Natural bioactive molecules: An alternative approach to the treatment and control of glioblastoma multiforme.

Glioblastoma multiforme is one of the most deadly malignant tumors, with more than 10,000 cases recorded annually in the United States. Various clinical analyses and studies show that certain chronic diseases, including cancer, interact between cell-reactive radicals rise and pathogenesis. Reactive oxygen and nitrogenous sources include endogenous (physiological processes), and exogenous sources contain reactive oxygen and nitrogen (xenobiotic interaction). The cellular oxidation/reduction shifts to oxidative stress when the regulation mechanisms of antioxidants are surpassed, and this raises the ability to damage cellular lipids, proteins, and nucleic acids. OBJECTIVE: This review is focused on how phytochemicals play crucial role against glioblastoma multiforme and to combat these, bioactive molecules and their derivatives are either used alone, in combination with anticancer drugs or as nanomedicine formulations for better cancer theranostics over the conventional approach. CONCLUSION: Bioactive molecules found in seeds, vegetables, and fruits have antioxidant, anti-inflammatory, and anticancer properties that may help cancer survivors feel better throughout chemotherapy or treatment. However, incorporating them into the nanocarrier-based drug delivery for the treatment of GBMs, which could be a promising therapeutic strategy for this tumor entity, increasing targeting effectiveness, increasing bioavailability, and reducing side effects with this target-specificity, drug internalization into cells is significantly improved, and off-target organ aggregation is reduced.

Publisher Correction: The Scales Project, a cross-national dataset on the interpretation of thermal perception scales.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Scales Project, a cross-national dataset on the interpretation of thermal perception scales.

Thermal discomfort is one of the main triggers for occupants' interactions with components of the built environment such as adjustments of thermostats and/or opening windows and strongly related to the energy use in buildings. Understanding causes for thermal (dis-)comfort is crucial for design and operation of any type of building. The assessment of human thermal perception through rating scales, for example in post-occupancy studies, has been applied for several decades; however, long-existing assumptions related to these rating scales had been questioned by several researchers. The aim of this study was to gain deeper knowledge on contextual influences on the interpretation of thermal perception scales and their verbal anchors by survey participants. A questionnaire was designed and consequently applied in 21 language versions. These surveys were conducted in 57 cities in 30 countries resulting in a dataset containing responses from 8225 participants. The database offers potential for further analysis in the areas of building design and operation, psycho-physical relationships between human perception and the built environment, and linguistic analyses.

Comparative Evaluation of Apical Transportation and Canal Centric Ability in Apical Region of Newer nickel-titanium File Systems Using cone-beam computed tomography on Extracted Molars: An In Vitro Study.

BACKGROUND: Objective in root canal preparation is to develop a shape that tapers from apical to coronal, maintaining the original canal shape. With advent of instruments manufactured from nickel-titanium (NiTi) alloys, there was a significant improvement of quality of root canal shaping, with predictable results and less iatrogenic damage. AIM: The aim of the study was to evaluate the canal centric ability and apical transportation in apical region of newer NiTi file system in root canal using cone-beam computed tomography (CBCT) on extracted molars. MATERIALS AND METHODS: Root canal of thirty extracted human permanent teeth with mature root apices with 20°-40° of curvature were collected and divided into three groups after initial bio-mechanical preparation: Group 1: canal prepared using ProTaperNext (PTN) file system; Group 2: canal prepared using Mani silk system; and Group 3: canal prepared using V-taper file system. All samples were scanned before and after biomechanical preparation using CBCT. The data collected were evaluated using the Kruskal-Wallis analysis of variance test and Mann-Whitney U-test. RESULTS: It was observed that in apical region Group I (PTN) showed significantly lower mean apical transportation and canal centric ability as compared to Group II (Mani Silk) and Group III (V-taper). CONCLUSION: It was concluded that PTN rotary system has no canal transportation and maintained centric ability in comparison to Mani and V-taper rotary file system in apical region of curved root canal.

Percutaneous closure of a large patent ductus arteriosus in a preterm newborn weighing 1400 g without using arterial sheath: an innovative technique.

Percutaneous closure of patent ductus arteriosus is well established in infants weighing >5 kg, but data regarding outcome of preterm especially very low birth weight infants is minimal. Although surgical ligation of patent ductus arteriosus is the preferred and well-accepted modality of treatment after failure of drug therapy in preterm infants, it has also got its own demerits in such a small and fragile subset. Device closure in infants weighing <1.5 kg is rarely attempted because of high chances of complications, especially acute arterial injury due to the arterial sheath. We received a 1.4-kg ventilator-dependent infant for closure of large patent ductus arteriosus. Percutaneous closure of patent ductus arteriosus was done successfully and the infant was discharged on room air with a weight of 1.8 kg. We present here an innovative technique in which successful patent ductus arteriosus device closure was done in a 1.4-kg infant without using arterial sheath.

Impact of Dietary Habits and Physical Activity on Bone Health among 40 to 60 Year Old Females at Risk of Osteoporosis in India.

Osteoporosis is a disorder of bones with increasing risk among women. However, a number of modifiable factors can help in combating this disorder. Present study examined the relationship of diet and physical activity and risk of osteoporosis through biochemical tests, bone mass density (BMD) scores, and standard questionnaires. Genetic risk for osteoporosis, presence of osteoarthritis, and thyroid problems were found among 8%, 7%, and 3% of participants, respectively; and 78% had onset of menopause between 47 to 55 years of age. Results revealed that less intake of proteins, minerals, and diverse fruit and vegetable consumption was significantly (p≤0.05; 0.01) correlated with decreased BMD score and serum calcium. It was concluded that adequate intake of varied fruits and vegetables, good protein, habit of daily physical activity, adequate sun exposure, and dietary calcium, may play a promising role in decreasing the risk of osteoporosis among women of this age group.

Altered frequencies of dendritic cells and IFN-gamma-secreting T cells with granulocyte colony-stimulating factor (G-CSF) therapy in acute-on- chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a serious hepatic ailment with impaired immunity and poor treatment options resulting high mortality. Treatment with granulocyte colony-stimulating factor(G-CSF) mobilizes CD34(+) cells in ACLF patients; however its effect on impaired immune responses remains to be elucidated. To analyse the effect of G-CSF in immune modulation in ACLF. METHODS: We have analysed the frequencies of circulating and intrahepatic myeloid (mDCs) and plasmacytoid(pDCs) dendritic cells (DCs) and T cells in ACLF patients treated with G-CSF (Group A; n = 23) and placebo (Group B; n = 24) using flow cytometry. IFN-c production was compared in both groups following stimulation of PBMCs with phorbol myristate acetate (PMA). RESULTS: In Group A, circulating and intrahepatic mDCs, pDCs (P < 0.04, P < 0.02) and T cells(CD3, CD4 and CD8) increased significantly post-G-CSF treatment in comparison to placebo group. Importantly in Group A, IFN-c-producing CD8 T cells were significantly decreased (P > 0.05) along with decreased serum bilirubin and international normalized ratio (INR). Intrahepatic DCs and IFN-clevel were compared in survivor and non-survivor. Non-survivors from both groups, showed decreased DCs, high IFN-c level and no improvement in clinical parameters including s-bilirubin and INR. CONCLUSIONS: G-CSF therapy increased the frequencies of dendritic cells and reduced IFN-c secreting CD8 T cells with improved clinical severity indices. Decreased IFN- c production may contribute to reduced hepatocellular damage in ACLF patients.Our observations support the basis for further use of G-CSF therapy as immune modulator in these patients.

Use of nitric oxide in thoracic surgery for a high risk cardiac patient.

Nitric oxide (NO) is a selective pulmonary vasodilator especially in the presence of pulmonary artery hypertension. With right ventricle (RV) dysfunction, inhaled NO may increase RV ejection fraction and cardiac output. The main advantage of NO over intravenous therapy is its inability to decrease systemic pressure thereby maintaining the coronary perfusion pressure and the myocardial perfusion. In this case report, we discuss the use of NO in a routine thoracic surgery patient suffering with severe left ventricular dysfunction and a potential candidate for a very high cardiac risk.

Comparative yield of fine needle aspiration cytology, ampullary biopsy, and needle knife assisted biopsy in the diagnosis of nonulcerated periampullary tumors.

AIM: Periampullary tumors (PAT) are defined as tumors arising within 2 cm of the major duodenal papilla. Studies on yield of preoperative biopsy for nonulcerated PAT are scarce. Needle knife papillotomy-assisted biopsy (NKAB) may sample the deeper tissues and thereby increase the histologic yield. We aimed to compare the diagnostic yield of fine needle aspiration cytology (FNAC), surface ampullary biopsy, and NKAB in nonulcerated PAT. METHODS: Patients with suspected PAT based on clinical, biochemical, and radiologic investigations were evaluated. Patients with smooth ampullary bulge on side viewing endoscopy (SVE) were included, while those with gastric outlet obstruction or obvious ulceration of ampulla on SVE were excluded. RESULTS: Twenty-five of 78 patients with PAT met the inclusion criteria. The median (range) age was 60 (43-75) years, and 13 were male. Serum CA 19.9 was 466 (2-9372) U/mL. Histopathological positivity rate for surface biopsy, FNAC, and NKAB was 10 (40 % and 95 % CI: 21.8 % to 61.1 %), 12 (48 % and 95 % CI: 28.3 % to 68.2 %), and 21 (84 % and 95 % CI: 63.1 % to 94.7 %), respectively. Diagnostic yield of NKAB was significantly better than surface biopsy (p = 0.001) and FNAC (p = 0.007). None of the patients subjected to NKAB had any complications other than self-limited minor ooze. CONCLUSION: NKAB was superior to surface biopsy or FNAC to establish preoperative tissue diagnosis of nonulcerated PAT. NKAB is safe and simple in expert hands and may be recommended as standard procedure to obtain histological specimen in these patients.

Effects of the adjunctive probiotic VSL#3 on portal haemodynamics in patients with cirrhosis and large varices: a randomized trial.

BACKGROUND: Probiotics, by altering gut flora, may favourably alter portal haemodynamics in patients with cirrhosis. AIM: To investigate the effect of probiotics on portal pressure in patients with cirrhosis. METHODS: Randomized double-blind placebo-controlled trial conducted in G.B. Pant Hospital, New Delhi. A total of 94 cirrhotic patients having large oesophageal varices without history of variceal bleeding were randomized to three treatment groups and given 2 months' treatment with propranolol plus placebo, propranolol plus antibiotics (norfloxacin 400 mg BD) or propranolol plus probiotic (VSL#3, 900 billion/day) randomly assigned in 1:1:1 ratio. Outcome measures were change in Hepatic venous pressure gradient (HVPG): Response rate (Percentage of patients having a decrease from baseline of ≥20% or to ≤12 mm Hg) and changes from baseline; biochemical markers of inflammation: changes from baseline. RESULTS: Adjunctive probiotics increased the response rate compared with propranolol alone (58% vs. 31%, P = 0.046), similar to adjunctive antibiotics (54%). The mean fall in HVPG was greater with either adjunctive probiotics (3.7 mm Hg vs. 2.1 mm Hg, P = 0.061) or adjunctive antibiotics (3.4 mm Hg) than with propranolol alone. Both adjunctive therapies were associated with greater decreases in TNF-α levels (in both peripheral and hepatic venous blood) that resulted from propranolol-only treatment. No clinically relevant between-group differences were observed in the type or frequency of adverse events. CONCLUSIONS: Adjunctive probiotic (VSL#3) improved the response rate to propranolol therapy and was safe and well tolerated in patients with cirrhosis. Adjunctive probiotic therapy merits further study for reduction in portal pressure.

Hepatic and systemic hemodynamic derangements predict early mortality and recovery in patients with acute-on-chronic liver failure.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a clinical entity where there is a potential for reversibility of hepatic dysfunction once the acute hepatic insult resolves. The portal and systemic hemodynamics in ACLF patients to study its relevance in determining the clinical outcomes was studied. METHODS: Clinical, laboratory, portal, and systemic hemodynamic assessments were done at admission and after 3 months. Standard medical care was given to all the patients. RESULTS: Fifty-seven patients with ACLF were enrolled, and they underwent baseline hepatic venous pressure gradient (HVPG) measurement. Twenty-six (46%) patients died during the 3-month follow-up. Presence of high HVPG and hepatic encephalopathy were found to be independent baseline predictors of mortality. Of the 31 surviving patients, 24 consented for a repeat HVPG. The baseline HVPG reduced from 16 (range 12-30) to 13 (range 6-21) mmHg; (P < 0.05). The reduction in HVPG correlated with clinical and biochemical recovery, and reduction in Child-Turcotte-Pugh score score (P < 0.05), while the aortic mean arterial pressure, cardiac index and systemic vascular resistance index improved significantly (< 0.05). Six (25%) patients developed upper gastrointestinal bleed; the median HVPG between bleeders and non-bleeders was not different possibly because of early onset of bleed (median 20 [15-45 days]). CONCLUSIONS: Baseline HVPG is an independent predictor of mortality in ACLF patients. The portal and systemic circulatory anomalies regress substantially by 90 days and correlate with clinical recovery. However, in the initial phase, the raised portal pressure predisposes these patients to high risk of variceal bleeding.

Increased number and function of endothelial progenitor cells stimulate angiogenesis by resident liver sinusoidal endothelial cells (SECs) in cirrhosis through paracrine factors.

BACKGROUND & AIMS: Recent studies have shown a pathological role of angiogenesis in the progression of chronic liver diseases (CLDs). The present study focused on numbers and angiogenic functions of circulating endothelial progenitor cells (EPCs) in patients with cirrhosis. METHODS: Circulating EPCs were counted by flow-cytometry, and correlated with different parameters of liver disease. They were cultured in patients and controls to compare colony-formation, proliferation and tube formation. Interactions of EPCs with hepatic stellate cells (HSCs) and sinusoidal endothelial cells (SECs) were examined by indirect and direct co-cultures in presence of EPCs and EPC-conditioned medium, respectively. ELISA and inhibition assays were performed to assess the role of EPC-derived angiogenic factors. RESULTS: The number of circulating EPCs was substantially higher in cirrhotic patients compared to controls (p<0.05), and showed good correlation with hepatic disease severity. Functional assays revealed that colonies and proliferation of EPCs were significantly increased in patients compared to controls (p<0.05). Direct and indirect co-cultures of patients' EPCs showed an increase in tube formation by SECs as compared to that observed with control EPCs (p<0.05). There was, however, no tube formation in HSC-EPC co-cultures. Levels of PDGF-BB and VEGF were substantially increased in patients' EPC media and inhibition of these factors by neutralizing antibodies led to a significant reduction in SECs proliferation. CONCLUSIONS: Mobilization and proliferation of EPCs are significantly enhanced in cirrhotic patients in comparison to controls. EPCs may play an important paracrine role in liver angiogenesis by stimulating resident SECs in cirrhosis.

Compression of undiagnosed aberrant right subclavian artery during transesophageal echocardiography probe insertion.

Transesophageal echocardiography (TEE) has become an important monitoring tool for the anesthesiologist during repair of intracardiac defects. Although the incidence of reported complications associated with its use is low, one should be careful during the insertion and use of TEE probe, as it may result in potential devastating problems. We present a case of undiagnosed aberrant right subclavian artery (ARSA) that got compressed by the TEE probe during its insertion. It was noticed because of the presence of the right radial artery catheter, else it would have passed unnoticed.

Endoscopic management of hepatic hydatid cyst with biliary communication.

BACKGROUND AND AIM: A serious complication of hepatic hydatid cyst disease is communication between the cyst and the biliary tree. Surgical management of biliary fistulas is associated with high morbidity and mortality. We carried out a prospective study of endoscopic management of hydatid cysts communicating with bile ducts in 28 patients. METHODS: Presence of biliary fistula was suspected by jaundice and/or persistent external biliary fistula after surgical excision and was confirmed by endoscopic retrograde cholangiopancreatography (ERCP). Patients underwent endoscopic sphincterotomy, and either biliary stenting or nasobiliary drainage. Nasobiliary drains were removed when bile leakage stopped and closure of the fistula was confirmed by cholangiography; stents were removed after 4-6 weeks. RESULTS: Of 120 patients with hepatic hydatid cyst seen over a 10-year period, 28 patients developed fistula between the hepatic hydatid cyst and intrahepatic bile ducts (right intrahepatic bile ducts in 20 patients, left intrahepatic bile ducts in eight patients). Nine of 28 patients had persistent external biliary fistula after surgery. Ten patients showed membranes in bile ducts on cholangiography. We carried out either sphincterotomy with insertion of a nasobiliary drain (n=6) or sphincterotomy with biliary stenting (n=22). In 10 patients, the membranes were removed from bile ducts during ERCP. Fistulas healed in all patients after a median time of 11 days (range 5-45 days) after endoscopic treatment. We were able to remove nasobiliary drainage catheters and stents 8-45 days after placement. CONCLUSIONS: Endoscopic therapy is an effective mode of treatment for biliary fistulas complicating hepatic hydatid cyst.

Clinical profile and predictors of mortality in patients of acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is characterised by acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in patients with previously diagnosed or undiagnosed chronic liver disease. We studied the clinical, biochemical and etiological profiles of ACLF patients investigating variables which could predict mortality. METHODS: Consecutive ACLF patients were enrolled and given standard intensive care management. They were monitored for predictors of 90-day mortality. RESULTS: 91 patients were included; besides jaundice (median bilirubin 23.1mg/dL) and coagulopathy, acute onset ascites with or without encephalopathy was the presenting symptom in 92%. In all patients a first diagnosis of chronic liver disease was made, mainly due to hepatitis B (37%) or alcohol (34%). Reactivation of chronic hepatitis B and alcoholic hepatitis were the common acute insults. The 90-day mortality was 63%. On multivariate analysis, hepatic encephalopathy, low serum sodium, and high INR were found to be independent baseline predictors of mortality. Amongst all severity scores studied, MELD, SOFA and APACHE-II scores had AUROCs of >0.8 which was significantly higher than that of Child-Turcotte-Pugh. CONCLUSIONS: ACLF has very high mortality. Hepatic encephalopathy, low serum sodium and high INR predict poor outcome. Mortality can also be predicted by baseline MELD, SOFA or APACHE-II scores.

Endoscopic management of liver abscess with biliary communication.

BACKGROUND AND STUDY AIMS: The formation of a communication between liver abscesses and intrahepatic bile ducts is an uncommon cause of bile leak. The surgical management of biliary fistulas is associated with high morbidity and mortality. We performed a prospective study of the endoscopic management of liver abscess communicating with bile ducts. PATIENTS AND METHODS: We studied 38 patients with liver abscesses that had ruptured into the intrahepatic bile ducts. The presence of a biliary fistula was suspected by jaundice and/or by the appearance of bile in percutaneous drainage effluent from a liver abscess and was confirmed by endoscopic retrograde cholangiopancreatography (ERCP). Subsequently, patients underwent treatment by endoscopic sphincterotomy and either biliary stenting or nasobiliary drainage. Nasobiliary drains or biliary stents (both 7-Fr) were placed according to standard techniques. Nasobiliary drains were removed when bile leakage stopped and closure of the fistula was confirmed by cholangiography; stents were removed after an interval of 4-6 weeks. RESULTS: Of the total of 586 patients with liver abscesses, seen over a 10-year period, there were 38 (30 amebic, 8 pyogenic) patients who developed a biliary fistula between the liver abscess cavity and the intrahepatic bile ducts (right intrahepatic bile ducts in 30 patients, left intrahepatic bile ducts in 8 patients). We performed either endoscopic sphincterotomy with insertion of a nasobiliary drain (n = 18) or endoscopic sphincterotomy with biliary stenting (n = 20). The fistulas healed in all patients after a median time of 6 days (range 4-40 days) after endoscopic treatment. The nasobiliary drainage catheters and stents were removed after 8-40 days of their placement. CONCLUSIONS: Endoscopic therapy is an effective mode of treatment for biliary fistulas complicating liver abscesses.

A Randomized Controlled Trial Comparing Efficacy of Pentoxifylline and Pioglitazone on Metabolic Factors and Liver Histology in Patients with Non-alcoholic Steatohepatitis.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) involves increased hepatic macrosteatosis due to increased insulin resistance and non-hepatic processes including oxidative stress, apoptosis, and increased pro-inflammatory cytokines. Present study compared the efficacy of pentoxifylline and pioglitazone therapy in improving the metabolic factors and liver histology in patients with NASH. METHODS: Sixty consecutive biopsy proven NASH patients aged 18-70 years with ALT > 1.2 times the upper limit of normal were randomized to receive either pentoxifylline 1200 mg/day in three divided doses orally every day or pioglitazone (30 mg/day) daily for 6 months. All the patients were also instructed to reduce their calorie intake by 500 kcal/day as well as to perform modest exercise (brisk walking) regularly at least 5 days per week. Before and after treatment, liver function tests, serum insulin, C-peptide levels, TNF-α, adiponectin, leptin levels, HOMA-IR and hepatocyte injury and fibrosis scores on liver histology were assessed. RESULTS: Both pentoxifylline and pioglitazone were effective in improving transaminases, insulin resistance (HOMA-IR) and adiponectin levels significantly. TNF-α levels improved with either of the drugs but did not achieve significant levels. Both the drugs improved the markers of acute liver injury. However, only steatosis improved significantly with either of the drugs. Patients treated with pioglitazone had significant improvement in lobular inflammation, portal inflammation and Brunts grade. Brunts grade improved significantly with pioglitazone as compared to pentoxifylline at the end of the therapy. CONCLUSIONS: Pioglitazone shows better improvement in both metabolic factors and liver histology in patients with NASH compared to pentoxifylline.

Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) develops in patients with chronic liver disease and has high mortality. Mobilization of bone marrow-derived stem cells with granulocyte colony-stimulating factor (G-CSF) could promote hepatic regeneration. METHODS: Consecutive patients with ACLF were randomly assigned to groups given 5 µg/kg G-CSF subcutaneously (12 doses; group A, n = 23) or placebo (group B, n = 24) plus standard medical therapy. We assessed survival until day 60; Child-Turcotte-Pugh (CTP), Model for End-Stage Liver Disease (MELD), and Sequential Organ Failure Assessment (SOFA) scores; and the development of other related complications. RESULTS: After 1 week of treatment, group A had higher median leukocyte and neutrophil counts than group B (P < .001). Sixteen patients in group A (69.6%) and 7 in group B (29%) survived; the actuarial probability of survival at day 60 was 66% versus 26%, respectively (P = .001). Treatment with G-CSF also reduced CTP scores in group A by a median of 33.3% compared with an increase of 7.1% in group B (P = .001), along with MELD (median reduction of 15.3% compared with an increase of 11.7% in group B; P = .008) and SOFA scores (median reduction of 50% compared with an increase of 50% in group B; P = .001). The percentages of patients who developed hepatorenal syndrome, hepatic encephalopathy, or sepsis were lower in group A than in group B (19% vs 71% [P = .0002], 19% vs 66% [P = .001], and 14% vs 41% [P = .04], respectively). After 1 month of treatment, G-CSF increased the number of CD34(+) cells in the liver (by 45% compared with 27.5% in group B; P = .01). CONCLUSIONS: G-CSF therapy more than doubles the percentage of patients with ACLF who survive for 2 months; it also significantly reduces CTP, MELD, and SOFA scores and prevents the development of sepsis, hepatorenal syndrome, and hepatic encephalopathy.