Unravelling the oxygen factor - An investigation of transcriptional activation of hypoxia associated placental angiogenesis in recurrent pregnancy loss (RPL) patients from Assam, India.

INTRODUCTION: Recurrent pregnancy loss (RPL) is defined as the spontaneous loss of two or more consecutive pregnancies before 20 weeks of gestation, and affects 7.46 % of the Indian population. About 40-50 % of RPL cases are idiopathic making it a therapeutic challenge for clinicians. This study focuses on elucidating the role of hypoxia-associated placental angiogenesis in these idiopathic RPL cases. METHODS: Whole blood and product of conception (POCs) were collected from RPL patients (N = 87) and cases of voluntary abortions (medically terminated pregnancy, MTP; n = 110) as controls with informed consent. Serum separated from whole blood was used to study the ROS-antioxidant status in the cases and controls through colorimetric assays and ELISA. The mRNA extracted from placental tissue samples were used to determine the hypoxic and angiogenic status in cases and controls through real time PCR. Statistical analysis was also carried out to correlate the differential hypoxic status between RPL and MTP cohorts with the expression of angiogenic factors (VEGFA, VEGFR1 and VEGFR2). RESULTS: HIF1α mRNA expression was found to be upregulated in the RPL cases. While the serum levels of H2O2 (p = 0.012), guanine oxides and lipid hydroperoxides (LPO) were increased in the RPL cases, reduced glutathione (GSH) was found to be significantly decreased (p = 0.012). Additionally, AUROC analysis also shows an excellent discriminatory ability of 0.850 for serum H2O2 levels. VEGF-A and VEGF-R1 mRNA expression was also found to be downregulated in the RPL cases compared to MTP. DISCUSSION: This study indicates that increased oxidative stress may lead to aberrations in the VEGF pathway resulting in improper placentation in RPL cases, and subsequently, pregnancy loss.

Expert Recommendations on Optimizing the Diagnosis and Management of Gastroesophageal Reflux Disease Associated with Comorbidities in the Indian Population.

Gastroesophageal reflux disease (GERD) is among the most prevalent gastrointestinal (GI) disorders. It is known to often coexist with other chronic diseases such as asthma, chronic obstructive pulmonary disease (COPD), obesity, diabetes mellitus (DM), and hypertension. Upper endoscopy, esophageal manometry, and impedance-pH monitoring are a few invasive diagnostic options that are reserved for selected GERD patients. Symptom assessment by using questionnaires, such as the frequency scale for the symptoms of GERD (FSSG), is simple, convenient, noninvasive, and inexpensive. These questionnaires are widely used to facilitate diagnosis and appropriate treatment. Early diagnosis of GERD and timely management may improve clinical outcomes in patients. Proton pump inhibitors (PPIs) are the preferred therapy for GERD. However, evidence indicates that excessive and extended use of PPIs is linked to adverse events. An overview of the diagnosis and management of GERD, as well as an evidence-based overview of the relationship between GERD and asthma, COPD, obesity, DM, and hypertension, is presented in this review. Expert opinions and recommendations for diagnosing GERD using invasive tests and validated questionnaires have also been mentioned.

Accuracy of ultrasound vs computed tomography scan for upper urinary tract malignancies and development of a risk-based diagnostic algorithm for haematuria in a UK tertiary centre.

PURPOSE: There is no consensus across guidelines on a diagnostic algorithm for upper urinary tract (UUT) evaluation following presentation with haematuria. Our aim is to compare the diagnostic accuracy of ultrasound (USS) compared to CT-scan for UUT malignancies and also determine the considerations important for a risk-based diagnostic protocol for haematuria. METHODS: We reviewed our 'haematuria clinic' database to identify patients who had both USS and CT-scan for UUT evaluation between September 2015 and August 2017, and calculated the diagnostic accuracy of these imaging modalities for histologically confirmed UUT cancers. Furthermore, we identified risk factors in our diagnostic algorithm for haematuria and conducted regression analysis to determine their ability to predict UUT malignancies. RESULTS: Overall, 575 patient records were studied. Age range was 21-92 years, M:F was 1.4:1, majority (81.2%) had visible haematuria, and 12 (2.1%) UUT cancers were diagnosed [renal cell carcinoma-1.4%; upper tract urothelial cancer-0.7%]. USS and CT-scan had diagnostic accuracy for UUT cancers of 95.8 and 99.1%, respectively (p < 0.001). Haematuria type was a significant consideration only on univariate analysis, while multivariate binary logistic regression showed that male gender, smoking, occupational exposure, and positive urologic history were the main risk factors associated with UUT malignancies. CONCLUSION: USS and CT-scan have comparably high diagnostic accuracy for detecting UUT malignancies. USS may, therefore, be considered as the first-line UUT imaging modality when utilized in a risk-based diagnostic algorithm. Larger, multicentred studies are needed to validate our findings and influence guideline development.

Technological and Clinical Challenges in Lead Placement for Cardiac Rhythm Management Devices.

Cardiac disease is a leading cause of death worldwide. Disturbance in the conduction system of the heart may trigger or aggravate heart dysfunction, affecting the efficiency of the heart, and lead to heart failure or cardiac arrest. Patients may require implantable cardiac rhythm management devices (ICRMDs) to maintain or restore the heart rhythm. ICRMDs have undergone important improvements, yet limitations still exist, presenting important technological challenges. Most ICRMDs consist of a subcutaneous control unit and intracardiac electrodes. The leads, which connect the electrodes to the control unit, are usually placed transvenously through the subclavian veins. Various locations inside the heart are used for placement of electrodes, depending on the specific condition. Some of the limitations to effective pacemaker therapy are associated with placement and location of the leads. Various approaches have been developed to overcome these challenges, such as multi-site pacing and leadless solutions. This paper aims to review the state of the art for the selection of placement sites for pacemakers, implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy devices (CRT) devices and discuss potential technological advancements to improve the results of ICRMD-therapy including development av leadless technology.

Skeletal Muscle Metastasis to Vastus Lateralis from a Urothelial Carcinoma: A Case Report and Review of Its Diagnosis and Management.

Bladder cancer is a common genitourinary tract malignancy. Urothelial carcinoma is the most frequent type of bladder cancer and it commonly metastasises to lymph nodes, bone, lung and liver by a haematogenous route. Skeletal metastases are very rare and are usually present in patients with advanced metastatic disease. We present an unusual case of a 71-year-old male with a urothelial carcinoma metastasis to the vastus lateralis muscle 3 months following a cystoprostatectomy for muscle invasive bladder cancer.

Expression pattern of NMDA receptors reveals antiepileptic potential of apigenin 8-C-glucoside and chlorogenic acid in pilocarpine induced epileptic mice.

The present study was aimed to evaluate the effect of apigenin 8-C-glucoside (Vitexin) and chlorogenic acid on epileptic mice induced by pilocarpine and explored its possible mechanisms. Intraperitonial administration of pilocarpine (85mg/kg) induced seizure in mice was assessed by behavior observations, which is significantly (p>0.05) reduced by apigenin 8-C-glucoside (AP8CG) (10mg/kg) and chlorogenic acid (CA) (5mg/kg), similar to diazepam. Seizure was accompanied by an imbalance in the levels of Gamma-aminobutyric acid (GABA) and glutamate in the pilocarpine administered group. Moreover, convulsion along with reduced acetylcholinesterase, increased monoamine oxidase and oxidative stress was observed in epileptic mice brain. AP8CG and CA significantly restored back to normal levels even at lower doses. Further, increased lipid peroxidation and nitrite content was also significantly attenuated by AP8CG and CA. However, CA was found to be more effective when compared to AP8CG. In addition, the mRNA expression of N-methyl-d-aspartate receptor (NMDAR), mGluR1 and mGlu5 was significantly (P≤0.05) inhibited by AP8CG and CA in a lower dose. The mRNA expression of GRIK1 did not differ significantly in any of the group and showed a similar pattern of expression. Our result shows that AP8CG and CA selectively inhibit NMDAR, mGluR1 and mGlu5 expression. Modification in the provoked NMDAR calcium response coupled with neuronal death. Hence, these findings underline that the polyphenolics, AP8CG and CA have exerted antiepileptic and neuroprotective activity by suppressing glutamate receptors.

Vortex-dislodged cells from bone marrow trephine biopsy yield satisfactory results for flow cytometric immunophenotyping.

INTRODUCTION: A good bone marrow (BM) sample is essential in evaluating many hematologic disorders. An unsuccessful BM aspiration (BMA) procedure precludes a successful flow cytometric immunophenotyping (FCI) in most hematologic malignancies. Apart from FCI, most ancillary diagnostic techniques in hematology are less informative. We describe the feasibility of FCI in vortex-dislodged cell preparation obtained from unfixed trephine biopsy (TB) specimens. METHODS: In pancytopenic patients and dry tap cases, routine diagnostic BMA and TB samples were complemented by additional trephine biopsies. These supplementary cores were immediately transferred into sterile tubes filled with phosphate-buffered saline, vortexed, and centrifuged. The cell pellet obtained was used for flow cytometric immunophenotyping. RESULTS: Of 7955 BMAs performed in 42 months, 34 dry tap cases were eligible for the study. Vortexing rendered a cell pellet in 94% of the cases (32 of 34), and FCI rendered a rapid diagnosis in 100% of the cases (32 of 32) where cell pellets were available. CONCLUSION: We describe an efficient procedure which could be effectively utilized in resource-limited centers and reduce the frequency of repeat BMA procedures.

MRI texture analysis predicts p53 status in head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: Head and neck cancer is common, and understanding the prognosis is an important part of patient management. In addition to the Tumor, Node, Metastasis staging system, tumor biomarkers are becoming more useful in understanding prognosis and directing treatment. We assessed whether MR imaging texture analysis would correctly classify oropharyngeal squamous cell carcinoma according to p53 status. MATERIALS AND METHODS: A cohort of 16 patients with oropharyngeal squamous cell carcinoma was prospectively evaluated by using standard clinical, histopathologic, and imaging techniques. Tumors were stained for p53 and scored by an anatomic pathologist. Regions of interest on MR imaging were selected by a neuroradiologist and then analyzed by using our 2D fast time-frequency transform tool. The quantified textures were assessed by using the subset-size forward-selection algorithm in the Waikato Environment for Knowledge Analysis. Features found to be significant were used to create a statistical model to predict p53 status. The model was tested by using a Bayesian network classifier with 10-fold stratified cross-validation. RESULTS: Feature selection identified 7 significant texture variables that were used in a predictive model. The resulting model predicted p53 status with 81.3% accuracy (P < .05). Cross-validation showed a moderate level of agreement (κ = 0.625). CONCLUSIONS: This study shows that MR imaging texture analysis correctly predicts p53 status in oropharyngeal squamous cell carcinoma with ∼80% accuracy. As our knowledge of and dependence on tumor biomarkers expand, MR imaging texture analysis warrants further study in oropharyngeal squamous cell carcinoma and other head and neck tumors.

Bone loss in a new rodent model combining spinal cord injury and cast immobilization.

OBJECTIVES: Characterize bone loss in our newly developed severe contusion spinal cord injury (SCI) plus hindlimb immobilization (IMM) model and determine the influence of muscle contractility on skeletal integrity after SCI. METHODS: Female Sprague-Dawley rats were randomized to: (a) intact controls, (b) severe contusion SCI euthanized at Day 7 (SCI-7) or (c) Day 21 (SCI-21), (d) 14 days IMM-alone, (e) SCI+IMM, or (f) SCI+IMM plus 14 days body weight supported treadmill exercise (SCI+IMM+TM). RESULTS: SCI-7 and SCI-21 exhibited a >20% reduction in cancellous volumetric bone mineral density (vBMD) in the hindlimbs (p⋜0.01), characterized by reductions in cancellous bone volume (cBV/TV%), trabecular number (Tb.N), and trabecular thickness. IMM-alone induced no observable bone loss. SCI+IMM exacerbated cancellous vBMD deficits with values being >45% below Controls (p⋜0.01) resulting from reduced cBV/TV% and Tb.N. SCI+IMM also produced the greatest cortical bone loss with distal femoral cortical area and cortical thickness being 14-28% below Controls (p⋜0.01) and bone strength being 37% below Controls (p⋜0.01). SCI+IMM+TM partially alleviated bone deficits, but values remained below Controls. CONCLUSIONS: Residual and/or facilitated muscle contractility ameliorate bone decrements after severe SCI. Our novel SCI+IMM model represents a clinically-relevant means of assessing strategies to prevent SCI-induced skeletal deficits.

The prognostic impact of a combined carbonic anhydrase IX and Ki67 signature in oral squamous cell carcinoma.

BACKGROUND: Tumour hypoxia is associated with impaired apoptosis, resistance to therapy and poor prognosis. We previously reported that high stromal expression of the endogenous marker of hypoxia, carbonic anhydrase IX (CAIX), is associated with significantly reduced survival in oral squamous cell carcinoma (OSCC). In addition to hypoxia, CAIX expression is regulated by proliferation-associated signalling. We hypothesised that incorporating Ki67, a proliferation marker, into our existing CAIX-based stratification of OSCC would identify patients with the least favourable prognosis. METHODS: Surgically resected tumours from 60 OSCC patients were analysed for CAIX, Ki67 and BAX expression using fluorescence immunohistochemistry and automated quantitative analysis (AQUA). RESULTS: In patients expressing high stromal CAIX (sCAIX), stratification by tumour Ki67 expression revealed significantly distinct survival outcomes (P=0.005). In our OSCC cohort, below-median Ki67 and top-quartile sCAIX expression (Ki67(lo)sCAIX(hi)) were associated with significantly worse disease-specific survival in univariate (HR 7.2 (2.5-20.4), P=0.001) and multivariate (HR 4.2 (1.4-12.8), P=0.011) analyses. Hypoxia is associated with decreased BAX expression; the Ki67(lo)sCAIX(hi) group was more strongly associated with low BAX expression than high sCAIX alone. CONCLUSION: These data suggest that combined analysis of tumour Ki67 and sCAIX expression may provide a more clinically relevant assessment of tumour hypoxia in OSCC.

ING1 induces apoptosis through direct effects at the mitochondria.

The ING family of tumor suppressors acts as readers and writers of the histone epigenetic code, affecting DNA repair, chromatin remodeling, cellular senescence, cell cycle regulation and apoptosis. The best characterized member of the ING family, ING1,interacts with the proliferating cell nuclear antigen (PCNA) in a UV-inducible manner. ING1 also interacts with members of the14-3-3 family leading to its cytoplasmic relocalization. Overexpression of ING1 enhances expression of the Bax gene and was reported to alter mitochondrial membrane potential in a p53-dependent manner. Here we show that ING1 translocates to the mitochondria of primary fibroblasts and established epithelial cell lines in response to apoptosis inducing stimuli, independent of the cellular p53 status. The ability of ING1 to induce apoptosis in various breast cancer cell lines correlates well with its degree of translocation to the mitochondria after UV treatment. Endogenous ING1 protein specifically interacts with the pro-apoptotic BCL2 family member BAX, and colocalizes with BAX in a UV-inducible manner. Ectopic expression of a mitochondria-targeted ING1 construct is more proficient in inducing apoptosis than the wild type ING1 protein. Bioinformatic analysis of the yeast interactome indicates that yeast ING proteins interact with 64 mitochondrial proteins. Also, sequence analysis of ING1 reveals the presence of a BH3-like domain. These data suggest a model in which stress-induced cytoplasmic relocalization of ING1 by14-3-3 induces ING1-BAX interaction to promote mitochondrial membrane permeability and represent a paradigm shift in our understanding of ING1 function in the cytoplasm and its contribution to apoptosis [corrected].

Detection of paroxysmal nocturnal hemoglobinuria-phenotype in patients with chronic lymphocytic leukemia and multiple myeloma.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) results due to decrease or absence of glycosylphosphatidylinositol-anchored (GPI) molecules, such as CD55 and CD59, from the surface of the affected cells. PNH-phenotype has been described in various hematological disorders, mainly aplastic anemia and myelodysplastic syndromes; recently it has been reported in patients with lymphoproliferative syndromes and multiple myeloma (MM). MATERIALS AND METHODS: We evaluated the presence of CD55 negative and/or CD59 negative red blood cell (RBC) populations in newly diagnosed treatment naive-54 chronic lymphocytic leukemia (CLL) and 29 MM patients by flow cytometry. RESULTS: PNH-phenotype was not reported in any patient; however, RBC populations deficient in CD55 were detected in 16.66% (9/54) CLL and 6.89% (2/29) MM patients. Clinical presentation or the hematological parameters did not show any relationship with the presence of CD55 deficient RBC population. CONCLUSION: Our study showed absence of PNH-phenotype in patients with CLL and MM; however, isolated CD55 deficient RBC were identified in both CLL and MM. Larger prospective studies by other centers, including simultaneous analysis of granulocytes for the presence of PNH-phenotype, are needed to corroborate these findings and to work out the mechanisms and the significance of the existence of this phenotype in these patients.

Simple theoretical analysis of the photoemission from quantum confined effective mass superlattices of optoelectronic materials.

The photoemission from quantum wires and dots of effective mass superlattices of optoelectronic materials was investigated on the basis of newly formulated electron energy spectra, in the presence of external light waves, which controls the transport properties of ultra-small electronic devices under intense radiation. The effect of magnetic quantization on the photoemission from the aforementioned superlattices, together with quantum well superlattices under magnetic quantization, has also been investigated in this regard. It appears, taking HgTe/Hg(1-) (x)Cd(x)Te and In(x)Ga(1-) (x)As/InP effective mass superlattices, that the photoemission from these quantized structures is enhanced with increasing photon energy in quantized steps and shows oscillatory dependences with the increasing carrier concentration. In addition, the photoemission decreases with increasing light intensity and wavelength as well as with increasing thickness exhibiting oscillatory spikes. The strong dependence of the photoemission on the light intensity reflects the direct signature of light waves on the carrier energy spectra. The content of this paper finds six different applications in the fields of low dimensional systems in general.

Central pontine myelinolysis without hyponatraemia.

A 55-year-old woman with a history of excess alcohol intake presented to the acute medical unit following concerns regarding her electrolyte disturbances. During correction of the electrolytes, the patient developed central pontine myelinolysis. The unusual features in the case were the absence of hyponatraemia which is usually associated with central pontine myelinolysis and also the good recovery that the patient made. Looking at the electrolyte changes, we suspect there may be a link to the rapid osmotic shifts occurring during refeeding and central pontine myelinolysis.

A review of tumour lysis syndrome with targeted therapies and the role of rasburicase.

WHAT IS KNOWN AND OBJECTIVE: Tumour lysis syndrome (TLS) is an oncologic emergency with potentially devastating consequences classically associated with cytotoxic chemotherapy. In recent years, molecularly targeted drugs have assumed an increasingly important role in cancer therapeutics. The possibility of TLS is often overlooked in this setting. Rasburicase, a recombinant urate oxidase, is remarkably effective in treating hyperuricemia, thought to be central to the pathogenesis of renal injury in TLS. Our objective is to review the literature on TLS especially as it pertains to targeted therapies and summarize current knowledge and provide future directions regarding the role of rasburicase in the management of TLS. METHODS: A MEDLINE search was conducted using PubMed and the keyphrase 'tumor lysis syndrome' to identify articles describing TLS with a broad range of novel anti-cancer agents. Meeting abstracts were also reviewed. Additionally, the biomedical literature was searched using the keyword 'rasburicase'. RESULTS AND DISCUSSION: Tumour lysis syndrome has been described with nearly every class of 'targeted therapy'. This is not surprising as any drug causing death of cancer cells by any mechanism may lead to TLS in the appropriate setting. Although there is a wealth of evidence suggesting that rasburicase is extremely effective in correcting hyperuricemia, prospective trials showing that it improves hard outcomes such as acute renal failure, need for dialysis and mortality are lacking. Furthermore, much lower doses and durations of therapy than approved appear to be effective in controlling hyperuricemia, potentially leading to enormous cost savings. WHAT IS NEW AND CONCLUSION: Any effective cancer therapy can lead to TLS. Physicians should consider the risk of TLS on a case-by-case basis and determine appropriate prophylaxis. The role of rasburicase continues to evolve. Randomized controlled trials evaluating clinically relevant outcomes are needed.

Three-day regimen improves faecal tagging for minimal preparation CT examination of the colon.

This study set out to determine whether extending the length of oral contrast administration in minimal preparation CT of the colon improves faecal tagging. Two cohorts of 50 patients each were compared, one with a 2-day the other with a 3-day faecal tagging regimen. The degree of faecal tagging was graded by two blinded observers. The 3-day regimen showed significantly better tagging in the rectum and sigmoid colon (p = 0.006 and p = 0.009, respectively, using the Mann-Whitney test). The percentage of patients who had faecal tagging in the sigmoid colon graded as "complete" was 64% for the 3-day regimen as opposed to 34% for the 2-day regimen. The corresponding percentages for the rectum were 64% for the 3-day regimen and 36% for the 2-day regimen. Extending the length of oral contrast administration from 2 to 3 days significantly improves the quality of faecal tagging in the rectum and sigmoid colon.

Further theoretical studies of modified cyclone separator as a diesel soot particulate emission arrester.

Soot particulate emission reduction from diesel engine is one of the most emerging problems associated with the exhaust pollution. Diesel particulate filters (DPF) hold out the prospects of substantially reducing regulated particulate emissions but the question of the reliable regeneration of filters still remains a difficult hurdle to overcome. Many of the solutions proposed to date suffer from design complexity, cost, regeneration problem and energy demands. This study presents a computer aided theoretical analysis for controlling diesel soot particulate emission by cyclone separator--a non contact type particulate removal system considering outer vortex flow, inner vortex flow and packed ceramic fiber filter at the end of vortex finder tube. Cyclone separator with low initial cost, simple construction produces low back pressure and reasonably high collection efficiencies with reduced regeneration problems. Cyclone separator is modified by placing a continuous ceramic packed fiber filter placed at the end of the vortex finder tube. In this work, the grade efficiency model of diesel soot particulate emission is proposed considering outer vortex, inner vortex and the continuous ceramic packed fiber filter. Pressure drop model is also proposed considering the effect of the ceramic fiber filter. Proposed model gives reasonably good collection efficiency with permissible pressure drop limit of diesel engine operation. Theoretical approach is predicted for calculating the cut size diameter considering the effect of Cunningham molecular slip correction factor. The result shows good agreements with existing cyclone and DPF flow characteristics.