Posttraumatic stress disorder (PTSD) has been linked to increased morbidity. An inflexibility of the autonomic nervous system may be the underlying mechanism. We aimed to assess whether PTSD and combat trauma exposure are associated with lower heart rate variability (HRV), a measure of autonomic function and a predictor of death.
We measured HRV by power spectral analysis on 24-hour ambulatory ECG in 459 middle-aged veteran male twins. Combat trauma was assessed with the combat exposure scale, and current and remitted PTSD with the Structured Clinical Interview for Psychiatry Disorders. Mixed-effects regression models were used to test associations of PTSD and HRV between and within twin pairs.
Of all twins, 211 had combat exposure, 31 had current PTSD, and 43 had remitted PTSD. Current PTSD was inversely associated with very-low frequency (VLF) and low frequency (LF) HRV both in individual twins and within 20 pairs discordant for current PTSD. Twins with current PTSD had a 49% lower LF HRV than their brothers without PTSD (p<0.001). Remitted PTSD was not associated with HRV. Results were robust to adjustment for depression and other risk factors. Combat exposure was inversely associated with most HRV frequencies, but this association mostly diminished after adjustment for current PTSD.
In middle-aged veteran men, combat exposure and current PTSD are associated with measures of autonomic inflexibility previously shown to have prognostic significance. The negative health impact of combat exposure on autonomic function is mediated largely through PTSD and may reverse with remission of PTSD.
Autonomic nervous system; heart rate variability; posttraumatic stress disorder; military combat trauma; mental stress; heart disease
RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT).
Eligible patients with T-scores of the hip (< −1.0, but > −2.5 vs. > −1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years.
Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm I and 34.8 months for Arm 2. Only two patients experienced a bone fracture (1 in each arm) resulting in no difference in freedom from any bone fracture (p=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs. −5%, p<0.0001), left total hip (1% vs. −8%, p=0.0002), and left femoral neck (3% vs. −8%, p=0.0007).
For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL.
radiation therapy; androgen deprivation therapy; osteoporosis; prostate cancer; bone fractures
There is increasing evidence that the growth and spread of cancers is driven by a small subpopulation of cancer stem cells (CSCs)—the only cells that are capable of long-term self-renewal and generation of the phenotypically diverse tumor cell population. CSCs have been identified and isolated in a variety of human cancers including head and neck squamous cell carcinoma (HNSCC). The concept of cancer stem cells may have profound implications for our understanding of tumor biology and for the design of novel treatments targeted toward these cells. The present review is an attempt to conceptualize the role of CSCs in HNSCC—its implication in tumorigenesis and the possible additional approach in current treatment strategies.
Current treatment guidelines support the role of lifestyle modification, in terms of increasing the quantity and quality of physical activity to achieve target glycemia in patients with type 2 diabetes mellitus.
To assess the effect of structured exercise training and unstructured physical activity interventions on glycemic control.
Materials and Methods:
This was a randomized six-month exercise intervention study conducted with previously inactive 279 patients of type 2 diabetes mellitus. Before randomization, all enrolled T2DM participants (n: 300; 30 to 60 year old, having diabetes for more than a year with HbA1c levels of 6.5% or higher) entered a one-month run-in phase to reduce dropout and maintain adherence.
A recommendation to increase physical activity was beneficial (0.14% HbA1c reduction; P = 0.12), but was not bringing significantly declines in HbA1c, whereas, structured exercise training is associated with a significant HbA1c decline of 0.59%. (P = 0.030). In a subgroup analysis limited to participants with a baseline HbA1c value > 7%, both the unstructured (0. 48%; P = 0.04) and structured exercise training (0.77%; P < 0.01) groups experienced significant decline in HbA1c Vs the control, whereas among participants with baseline hemoglobin A1c values less than 7%, significant reduction occurred only in the structured exercise training group. Changes in blood pressure; total cholesterol, HDL-cholesterol (high-density lipoprotein), LDL-cholesterol (low-density lipoprotein) and the atherogenic index factors did not statistically significantly differ within (baseline to follow-up) and among groups.
Supervised structured training was more efficacious than unstructured activity in achieving declines in HbA1c. Although both structured and unstructured training provide benefits, only the former was associated with significant reductions in HbA1c levels. Therefore, T2DM patients should be stimulated to participate in specifically designed exercise intervention programs.
Hemoglobin A1c; physical activity; structured exercise; type 2 diabetes mellitus
Although common during the early stages of recovery from severe traumatic brain injury (TBI), attention deficits have been scarcely investigated. Encouraging evidence suggests beneficial effects of attention training in more chronic and higher functioning patients. Interactive technology may provide new opportunities for rehabilitation in inpatients who are earlier in their recovery.
We designed a “virtually minimal” approach using robot-rendered haptics in a virtual environment to train severely injured inpatients in the early stages of recovery to sustain attention to a visuo-motor task. 21 inpatients with severe TBI completed repetitive reaching toward targets that were both seen and felt. Patients were tested over two consecutive days, experiencing 3 conditions (no haptic feedback, a break-through force, and haptic nudge) in 12 successive, 4-minute blocks.
The interactive visuo-haptic environments were well-tolerated and engaging. Patients typically remained attentive to the task. However, patients exhibited attention loss both before (prolonged initiation) and during (pauses during motion) a movement. Compared to no haptic feedback, patients benefited from haptic nudge cues but not break-through forces. As training progressed, patients increased the number of targets acquired and spontaneously improved from one day to the next.
Interactive visuo-haptic environments could be beneficial for attention training for severe TBI patients in the early stages of recovery and warrants further and more prolonged clinical testing.
Virtual reality; Robotics; Attention; Rehabilitation; TBI
This case study describes how we are translating a diabetes care quality improvement initiative from an insured (HMO) setting into federally qualified health centers (FQHCs). We outline the innovative collaborative processes whereby researchers and FQHC providers adapted this initiative, which includes health information technology tools, to meet the FQHCs’ needs.
Translational research; practice-based research; quality improvement; electronic health record
Assisted reproductive technology (ART) has revolutionized the management of subfertility as many couples who previously had no hope of achieving a pregnancy are able to do so. Several factors contribute to the successful outcome of assisted conception. The period of waiting for the pregnancy test after assisted conception could be very crucial to the patient. One outcome of assisted conception could be a positive pregnancy test which could lead to a clinical pregnancy resulting in a live birth, clinical pregnancy resulting in a miscarriage or a biochemical pregnancy. A negative pregnancy test, failure to fertilise and failure to respond to stimulation usually lead to a big blow to the couple. As far as biochemical pregnancy is concerned, its exact aetiology remains unknown. There are no definite predictive factors for its occurrence that can be remedied in subsequent cycles. Several associated aetiologies have been suggested in the literature. This review aims at addressing the issue of biochemical pregnancy after assisted conception as a prelude to conducting further studies to assess if there are any predictive factors for its occurrence.
Biochemical pregnancy; In vitro fertilisation; Assisted reproductive technology; Beta human chorionic gonadotropin; Embryo transfer; Intracytoplasmic sperm injection
The number of procedures involving upgrade or revision of cardiac implantable electronic devices (CIEDs) is increasing and the risks of adding additional leads are significant. Central venous occlusion in patients with pre-existing devices is often asymptomatic and optimal management of such patients in need of device revision/upgrade is not clear. We sought to assess our use of laser lead extraction in overcoming venous obstruction.
Methods and results
Patients in need of device upgrade/revision underwent pre-procedure venography to assess venous patency. In patients with venous occlusion or stenosis severe enough to preclude passage of a hydrophilic guide wire, laser lead extraction with retention of the outer sheath in the vasculature was performed with the aim of maintaining a patent channel through which new leads could be implanted. Data were recorded on a dedicated database and patient outcomes were assessed. Between July 2004 and April 2012, laser lead extractions were performed in 71 patients scheduled for device upgrade/revision who had occluded or functionally obstructed venous anatomy. New leads were successfully implanted across the obstruction in 67 (94%) cases. There were two major complications (infection) and four minor complications with no peri-procedural mortality. Device follow-up was satisfactory in 65 (92%) cases with mean follow-up up to 26 ± 19 months.
Laser lead extraction is a safe and effective option when managing patients with central venous obstruction in need of CIED revision or upgrade.
Laser lead extraction; Venous obstruction; Pacemaker; Implantable cardiac defibrillator; Cardiac resynchronization therapy
Heart rate variability (HRV), a measure of autonomic function, has been associated with cognitive function, but studies are conflicting. Previous studies have also not controlled for familial and genetic influences.
We performed power spectral analysis on 24-hour ambulatory ECG’s in 416 middle-aged male twins from the Vietnam Era Twin Registry. Memory and learning were measured by verbal and visual selective reminding tests (SRT). Mixed-effect regression models were used to calculate associations between and within twin pairs, while adjusting for covariates.
The mean age (SD) was 55 (2.9) years. A statistically significant positive association was found between measures of HRV and verbal, but not visual, SRT scores. The most statistically significant unadjusted association was found between very low frequency (VLF) HRV and verbal total recall SRT, such that each logarithm of increase in VLF was associated with an increased verbal SRT score of 4.85 points (p=0.002). The association persisted despite adjustment for demographic and cardiovascular risk factors, and after accounting for familial, and genetic factors by comparing twins within pairs. A significant interaction was found between post-traumatic stress disorder (PTSD) and HRV, such that total power and ultra low frequency were associated with SRT in twins (n=362) without PTSD, but not in those with PTSD.
In conclusion, lower frequency spectra of HRV are associated with verbal, but not visual, learning and memory, particularly in subjects without PTSD. This association may indicate that autonomic nervous system dysregulation plays a role in cognitive decline.
memory; autonomic function; heart rate variability; cognitive function
Patients receive care in safety net clinics regardless of insurance status; however, diabetes preventive care receipt might vary in patients with differing levels of insurance continuity.
In a retrospective cohort study, using electronic health record data from adults with diabetes receiving care in 50 safety net clinics in Oregon in 2005–2007, we conducted adjusted logistic regressions to model the associations between amount of time with insurance and rates of receipt of lipid screening, influenza vaccination, nephropathy screening (urine microalbumin), and DM control (glycosylated hemoglobin) screening.
Of 3,384 adults with diabetes, 711 were ‘partially’ insured (covered 1–99% of the 3-year study period), 909 had no coverage, and 1,764 were continuously insured. In adjusted models, persons with partial or no coverage during the 3-year study period were less likely to receive most preventive services, compared to those with continuous coverage. We found no evidence of a dose-response relationship with increasing duration of coverage, nor of a threshold amount of partial coverage, associated with better receipt of care.
Safety net clinic patients need both access to primary care and continuous insurance. All patients with partial coverage, regardless of the extent of time with insurance, had lower odds of receiving preventive care.
diabetes care; discontinuous health insurance coverage; health policy; safety net populations; electronic health record data
Although depression is associated with increased cardiovascular morbidity and mortality, there is virtually no information on whether it also increases the risk in young populations.
We sought to determine the association of unipolar and bipolar depression and a history of attempted suicide with mortality due to ischemic heart disease (IHD) and cardiovascular disease (CVD) in young US adults and to examine potential sex differences.
Longitudinal epidemiologic study.
Nationally representative sample of US adults.
A total of 7641 US adults aged 17 to 39 years from the 1988–1994 Third National Health and Nutrition Examination Survey.
Main Outcome Measures
Cardiovascular disease and IHD mortality. Unipolar/bipolar depression and a history of attempted suicide were assessed via the Diagnostic Interview Schedule.
After a median follow-up of 14.9 years, a total of 51 subjects (0.67%) died of CVD causes and 28 (0.37%) died of IHD. Depression (538 individuals [7.04%]) and history of attempted suicide (419 [5.48%]) were each associated with an increased risk of IHD death, with adjusted hazard ratios of 3.70 (95% CI, 1.32–10.35) for depression and 7.12 (2.67–18.98) for a history of attempted suicide. Women with depression or a history of attempted suicide had a 3-fold adjusted risk of CVD (adjusted hazard ratio, 3.20 [95% CI, 1.12–9.17]) and a 14-fold adjusted risk of IHD (14.57 [2.65–80.10]). Corresponding figures for men were 2.37 (0.85–6.58) and 3.52 (1.05–11.76).
In adults younger than 40 years, depression and history of attempted suicide are significant independent predictors of premature CVD and IHD mortality in both sexes.
The non-tuberculous mycobacteria (NTM) have emerged as important opportunistic pathogens in the recent years. The NTM are rapid growing mycobacteria (RGM), which include Mycobacterium fortuitum and M. chelonae and are grouped as M. fortuitum-chelonae complex. Non-healing postoperative wound infections that do not respond to antibiotics used for pyogenic infections and having sterile routine aerobic cultures should raise a suspicion of NTM.
Patients and methods
All patients with post operative wound infection over a five year period were included in the study. All wound infections were evaluated with wound culture and sensitivity and treated with appropriate antibiotics. All infections with underlying mesh were initially managed with dressings/debridement, long term antibiotics. Explantation of the mesh was to be used as a last resort.
We analyzed the records of patients with post operative wound infections who had wound cultures taken and found that 16 of our patients had initial sterile cultures. In all these cases, wound infection manifested itself as discharging sinuses between 2–3 weeks after surgery. Of these seven patients grew NTM on their repeat cultures. The commonest organism isolated was M. fortuitum (57%). The commonest antibiotic used for treatment was Tab Clarithromycin and the mean duration of treatment was 6 to 9 months. No patients required debridement or removal of mesh.
NTM infections in post operative wound though rare should be suspected in all post operative wound infections which occurs late, lack local and systemic signs of pyogenic infections and have sterile cultures. High index of suspicion for NTM infection will allow identification and treatment of these patients with long-term antimicrobial therapy alone without the need for surgical explantation of the mesh.
Non tubercular mycobacterium; Atypical mycobacterium; Post operative wound infection; SSI; Rapid growers; M. fortuitum-chelonae complex; Mycobacterium fortuitum; Mycobacterium chelonae
Local aromatization of testosterone into 17β-estradiol (E2) is often required for the physiological and behavioral actions of testosterone. In most vertebrates, aromatase is expressed in a few discrete brain regions. While many studies have measured brain aromatase mRNA or activity, very few studies have measured brain E2 levels, particularly in discrete brain regions, because of technical challenges. Here, we used the Palkovits punch technique to isolate 13 discrete brain nuclei from adult male zebra finches. Steroids were extracted via solid phase extraction. E2 was then measured with an ultrasensitive, specific and precise radioimmunoassay. Our protocol leads to high recovery of E2 (84%) and effectively removes interfering brain lipids. E2 levels were high in aromatase-rich regions such as caudal medial nidopallium and hippocampus. E2 levels were intermediate in the medial preoptic area, ventromedial nucleus of the hypothalamus, lateral and medial magnocellular nuclei of anterior nidopallium, nucleus taeniae of the amygdala, and Area X. E2 levels were largely non-detectable in the cerebellum, HVC, lateral nidopallium and optic lobes. Importantly, E2 levels were significantly lower in plasma than in the caudal medial nidopallium. This protocol allows one to measure E2 in discrete brain regions and potentially relate local E2 concentrations to aromatase activity and behavior.
steroid; estrogens; songbird; aromatase; solid phase extraction; neurosteroid; testosterone; NCM; fadrozole; song; hippocampus
The Canadian CT Head Rule was developed to allow physicians to be more selective when ordering computed tomography (CT) imaging for patients with minor head injury. We sought to evaluate the effectiveness of implementing this validated decision rule at multiple emergency departments.
We conducted a matched-pair cluster-randomized trial that compared the outcomes of 4531 patients with minor head injury during two 12-month periods (before and after) at hospital emergency departments in Canada, six of which were randomly allocated as intervention sites and six as control sites. At the intervention sites, active strategies, including education, changes to policy and real-time reminders on radiologic requisitions were used to implement the Canadian CT Head Rule. The main outcome measure was referral for CT scan of the head.
Baseline characteristics of patients were similar when comparing control to intervention sites. At the intervention sites, the proportion of patients referred for CT imaging increased from the “before” period (62.8%) to the “after” period (76.2%) (difference +13.3%, 95% CI 9.7%–17.0%). At the control sites, the proportion of CT imaging usage also increased, from 67.5% to 74.1% (difference +6.7%, 95% CI 2.6%–10.8%). The change in mean imaging rates from the “before” period to the “after” period for intervention versus control hospitals was not significant (p = 0.16). There were no missed brain injuries or adverse outcomes.
Our knowledge–translation-based trial of the Canadian CT Head Rule did not reduce rates of CT imaging in Canadian emergency departments. Future studies should identify strategies to deal with barriers to implementation of this decision rule and explore more effective approaches to knowledge translation. (ClinicalTrials.gov trial register no. NCT00993252)
Necrotising soft tissue infections (NSTI) are relatively common infections with high morbidity and mortality rate, as they often present late in their course. Quick and aggressive surgical treatment improves survival and decreases hospital stay.
Materials and methods
All patients with NSTI managed at our centre from June 2007 to January 2009 were included in this prospective study. We evaluated various parameters like age, co-morbidities, biochemical parameters, time interval between admission and first operative intervention, against duration of hospital stay and out come of the case.
Fifty-four patients with NSTI were admitted and treated during the study period. Male to female ratio was 6:1. Mean time interval between admission and operative intervention was 6 hours. Mean period of hospitalisation was 53 days and we had limb salvage rate of 100% and one mortality (1.85%). Diabetes mellitus was the most common co-morbid condition and Staphylococcus aureus the most common isolate. Presence of leucocytosis, hyponatraemia, hypoalbuminaemia, anaemia and deranged renal functions were found to be poor prognostic factors.
Late and varied presentation is the rule rather than exception with NSTI. Early recognition of the condition, with emergency operative intervention and repeated debridement by a dedicated surgical team, is the key to patient survival and limb salvage.
Necrotising soft tissue infections; Fournier’s gangrene; Meleney’s ulcers; Necrotising fasciitis; Sepsis; Debridement; APACHE; LRINEC
Supine anteroposterior (AP) chest radiography is an insensitive test for detecting posttraumatic pneumothoraces (PTXs). Computed tomography (CT) often identifies occult pneumothoraces (OPTXs) not diagnosed by chest radiography. All previous literature describes the epidemiology of OPTX in patients with blunt polytrauma. Our goal was to identify the frequency of OPTXs in patients with penetrating trauma.
All patients with penetrating trauma admitted over a 10-year period to Grady Memorial Hospital with a PTX were identified. We reviewed patients’ thoracoabdominal CT scans and corresponding chest radiographs.
Records for 1121 (20%) patients with a PTX (penetrating mechanism) were audited; CT imaging was available for 146 (13%) patients. Of these, 127 (87%) had undergone upright chest radiography. The remainder (19 patients) had a supine AP chest radiograph. Fifteen (79%) of the PTXs detected on supine AP chest radiographs were occult. Only 10 (8%) were occult when an upright chest radiograph was used (p < 0.001). Posttraumatic PTXs were occult on chest radiographs in 17% (25/146) of patients. Fourteen (56%) patients with OPTXs underwent tube thoracostomy, compared with 95% (115/121) of patients with overt PTXs (p < 0.001).
Up to 17% of all PTXs in patients injured by penetrating mechanisms will be missed by standard trauma chest radiographs. This increases to nearly 80% with supine AP chest radiographs. Upright chest radiography detects 92% of all PTXs and is available to most patients without spinal trauma. The frequency of tube thoracostomy use in patients with overt PTXs is significantly higher than for OPTXs in blunt and penetrating trauma.
Background and Objectives
Having health insurance is usually associated with better access to care and better health outcomes. For patients receiving care at Federally Qualified Health Centers (FQHCs), where care is provided regardless of insurance status, the role health insurance status plays in affecting receipt of services is less well understood.
We used practice management data from a coalition of FQHCs in Oregon, and linked to Oregon’s electronic insurance data, to examine whether receipt of diabetes preventive care services was associated with continuity of insurance coverage among adult FQHC patients receiving diabetes care in 2005.
About one-third (32%) of patients with diabetes received a flu vaccination in 2005, 36% an LDL screening, 54% at least one HbA1c screening, and 21% a nephropathy screening. Compared to the continuously insured, the continuously uninsured were less likely to receive an LDL screening, a flu vaccination, and/or a nephropathy screening; those with partial coverage were less likely than the continuously insured to receive a flu shot, at least one HbA1c screening, or an LDL screening.
Our results suggest that FQHCs do an excellent job in delivering most services to their uninsured and partially insured patients, but also underscore that for diabetic patients from underserved communities, having both an FQHC medical home and continuous health insurance plays a critical role in receiving optimal chronic disease management. Our study is one of the first to demonstrate how electronic administrative data from a network of FQHCs can be successfully used to gauge the state of healthcare delivery.
diabetes care; safety net; health insurance
Objective To evaluate the effectiveness of an active strategy to implement the validated Canadian C-Spine Rule into multiple emergency departments.
Design Matched pair cluster randomised trial.
Setting University and community emergency departments in Canada.
Participants 11 824 alert and stable adults presenting with blunt trauma to the head or neck at one of 12 hospitals.
Interventions Six hospitals were randomly allocated to the intervention and six to the control. At the intervention sites, active strategies were used to implement the Canadian C-Spine Rule, including education, policy, and real time reminders on radiology requisitions. No specific intervention was introduced to alter the behaviour of doctors requesting cervical spine imaging at the control sites.
Main outcome measure Diagnostic imaging rate of the cervical spine during two 12 month before and after periods.
Results Patients were balanced between control and intervention sites. From the before to the after periods, the intervention group showed a relative reduction in cervical spine imaging of 12.8% (95% confidence interval 9% to 16%; 61.7% v 53.3%; P=0.01) and the control group a relative increase of 12.5% (7% to 18%; 52.8% v 58.9%; P=0.03). These changes were significant when both groups were compared (P<0.001). No fractures were missed and no adverse outcomes occurred.
Conclusions Implementation of the Canadian C-Spine Rule led to a significant decrease in imaging without injuries being missed or patient morbidity. Final imaging rates were much lower at intervention sites than at most US hospitals. Widespread implementation of this rule could lead to reduced healthcare costs and more efficient patient flow in busy emergency departments worldwide.
Trial registration Clinical trials NCT00290875.
1) To determine if detorsion of the twisted adnexa is better than traditional adnexectomy to conserve the adnexa and preserve its function. 2) To determine the feasibility of detorsion in conservation of adnexa.
Prospective Study from September 2004 to September 2008.
Private IVF and Endoscopy Centre.
22 patients with twisted adnexa (15 non-pregnant and 7 pregnant).
Surgical intervention and either detorsion of adnexa or adnexectomy.
Main Outcome Measures:
Ovarian preservation and conservation of ovarian function in 77.2% cases determined by: a) Follicular development on sonography (performed for one year after adnexectomy). b) Subsequent surgery for unrelated cause showing healthy ovaries. c) controlled ovarian hyperstimulation and successful oocyte retrieval subsequently.
We could conserve the adenexa in 77.2% cases. Laparoscopic detorsion was performed in 11/15(73.33 %) of non-pregnant women and adnexectomy done in four women 26.66%. Among the seven pregnant women, adnexa could be preserved in 6/7(85.7%) and only one woman required adnexectomy. Laparotomy was required in 2/22(9%) women both of which were in late second trimester of pregnancy. In one case (4.54%) we had recurrence of torsion. 88.23% of the women with conserved adnexa showed preservation of ovarian function.
Our study showed that timely diagnosis and intervention could make the difference between ovarian loss and salvage- an outcome of great importance in population of reproductive age females. Laparoscopy with its many benefits proves to be superior to laparotomy.
Twisted adnexa; torsion; untwisting; detorsion; conservation
Overview of the Disease
IncidencePrognosisCurrent Therapy Standards
Colorectal Liver Metastases (CRLM)
Resectable TumorsStrategies To Convert Nonresectable Liver Metastases to Resectable StatusSynchronous Colorectal Liver MetastasesPredictors of Survival After Resection of CRLMPeritoneal Carcinomatosis (PC) From Colorectal CancerColorectal Pulmonary Metastases (CRPM)Colorectal Liver Metastases With Extrahepatic DiseaseAccomplishments (or Lack of Accomplishments) During the Year
New Staging SystemPreventive Measures for CRLMSystemic ChemotherapySelective Internal Radiation Therapy (SIRT)Proposed Definition of Cure From CRLMBasic ScienceWhat Needs To Be Done?
Optimizing Patient CareControversies and DisagreementsFuture Directions
Comments on ResearchObstacles to Progress
Loss of granule content during exocytosis requires the opening of a fusion pore between the secretory granule and plasma membrane. In a variety of secretory cells, this fusion pore has now been shown to subsequently close. However, it is still unclear how pore closure is physiologically regulated and contentious as to how closure relates to granule content loss. Here, we examine the behavior of the fusion pore during zymogen granule exocytosis in pancreatic acinar cells. By using entry of high-molecular-weight dyes from the extracellular solution into the granule lumen, we show that the fusion pore has a diameter of 29–55 nm. We further show that by 5 min after granule fusion, many granules have a closed fusion pore with evidence indicating that pore closure is a prelude to endocytosis and that in granules with a closed fusion pore the chymotrypsinogen content is low. Finally, we show that latrunculin B treatment promotes pore closure, suggesting F-actin affects pore dynamics. Together, our data do not support the classical view in acinar cells that exocytosis ends with granule collapse. Instead, for many granules the fusion pore closes, probably as a transition to endocytosis, and likely involving an F-actin–dependent mechanism.
Phytochemical-mediated modulation of cytochrome P-450 activity may underlie many herb-drug interactions. Single time-point, phenotypic metabolic ratios were used to determine whether long-term supplementation of goldenseal (Hydrastis canadensis), black cohosh (Cimicifuga racemosa), kava kava (Piper methysticum), or valerian (Valeriana officinalis) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4/5 activity.
Twelve healthy volunteers (6 females) were randomly assigned to receive goldenseal, black cohosh, kava kava, or valerian for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe drug cocktails of midazolam and caffeine, followed 24 hours later by chlorzoxazone and debrisoquine were administered before (baseline) and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP3A4/5, CYP1A2, CYP2E1, and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquine urinary recovery ratios (8-hour collection), respectively. The content of purported “active” phytochemicals was determined for each supplement.
Comparisons of pre- and post-supplementation phenotypic ratio means revealed significant inhibition (~40%) of CYP2D6 (difference = −0.228; 95% CI = −0.268 to −0.188) and CYP3A4/5 (difference = −1.501; 95% CI = −1.840 to −1.163) activity for goldenseal. Kava produced significant reductions (~40%) in CYP2E1 only (difference = −0.192; 95% CI = −0.325 to −0.060). Black cohosh also exhibited statistically significant inhibition of CYP2D6 (difference = −0.046; 95% CI = −0.085 to −0.007), but the magnitude of the effect (~7%) did not appear clinically relevant. No significant changes in phenotypic ratios were observed for valerian.
Botanical supplements containing goldenseal strongly inhibited CYP2D6 and CYP3A4/5 activity in vivo, while kava inhibited CYP2E1 and black cohosh weakly inhibited CYP2D6. Accordingly, serious adverse interactions may result from the concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 and CYP3A4/5 substrates. Kava kava and black cohosh may interact with CYP2E1 and CYP2D6 substrates, respectively. Valerian appears less likely to produce CYP-mediated herb-drug interactions.
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer of the pleura with a well-established male predominance and causative link with asbestos exposure. We report four cases of female patients with MPM referred for palliation of symptoms thought to be due to previous non-pleural malignancy.
With emerging novel treatments for MPM, this article discusses four unusual cases of MPM occurring in the setting of other malignancy, highlights the importance of considering a primary diagnosis of MPM even in patients with other malignancy, and reinforces the benefits of video-assisted surgical biopsy which allows simultaneous diagnosis and treatment.