A study on the action of vitamin E supplementation on plasminogen activator inhibitor type 1 and platelet nitric oxide production in type 2 diabetic patients

Background and aimType 2 diabetic (T2DM) patients show decreased fibrinolysis, mainly linked to high plasminogen activator inhibitor type 1 (PAI-1) production, together with a reduced bioavailability of nitric oxide and an impairment in Na⁺/K⁺-ATPase activity possibly involved in increased cardiovascular risk. Vitamin E is the major natural lipid-soluble antioxidant in human plasma. The present work was conducted in order to measure PAI-1, ICAM and VCAM-1 plasma levels, platelet nitric oxide production and membrane Na⁺/K⁺-ATPase activity in type 2 diabetic subjects treated with vitamin E (500 IU/day) for 10 weeks and then followed for other 20 weeks.Methods and resultsThirty-seven T2DM patients (24 males and 13 females) were studied. None of them were affected by any other disease or diabetic complications. Significant differences were detected for PAI-1 antigen (p < 0.001), PAI-1 activity (p < 0.001), nitric oxide (NO) production (p < 0.001), and Na⁺/K⁺-ATPase activity (p < 0.001) among the 4 phases of the study. A significant decrease both in ICAM and VCAM-1 plasma levels was also found at the 10th week compared with baseline (respectively p < 0.001 and p < 0.05).ConclusionOur data suggest that vitamin E counteracts endothelial activation in T2DM patients possibly representing a new tool for endothelial protection.     

Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor

Histone deacetylases (HDACs) are a family of enzymes involved in the regulation of gene expression, DNA repair, and stress response. These processes often are altered in tumors, and HDAC inhibitors have had pronounced antitumor activity with promising results in clinical trials. Here, we report the crystal structure of human HDAC8 in complex with a hydroxamic acid inhibitor. Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously. Similar to bacterial HDAC-like protein, HDAC8 folds in a single alpha/beta domain. The inhibitor and the zinc-binding sites are similar in both proteins. However, significant differences are observed in the length and structure of the loops surrounding the active site, including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues. CD data suggest a direct role of potassium in the fold stabilization of HDAC8. Knockdown of HDAC8 by RNA interference inhibits growth of human lung, colon, and cervical cancer cell lines, highlighting the importance of this HDAC subtype for tumor cell proliferation. Our findings open the way for the design and development of selective inhibitors of HDAC8 as possible antitumor agents.     

A critical appraisal of daclizumab use as emerging therapy in multiple sclerosis

Introduction: Daclizumab (DAC) is a mAb that binds to CD25, a receptor on the surface of lymphocytes for IL-2, a chemical messenger in the immune system. This prevents activation and proliferation of lymphocytes, which are involved in the immune attack in multiple sclerosis (MS).

Areas covered: In this review, we will focus on newly emerging DAC-high-yield process (HYP) therapy for MS. Based on published original articles and citable meeting abstracts, we will discuss its mode of action as well as data on efficacy and safety.

Expert opinion: DAC has been observed to have multiple (biological) effects, which may contribute to beneficial effects in immune-related disease and particularly in relapsing-remitting MS. The positive results in the clinical studies represent achievement of an important milestone in the development of DAC-HYP as a potential new treatment option for MS patients. The benefit/risk ratios of this new biological agent in MS therapy are still being evaluated. Soon, DAC-HYP might qualify as MS therapy. A safety monitoring program is recommended in the clinical practice.     

Use of trephine stoma in sigmoid volvulus

Introduction: Sigmoid volvulus is a disease of the elderly who often have severe comorbid conditions that increase their operative risk and limit treatment options. Conservative treatment with decompression via sigmoidoscopy with rectal tube placement has high success and recurrence rates. Surgical resection with primary anastomosis is the treatment of choice when decompression fails or if the volvulus recurs. Unfortunately, perioperative complications are frequent. Moreover, many patients with sigmoid volvulus are bedridden or incontinent of stool and do not benefit from extensive resection and maintenance of bowel continuity. METHODS: Twelve debilitated patients with sigmoid volvulus determined preoperatively to be poor candidates for laparotomy and reanastomosis were treated with a trephine stoma. Initially, each patient had decompression via rigid sigmoidoscopy and rectal tube placement. Surgical intervention consisted of formation of a small hole (trephine) in the left lower quadrant. Through this hole, a sigmoid resection and end colostomy were performed. No midline laparotomy was required. RESULTS: Operative times and analgesia requirements were significantly decreased (P =0.05) compared with patients who underwent formal laparotomy. Length of hospital stay, complication rates, and length of bowel resected were similar using either surgical technique. CONCLUSIONS: The trephine stoma procedure offers significantly shorter operative times, with decreased perioperative morbidity. For high operative risk or debilitated patients with sigmoid volvulus, resection with end colostomy using the trephine stoma technique is the procedure of choice.Presented at the meeting of the Zollinger Surgical Society, Columbus, Ohio, September 5 to 7, 1996.     

Laparoscopic resections for colorectal carcinoma

Laparoscopic resection for carcinoma of the colon and rectum is currently under intense scrutiny. PURPOSE: The purpose of this study is to review our three-year experience of laparoscopic surgery for colon and rectal carcinoma. METHODS: From October 1991 to September 1994, 76 laparoscopic procedures were performed for colorectal neoplasia (32 males and 44 females; mean age, 69 years). Fifty-five procedures were done for carcinoma, 16 for large polyps, and five for diversion in patients with unresectable cancer. For resectable tumors, the average size was 4 cm; staging was as follows: Dukes A, 10 patients; Dukes B1, 11; Dukes B2, 18; Dukes C1, 1; Dukes C2, 9; and Dukes D, 8. Fourteen cases (25 percent) that were converted to open procedures were compared with the 41 cases that were completed laparoscopically for differences in tumor size, surgical margins, number of lymph nodes harvested, length of hospital stay, and evidence of recurrence. Procedures completed laparoscopically were then compared with a group of open controls completed during the same time period. RESULTS: During the first six months, the conversion rate was 32 percent but dropped to 8 percent in the last six months. There were a total of 19 complications (25 percent), of which 8 (14 percent) were directly related to the laparoscopic technique. The mean number of lymph nodes harvested in laparoscopic resection for carcinoma was 8.5, and the average closest tumor margin was 4.5 cm. When laparoscopic resections were compared with converted and standard open colectomies, there was no significant difference in tumor margins or numbers of nodes resected. Length of stay was significantly shorter for anterior resections completed laparoscopically than for converted or conventional colectomies. Although this was also the trend for right hemicolectomies, it did not reach statistical significance. Mean follow-up of the group completed laparoscopically was 16.7 months, during which there was one recurrence. There were no trocar site recurrences. CONCLUSIONS: This early experience seems to indicate that laparoscopic surgery for colorectal carcinoma does not per se compromise surgical oncologic principles and encourages us to continue our critical appraisal of this technique.Read at the meeting of The American Society of Colon and Rectal Surgeons, Montreal, Quebec, Canada, May 7 to 12, 1995.     

High circulating levels of endogenous ouabain in the offspring of hypertensive and normotensive individuals

OBJECTIVE: Impaired diastolic function and left ventricular hypertrophy can occur early in the natural history of essential hypertension. High circulating levels of endogenous ouabain (EO) have been described in essential hypertension and have also been associated with left ventricular hypertrophy. The aim of this study was to investigate whether these cardiac modifications are related to plasma EO levels in the offspring of hypertensive families. METHODS: The study involved 41 subjects with (FAM+) and 45 subjects without (FAM-) a family history of hypertension. Arterial blood pressure, left ventricular geometry and function, and plasma EO levels were measured in each subject. RESULTS: Plasma EO levels were higher in the FAM+ subjects (221.5 +/- 10.95 versus 179.6 +/- 9.58 pmol/l, P = 0.004), and directly correlated with both systolic (r = 0.417, P < 0.0001) and diastolic blood pressure (r = 0.333, P = 0.002). Plasma EO was inversely related to an index of cardiac diastolic function determined as the ratio between the early and late peak flow velocity (r = -0.286, P = 0.012) and isovolumetric relaxation time (IVRT) (r = 0.32, P = 0.003). The IVRT was also significantly higher in FAM+, correlated with the IVRT (r = 0.32, P = 0.003). The IVRT was also significantly higher in FAM+, whereas the other echocardiographic parameters were similar to FAM-. CONCLUSIONS: Among the offspring of families with a positive history of hypertension, circulating EO levels and blood pressure are increased. Plasma EO levels are related to alterations of some indexes of diastolic heart function in these individuals.     

A Preliminary Formula to Predict Timing of Symptom Resolution for Collegiate Athletes Diagnosed With Sport Concussion

ContextSymptom presentation and recovery after sport concussion (SC) are variable. Empirically based models documenting typical symptom duration would assist health care providers in managing return to play after SC.ObjectiveTo develop a prediction model for SC symptom duration.DesignCross-sectional study.SettingTwo National Collegiate Athletic Association Division I university laboratories.Intervention(s)Participants completed the Revised Head Injury Scale (HIS-r), Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), and Sensory Organization Test within 24 hours of SC diagnosis.ResultsThe final formula consisted of the HIS-r''s self-reported neck pain, drowsiness, tingling, and nervousness duration and ImPACT total symptom severity (R = 0.62, R² = 39%, R²_adj = 34.2%, P < .001). Approximately 29% (R²_cv = 29%) of the variance associated with total days symptomatic after SC was explained by our preliminary formula when cross-validated. The current formula correctly identified 76% of participants who recovered within 10 days of injury.ConclusionsOur results suggest that self-reported duration of 4 symptoms during the initial 24 hours after injury along with total symptom severity as measured by ImPACT accounted for a considerable amount of variance associated with days symptomatic after SC in collegiate athletes. Until the formula is cross-validated in a college-aged sample, caution is warranted in using it clinically.Key Words: traumatic brain injuries, prediction, prolonged recovery, symptom severity, symptom duration

Key Points

• A formula to predict symptom resolution after sport concussion primarily consisting of initial symptom duration and severity correctly identified 76% of National Collegiate Athletic Association Division I collegiate athletes who recovered within 10 days.
• Before it can be used clinically, the formula must be cross-validated on larger samples.

The clinical presentation of and recovery from sport concussion (SC) are variable among athletes. Recovery curves based on animal models suggest the metabolic vulnerability associated with concussion resolves within approximately 7 to 10 days.^1,2 During this period of metabolic dysfunction, athletes experience neurocognitive and motor deficits as well as a constellation of symptoms.^3–5 These sequelae serve as markers that clinicians can measure to track recovery and make informed return-to-play and return-to-learn decisions.⁶The resolution of motor (eg, postural stability) and neurocognitive (eg, memory, reaction time, information-processing speed) deficits, along with self-reported symptoms (eg, headache, nausea, dizziness), varies based on a number of factors. These factors include age, sex, background history, comorbid conditions, and signs and symptoms reported or observed at the time of injury.^7–12 For example, in terms of age, only 50% of high school athletes (14–18 years of age) were reported to recover from SC in approximately 7 days, whereas 90% of adult athletes ≥18 years of age recovered in 7 days.^8,13–15 Regarding sex differences, Covassin et al¹⁶ observed that female high school athletes may take up to 14 days to recover in terms of memory and processing speed after concussion. In a separate study, Covassin et al¹² noted that concussed high school- and college-aged females consistently demonstrated higher symptom levels than male participants up to 14 days after concussion.Though the majority of concussion symptoms in older athletes resolve in ≤7 days of injury, approximately 10% of concussed athletes experience persistent symptoms up to 3 months after their diagnosis.¹⁷ Additionally, a subset of patients may experience 3 or more postconcussion symptoms for 3 months or longer, which is classified as postconcussion syndrome (PCS). Babcock et al¹⁸ found that 29% of pediatric concussion patients diagnosed in the emergency department for whom sport was the primary mechanism of injury (35%) were later diagnosed with PCS, which equates to 105 000 cases of pediatric PCS annually in the United States. The authors suggested that being able to prospectively identify candidates at risk for PCS would assist clinicians in discharge planning (eg, education, medications, and ongoing follow-up), ultimately resulting in improved patient outcomes.Studies examining predictors of SC recovery have usually addressed the dichotomy of typical recovery (7–13 days) versus protracted recovery.^3,12 Protracted recovery has been defined as resolution of SC lasting longer than 14,¹⁰ 21,¹¹ 45, or 90 days.^17,19 Several predictors, including loss of consciousness (LOC), posttraumatic amnesia (PTA), retrograde amnesia, total symptom severity, dizziness severity, and headache severity, have been associated with a 1.8- to 6-fold increase in risk for protracted recovery.^11,17,18 Of these predictors, LOC and amnesia are points of debate because of their infrequent occurrence and questionable relationship with injury severity and recovery.^8,11,20The objective of our study was to determine if the number of days an athlete reported concussion-related symptoms could be predicted from dependent variables derived from clinical measures commonly used to manage this injury. The ability to determine how many days an athlete will report SC-related symptoms may assist clinicians by allowing identification of athletes at risk for prolonged recoveries and institution of the appropriate medical and psychosocial infrastructure to assist in a full recovery.     

Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories

Stored memories enter a temporary state of vulnerability following retrieval known as ‘reconsolidation'', a process that can allow memories to be modified to incorporate new information. Although reconsolidation has become an attractive target for treatment of memories related to traumatic past experiences, we still do not know what new information triggers the updating of retrieved memories. Here, we used biochemical markers of synaptic plasticity in combination with a novel behavioral procedure to determine what was learned during memory reconsolidation under normal retrieval conditions. We eliminated new information during retrieval by manipulating animals'' training experience and measured changes in proteasome activity and GluR2 expression in the amygdala, two established markers of fear memory lability and reconsolidation. We found that eliminating new contextual information during the retrieval of memories for predictable and unpredictable fear associations prevented changes in proteasome activity and glutamate receptor expression in the amygdala, indicating that this new information drives the reconsolidation of both predictable and unpredictable fear associations on retrieval. Consistent with this, eliminating new contextual information prior to retrieval prevented the memory-impairing effects of protein synthesis inhibitors following retrieval. These results indicate that under normal conditions, reconsolidation updates memories by incorporating new contextual information into the memory trace. Collectively, these results suggest that controlling contextual information present during retrieval may be a useful strategy for improving reconsolidation-based treatments of traumatic memories associated with anxiety disorders such as post-traumatic stress disorder.