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Telomere attrition, DNA damage and constitutive mitogenic signaling can all trigger cellular senescence in normal cells and serve as a defense against tumor progression. Cancer cells may circumvent this cellular defense by acquiring genetic mutations in checkpoint proteins responsible for regulating permanent cell cycle arrest. A small family of tumor suppressor genes encoding the retinoblastoma susceptibility protein family (Rb, p107, p130) exerts a partially redundant control of entry into S phase of DNA replication and cellular proliferation. Here we report that activation of the p53-dependent DNA damage response has been found to accelerate senescence in human prostate cancer cells lacking a functional Rb protein. This novel form of irradiation-induced premature cellular senescence reinforces the notion that other Rb family members may compensate for loss of Rb protein in the DNA damage response pathway. Consistent with this hypothesis, depletion of p107 potently inhibits the irradiation-induced senescence observed in DU145 cells. In contrast, p130 depletion triggers a robust and unexpected form of premature senescence in unirradiated cells. The dominant effect of depleting both p107 and p130, in the absence of Rb, was a complete blockade of irradiation-induced cellular senescence. Onset of the p107-dependent senescence was temporally associated with p53-mediated stabilization of the cyclin-dependent kinase inhibitor p27 and decreases in c-myc and cks1 expression. These results indicate that p107 is required for initiation of accelerated cellular senescence in the absence of Rb and introduces the concept that p130 may be required to prevent the onset of terminal growth arrest in unstimulated prostate cancer cells lacking a functional Rb allele.

Objective: A damage control (DC) approach was developed to improve survival in severely injured trauma patients. The role of DC in acute surgery (AS) patients who are critically ill, as a result of sepsis or overwhelming haemorrhage continues to evolve. The goal of this study was to assess morbidity and mortality of AS patients who underwent DC, and to compare observed and predicted morbidity and mortality as calculated from APACHE II and physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) scores., Methods: Consecutive acute surgery patients who underwent DC from 2002 to 2004 were included. Retrospectively collected data included patient demographics, physiological parameters, surgical indications and procedures, mortality, morbidity, as well as volumes of crystalloid and colloid (plasma and red blood cell) resuscitation. Observed mortality and complications were compared to those calculated from APACHE II and POSSUM scores. Data were analysed using the Mann-Whitney test for median values, chi-square and Fisher's exact tests for proportions., Results: Sixteen patients (mean age 53 years, seven men, nine women) underwent DC. The most common indications for DC included abdominal sepsis (6/15), intraoperative bleeding (5/15), and bowel ischaemia (3/15). The mean intraoperative blood loss during the index procedure was 2060mL. There were 2.4 average procedures per patient. At the end of DC II (36.5h), mean infusion of crystalloid was 17L, packed red blood cells was 3.6L, and plasma was 3L. Eight of 16 patients required vasopressor administration during resuscitation. At 28 days, there were five unexpected survivors as predicted by POSSUM and three by APACHE II (observed mortality seven, predicted mortality by the two methods: 12 (P=0.074), and 10 (P=0.24), respectively). Five patients died prior to definitive abdominal closure. Split thickness skin grafting (4/16) and primary fascial closure (4/16) constituted the most common methods of abdominal closure. Surgical morbidity predicted by POSSUM (98%) and actual morbidity (100%) were similar., Conclusion: Although the morbidity and mortality of AS patients undergoing DC is high, the application of DC principles in this group may reduce mortality compared to that predicted by POSSUM or APACHE II. In order to adequately demonstrate this contention, large, multi-institutional studies of DC in AS patients need to be performed. The POSSUM score appears to accurately estimate the high morbidity in general surgery DC patients, and supports the importance of team management of these complex patients by acute care surgery specialists.

Unlabelled: Opioid dependence is a growing public health problem. Maintenance on the antagonist naltrexone for clinic- or office-based treatment of opioid dependence is plagued by high rates of relapse. This paper identifies critical determinants of lapses to opioid use during naltrexone maintenance. Time retained in treatment was examined as a function of whether lapses to opioid use occurred while adherent to naltrexone (blocked use), or after having missed naltrexone doses (unblocked)., Method: Participants (N=83) met DSM-IV criteria for opioid dependence and identified a significant other willing to participate in their treatment. Following inpatient detoxification, participants were enrolled in a 26-week outpatient course of therapy and naltrexone maintenance., Results: Patients with unblocked use had a very high rate of dropout (10% retained at 6 months), dropout usually occurring within 2 weeks after unblocked use. Patients with only blocked use had less dropout (33% retained at 6 months). However, episodes of blocked use were often followed by unblocked use and dropout., Conclusions: During naltrexone maintenance for opioid dependence unblocked opioid use calls for immediate intervention, such as detoxification or switching to the partial agonist buprenorphine. Episodes of blocked use warrant increased clinical attention, such as direct observation of naltrexone ingestion, increased dose, or increased intensity of treatment contact. Maintenance on oral naltrexone is a fragile treatment because it is so easily undermined by episodes of opioid use while non-compliant. New long-acting injectable or implantable formulations of naltrexone may address this limitation and should be investigated for treatment of opioid dependence.

Background: The optimal duration of hepatic vascular inflow occlusion (Pringle maneuver) and reperfusion during liver resection are not defined. The aim of this study was to describe the changes that occur in liver tissue pH, partial pressure of carbon dioxide (P(L)CO(2)), and partial pressure of oxygen (P(L)O(2)) and by using the P(L)CO(2) as a predictor of hepatocellular damage define the optimal clamp/release regime for intermittent portal clamping during liver resection., Methods: Continuous pH, P(L)CO(2), and P(L)O(2) measurements were obtained using a Paratrend multi-parameter sensor (Diametrics Medical Inc., Roseville, MN) in 13 patients undergoing elective partial liver resection. Patients were randomly allocated to undergo a 10-min clamp/5-min release regime (group 1) or a 20-min clamp/10-min release regime (group 2)., Results: In group 1 (n = 6) P(L)CO(2) increased and pH decreased significantly after 10 min of clamping and returned to baseline within 5 min of reperfusion. In group 2 (n = 7) the P(L)CO(2) increased and pH decreased significantly after 10 min of clamping, with a further significant change after 20 min. Following 10 min of reperfusion, pH and P(L)CO(2) had not returned to baseline. P(L)O(2) did not change significantly with either intermittent portal clamping regime., Conclusions: A reperfusion of 5 min is sufficient to restore the P(L)CO(2) and liver tissue pH to normal after 10 min of clamping, but more than 10 min of reperfusion is required after 20 min of clamping. To minimize hepatic ischemia during liver resection, a 10-min clamp/5-min release regime should be used.

We present experimental observations and quantified theoretical predictions of the nanoscale hydrodynamics induced by nanorod precession emulating primary cilia motion in developing embryos. We observe phenomena including micron size particles which exhibit epicyclic orbits with coherent fluctuations distinguishable from comparable amplitude thermal noise. Quantifying the mixing and transport physics of such motions on small scales is critical to understanding fundamental biological processes such as extracellular redistribution of nutrients. We present experiments designed to quantify the trajectories of these particles, which are seen to consist of slow orbits about the rod, with secondary epicycles quasicommensurate with the precession rate. A first-principles theory is developed to predict trajectories in such time-varying flows. The theory is further tested using a dynamically similar macroscale experiment to remove thermal noise effects. The excellent agreement between our theory and experiments confirms that the continuum hypothesis applies all the way to the scales of such submicron biological motions.

During a high-speed road traffic accident, a 26-year-old man suffered multiple fractures of his thoracic vertebrae and bilateral pneumothoraces. The day after admission and commencement of nasogastric feeding, milky fluid was noted in his right chest drain. Feeding was stopped and a contrast oesophogram and oesophagoscopy were performed, which were normal. The chylothorax quickly resolved and both drains were removed on day 6. Initial treatment of chylothorax aims to decompress the pleural space and minimise chyle production by not feeding the patient via the enteral route. Most authors recommend conservative management for 2 weeks or more unless certain parameters are met: average daily chyle loss of > 1.5 l for a 5-day period, or imminent nutritional complications. In this case, surgical management of the chylothorax and spinal fractures was planned. However, conservative management was successful, highlighting the fact that early aggressive surgical intervention for chyle leaks in blunt trauma is not necessary.

Teleconferencing Supervision is a method for training community-based substance abuse clinicians in Motivational Interviewing (MI). Following a 2-day workshop, 13 clinicians received live supervision via telephone during 5 counseling sessions conducted at their community treatment facilities. Clinicians were assessed for skill level at post-workshop, at post-training, and 3 months later; learning was assessed using the MI Treatment Integrity instrument. All summary scores and therapist behavior frequency counts improved by post-training or by the 3 month follow-up, although some gains were not statistically significant. Teleconferencing Supervision may help facilitate the proficient use of MI community clinicians following workshop instruction.

Background: The safest and most effective method of early cervical spine clearance in unconscious patients is the subject of intense debate. We hypothesize that helical computed tomography (CT) is a sufficiently sensitive investigation to render dynamic screening redundant., Method: We retrospectively reviewed the records of 839 trauma patients admitted to the intensive care unit under the orthopedic surgeons from April 1994 to September 2004. Our protocol for cervical spinal clearance in the unconscious patient involves plain radiographs, CT scanning, and dynamic screening. We recorded the presence of any unstable cervical spine injury and any cases that were missed by CT but detected by dynamic screening., Results: There were 87 patients with an unstable cervical spine. Of these, 85 were detected by CT. Two cases were missed by CT (sensitivity 97.7%, specificity 100%). In one of these patients, dynamic screening detected an unstable spine and in the other patient dynamic screening missed an atlanto-occipital dislocation (sensitivity 98.8%, specificity 100%). Critical analysis of this case revealed that a powers ratio calculation on the CT scan would have detected the injury. There were no complications as a result of dynamic screening., Conclusion: Dynamic screening is a safe procedure but has no real advantage over helical CT. Power's ratio calculation is essential to reduce the chance of a missing an upper cervical injury. The cervical spine can be reliably cleared using helical CT alone.

Previously, we found that impaired cognition predicted treatment dropout from cognitive behavioral therapy (CBT) in a small sample of cocaine dependent patients. To further address the role of impaired cognition in retention and treatment outcome of cocaine-dependent patients in CBT, we expanded a previous investigation to a larger sample, added depressed cocaine patients, and added an additional cognitive assessment. Fifty-six cocaine dependent patients receiving CBT in outpatient clinical trials were assessed for cognitive performance at treatment entry with the computerized MicroCog (MC) and the Wisconsin Card Sort Test (WCST). Treatment completion was defined as 12 or more weeks. Treatment dropouts had significantly lower MC scores (poorer cognitive functioning) than completers on attention, memory, spatial ability, speed, accuracy, global functioning, and cognitive proficiency, with effect sizes in the moderate to large range. These findings were not affected by depression, demographics (age, gender, race, sex, marital status) or drug use (years of cocaine use or average weekly cocaine expenditure in the prior 30 days). In contrast, patients' performance on the WCST was in the average or near-average range, and WCST scores did not differentiate between completers and dropouts. Consistent with previous research, results suggest that mild cognitive impairments (< or =1 S.D. below the mean) negatively affect retention in outpatient CBT treatment for cocaine dependence. Future studies should examine whether there are specific effects of different executive functioning abilities on treatment outcome. Modified behavioral and pharmacologic interventions should be considered to target mild cognitive impairments to improve substance treatment outcome.

Objective: To determine opportunities for improvement (OI) in the critical care management of severely injured patients in a general adult intensive care unit through a performance improvement (PI) process., Methods: Retrospective review of patient records from intensive care patients who had sustained traumatic injuries, except isolated head injury, over a 1-year period. Three assessors independently audited the notes using performance improvement methodology to determine complications, errors in management and preventability. Complications were included when two or more assessors independently detected the complication., Measurements and Results: Records from 90 patients with a diagnosis of 'trauma' were reviewed, 14 patients with isolated head injury were excluded. The mean injury severity score was 23 (range 4-43). No complications or errors of management were identified from 41 patients, including ten patients who died. Seventy-two complications were identified in 35 patients including 15 pneumonias, 6 cases of peri-operative hypothermia and 5 recurrent pneumothoraces. Fourteen preventable complications were identified., Conclusions: The PI OI process highlighted specific opportunities for the improvement of critical care management of trauma patients in our unit. These will be addressed through the introduction of formal tertiary surveys and clinical management guidelines addressing hypothermia and management of coagulopathy.

Pancreatitis is a well recognised but rare complication following liver resection. The precise aetiology is not well understood and the clinical diagnosis may frequently be obscured by the postoperative state. Postoperative pancreatitis has a high mortality rate and should always be considered in patients who unexpectantly deteriorate postoperatively. We present three fatal cases of pancreatitis following liver resection. The literature is reviewed to elucidate common factors in patients who develop postoperative pancreatitis.

Psychiatric comorbidity, particularly depressive disorders, is associated with continued substance use and poor social functioning among methadone maintained patients. Evidence suggests similar neurochemical and environmental pathways may link the two disorders and it is reasonable to hypothesize that pharmacological and environmental factors play important roles in the treating comorbid depression and substance use. The present study tested the efficacy of sertraline for treating syndromally defined depressive disorders among non-abstinent methadone maintained opiate dependent patients. The moderating effects of environmental context on treatment outcome were also examined. Ninety-five patients were randomized in a 12-week, double-blind, placebo-controlled trial of sertraline, a serotonin-selective re-uptake inhibitor. There was no main effect of sertraline on either depression or substance use outcomes. However, sertraline demonstrated significant ameliorative effects on depression among patients with a more positive environment or less negative environment. The odds of being abstinent from heroin and cocaine were greater for patients on sertraline in environments with relatively less adversity. The findings support the hypothesis that contextual factors moderate the efficacy of pharmacological treatment for depression among methadone patients. They also suggest future research should examine a pharmacological treatment that is combined with a behavioral intervention targeting the accessibility of reinforcement or reducing the impact of aversive environmental interactions.

Objectives: To determine the incidence, aetiology and contributing factors to injuries being missed during the primary and secondary surveys in patients with major trauma managed on a general Adult Intensive Care Unit (AICU)., Methods: The records for patients admitted to the AICU following severe injury (defined as injury severity score (ISS) >16) over a 1-year period were reviewed. Diagnostic imaging performed during the resuscitation was reviewed in cases where missed injuries were discovered., Results: Forty-five patients with a median injury severity score of 26 were included in the study. Twelve missed injuries were discovered in 10 patients during the intensive care admission; three required an additional surgical procedure. There was no significant difference in Glasgow Coma Score, revised trauma score, ISS or admission systolic blood pressure between patients with missed injuries and those patients where all injures were found at resuscitation (P > 0.05). Three quarters of the undetected injuries were orthopaedic., Conclusions: Significant injuries can be missed during the primary and secondary surveys in severely injured patients. A tertiary survey should be completed in all trauma patients admitted to an intensive care unit.

Objective: To determine the level of training of General Surgeons in the UK in the Advanced Trauma Life Support (ATLS) course and their involvement with hospital trauma teams., Methods: Postal questionnaire sent to General Surgical Consultants and Higher Surgical Trainees (HSTs)., Results: 58% of General Surgeons who responded had attended ATLS, but only 30% of those who had been Consultants for more than 10 years. Eighty-seven percent considered the course 'essential' or 'some value'. Sixty-one percent of hospitals represented had a trauma team. A Consultant General Surgeon was a member of the team in 50% and the General Surgical HST in 82%., Conclusion: ATLS has been widely accepted by General Surgical Trainees and recently appointed Consultants. The trauma team approach to resuscitation has yet to become fully established in the UK and there is limited input from Consultant General Surgeons.

Humeroradial synostosis may occur sporadically or as an extremely rare inheritable disorder. The current classification divides cases into class I (fixed in extension with ulnar ray hypoplasia) or class II (fixed in flexion without hypoplasia). Familial cases of class II synostosis segregate into autosomal recessive and autosomal dominant groups. Autosomal recessive pedigrees are heterogeneous. However, when inherited as an autosomal dominant some cases of humeroradial synostosis demonstrate striking similarities limited to the musculoskeletal system: class II humeroradial synostosis, proximal symphalangism, short first metacarpal and metatarsal bones, carpal and tarsal coalitions and a prominent nasal bridge. We believe that when class II humeroradial synostosis is associated with these features, the primary diagnosis is the multiple synostosis syndrome. Furthermore, a prominent nasal bridge is present in the neonate and may aid diagnosis at this stage. We illustrate these findings with the case of a mother and only child, both demonstrating class II humeroradial synostosis and features characteristic of the multiple synostosis syndrome.