Neurogenic claudication resulting from focal hypertrophy of the ligamentum flavum in the lumbar spine due to ochronotic deposits has not been reported till date. The authors discuss one such case highlighting the pathogenesis, histological and radiological features. Salient features of management are also emphasized upon.
Alkaptonuria ; Hypertrophy ; Ligamentum Flavum ; Spinal Stenosis ; Spine

Background/Aims: Per-oral endoscopic myotomy (POEM) is an established treatment for achalasia. The technique of POEM is still evolving and the impact of length of esophageal myotomy on the outcomes of POEM is not known. In this study, we aim to compare the outcomes of short (3 cm) versus long (6 cm and above) esophageal myotomy in patients undergoing POEM for achalasia cardia. Methods: Consecutive patients with idiopathic achalasia (type I and II) were randomized to receive short (3 cm) or long esophageal myotomy (≥ 6 cm).Both groups were compared for clinical success, operative time, adverse events, and gastroesophageal reflux disease (GERD). Results: Seventy-one consecutive patients with type I and II achalasia underwent POEM with short (n = 34) or long (n = 37) esophageal myotomy techniques. Mean length of esophageal myotomy in short and long groups was 2.76 ± 0.41 and 7.97 ± 2.40, respectively (P < 0.001). Mean operative time was significantly shorter in short myotomy group (44.03 ± 13.78 minutes and 72.43 ± 27.28 minutes, P < 0.001). Clinical success was comparable in both arms at 1-year (Eckardt score 0.935 ± 0.929 vs 0.818 ± 0.983, P = 0.627).Improvement in objective parameters including integrated relaxation pressure and barium column height at 5 minutes was similar in both groups. GERD was detected in 50.88% patients with no significant difference in short and long myotomy groups (44.44% vs 56.67%, P = 0.431). Conclusions A short esophageal myotomy is non-inferior to long myotomy with regards to clinical success, adverse events, and GERD in cases with type I and II achalasia. Reduced operating duration favors short esophageal myotomy in these patients.

In our previous studies, we have demonstrated the association of certain variants of the thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), and thyroglobulin (TG) genes with congenital hypothyroidism. Herein, we explored the mechanistic basis for this association using different in silico tools. The mRNA 3'-untranslated region (3'-UTR) plays key roles in gene expression at the post-transcriptional level. In TSHR variants (rs2268477, rs7144481, and rs17630128), the binding affinity of microRNAs (miRs) (hsa-miR-154-5p, hsa-miR-376a-2-5p, hsa-miR-3935, hsa-miR-4280, and hsa-miR-6858-3p) to the 3'-UTR is disrupted, affecting post-transcriptional gene regulation. TPO and TG are the two key proteins necessary for the biosynthesis of thyroid hormones in the presence of iodide and H2O2. Reduced stability of these proteins leads to aberrant biosynthesis of thyroid hormones. Compared to the wild-type TPO protein, the p.S398T variant was found to exhibit less stability and significant rearrangements of intra-atomic bonds affecting the stoichiometry and substrate binding (binding energies, ΔG of wild-type vs. mutant: ‒15 vs. ‒13.8 kcal/mol; and dissociation constant, Kd of wild-type vs. mutant: 7.2E-12 vs. 7.0E-11 M). The missense mutations p.G653D and p.R1999W on the TG protein showed altered ΔG (0.24 kcal/mol and 0.79 kcal/mol, respectively). In conclusion, an in silico analysis of TSHR genetic variants in the 3'-UTR showed that they alter the binding affinities of different miRs. The TPO protein structure and mutant protein complex (p.S398T) are less stable, with potentially deleterious effects. A structural and energy analysis showed that TG mutations (p.G653D and p.R1999W) reduce the stability of the TG protein and affect its structure-functional relationship.

BACKGROUND/AIMS: High-resolution manometry (HRM) with pressure topography is used to subtype achalasia cardia, which has therapeutic implications. The aim of this study was to compare the clinical characteristics, manometric variables and treatment outcomes among the achalasia subtypes based on the HRM findings. METHODS: The patients who underwent HRM at the Asian Institute of Gastroenterology, Hyderabad between January 2008 and January 2009 were enrolled. The patients with achalasia were categorized into 3 subtypes: type I - achalasia with minimum esophageal pressurization, type II - achalasia with esophageal compression and type III - achalasia with spasm. The clinical and manometric variables and treatment outcomes were compared. RESULTS: Eighty-nine out of the 900 patients who underwent HRM were diagnosed as achalasia cardia. Fifty-one patients with a minimum follow-up period of 6 months were included. Types I and II achalasia were diagnosed in 24 patients each and 3 patients were diagnosed as type III achalasia. Dysphagia and regurgitation were the main presenting symptoms in patients with types I and II achalasia. Patients with type III achalasia had high basal lower esophageal sphincter pressure and maximal esophageal pressurization when compared to types I and II. Most patients underwent pneumatic dilatation (type I, 22/24; type II, 20/24; type III, 3/3). Patients with type II had the best response to pneumatic dilatation (18/20, 90.0%) compared to types I (14/22, 63.3%) and III (1/3, 33.3%). CONCLUSIONS: The type II achalasia cardia showed the best response to pneumatic dilatation.
Asian Continental Ancestry Group ; Cardia ; Deglutition Disorders ; Dilatation ; Esophageal Achalasia ; Esophageal Motility Disorders ; Esophageal Sphincter, Lower ; Follow-Up Studies ; Gastroenterology ; Humans ; Manometry ; Spasm

Background: Evaluate morbidities and “quality” of fiducial marker placement in primary liver tumours (hepatocellular carcinoma [HCC]) for CyberKnife. Materials and Methods: Thirty-six HCC with portal vein thrombosis(PVT) were evaluated for “quality” of fiducial placement, placement time, pain score, complications, recovery time and factors influencing placement. Results: One hundred eight fiducials were placed in 36 patients. Fiducial placement radiation oncologist score was “good” in 24(67%), “fair” in 4(11%), and “poor” in 3(8%) patients. Concordance with radiologist score in “poor”, “fair”, and “good” score was 2/2(100%), 4/5(80%), and 24/27(89%), respectively(p=0.001). Child-Pugh score(p=0.080), performance status(PS) (p=0.014) and accrued during “learning curve”(p=0.013) affected placement score. Mean placement time(p=0.055), recovery time(p=0.025) was longer and higher major complications(p=0.009) with poor PS. Liver segment involved(p=0.484) and the Barcelona Clinic Liver Cancer(BCLC) stage did not influence placement score. “Good” placement score was 30% in first cohort whereas 93% in last cohort(p=0.023). Time for placement was 42.2 and 14.3 minutes, respectively(p=0.069). Post-fiducial pain score 0–1 in 26 patients(72%) and pain score 3–4 was in 2(6%). Five patients (14%) admitted in “day-care”(2 mild pneumothorax, 3 pain). Mortality in 1 patient(3%) admitted for hemothorax. Conclusion Fiducial placement is safe and in experienced hands, “quality” of placement is “good” in majority. Major complications and admission after fiducial placement are rare. Complications, fiducial placement time, recovery time is more during the “learning curve”. Poor Child-Pugh score, extensive liver involvement, poor PS have higher probability of complications.

Background: Evaluate morbidities and “quality” of fiducial marker placement in primary liver tumours (hepatocellular carcinoma [HCC]) for CyberKnife. Materials and Methods: Thirty-six HCC with portal vein thrombosis(PVT) were evaluated for “quality” of fiducial placement, placement time, pain score, complications, recovery time and factors influencing placement. Results: One hundred eight fiducials were placed in 36 patients. Fiducial placement radiation oncologist score was “good” in 24(67%), “fair” in 4(11%), and “poor” in 3(8%) patients. Concordance with radiologist score in “poor”, “fair”, and “good” score was 2/2(100%), 4/5(80%), and 24/27(89%), respectively(p=0.001). Child-Pugh score(p=0.080), performance status(PS) (p=0.014) and accrued during “learning curve”(p=0.013) affected placement score. Mean placement time(p=0.055), recovery time(p=0.025) was longer and higher major complications(p=0.009) with poor PS. Liver segment involved(p=0.484) and the Barcelona Clinic Liver Cancer(BCLC) stage did not influence placement score. “Good” placement score was 30% in first cohort whereas 93% in last cohort(p=0.023). Time for placement was 42.2 and 14.3 minutes, respectively(p=0.069). Post-fiducial pain score 0–1 in 26 patients(72%) and pain score 3–4 was in 2(6%). Five patients (14%) admitted in “day-care”(2 mild pneumothorax, 3 pain). Mortality in 1 patient(3%) admitted for hemothorax. Conclusion Fiducial placement is safe and in experienced hands, “quality” of placement is “good” in majority. Major complications and admission after fiducial placement are rare. Complications, fiducial placement time, recovery time is more during the “learning curve”. Poor Child-Pugh score, extensive liver involvement, poor PS have higher probability of complications.

OBJECTIVE: The current study evaluated various new colchicine analogs for their anticancer activity and to study the primary mechanism of apoptosis and in vivo antitumor activity of the analogs with selective anticancer properties and minimal toxicity to normal cells. METHODS: Sulforhodamine B (SRB) assay was used to screen various colchicine analogs for their in vitro cytotoxicity. The effect of N-[(7S)-1,2,3-trimethoxy-9-oxo-10-(pyrrolidine-1-yl)5,6,7,9-tetrahydrobenzo[a] heptalene-7-yl] acetamide (IIIM-067) on clonogenicity, apoptotic induction, and invasiveness of A549 cells was determined using a clonogenic assay, scratch assay, and staining with 4',6-diamidino-2-phenylindole (DAPI) and annexin V/propidium iodide. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were observed using fluorescence microscopy. Western blot analysis was used to quantify expression of proteins involved in apoptosis, cell cycle, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. Pharmacokinetic and in vivo efficacy studies against Ehrlich ascites carcinoma (EAC) and Ehrlich solid tumor models were conducted using Swiss albino mice. RESULTS: IIIM-067 showed potent cytotoxicity and better selectivity than all other colchicine analogs screened in this study. The selective activity of IIIM-067 toward A549 cells was higher among other cancer cell lines, with a selectivity index (SI) value of 2.28. IIIM-067 demonstrated concentration- and time-dependent cytotoxicity against A549 cells with half-maximal inhibitory concentration values of 0.207, 0.150 and 0.106 μmol/L at 24, 48 and 72 h, respectively. It also had reduced toxicity to normal cells (SI > 1) than the parent compound colchicine (SI = 1). IIIM-067 reduced the clonogenic ability of A549 cells in a dose-dependent manner. IIIM-067 enhanced ROS production from 24.6% at 0.05 μmol/L to 82.1% at 0.4 μmol/L and substantially decreased the MMP (100% in control to 5.6% at 0.4 μmol/L). The annexin V-FITC assay demonstrated 78% apoptosis at 0.4 μmol/L. IIIM-067 significantly (P < 0.5) induced the expression of various intrinsic apoptotic pathway proteins, and it differentially regulated the PI3K/AKT/mTOR signaling pathway. Furthermore, IIIM-067 exhibited remarkable in vivo anticancer activity against the murine EAC model, with tumor growth inhibition (TGI) of 67.0% at a dose of 6 mg/kg (i.p.) and a reduced mortality compared to colchicine. IIIM-067 also effectively inhibited the tumor growth in the murine solid tumor model with TGI rates of 48.10%, 55.68% and 44.00% at doses of 5 mg/kg (i.p.), 6 mg/kg (i.p.) and 7 mg/kg (p.o.), respectively. CONCLUSION IIIM-067 exhibited significant anticancer activity with reduced toxicity both in vitro and in vivo and is a promising anticancer candidate. However, further studies are required in clinical settings to fully understand its potential.
Animals ; Mice ; Proto-Oncogene Proteins c-akt/metabolism* ; Antineoplastic Agents, Phytogenic/pharmacology* ; Phosphatidylinositol 3-Kinases/metabolism* ; Reactive Oxygen Species/metabolism* ; TOR Serine-Threonine Kinases/metabolism* ; Colchicine/pharmacology* ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Mammals/metabolism*