Dose-dependent benefits of quercetin on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer

Breast cancer is the leading cause of cancer related death in women. Quercetin is a flavonol shown to have anti-carcinogenic actions. However, few studies have investigated the dose-dependent effects of quercetin on tumorigenesis and none have used the C3(1)/SV40 Tag breast cancer mouse model. At 4 weeks of age female C3(1)/SV40 Tag mice were randomized to one of four dietary treatments (n = 15–16/group): control (no quercetin), low-dose quercetin (0.02% diet), moderate-dose quercetin (0.2% diet), or high-dose quercetin (2% diet). Tumor number and volume was assessed twice a week and at sacrifice (20 wks). Results showed an inverted ‘U’ dose-dependent effect of dietary quercetin on tumor number and volume; at sacrifice the moderate dose was most efficacious and reduced tumor number 20% and tumor volume 78% compared to control mice (C3-Con: 9.0 ± 0.9; C3-0.2%: 7.3 ± 0.9) and (C3-Con: 2061.8 ± 977.0 mm³; and C3-0.2%: 462.9 ± 75.9 mm³). Tumor volume at sacrifice was also reduced by the moderate dose compared to the high and low doses (C3-2%: 1163.2 ± 305.9 mm³; C3-0.02%: 1401.5 ± 555.6 mm³), as was tumor number (C3-2%: 10.7 ± 1.3 mm³; C3-0.02%: 8.1 ± 1.1 mm³). Gene expression microarray analysis performed on mammary glands from C3-Con and C3-0.2% mice determined that 31 genes were down-regulated and 9 genes were up-regulated more than 2-fold (P < 0.05) by quercetin treatment. We report the novel finding that there is a distinct dose-dependent effect of quercetin on tumor number and volume in a transgenic mouse model of human breast cancer, which is associated with a specific gene expression signature related to quercetin treatment.     

Fractures in the Maxillofacial Region: A Four Year Retrospective Study

Introduction

The incidence of maxillofacial injuries is on the rise due to motor vehicle accidents and increased incidence of violence in recent times. The aim of this retrospective study was to determine the incidence, aetiology, the pattern of fractures, their management with open reduction and internal fixation (ORIF) and complications, if any.

Methods

A retrospective analysis of 621 fractures in 361 patients managed by ORIF over a four year period was carried out.

Result

The average age of patients was 24.3 years with a male to female ratio of 21.2:1. Panfacial fractures comprised 4.7%, frontal bone fractures 8.9%, orbital fractures 0.7%, naso-orbito-ethmoid complex (NOE) fractures 0.7%, zygomatic complex fractures 23.5%, fracture maxilla 11.5% and mandibular fractures 52.2% of all facial fractures. All the cases were successfully managed by ORIF under general anaesthesia (GA). Complications were noticed in 6.8% of cases in the form of reactive implants in 3.6%, deranged occlusion in 1% and infection at operated site in 1% cases which were managed satisfactorily.

Conclusion

The findings of this study reveal sharp annual increase in the number of cases of maxillofacial trauma. Road traffic accidents (RTA) were the commonest cause and the age group most affected was between 20-25 years. ORIF of these fractures was chosen for its obvious advantages of direct anatomical reduction, early return to function and minimal complications.Key Words: Road traffic accidents (RTA), Inter maxillary fixation (IMF), Open reduction and internal fixation (ORIF)     

The effect of Gleason score on the predictive value of prostate‐specific antigen doubling time

Study Type – Prognosis (individual cohort series)
Level of Evidence 2b

OBJECTIVE

To evaluate the influence of the pathological Gleason score on the predictive value of the prostate‐specific antigen (PSA) doubling time (DT), as this variable predicts a patient’s risk of disease progression both before and after definitive therapy for prostate cancer, and there is an inverse correlation between the Gleason score and PSA production.

PATIENTS AND METHODS

We evaluated all men treated with radical prostatectomy (RP) between 1990 and 1999 who did not receive neoadjuvant or adjuvant therapy. We identified 2296 patients who had multiple PSA values available before RP, and 1323 who had biochemical recurrence after RP and had at least two PSA values available before starting secondary therapy. Systemic progression and cancer‐specific survival (CSS) rates were estimated using the Kaplan‐Meier method and Cox proportional hazard regression models.

RESULTS

A PSA DT of <18 vs >18 months predicted a lower 10‐year systemic progression‐free survival for patients with tumours having a pathological Gleason score of <7 (98% vs 99%, P = 0.005), 7 (82% vs 91%, P = 0.003) and 8–10 (57% vs 73%, P = 0.042). A PSA DT after RP of <12 months was significantly associated with a lower 10‐year systemic progression‐free survival for patients with tumours having a Gleason score of <7 (77% vs 94%, P < 0.001) and 7 (61% vs 86%, P < 0.001), but not 8–10 (61% vs 75%, P = 0.11). The ability of PSA DT before and after RP to predict systemic progression and CSS decreased with increasing Gleason score.

CONCLUSIONS

The PSA DT remains associated with outcome both before and after RP across increasing pathological Gleason scores, although the predictive ability of PSA DT is diminished in Gleason 8–10 cancers.     

Early predictors of success of non-invasive positive pressure ventilation in hypercapnic respiratory failure

Background

Non-invasive positive pressure ventilation (NIPPV) has emerged as a significant advancement in the management of acute hypercapnic respiratory failure.

Method

Patients with hypercapnic respiratory failure requiring ventilation therapy (respiratory rate [RR] of > 30 breaths per minutes, PaCO2 > 55 mmHg and arterial pH < 7.35) were included in the study. Baseline clinical parameters and arterial blood gas (ABG) were recorded before initiating NIPPV. Clinical parameters including heart rate (HR), RR, oxygen saturation and ABG were revaluated at 1, 4, and 24 hours after initiation of NIPPV. Change in these parameters and need for intubation was evaluated.

Results

Of the 100 patients, 76 (76%) showed improvement in clinical parameters and ABG. There was improvement in HR and RR, pH, and PCO2 within the first hour in the success group and these parameters continued to improve even after four and 24 hours of NIPPV treatment. Out of 24 (24%) patients who failed to respond, 13 (54%) needed endotracheal intubation within one hour. The failure group had higher baseline HR than the success group.

Conclusion

Improvement in HR, RR, pH, and PCO2 one hour after putting the patient on NIPPV predicts success of non-invasive positive pressure ventilation in hypercapnic respiratory failure.     

Article not available electronically: Neurocognitive impairment in alcohol-dependence syndrome cases and its response to treatment

Background

A sizeable portion of psychiatric ward beds in military hospitals is occupied by patients with psychoactive substance abuse and especially by alcohol-dependence syndrome (ADS) cases. Though there have been significant advances in the diagnosis and management of these cases, not much of work has been done in our set up for the evaluation of their cognitive impairment and its response to treatment.

Methods

Neuropsychological evaluation of 100 cases of freshly diagnosed ADS was done by using postgraduate battery of brain dysfunction (PGI-BBD). The findings were compared with controls. They were detoxified, treated and after four weeks were re-evaluated and the findings were analysed.

Results

There was significant impairment in all parameters of cognition. All of them showed improvement with treatment but after four weeks, the impairment persisted to significant level in some parameters.

Conclusion

Alcohol-dependence syndrome cases have significant cognitive impairment but improve with detoxification, multivitamin supplement and abstinence. This aspect has to be kept in mind while deploying them in sensitive appointments.     

The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV1

Although the dominant approach to drug development is the design of compounds selective for a given target, compounds targeting more than one biological process may have superior efficacy, or alternatively a better safety profile than standard selective compounds. Here, this possibility has been explored with respect to the endocannabinoid system and pain. Compounds inhibiting the enzyme fatty acid amide hydrolase (FAAH), by increasing local endocannabinoid tone, produce potentially useful effects in models of inflammatory and possibly neuropathic pain. Local increases in levels of the endocannabinoid anandamide potentiate the actions of cyclooxygenase inhibitors, raising the possibility that compounds inhibiting both FAAH and cyclooxygenase can be as effective as non-steroidal anti-inflammatory drugs but with a reduced cyclooxygenase inhibitory ‘load’. An ibuprofen analogue active in models of visceral pain and with FAAH and cyclooxygenase inhibitory properties has been identified. Another approach, built in to the experimental analgesic compound N-arachidonoylserotonin, is the combination of FAAH inhibitory and transient receptor potential vanilloid type 1 antagonist properties. Although finding the right balance of actions upon the two targets is a key to success, it is hoped that dual-action compounds of the types illustrated in this review will prove to be useful analgesic drugs.     

Novel Molecular Targets of Azadirachta indica Associated with Inhibition of Tumor Growth in Prostate Cancer

Advanced prostate cancer has significant long-term morbidity, and there is a growing interest in alternative and complimentary forms of therapy that will improve the outcomes of patients. Azadirachta indica (common name: neem) contains multiple active compounds that have potent anti-inflammatory and anticancer properties. The present study investigates the novel targets of the anticancer activity of ethanol extract of neem leaves (EENL) in vitro and evaluates the in vivo efficacy in the prostate cancer models. Analysis of the components in the EENL by mass spectrometry suggests the presence of 2',3'-dehydrosalannol, 6-desacetyl nimbinene, and nimolinone. Treatment of C4-2B and PC-3M-luc2 prostate cancer cells with EENL inhibited the cell proliferation. Genome-wide expression profiling, using oligonucleotide microarrays, revealed genes differentially expressed with EENL treatment in prostate cancer cells. Functional analysis unveiled that most of the up-regulated genes were associated with cell death, and drug metabolism, and the down-regulated genes were associated with cell cycle, DNA replication, recombination, and repair functions. Quantitative PCR confirmed significant up-regulation of 40 genes and immunoblotting revealed increase in the protein expression levels of HMOX1, AKR1C2, AKR1C3, and AKR1B10. EENL treatment inhibited the growth of C4-2B and PC-3M-luc2 prostate cancer xenografts in nude mice. The suppression of tumor growth is associated with the formation of hyalinized fibrous tumor tissue and the induction of cell death by apoptosis. These results suggest that EENL-containing natural bioactive compounds could have potent anticancer property and the regulation of multiple cellular pathways could exert pleiotrophic effects in prevention and treatment of prostate cancer.