Hydroxychloroquine attenuates cigarette smoke induced autophagic signaling in the mouse ovary.

We previously demonstrated that Cigarette Smoke (CS) induces autophagy in the ovary. Therefore we aimed to determine if chloroquine (CQ) could inhibit CS-induced autophagy in the ovary. Eight week old mice were implanted with CQ pellets; 0, 25, and 50mg CQ/kg. Half of the animals in each group were exposed to room air and the other half were exposed to CS twice daily for 8 weeks. Ovaries were harvested for electron microscopy, gene and protein expression analysis. There was a significant increase in the production of autophagosomes in granulosa cells of mice exposed to CS (p=0.0297). However 25 and 50mg/kg CQ treatment significantly decreased the CS-induced autophagosomes (p=0.0505; p=0.0065) and attenuated the effects of CS on LC3B and BECN1 expression. In summary, this suggests that CQ attenuates CS-induced autophagy in the ovary and that ovarian protection from toxic insult is potentially feasible.

Chemoradiotherapy, with adjuvant surgery for local control, confers a durable survival advantage in adenocarcinoma and squamous cell carcinoma of the oesophagus.

INTRODUCTION: Oesophageal cancer usually presents with systemic disease, necessitating systemic therapy. Neo-adjuvant chemoradiotherapy improves short-term survival, but its long-term impact is disputed because of limited accrual, treatment-protocol heterogeneity and a short follow-up of randomised trials. AIMS: Long-term results of two simultaneous randomised controlled trials (RCTs) comparing neo-adjuvant chemo-radiotherapy and surgery (MMT) with surgical monotherapy were examined, and the response of adenocarcinoma (AC) and squamous cell carcinoma (SCC) to identical regimens compared. METHODS: Between 1990 and 1997, two RCTs were undertaken on 211 patients. Patients with AC (n=113) or SCC (n=98) were separately-randomised to identical protocols of MMT or surgical monotherapy. RESULTS: 211 patients were followed to 206 months; 104 patients were randomised to MMT (58 AC and 46 SCC, respectively) and 107 to surgery. MMT provided a significant survival-advantage over surgical monotherapy for AC (P=0.004), SCC (P=0.01). There was a 54% relative risk-reduction in lymph-node metastasis following MMT, compared with surgery (64% versus 29%, P<0.001). MMT produced a pathologic complete response (pCR) in 25% and 31% of AC and SCC, respectively. Survival advantage accrued to MMT, pCR and node-negative patients: AC pCR versus surgical monotherapy (P=0.001); residual disease following MMT versus surgical monotherapy (P=0.008); SCC pCR versus surgical monotherapy (P=0.033). CONCLUSIONS: A survival advantage for MMT persisted long-term in AC and was replicated in SCC. MMT produced loco-regional tumour down-staging to extinction in 25-31% of patients, potentially permitting personalised treatment in this cohort that avoids the morbidity and mortality associated with resection. Node-negative patients with residual localised disease following MMT had a survival advantage over node-negative patients following surgery alone, supporting a systemic effect on micro-metastatic disease.

NAC1, A POZ/BTB protein interacts with Parkin and may contribute to Parkinson's disease.

Loss-of-function in the Parkin protein is thought to play a part in causing neuronal cell death in patients with Parkinson's disease. This study explores the effect of Parkin degradation, via the overexpression of nucleus accumbens 1 (NAC1), on cell viability. It was found that NAC1 and Parkin are co-localized within the cell and interact with one another, leading to a decrease in Parkin levels. Moreover, NAC1 down-regulates Parkin by presenting it for ubiquitin-dependent proteasome degradation, which causes a decrease in proteasomal activity in neuronal cells. Consequently, this decrease in proteasomal activity leads to an increase in the cells' susceptibility to proteasome inhibition-induced toxicity. It was also found that Parkin and NAC1 are key proteins found to be present mainly in the cytoplasm and are co-localized in neurons of Parkinson's disease patients. Interestingly, mutation in the POZ/BTB domain (Q23L) of NAC1 disrupts the co-localization and interaction of NAC1 with Parkin and it further abrogates the proteasome inhibition-induced toxicity. We further observed that co-transfection of the mutant form of NAC1 with Parkin reversed the proteasome activity and 20S proteasome protein levels. These results indicate a novel interaction between NAC1 and Parkin that leads to neuronal cell death, a main characteristic in Parkinson's disease.

The introduction of an acute physiological support service for surgical patients is an effective error reduction strategy.

INTRODUCTION: Acute surgical patients are particularly vulnerable to human error. The Acute Physiological Support Team (APST) was created with the twin objectives of identifying high-risk acute surgical patients in the general wards and reducing both the incidence of error and impact of error on these patients. A number of error taxonomies were used to understand the causes of human error and a simple risk stratification system was adopted to identify patients who are particularly at risk of error. RESULTS: During the period November 2012-January 2013 a total of 101 surgical patients were cared for by the APST at Edendale Hospital. The average age was forty years. There were 36 females and 65 males. There were 66 general surgical patients and 35 trauma patients. Fifty-six patients were referred on the day of their admission. The average length of stay in the APST was four days. Eleven patients were haemo-dynamically unstable on presentation and twelve were clinically septic. The reasons for referral were sepsis,(4) respiratory distress,(3) acute kidney injury AKI (38), post-operative monitoring (39), pancreatitis,(3) ICU down-referral,(7) hypoxia,(5) low GCS,(1) coagulopathy.(1) The mortality rate was 13%. A total of thirty-six patients experienced 56 errors. A total of 143 interventions were initiated by the APST. These included institution or adjustment of intravenous fluids (101), blood transfusion,(12) antibiotics,(9) the management of neutropenic sepsis,(1) central line insertion,(3) optimization of oxygen therapy,(7) correction of electrolyte abnormality,(8) correction of coagulopathy.(2) CONCLUSION: Our intervention combined current taxonomies of error with a simple risk stratification system and is a variant of the defence in depth strategy of error reduction. We effectively identified and corrected a significant number of human errors in high-risk acute surgical patients. This audit has helped understand the common sources of error in the general surgical wards and will inform on-going error reduction initiatives.

Excision and primary closure of pilonidal sinus disease: worthwhile option with an acceptable recurrence rate.

BACKGROUND: Treatment of pilonidal sinus disease is controversial. Many claim policy of marsupialisation and healing by secondary intention. This is demanding in terms of nursing care and time lost from work. AIMS: To examine outcome of excision and primary closure of chronic pilonidal disease on recurrence rate and patient's daily activities. PATIENTS AND METHODS: One hundred and fourteen consecutive elective patients who had excision and primary closure of pilonidal sinus disease were reviewed. The demographic data and the post-operative outcome were studied. RESULTS: The recurrence of pilonidal sinus was noted in 9% of patients, wound breakdown occasioning delayed healing in 9%, patients able to drive by day 16 on average. The mean time to return to work was 20.5 days; duration of analgesia, 2.4 days; and duration of antibiotic treatment, 4.7 days. CONCLUSION: Excision and primary closure of chronic pilonidal sinus has low recurrence rate with early return to activities. Primary closure appears to be a cost-effective option for uncomplicated pilonidal sinus disease.

Interns as teachers of medical students: a pilot programme.

BACKGROUND: In recent years, rising numbers of medical students and an increasingly demanding clinical workload has put pressures on the educational systems for medical students in the hospital. Bedside teaching remains central to education, but tutorial delivery by registrars, tutors and consultants has proven to be increasingly difficult with the greater numbers of students now in the undergraduate system. AIMS: We have performed a pilot study to determine the feasibility of developing a Junior Tutor Programme, to assist in the delivery of tutorials to undergraduate medical students. METHODS: This was designed and delivered by interns under the supervision of the academic staff in the Departments of Medicine and Surgery in Connolly Hospital. The programme was evaluated by a questionnaire filled in by the students anonymously. RESULTS: A supervised programme of tutorials delivered by interns is a potentially useful way to ensure delivery of clinical teaching to undergraduate medical students.

Lack of awareness of oesophageal carcinoma among the public in Ireland.

BACKGROUND: Oesophageal cancer is advanced in the majority at presentation and its symptoms are usually present for many months suggesting poor awareness of its symptoms. Few studies have examined awareness of oesophageal cancer amongst the public. AIMS: This study aimed to identify the level of awareness among the general public of oesophageal cancer, of its symptoms, of its awareness campaigns and to compare it with other common cancers. METHODS: Face-to-face interviews were conducted with 279 members of the public. People were asked about their awareness of a range of cancers, and their knowledge of cancer symptoms and cancer awareness campaigns. RESULTS: Awareness of oesophageal cancer was low and knowledge of its symptoms was even lower. Despite the efforts of awareness campaigns, knowledge of these campaigns was poor amongst the public. CONCLUSION: Awareness of oesophageal cancer and its symptoms is low amongst the public. This needs to be addressed if disease is to be detected at an earlier and curable stage.