Improved patient survival after acute variceal bleeding: a multicenter,cohort study

OBJECTIVE: Existing literature indicates that the mortality rate with each variceal bleeding episode is 30-50%. Over the past 2 decades, there have been significant developments in the management of variceal bleeding. The effect of these developments on the natural history of variceal bleeding is unclear. Therefore, a retrospective, multicenter study was conducted to define the outcomes of variceal bleeding and to describe the patterns of current practice in the management of variceal bleeding. METHODS: All patients with documented variceal bleeding hospitalized at four large county hospitals from January 1, 1997, to June 30, 2000, were included. Study outcomes were in-hospital, 6-wk, and overall mortality, rate of rebleeding, transfusion requirement, and length of stay. After discharge, patients were followed until death or study closure date, on June 30, 2000. RESULTS: A total of 231 subjects were included, and their in-hospital, 6-wk, and overall mortality rates were 14.2%, 17.5%, and 33.5%, respectively. The frequency of rebleeding during follow-up was 29%. Median length of total hospital stay was 8 days (0-34 days). Median number of packed red cell units transfused was 4 U (0-60 U). Upper endoscopy was performed in 95% of patients within 24 h, and endoscopic therapy was done in all but eight patients (ligation 64%, sclerotherapy 33%). Octreotide was administered in 74% of the patients. Portasystemic shunts were performed in 7.5% of the patients for controlling acute variceal bleeding. CONCLUSIONS: The mortality rate after variceal bleeding in this study was substantially lower than previously reported. This suggests that advances made in the management of variceal bleeding have improved outcomes after variceal bleeding.     

The natural history of post-traumatic hypopituitarism: implications for assessment and treatment

Purpose

Hypopituitarism has been reported in up to half of long-term survivors of traumatic brain injury. We attempted to define the natural history of post-traumatic hypopituitarism to devise guidelines for the optimal timing of patients’ assessment and hormone replacement.

Subjects and methods

Fifty consecutive patients with severe or moderate head trauma were enrolled in a prospective study of pituitary function during the acute phase, at 6 months, and at 12 months after injury. Growth hormone and adrenocorticotropin hormone reserves were assessed using the glucagon stimulation test. Baseline serum concentrations of other anterior pituitary hormones were measured. Results were compared with normative data obtained from matched healthy controls.

Results

Nine patients (18%) had growth hormone deficiency in the acute phase; at 6 months, 5 patients recovered function and 2 new deficiencies were detected; at 12 months, 1 patient recovered, leaving 5 patients (10%) with growth hormone deficiency. Eight patients (16%) showed subnormal cortisol response in the acute phase; at 6 months, 4 patients had recovered and 5 new deficiencies were detected; all 9 patients had persistent abnormalities at 2 months. Forty patients (80%) had gonadotropin deficiency in the acute phase, of whom 29 (73%) recovered by 6 months and 34 (85%) recovered by 12 months. Thyrotropin deficiency was present in 1 patient in the acute phase, who recovered by 6 months; 1 new case was diagnosed at 6 months, which persisted at 12 months.

Conclusion

After traumatic brain injury, early neuroendocrine abnormalities are sometimes transient, whereas late abnormalities present during the course of rehabilitation. A follow-up strategy with periodic evaluation is a necessary part of the optimal care for patients with traumatic brain injury.     

Receptor for advanced glycation endproduct modulators: a new therapeutic target in Alzheimer’s disease

Introduction: Reduction in the deposition of amyloid β (Aβ) has been the primary target for Alzheimer’s disease (AD) therapeutics recently, but in clinical trials this approach has generally been unsuccessful. A common feature of AD pathology is a complex inflammatory component that could be a target for treatment. One feature of this inflammation has been the involvement of the receptor for advanced glycation endproducts (RAGE), whose ligands include advanced glycation-endproduct-modified proteins as well as lipids and Aβ, which are found at elevated levels in AD brains.

Areas covered: In this article, the authors describe the key features of RAGE and how it could have a role in AD pathogenesis. They also summarize experimental animal and clinical data that demonstrate the therapeutic effect of RAGE inhibition and consider what these findings mean for human disease.

Expert opinion: RAGE has multiple ligands, including Aβ, that are increased in AD brains. Inhibiting RAGE-ligand interactions without activating receptor signaling can reduce multiple pathological pathways relevant for AD. Several RAGE inhibitors and modulators are now being tested as therapeutics for AD. Recent Phase II studies have established the good safety and tolerability of TTP448 with some evidence of positive benefit at lower dose. This suggests that further studies are required.     

Novel markers of cell kinetics to evaluate progression from cirrhosis to hepatocellular carcinoma.

BACKGROUND: We investigated cell cycle kinetics of nodular lesions in cirrhosis to differentiate hepatocellular carcinoma (HCC) from its precursor lesions. METHODS: Twelve small HCC, 10 regenerative (RN), six large regenerative (LRN), and five dysplastic nodules (DN), identified in explant cirrhotic livers of five consecutive patients transplanted at Royal Free Hospital in 2002. Immunoperoxidase for MCM2, geminin and Ki67 was performed and the percentage of positive cells counted. RESULTS: The proportion of cells expressing MCM2 was more than those expressing Ki67, which in turn was more than those expressing geminin (overall median=16%, 2% and 0.5%, respectively, P<0.001). There was a statistically significant trend of increasing Ki67 expression (P=0.006), from RN to HCC; this trend was not statistically significant for geminin (P=0.18) or MCM2 (P=0.51). The median percentage of cells expressing Ki67 was 1% in RN, 0.5% in LRN, 2.2% in DN and 5.4% in HCC. The combination of these markers identified four different cell kinetics patterns: 'resting' (G0 cells: MCM2 -ve, Ki67 -ve, geminin -ve); 'licensed' (MCM2 +ve, Ki67 -ve, geminin -ve); 'slowly growing' (G1 phase arrest, MCM2 +ve, Ki67 +ve, low (0.4%) geminin) and expanding (MCM2 +ve, Ki67 +ve, geminin +ve) nodules. CONCLUSIONS: The combination of MCM2, geminin and Ki67 could represent a valuable tool in the understanding of HCC progression in cirrhosis.     

Development and Validation of the Athlete Fear Avoidance Questionnaire

Context

The fear-avoidance model was developed in an attempt to explain the process by which “pain experience” and “pain behavior” become dissociated from the actual pain sensation in individuals who manifest the phenomenon of exaggerated pain perception. High levels of fear avoidance can lead to chronic pain and disability and have successfully predicted rehabilitation time in the work-related–injury population. Existing fear-avoidance questionnaires have all been developed for the general population, but these questionnaires may not be specific enough to fully assess fear avoidance in an athletic population that copes with pain differently than the general population.

Objective

To develop and validate the Athlete Fear Avoidance Questionnaire (AFAQ).

Design

Qualitative research to develop the AFAQ and a cross-sectional study to validate the scale.

Patients or Other Participants

For questionnaire development, a total of 8 experts in the fields of athletic therapy, sport psychology, and fear avoidance were called upon to generate and rate items for the AFAQ. For determining concurrent validity, 99 varsity athletes from various sports participated.

Data Collection and Analysis

A total of 99 varsity athletes completed the AFAQ, the Fear-Avoidance Beliefs Questionnaire, and the Pain Catastrophizing Scale. We used Pearson correlations to establish concurrent validity.

Results

Concurrent validity was established with significant correlations between the AFAQ and the Fear Avoidance Beliefs Questionnaire-Physical Activity (r = 0.352, P > .001) as well as with the Pain Catastrophizing Scale (r = 0.587, P > .001). High internal consistency of our questionnaire was established with a Cronbach α coefficient of 0.805. The final version of the questionnaire includes 10 items with good internal validity (P < .05).

Conclusions

We developed a questionnaire with good internal and external validity. The AFAQ is a scale that measures sport-injury–related fear avoidance in athletes and could be used to identify potential psychological barriers to rehabilitation.Key Words: fear-avoidance model, scale, sports, athletic injuries, rehabilitation, psychology

Key Points

• We developed and validated the Athlete Fear Avoidance Questionnaire to assess pain-related fear in athletes.
• Pain-related fear or fear avoidance plays a critical role in the rehabilitation of patients with low back pain and work-related injuries. High levels of fear avoidance in athletes may affect rehabilitation times.

Most health professionals who work with injured athletes have encountered situations in which an athlete was struggling psychologically to return to play or the duration of rehabilitation was disproportionate to the athlete''s initial physical dysfunction. To date, a few scales measure athletes'' readiness to return to play, such as the Sports Inventory for Pain and the Injury–Psychological Readiness to Return to Sport Scale.^1,2 The Sports Inventory for Pain was developed specifically to identify beneficial and detrimental pain-coping strategies among the athletic population, but the authors worked with a student population to generate the items on the questionnaire, rather than a panel of experts in the field, and they did not establish concurrent validity. The Injury–Psychological Readiness to Return to Sport Scale was developed as a tool to assess an athlete''s confidence and psychological readiness to go back to play; however, it was designed to be administered at the end of an athlete''s rehabilitation process and, therefore, cannot be used to address psychological barriers at the beginning of rehabilitation that may lengthen the time to return to play.² Neither scale has been used extensively, but the fear-avoidance model (FAM), a psychological model well established in the general population, has been used extensively for its predictive value. For example, Sullivan et al³ noted that the Pain Catastrophizing Scale (PCS) has been cited more than 900 times on Web of Science since 1995.The FAM is based on the emotional reaction of pain perception and high levels of fear avoidance that can lead to dysfunction.⁴ The FAM was created in an attempt to explain the development of chronic pain from acute pain. The model comprises 4 components: fear of pain, kinesiophobia, fear-avoidance belief, and catastrophizing. According to the FAM, exaggerated pain perception could lead to the development of chronic pain,⁴ and fear of pain is a main focus. There are 2 possible coping reactions to fear of pain: confrontation and avoidance. Individuals who experience elevated levels of fear of pain with signs of fear avoidance in response to acute pain are more likely to develop chronic pain than those who confront their fear of pain.⁴ The FAM assessment tools were all developed for the general population or patients with chronic low back pain. The main questionnaires used to assess the 4 components of the FAM are the Fear of Pain Questionnaire-III, the PCS, the Tampa Scale for Kinesophobia, and the Fear-Avoidance Beliefs Questionnaire (FABQ). The FABQ was developed in part for patients with work-related injuries.⁵ Injured varsity athletes may not relate to work-specific items on the FABQ, such as “My pain was caused by my work or by an accident at work.” Although some of the questionnaires, such as the PCS, have been validated on athletes, they were not developed specifically for the athletic population.⁶ In fact, the FAM questionnaires can be used to predict outcomes.^7,8 Klenerman et al⁷ conducted a study to determine whether chronic pain could be predicted from acute low back pain in the general population. Results indicated that patients with acute low back pain either will improve within 2 months or will develop chronic pain and that the FAM appears to be the best predictor of the course of low back pain within the first 2 months.⁷ In another study, Fritz and George⁸ aimed to identify psychosocial factors that could predict return to work in patients with acute work-related back pain. The results revealed that the FABQ-Work (FABQ-W) was the strongest predictor of work status and may be used to predict return to work in patients with acute work-related low back pain.⁸ The authors of the PCS also established that people who catastrophize have higher levels of pain and disability than people who do not.⁹Some studies have indicated that parts of the FAM can influence athletes'' rehabilitation.^6,10,11 Kvist et al¹⁰ also reported on the psychological effect an injury can have on a player. Of the 47% who did not return to their sport, 24% did not return to play because of their fear of reinjury.¹⁰ People who returned to their preinjury levels of activity had the lowest levels of fear of reinjury, whereas people who did not return to their preinjury levels of activity had a higher fear of reinjury.¹⁰ The results of these studies might have been stronger using a scale that was developed specifically for athletes. To date, no questionnaire or scale has been specifically developed to assess fear avoidance or pain-related fear in athletes, who differ from the general population in their mentality and reality (ie, the role of sports or activity in their lives). Furthermore, athletes are exposed to pain and sports injuries relatively often, so knowing whether fear avoidance is a major concern among that population is important. Therefore, taking fear avoidance into account might be useful to establish the most appropriate and effective rehabilitation plan and, consequently, to reduce the time for return to play. A questionnaire specific to athletes might help establish how the FAM or pain-related fear can influence the athletic population, specifically regarding rehabilitation.Therefore, the aims of our study were to develop and validate the Athlete Fear Avoidance Questionnaire (AFAQ). We used a qualitative study design, a modified Delphi technique, to develop the scale and then a cross-sectional study to establish its validity.     

Angioarchitectural Evolution of Clival Dural Arteriovenous Fistulas in Two Patients

Dural arteriovenous fistulas (dAVFs) may present in a variety of ways, including as carotid-cavernous sinus fistulas. The ophthalmologic sequelae of carotid-cavernous sinus fistulas are known and recognizable, but less commonly seen is the rare clival fistula. Clival dAVFs may have a variety of potential anatomical configurations but are defined by the involvement of the venous plexus just overlying the bony clivus. Here we present two cases of clival dAVFs that most likely evolved from carotid-cavernous sinus fistulas.Key Words: Neuro-ophthalmology, Carotid-cavernous sinus fistula, Clivus, Clival fistula, Dural arteriovenous fistula     

Novel immunosuppressive agent caerulomycin A exerts its effect by depleting cellular iron content

Background and Purpose

Recently, we have described the use of caerulomycin A (CaeA) as a potent novel immunosuppressive agent. Immunosuppressive drugs are crucial for long-term graft survival following organ transplantation and treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. The objective of this study was to identify cellular targets of CaeA and decipher its mechanism of action.

Experimental Approach

Jurkat cells were treated with CaeA and cellular iron content, iron uptake/release, DNA content and deoxyribonucleoside triphosphate pool determined. Activation of MAPKs; expression level of transferrin receptor 1, ferritin and cell cycle control molecules; reactive oxygen species (ROS) and cell viability were measured using Western blotting, qRT-PCR or flow cytometry.

Key Results

CaeA caused intracellular iron depletion by reducing its uptake and increasing its release by cells. CaeA caused cell cycle arrest by (i) inhibiting ribonucleotide reductase (RNR) enzyme, which catalyses the rate-limiting step in the synthesis of DNA; (ii) stimulating MAPKs signalling transduction pathways that play an important role in cell growth, proliferation and differentiation; and (iii) by targeting cell cycle control molecules such as cyclin D1, cyclin-dependent kinase 4 and p21^CIP1/WAF1. The effect of CaeA on cell proliferation was reversible.

Conclusions and Implications

CaeA exerts its immunosuppressive effect by targeting iron. The effect is reversible, which makes CaeA an attractive candidate for development as a potent immunosuppressive drug, but also indicates that iron chelation can be used as a rationale approach to selectively suppress the immune system, because compared with normal cells, rapidly proliferating cells require a higher utilization of iron.     

Effect of brain monoamines on the secretion of adrenocorticotrophic hormone

The role of brain monoamines (5-HT, NA and DA) in the secretion of adrenocorticotrophic hormone (ACTH) was studied in view of contradictory reports. Plasma corticosterone levels and the rate of synthesis of corticosterone in vitro by the adrenal gland were estimated in albino rats and have been taken as the index of ACTH activity. These estimations were done in unstressed and stressed, and in untreated and treated rats. Drugs were administered intracerebroventricularly to the rats to cause selective degeneration of tryptaminergic, noradrenergic or dopaminergic neurons. The results show that plasma corticosterone levels and the rate of synthesis of corticosterone were significantly decreased after selective degeneration of tryptaminergic neurons in unstressed rats. After selective degeneration of either tryptaminergic or noradrenergic neurons, the acute increase in the plasma corticosterone levels and rate of synthesis of corticosterone in vitro by adrenal glands in stressed rats were significantly inhibited. These results have been interpreted to suggest that the central tonic control on adrenal glands may be 5-HT mediated and that during stress ACTH secretion may be both 5-HT and NA mediated. DA does not seem to have significant role in the regulation of ACTH secretion.