Practical consensus recommendations on duration of adjuvant hormonal therapy in breast cancer.

Optimization of adjuvant systemic therapy in women with early-stage hormone receptor-positive breast cancer includes the consideration of chemotherapy and duration of hormone therapy. Adjuvant hormonal therapy significantly improves long-term survival of breast cancer patients with hormone receptor-positive disease. Despite the proven clinical efficacy of tamoxifen and aromatase inhibitors, many breast cancer survivors either fail to take the correct dosage at the prescribed frequency (adherence) or discontinue therapy (persistence). Expert oncologist discussed on the duration of adjuvant hormonal therapy for improvement of OS and quality of life of breast cancer patients by providing reduction in recurrence and mortality. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists.

Practical consensus recommendations for neo-adjuvant chemotherapy in triple negative breast cancer.

This manuscript provides a practical and easy to use consensus recommendation to community oncologists on how to use neoadjuvant chemotherapy in triple negative breast cancer patients.

Retinoic acid receptor signalling directly regulates osteoblast and adipocyte differentiation from mesenchymal progenitor cells.

Low and high serum retinol levels are associated with increased fracture risk and poor bone health. We recently showed retinoic acid receptors (RARs) are negative regulators of osteoclastogenesis. Here we show RARs are also negative regulators of osteoblast and adipocyte differentiation. The pan-RAR agonist, all-trans retinoic acid (ATRA), directly inhibited differentiation and mineralisation of early osteoprogenitors and impaired the differentiation of more mature osteoblast populations. In contrast, the pan-RAR antagonist, IRX4310, accelerated differentiation of early osteoprogenitors. These effects predominantly occurred via RARγ and were further enhanced by an RARα agonist or antagonist, respectively. RAR agonists similarly impaired adipogenesis in osteogenic cultures. RAR agonist treatment resulted in significant upregulation of the Wnt antagonist, Sfrp4. This accompanied reduced nuclear and cytosolic ß-catenin protein and reduced expression of the Wnt target gene Axin2, suggesting impaired Wnt/ß-catenin signalling. To determine the effect of RAR inhibition in post-natal mice, IRX4310 was administered to male mice for 10 days and bones were assessed by µCT. No change to trabecular bone volume was observed, however, radial bone growth was impaired. These studies show RARs directly influence osteoblast and adipocyte formation from mesenchymal cells, and inhibition of RAR signalling in vivo impairs radial bone growth in post-natal mice.

Knockdown of PTHR1 in osteosarcoma cells decreases invasion and growth and increases tumor differentiation in vivo.

Osteosarcoma (OS) is the most common cancer of bone. Parathyroid hormone (PTH) regulates calcium homeostasis and bone development, while the paracrine/autocrine PTH-related protein (PTHrP) has central roles in endochondral bone formation and bone remodeling. Using a murine OS model, we found that OS cells express PTHrP and the common PTH/PTHrP receptor (PTHR1). To investigate the role of PTHR1 signaling in OS cell behavior, we used shRNA to reduce PTHR1 expression. This only mildly inhibited proliferation in vitro, but markedly reduced invasion through collagen and reduced expression of RANK ligand (RANKL). Administration of PTH(1-34) did not stimulate OS proliferation in vivo but, strikingly, PTHR1 knockdown resulted in a profound growth inhibition and increased differentiation/mineralization of the tumors. Treatment with neutralizing antibody to PTHrP did not recapitulate the knockdown of PTHR1. Consistent with this lack of activity, PTHrP was predominantly intracellular in OS cells. Knockdown of PTHR1 resulted in increased expression of late osteoblast differentiation genes and upregulation of Wnt antagonists. RANKL production was reduced in knockdown tumors, providing for reduced homotypic signaling through the receptor, RANK. Loss of PTHR1 resulted in the coordinated loss of gene signatures associated with the polycomb repressive complex 2 (PRC2). Using Ezh2 inhibitors, we demonstrate that the increased expression of osteoblast maturation markers is in part mediated by the loss of PRC2 activity. Collectively these results demonstrate that PTHR1 signaling is important in maintaining OS proliferation and undifferentiated state. This is in part mediated by intracellular PTHrP and through regulation of the OS epigenome.

Characterization and anti-microbial susceptibility of bacterial isolates: Experience from a tertiary care cancer center in Delhi.

BACKGROUND: Hospitalization for fever in cancer patients is associated with considerable morbidity, mortality, and cost. AIM: The aim of this study was to study the bacterial spectrum and susceptibility patterns of pathogens in culture positive patients from the oncology unit of our hospital. METHODS: We retrospectively reviewed the medical records of patients admitted in our cancer center (medical, radiation, and surgical oncology) from January to December 2013. Blood and respiratory secretions from the indoor patients were evaluated. RESULTS: Of the total 693 samples, 76.4% were Gram-negative and 23.6% were Gram-positive. The most common bacterial isolates among Gram-negative organisms in blood were Escherichia coli, Salmonella and among the Gram-positive organism were Staphylococcus aureus and Enterococcus. Among the blood isolates extended spectrum of beta-lactamase, multidrug-resistant (carbapenem-resistant) and pan resistant bugs were seen in 47%, 15%, and 5% of the blood isolates. Among the Gram-positive organisms, 25% respiratory isolates were vancomycin-resistant Enterococci. CONCLUSION: We observed a high incidence of Gram-negative isolates with clinically significant resistance to first-line antibiotics such as cephalosporin's, piperacillin tazobactum, and fluoroquinolones.

Evaluation of Antioxidant Activity of Picrorhiza kurroa (Leaves) Extracts.

Picrorhiza kurroa is a well-known herb in Ayurvedic medicine. Although it shows antioxidant, antiinflammatory and immunomodulatory activities, it is most valued for its hepatoprotective effect. The rhizomes are widely used against indigestion problems since ancient times due to improper digestive secretions. Aim of this study was to explore antioxidant study of P. kurroa leaves for a new source of naturally occurring antioxidants. Two pure compounds, luteolin-5-O-glucopyranoside (1) and picein (2) were isolated from butanol extract through column chromatography. Different extracts of P. kurroa leaves (ethanol, ethyl acetate, butanol) were quantified for isolated compound (2) by high-performance liquid chromatography. All the extracts and isolated compounds were evaluated for its antioxidant activity using two assays, 2,2-diphenyl-1-picrylhydrazyl radical and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) assay. The linear detection range was 1.56-200 µg/ml for picein. The limit of detection and limit of quantification for picein were 2.34 and 7.81 µg/ml, respectively. Butanol and ethyl acetate extract showed greater antioxidant activity as compare to ethanol extract. Compound 1 and ascorbic acid showed nearly similar antioxidant activity where as 2 showed no activity at standard concentration. The IC50 values for 2,2-diphenyl-1-picrylhydrazyl radical and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) assay for ascorbic acid, compound 1, ethanol extract and its different fractions (ethyl acetate and butanol) were found to be 0.81, 1.04, 67.48, 39.58, 37.12 and 2.59, 4.02, 48.36, 33.24, 29.48 µg, respectively.

Gemella haemolysans spondylodiscitis: a report of two cases.

We report on two cases of infective spondylodiscitis caused by Gemella haemolysans in otherwise healthy patients. This organism has only rarely been identified as a cause of bone and joint infection, with only two previous reports of infective spondylodiscitis. We describe the clinical features, investigations and treatment options.

Idiopathic pulmonary hemosiderosis: clinical profile and follow up of 26 children.

OBJECTIVES: To describe the clinical details and follow up of children with idiopathic pulmonary hemosiderosis. DESIGN: Retrospective case series. SETTING: Pediatric chest clinic of a tertiary care hospital. SUBJECTS: Children diagnosed as suffering from idiopathic pulmonary hemosiderosis (IPH). METHODS: Charts of patients diagnosed as IPH were reviewed for clinical features and treatment regimen. Diagnosis was based on presence of iron deficiency anemia, chest radiography and demonstration of hemosiderin laden macrophages in bronchoalveolar lavage (BAL), gastric aspirate, or sputum. Treatment consisted of oral prednisolone, hydroxychloroquine (HCQ) and inhaled corticosteroids (ICS). RESULTS: The common clinical features in 26 children with IPH (mean age 75 months) included: cough, breathlessness, fever, hemoptysis and wheezing in 26 (100%), 22 (85%), 19 (73%),15 (58%) and 14 (54%) children, respectively. Clubbing, hepatomegaly and splenomegaly was seen in 16 (62%), 15 (58%) and 10 (38%) children, respectively. Hemosiderin laden macrophages were documented in BAL and gastric aspirate in 92% and 30% patients, respectively. Symptoms did not recur in 17 patients who received prednisolone and HCQ initially. 5 patients had recurrence of symptoms and required short courses of oral prednisolone, 4 patients required frequent courses of prednisolone and were started on azathioprine. Older age, longer duration of illness, history of hemoptysis and jaundice were associated with poor response. CONCLUSION: Treatment with prednisolone and hydroxychloroquine followed by inhaled corticosteroids may improve survival in children with IPH.

Caloxin: a novel plasma membrane Ca2+ pump inhibitor.

Plasma membrane (PM) Ca2+ pump is a Ca+-Mg2+-ATPase that expels Ca2+ from cells to help them maintain low concentrations of cytosolic Ca2+ . There are no known extracellularly acting PM Ca2+ pump inhibitors, as digoxin and ouabain are for Na+ pump. In analogy with digoxin, we define caloxins as extracellular PM Ca2+ pump inhibitors and describe caloxin 2A1. Caloxin 2A1 is a peptide obtained by screening a random peptide phage display library for binding to the second extracellular domain (residues 401-413) sequence of PM Ca2+ pump isoform 1b. Caloxin 2A1 inhibits Ca2+-Mg2+-ATPase in human erythrocyte leaky ghosts, but it does not affect basal Mg2+-ATPase or Na+-K+-ATPase in the ghosts or Ca2+-Mg2+-ATPase in the skeletal muscle sarcoplasmic reticulum. Caloxin 2A1 also inhibits Ca2+-dependent formation of the 140-kDa acid-stable acylphosphate, which is a partial reaction of this enzyme. Consistent with inhibition of the PM Ca2+ pump in vascular endothelium, caloxin 2A1 produces an endothelium-dependent relaxation that is reversed by N(G)-nitro-L-arginine methyl ester. Thus caloxin 2A1 is a novel PM Ca2+ pump inhibitor selected for binding to an extracellular domain.

Effects of hydrogen peroxide on pig coronary artery endothelium.

Peroxides and other reactive oxygen species damage arteries during ischemia-reperfusion. Here, we report on the effects of H(2)O(2) on contractility of pig coronary artery. We either treated 3-mm coronary artery rings with 0 to 0.5 mM H(2)O(2) in organ baths or we perfused the arteries with H(2)O(2) and then cut them into rings. In each instance, we monitored the force of contraction of 3-mm rings in H(2)O(2)-free solution with 30 mM KCl and then we determined the A23187 induced endothelium dependent relaxation as a percent of this contraction. Treatment with H(2)O(2) in the organ bath caused a decrease in the contraction but it did not affect the percent relaxation. Treating arteries with H(2)O(2) by luminal perfusion did not affect the contraction but it decreased the percent relaxation. Perfusion alone decreased the amount of endothelium remaining in the arteries and perfusing with H(2)O(2) decreased it further. The percent relaxation with A23187 correlated well with the endothelium remaining in the arteries. We propose that H(2)O(2) and shear stress can cause a loss of endothelium and that endothelium can also protect the underlying smooth muscle against luminal H(2)O(2).

Prevalence of coronary risk factors in non-insulin dependent (type 2) diabetics.

OBJECTIVES: A cross sectional study was conducted to find the prevalence of coronary risk factors in non-insulin dependent diabetic (NIDDM) patients and to compare and co-relate these risk factors in type II diabetics with and without electrocardiographic and/or symptomatic evidence of coronary heart disease (CHD). METHODS: One hundred sixty-seven consecutive NIDDM patients (77 males, and 90 females) attending the diabetic clinic at Dr. RML Hospital, New Delhi were studied. Only known NIDDM cases, already on treatment and without any history of ketosis or congestive heart failure were included. Coronary risk factors comprising of age, gender, duration and treatment for diabetes, smoking, physical activity, hypertension, truncal obesity, lipids, microalbuminuria (semiquantitative) and glycemic control have been particularly ascertained in all the cases. The data was analysed using 'Epi Info version 6.0'. RESULTS: The mean age of patients was 53.12 year and 8.86 year was the mean duration of diabetes. 28.6% of the diabetic men were found to be currently smoking and/or consuming alcohol, 82% were involved in sedentary physical activity and 20.4% had family history of CHD. Central obesity was observed in 46.7% of the cases; more so in females. 31.74% of cases were hypertensive; more females than males had hypertension (33.8% vs 30%). Poor glycemic control (HbA1c > = 9.5%) was seen in 16.8% of the cases. In about 52.5% of the total group hypertriglyceridemia was noted. Microalbuminuria could be found in 35.93%. CHD was diagnosed in 15.57% of cases in this study. CONCLUSIONS: The present study revealed that high levels of serum cholesterol (p = 0.000004), LDL (p = 0.00003), HbA1c (p = 0.002), microalbuminuria (p = 0.000006) and hypertension (p = 0.00006) are significant associates of CHD in NIDDM (both the sexes). Among the female NIDDM cases, in addition BMI (p = 0.01), Waist-hip ratio (WHR) (p = 0.003) and low HDL level (p = 0.008) are important correlates of CHD. Multiple logistic regression analysis was used to allow for confounding between variables. Microalbuminuria alone entered the 'best' model for CHD prediction. Other risk factors, though significant, provided inadequate models for CHD prediction.

AIDS awareness among nursing students of Delhi.

A total of 233 students of nursing school affiliated to a major hospital of Delhi were surveyed anonymously employing a predesigned, pretested and self-administered questionnaire. Although, 78.6 per cent students knew that AIDS stands for "Acquired Immuno-deficiency Syndrome," 15.5 per cent students were unaware of the fact that AIDS had reached India. Majority of them were aware of various aspects of HIV/AIDS. However, they also had few misconceptions particularly regarding HIV transmission. Contrary to our belief, only one-fourth students acquired AIDS information from scientific journals. One training session on AIDS conducted for a small group of students could not bring any significant change in their knowledge. Findings suggest organization of AIDS-training sessions at regular intervals from the very inception of nursing programme to impart complete and correct knowledge of these future Florence Nightingales regarding various aspects of HIV/AIDS and for removal of misconceptions.

Serum adenosine deaminase, 5'-nucleotidase & alkaline phosphatase in breast cancer patients.

Serum levels of adenosine deaminase (ADA), 5-nucleotidase (5'-NT) and alkaline phosphatase (ALP) were studied in 25 patients of carcinoma breast and 25 normal subjects. Adenosine deaminase was found to be the better probable parameter for the detection of cancer and to assess the development of various stages of cancer whereas 5'-nucleotidase had only diagnostic significance. Serum alkaline phosphatase levels were important for assessing the spread of cancer at secondary sites. After mastectomy a significant decrease was found in the levels of serum ADA and 5'-NT whereas no variations were found in case of serum ALP.

Pediatric trauma: differences in pathophysiology, injury patterns and treatment compared with adult trauma.

Although multiple trauma remains the leading cause of death among children, fewer resources and less attention have been directed to treatment of the injured child than to treatment of the injured adult. Insufficient training of medical personnel and hence lack of expertise in the management of injured children are factors contributing to disability and death in such children. Although the principles of resuscitation of injured children are similar to those for adults, appreciation of the differences in cardiorespiratory variables, airway anatomy, response to blood loss, thermoregulation and equipment required is essential for successful initial resuscitation. Cerebral, abdominal and thoracic injuries account for most of the disability and death among injured children. Cerebral damage may be due to secondary injuries to the brain and is potentially preventable. The need to preserve the spleen in children complicates the management of abdominal trauma. Although children usually have large cardiorespiratory reserves, they are likely to need airway control and ventilation with thoracic injuries. The psychologic effect of trauma may pose long-term problems and needs close follow-up.

The critically ill child in the pediatric emergency department.

A retrospective study of the charts of all critically ill patients visiting our pediatric emergency department over an 18-month period was conducted to determine age, diagnosis, time of presentation to the pediatric ED, Physiologic Stability Index (PSI) and Therapeutic Intervention Scoring System (TISS) score, and eventual outcome. Eighty percent of critically ill patients were less than 6 years old. Of these patients, 35% had neurological problems, 23% had lower airway disease, and 15% had upper airway obstruction. Forty-one percent of children presented during the day shift, 33% during the evening shift, and 26% at night. One hundred fifteen patients survived to discharge from the intensive care unit; eight patients died. A statistically significant difference in retrospectively assigned PSI scores in nonsurvivors (18.1 +/- 6.5) compared with those in survivors (5.2 +/- 3.5) was observed. There was also a statistically significant difference in retrospectively assigned TISS scores in nonsurvivors (32.4 +/- 3.2) compared with those in survivors (13.5 +/- 2.1). Implications for physicians involved in the emergency care of critically ill children and for designs of pediatric advanced life support programs are outlined.