) was determined as an upper limit for exponential growth. Cell growth was greatest on the group of specimens with Ra value below 0.127μm. Specimens polished by the manufacturer's method produced surface roughness of 0.118 μm and below.
Conclusions
PICN material polished to a smooth surface (Ra < 0.254 μm) resulted in exponential growth of HGE cell growth compared to rough surfaces. Polishing PICN material as smooth as possible (below a Ra of 0.127 μm) was found to maximize epithelial cell growth on the PICN material surface. The manufacturer's polishing method achieved a sufficiently smooth surface. These results are contrary to previous research regarding surface roughness of transgingival implant restoration components. The study results suggest that smoother restorative material surfaces could improve peri‐implant soft tissue health.
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Natural history, prevalence, and pathophysiology of cervical spondylotic myelopathy Highly accessed articlep. 5
Gomatam Raghavan Vijay Kumar, Dibyendu Kumar Ray, Rupant Kumar Das
DOI:10.4103/isj.isj_48_18
This study is a narrative review performed to summarize the current knowledge about the epidemiology, natural history and pathogenesis of cervical spondylotic myelopathy (CSM). A comprehensive search was undertaken to look at all available articles between January 1, 1956 to May 1, 2018, on PubMed and the Cochrane Collaboration Library. The natural history of CSM is variable. The main determinants of the clinical course of CSM are the extent of neurological impairment, age, cervical instability, abnormalities of cord conduction, canal diameter, congenitally stenotic spinal canal and the extent of involvement and tract disruption on diffusion tensor imaging (DTI) imaging. There is little data on the true incidence and prevalence of CSM across the globe and none from India. The pathoanatomic basis of CSM is cord compression, either dynamic or static. The biological events that are thought to play a significant role in the development of CSM are ischemia, derangement of the blood-spinal cord barrier, chronic neuronal inflammation, and apoptosis. Emerging knowledge about the molecular biology holds promise for potential intervention, both for prevention and for cure, of this common and debilitating condition.
Clinical spectrum and importance of evaluation systems in degenerative cervical myeloradiculopathyp. 13
Ganesh Swaminathan, Vetrivel Muralidharan, Baylis Vivek Joseph
DOI:10.4103/isj.isj_61_18
Degenerative cervical myelopathy includes facet joint arthropathy and/or intervertebral disc prolapse, as well as aberration (hypertrophy, calcification, or ossification) in the ligamentum flavum, and/or posterior longitudinal ligament. Cervical spondylotic myelopathy and ossification of posterior longitudinal ligament are two major conditions under this spectrum. Patients with degenerative changes of the cervical spine can present with wide spectrum of symptoms and signs ranging from axial neck pain, radiculopathy or myelopathy. A combination of history, physical examination, and provocative tests such as Spurling's sign, shoulder abduction test, neck distraction test, Valsalva maneuver, Elvey's upper limb tension/brachial plexus tension test increase the likelihood of diagnosis of cervical radiculopathy. Myelopathy can manifest in the early stage as subtle changes in the upper limb dexterity or mild walking difficulty and in late stage with severe spasticity and flexor spasms. Clinicians are increasingly using quantitative or semi-quantitative scales of neurological impairment. However, there is no gold standard evaluation systems that can reliably assess disease severity.
Anterior surgical options for cervical spondylotic myelopathyp. 33
Andrei Fernandes Joaquim, John Alex Sielatycki, K Daniel Riew
DOI:10.4103/isj.isj_39_18
Cervical spondylotic myelopathy (CSM) is one of the most common among causes of spinal cord dysfunction worldwide. In this article, we provide a broad narrative review of the options to treat CSM from an anterior approach to the cervical spine. Anterior procedures are effective and safe, especially for one or two level disease (although can be used up to 7-8 levels). This approach can be used in patients with lordotic, neutral, or kyphotic cervical spine alignment and provide excellent access for direct neural decompression. The most common adverse effects of anterior cervical operations are dysphagia and dysphonia, but fortunately, these are mild and transient in the majority of cases. Severe complications, such as vertebral arterial injury, spinal cord injury or airway compromise, are rare but must be taken into consideration, especially when additional risk factors are present (multilevel procedures, revision surgeries, older, and infirm patients). The primary anterior cervical procedures for treating CSM are anterior cervical discectomy and fusion (ACDF), anterior cervical corpectomy and fusion (ACCF), oblique cervical corpectomy, and cervical disc arthroplasty. A combination (hybrid) of ACDF and ACCF is also utilized as an option to allow for wide decompression, deformity correction, and provide more surface area of exposed, and bleeding cancellous bone. More recently, the senior author (KDR) has utilized a hemi-corpectomy and fusion hybrid technique which will be described in this text. Advantages and disadvantages of each of these options are discussed in detail, as well as the need for posterior instrumentation supplementation in selected patients; such as those with concomitant cervical deformity, poor bone quality, or those at risk for pseudarthrosis following multilevel arthrodeses. The management of patients with cervical spinal cord compression without myelopathy or with mild symptoms is also discussed.
Posterior surgical options for spondylotic cervical myelopathyp. 42
Shankar Acharya, Nikhil Jain
DOI:10.4103/isj.isj_57_18
Cervical spondylotic myelopathy (CSM) is a common presentation in the middle-aged to elderly population. The cause of myelopathy is multifactorial, and cervical spondylosis is the most common cause. This review looks into the treatment options, timing of the surgery, and the advantages and disadvantages of the various posterior approaches for multilevel spondylotic myelopathy. CSM is a disabling disorder that should be addressed in its early phases. There are limited surgical options available, and each procedure has its advantages and disadvantages. Since the neurological and functional outcomes are the same for all well-performed decompressions, the choice of surgical approach depends on various other factors. Posterior approaches are good for multilevel disease as they make the surgery simpler, shorter and with reduced complications in comparison to multilevel anterior surgeries.
: Etiology, prevalence, progression, and surgical strategiesp. 52
Yoshiharu Kawaguchi
DOI:10.4103/isj.isj_41_18
Ossification of the posterior longitudinal ligament (OPLL) is characterized by replacement of the ligamentous tissue by ectopic new bone formation. OPLL often causes narrowing of the spinal canal and has been recognized as a cause of cervical myelopathy and/or radiculopathy. Although a clear inheritance of OPLL has not been identified, there is a strong genetic background for OPLL. A recent genome-wide association study using all Japan cohort reported that there were 6 susceptible loci for OPLL. In addition, there were several studies to seek the biomarkers of OPLL. OPLL is frequently found in the cervical spine. However, 53.4% had OPLL not only in the cervical spine, but also in other spinal regions in patients with cervical OPLL. Further, 65.2% with cervical OPLL had ossification of the ligamentum flavum (OLF) especially at the levels of the thoracic and the lumbar spine. There is no effective conservative treatment. Surgical decompression is considered in patients with severe and/or progressive myelopathy. Early surgical decompression of the spinal cord is recommended in patients with apparent myelopathy. Operative methods are divided into two procedures, anterior decompressive surgery and posterior decompressive surgery. The choice of the surgical procedure is determined according to several factors, such as local pathology of OPLL and spinal alignment.
K Venugopal Menon, Hood Al Saqri, Renjit Kumar, Maruti Kambali DOI:10.4103/isj.isj_8_18
Background: Wide exposure to the anterior part of the upper cervical spine is difficult due to anatomical constraints. The Labio-Mandibulo-Glossotomy (LMG) approach is considered a difficult approach with high morbidity. The objective of this study is to describe the authors experience with the approach and it's outcomes in six cases and offer tips and pearls to the surgical access. Methods: This is a retrospective review of a small series of six cases that were operated for upper cervical lesions by the LMG approach. Two had mandible fractures that needed fixation and in the others osteotomy of the mandible was performed. The patients were followed up for minimum two years or death (in malignancy). We specifically looked for cosmetic or functional problems related to osteotomy, glossotomy, and, hospital and ICU stay duration. Surgical access is described in detail. Results: The hospital stay was similar to other major spine trauma or tumour surgeries at our center (median 14 days) and mean ICU stay 2.8 days. There were no long-term issues related to the access. Several tips and tricks are offered to minimize intra and post-operative problems. Conclusions: The LMG approach, though apparently formidable, is quite a safe and simple procedure with few residual complications.
This study is a narrative review performed to summarize the current knowledge about the epidemiology, natural history and pathogenesis of cervical spondylotic myelopathy (CSM). A comprehensive search was undertaken to look at all available articles between January 1, 1956 to May 1, 2018, on PubMed and the Cochrane Collaboration Library. The natural history of CSM is variable. The main determinants of the clinical course of CSM are the extent of neurological impairment, age, cervical instability, abnormalities of cord conduction, canal diameter, congenitally stenotic spinal canal and the extent of involvement and tract disruption on diffusion tensor imaging (DTI) imaging. There is little data on the true incidence and prevalence of CSM across the globe and none from India. The pathoanatomic basis of CSM is cord compression, either dynamic or static. The biological events that are thought to play a significant role in the development of CSM are ischemia, derangement of the blood-spinal cord barrier, chronic neuronal inflammation, and apoptosis. Emerging knowledge about the molecular biology holds promise for potential intervention, both for prevention and for cure, of this common and debilitating condition.
Clinical spectrum and importance of evaluation systems in degenerative cervical myeloradiculopathy
p. 13
Ganesh Swaminathan, Vetrivel Muralidharan, Baylis Vivek Joseph DOI:10.4103/isj.isj_61_18
Degenerative cervical myelopathy includes facet joint arthropathy and/or intervertebral disc prolapse, as well as aberration (hypertrophy, calcification, or ossification) in the ligamentum flavum, and/or posterior longitudinal ligament. Cervical spondylotic myelopathy and ossification of posterior longitudinal ligament are two major conditions under this spectrum. Patients with degenerative changes of the cervical spine can present with wide spectrum of symptoms and signs ranging from axial neck pain, radiculopathy or myelopathy. A combination of history, physical examination, and provocative tests such as Spurling's sign, shoulder abduction test, neck distraction test, Valsalva maneuver, Elvey's upper limb tension/brachial plexus tension test increase the likelihood of diagnosis of cervical radiculopathy. Myelopathy can manifest in the early stage as subtle changes in the upper limb dexterity or mild walking difficulty and in late stage with severe spasticity and flexor spasms. Clinicians are increasingly using quantitative or semi-quantitative scales of neurological impairment. However, there is no gold standard evaluation systems that can reliably assess disease severity.
Rajavelu Rajesh, Shanmuganathan Rajasekaran, Sri Vijayanand DOI:10.4103/isj.isj_63_18
This is a narrative review. The objective of this study is to provide an overview on the imaging modalities and their utilization in cervical myelopathy (CM). Using PubMed, studies published on the "imaging modalities in CM," "cervical spondylotic myelopathy (CSM) imaging," "computed tomography (CT) and magnetic resonance imaging (MRI) in CM," "imaging in ossified posterior longitudinal ligament (OPLL)," "dural ossification in OPLL," "diffusion tensor imaging (DTI) in CSM," and "dynamic MRI, functional MRI, and magnetic resonance spectroscopy (MRS) in CSM" were evaluated. The review addresses the evaluation of CM with various imaging modalities ranging from radiographs, CT, and MRI to advanced imaging techniques such as DTI and MRS. Each investigation contributes specific detail to the disease process in a different dimension. Specific parameters for CSM and OPLL, and their influence on outcome are discussed. Imaging in CM plays an important role in analyzing the cause of myelopathy, defining the level of the lesion, parameters to assess the time of intervention and to predict the outcome.
Anterior surgical options for cervical spondylotic myelopathy
p. 33
Andrei Fernandes Joaquim, John Alex Sielatycki, K Daniel Riew DOI:10.4103/isj.isj_39_18
Cervical spondylotic myelopathy (CSM) is one of the most common among causes of spinal cord dysfunction worldwide. In this article, we provide a broad narrative review of the options to treat CSM from an anterior approach to the cervical spine. Anterior procedures are effective and safe, especially for one or two level disease (although can be used up to 7-8 levels). This approach can be used in patients with lordotic, neutral, or kyphotic cervical spine alignment and provide excellent access for direct neural decompression. The most common adverse effects of anterior cervical operations are dysphagia and dysphonia, but fortunately, these are mild and transient in the majority of cases. Severe complications, such as vertebral arterial injury, spinal cord injury or airway compromise, are rare but must be taken into consideration, especially when additional risk factors are present (multilevel procedures, revision surgeries, older, and infirm patients). The primary anterior cervical procedures for treating CSM are anterior cervical discectomy and fusion (ACDF), anterior cervical corpectomy and fusion (ACCF), oblique cervical corpectomy, and cervical disc arthroplasty. A combination (hybrid) of ACDF and ACCF is also utilized as an option to allow for wide decompression, deformity correction, and provide more surface area of exposed, and bleeding cancellous bone. More recently, the senior author (KDR) has utilized a hemi-corpectomy and fusion hybrid technique which will be described in this text. Advantages and disadvantages of each of these options are discussed in detail, as well as the need for posterior instrumentation supplementation in selected patients; such as those with concomitant cervical deformity, poor bone quality, or those at risk for pseudarthrosis following multilevel arthrodeses. The management of patients with cervical spinal cord compression without myelopathy or with mild symptoms is also discussed.
Cervical spondylotic myelopathy (CSM) is a common presentation in the middle-aged to elderly population. The cause of myelopathy is multifactorial, and cervical spondylosis is the most common cause. This review looks into the treatment options, timing of the surgery, and the advantages and disadvantages of the various posterior approaches for multilevel spondylotic myelopathy. CSM is a disabling disorder that should be addressed in its early phases. There are limited surgical options available, and each procedure has its advantages and disadvantages. Since the neurological and functional outcomes are the same for all well-performed decompressions, the choice of surgical approach depends on various other factors. Posterior approaches are good for multilevel disease as they make the surgery simpler, shorter and with reduced complications in comparison to multilevel anterior surgeries.
Ossification of the posterior longitudinal ligament: Etiology, prevalence, progression, and surgical strategies
p. 52
Yoshiharu Kawaguchi DOI:10.4103/isj.isj_41_18
Ossification of the posterior longitudinal ligament (OPLL) is characterized by replacement of the ligamentous tissue by ectopic new bone formation. OPLL often causes narrowing of the spinal canal and has been recognized as a cause of cervical myelopathy and/or radiculopathy. Although a clear inheritance of OPLL has not been identified, there is a strong genetic background for OPLL. A recent genome-wide association study using all Japan cohort reported that there were 6 susceptible loci for OPLL. In addition, there were several studies to seek the biomarkers of OPLL. OPLL is frequently found in the cervical spine. However, 53.4% had OPLL not only in the cervical spine, but also in other spinal regions in patients with cervical OPLL. Further, 65.2% with cervical OPLL had ossification of the ligamentum flavum (OLF) especially at the levels of the thoracic and the lumbar spine. There is no effective conservative treatment. Surgical decompression is considered in patients with severe and/or progressive myelopathy. Early surgical decompression of the spinal cord is recommended in patients with apparent myelopathy. Operative methods are divided into two procedures, anterior decompressive surgery and posterior decompressive surgery. The choice of the surgical procedure is determined according to several factors, such as local pathology of OPLL and spinal alignment.
Clinical predictors of complications and outcomes in degenerative cervical myeloradiculopathy
p. 59
Jamie R F Wilson, Fan Jiang, Michael G Fehlings DOI:10.4103/isj.isj_60_18
Degenerative cervical myelopathy (DCM) is the leading cause of adult spinal cord dysfunction worldwide, and surgical decompression remains the mainstay treatment to arrest the progression of neurological deterioration. A number of clinical factors can predict and influence the outcomes of surgery, including patient demographics, baseline myelopathy severity, duration of symptoms, imaging characteristics, and types of surgical approach. Understanding the influence and relationship of these factors on surgical outcomes allows the treating clinician the ability to provide the patient with realistic expectations when discussing surgical intervention for DCM.
The spine clinics – Cervical spondylotic myelopathy – Clinical scenarios
p. 68
Ankur Nanda, KR Renjith, Abhinandan Mallepally, C S Vishnu Prasath, Ajoy P Shetty DOI:10.4103/isj.isj_67_18
This section of the symposium deals with different case scenarios related to cervical spondylotic myelopathy (CSM) which in our daily clinical practice not only act as diagnostic challenges but also test our decision-making abilities. These cases have been handled by different experts and hence help the readers in providing a wider perspective to the problem of cervical myelopathy and its management. This section ends with comments by the authors on key takeaway points from each case scenario, and some literature supported recommendations for the management of CSM.
Cell-based treatment strategies for intervertebral disc degeneration: An overview on potentials and shortcomings
p. 81
Prasanthi Sampara, Rajkiran Reddy Banala, Satish Kumar Vemurit, AV Gurava Reddy, G P V Subbaiah DOI:10.4103/isj.isj_21_17
The intervertebral discs (IVDs) are the cushioning pads of fibrocartilage, which are immeasurably vital for the uprightness of vertebral column and for its function. IVD provides flexibility, tensile strength to the spine, and also cope up with varied types of biomechanical stresses. IVD degeneration (IVDD) is one of the musculoskeletal disorders mostly seen in older population, and it is the foremost cause of low back pain and consequences of IVDD are disc herniation, spinal stenosis, and degenerative lumbar scoliosis. Yet the therapeutic options are restricted and the treatments given remain unsatisfactory putting more economical burden on world's population. IVDD is considered as a multifactorial disorder, due to the involvement of factors such as genetic inheritance, alterations in cellular composition, and anabolic and catabolic reactions, which could initiate degenerative process in the IVD. However, our conception on IVD genesis and the etiopathology of IVDD have given us an opportunity for exploring and formulate appropriate therapies to tackle IVDD. The cell therapy gives scope for sustained matrix synthesis, controlled inflammation, and prevention of osteophyte formation in IVD. The present review focuses on the existing issues related to current therapeutic approaches and about latest evidence on cell therapy-based regeneration of IVD and maintaining the microenvironment of cellular matrix which holds a promise for future therapeutic applications.
The median labio-mandibulo-glossotomy approach to the upper cervical spine: A personal series and tips and pearls
p. 92
K Venugopal Menon, Hood Al Saqri, Renjit Kumar, Maruti Kambali DOI:10.4103/isj.isj_8_18
Background: Wide exposure to the anterior part of the upper cervical spine is difficult due to anatomical constraints. The Labio-Mandibulo-Glossotomy (LMG) approach is considered a difficult approach with high morbidity. The objective of this study is to describe the authors experience with the approach and it's outcomes in six cases and offer tips and pearls to the surgical access. Methods: This is a retrospective review of a small series of six cases that were operated for upper cervical lesions by the LMG approach. Two had mandible fractures that needed fixation and in the others osteotomy of the mandible was performed. The patients were followed up for minimum two years or death (in malignancy). We specifically looked for cosmetic or functional problems related to osteotomy, glossotomy, and, hospital and ICU stay duration. Surgical access is described in detail. Results: The hospital stay was similar to other major spine trauma or tumour surgeries at our center (median 14 days) and mean ICU stay 2.8 days. There were no long-term issues related to the access. Several tips and tricks are offered to minimize intra and post-operative problems. Conclusions: The LMG approach, though apparently formidable, is quite a safe and simple procedure with few residual complications.
A novel surgical technique for hydatid cyst involving cervicothoracic anterior epidural space
p. 99
Bharat R Dave, Degulmadi Devanand, Ganesh Deshmukh DOI:10.4103/isj.isj_17_18
Spinal hydatid cyst comprises <1% of the total cases of hydatid disease. There is very little literature on the involvement of anterior epidural space by hydatid cyst and its management. This report presents a unique presentation of spinal hydatidosis in cervicothoracic anterior epidural space and a novel technique in surgical management.
Sacral chordoma with degenerative spondylolisthesis and upper lumbar disc herniation
p. 102
Shakti A Goel, Hitesh N Modi, Yatin J Desai, Bhavin Patel DOI:10.4103/isj.isj_24_17
Sacral chordoma is a rare condition requiring multidisciplinary approach for management. Here, we report a 72-year-old male patient who was diagnosed with sacral chordoma with L2–L3 disc herniation and L5–S1 degenerative spondylolisthesis and L1 body fracture. The patient was first managed by discectomy L2–L3 with D12–L3 decompression and fixation. Sacral chordoma excision was done 10 months later. The chordoma was excised by anterior laparoscopic resection and mobilization of tissues from the tumor followed by posterior sacrectomy with L5–S1 decompression and extension of fixation in a single stage. Proline mesh was used to support the colon posteriorly. This was further complicated by proximal junction fracture due to fall which was further managed by proximal extension of the rod-screw construct. The patient became symptom free without any radiotherapy or chemotherapy and is able to walk independently, two years following the primary surgery without recurrence of tumor.
Alkaptonuria is a rare metabolic, autosomal recessive disorder caused by the deficiency of homogentisic acid oxidase and it is characterized by bluish-black discoloration of cartilages, skin (Ochronosis), degenerative changes in the articular, extra-articular cartilages, intervertebral disc, other tissues causing pain in the joints and spinal column. Although intervertebral disc degeneration is common in these patients, those presenting with symptoms severe enough to warrant surgery are rare. Only a few patients have been treated surgically. We present a case of alkaptonuria presenting with radiculopathy and lumbar disc herniation. The case presented demonstrates that although lumbar disc herniation is rare in alkaptonuria, it should be sought in such patients and surgical treatment yields good functional outcome.
