Minocycline and matrix metalloproteinase inhibition in acute intracerebral hemorrhage: a pilot study.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating cerebrovascular disorder with high morbidity and mortality. Minocycline is a matrix metalloproteinase-9 (MMP-9) inhibitor that may attenuate secondary mechanisms of injury in ICH. The feasibility and safety of minocycline in ICH patients were evaluated in a pilot, double-blinded, placebo-controlled randomized clinical trial. METHODS: Patients with acute onset (<12 h from symptom onset) ICH and small initial hematoma volume (<30 ml) were randomized to high-dose (10 mg/kg) intravenous minocycline or placebo. The outcome events included adverse events, change in serial National Institutes of Health Stroke Scale score assessments, hematoma volume and MMP-9 measurements, 3-month functional outcome (modified Rankin score) and mortality. RESULTS: A total of 20 patients were randomized to minocycline (n = 10) or placebo (n = 10). The two groups did not differ in terms of baseline characteristics. No serious adverse events or complications were noted with minocycline infusion. The two groups did not differ in any of the clinical and radiological outcomes. Day 5 serum MMP-9 levels tended to be lower in the minocycline group (372 ± 216 ng/ml vs. 472 ± 235 ng/ml; P = 0.052). Multiple linear regression analysis showed that minocycline was associated with a 217.65 (95% confidence interval -425.21 to -10.10, P = 0.041) decrease in MMP-9 levels between days 1 and 5. CONCLUSIONS: High-dose intravenous minocycline can be safely administered to patients with ICH. Larger randomized clinical trials evaluating the efficacy of minocycline and MMP-9 inhibition in ICH patients are required.

The association between prucalopride efficacy and constipation type.

BACKGROUND: Prucalopride is a selective serotonin receptor agonist with prokinetic activity, indicated for women with chronic constipation in whom laxatives have failed to provide adequate relief. Data suggests an improvement in about 50 % of such patients but whether the therapeutic effect is on patients with slow transit constipation (STC) and/or obstructed defaecation syndrome (ODS), or even those with constipation-predominant irritable bowel syndrome (IBS-C) is unknown. We therefore assessed whether there is any association between prucalopride efficacy and constipation type. METHODS: All patients receiving prucalopride between June 2010 and April 2012 at our institution were identified, and data analysed following a 4-week "test" period. Patients were sub-grouped as those suffering with ODS, STC, mixed (ODS and STC) or IBS-C based on symptomatology and investigations. Subjective assessment of patient satisfaction and continuation of medication were taken as positive outcomes and analysed for each sub-type along with any side effects. RESULTS: Sixty-nine patients met our criteria. Data were available for 59 women (median age 46 years, range 17-79 years). Sixty-five per cent of prescriptions came from colorectal surgeons. Overall, 25 out of 59 (42 %) patients improved, according to our criteria, after the 4-week trial period. Seventeen patients (29 %) had ODS, 26 (44 %) had STC, 7 (12 %) had mixed symptoms and 9 (15 %) had IBS-C. At 4 weeks, 10 out of 17 patients (59 %) with ODS had improved compared with 4 out of 9 patients (44 %) with IBS-C, 3 out of 7 patients (43 %) with mixed symptoms and 8 out of 26 (31 %) patients with STC. The underlying disorder did not predict whether or not a patient responded to the 4-week trial period (p = 0.32). Nine patients (15 %) experienced side effects that precluded further use. CONCLUSIONS: Patients with all categories of constipation may respond to prucalopride. A trial regime may be indicated regardless of the aetiology of the constipation.

Brain Metastases: Insights from Statistical Modeling of Size Distribution.

BACKGROUND AND PURPOSE: Brain metastases are a common finding on brain MRI. However, the factors that dictate their size and distribution are incompletely understood. Our aim was to discover a statistical model that can account for the size distribution of parenchymal metastases in the brain as measured on contrast-enhanced MR imaging. MATERIALS AND METHODS: Tumor volumes were calculated on the basis of measured tumor diameters from contrast-enhanced T1-weighted spoiled gradient-echo images in 68 patients with untreated parenchymal metastatic disease. Tumor volumes were then placed in rank-order distributions and compared with 11 different statistical curve types. The resultant R 2 values to assess goodness of fit were calculated. The top 2 distributions were then compared using the likelihood ratio test, with resultant R values demonstrating the relative likelihood of these distributions accounting for the observed data. RESULTS: Thirty-nine of 68 cases best fit a power distribution (mean R 2 = 0.938 ± 0.050), 20 cases best fit an exponential distribution (mean R 2 = 0.957 ± 0.050), and the remaining cases were scattered among the remaining distributions. Likelihood ratio analysis revealed that 66 of 68 cases had a positive mean R value (1.596 ± 1.316), skewing toward a power law distribution. CONCLUSIONS: The size distributions of untreated brain metastases favor a power law distribution. This finding suggests that metastases do not exist in isolation, but rather as part of a complex system. Furthermore, these results suggest that there may be a relatively small number of underlying variables that substantially influence the behavior of these systems. The identification of these variables could have a profound effect on our understanding of these lesions and our ability to treat them.

Pulseless electrical activity following traumatic cardiac arrest: Sign of life or death?

BACKGROUND: Generally considered a sign of life, PEA is the most common arrhythmia encountered following pre-hospital traumatic cardiac arrest. Some recommend cardiac ultrasound (CUS) to determine cardiac wall motion (CWM) prior to terminating resuscitation efforts. This purpose of this study was to evaluate the outcomes of patients with traumatic cardiac arrest presenting with PEA, with and without CWM. METHODS: Trauma patients who underwent pre-hospital CPR were identified from the registries of two level-1 trauma centers. Pre-hospital management by emergency medical transport services was guided by advanced life support protocols. The on-duty trauma surgeon directed the resuscitations and performed or supervised CUS and determined CWM. RESULTS: Among 277 patients who underwent pre-hospital CPR, 110 patients had PEA on arrival to ED. 69 (62.7%) were injured by blunt mechanisms. Median CPR duration was 20.0 and 8.0 min for pre-hospital and ED, respectively. Sixty-three patients (22.7%) underwent resuscitative thoracotomy. One hundred seventy-two patients (62.1%) received CUS and of these 32 (18.6%) had CWM. CWM was significantly associated with survival to hospital admission (21.9% vs. 1.4%; P < 0.001); however, no patient with CUS survived to hospital discharge. Overall, only one patient with PEA on arrival survived to discharge. CONCLUSION: Following pre-hospital traumatic cardiac arrest, PEA on arrival portends death. Although CWM is associated with survival to admission, it is not associated with meaningful survival. Heroic resuscitative measures may be unwarranted for PEA following pre-hospital traumatic arrest, regardless of CWM.

Cyclooxygenase-2 expression in colorectal cancer liver metastases.

Cyclooxygenase-2 (COX-2) is up-regulated in 85-90% of primary human colorectal cancers and is a putative target for the chemopreventative activity of non-steroidal anti-inflammatory drugs. However, COX-2 expression by human colorectal cancer liver metastases has been poorly characterized. We studied a consecutive series of 38 patients who underwent liver resection for metastatic disease, for whom long-term (up to 57 months), prospective follow-up data were available. Semi-quantitative immunohistochemistry for COX-2 was performed on 54 metastases from 35 patients, for whom adequate histological material was available. Diffuse cytoplasmic staining for COX-2 protein was detected in cancer cells in 100% of metastases (COX-2 score 1, n = 25; score 2, n = 29). There was no relationship between metastasis size or differentiation grade and the level of COX-2 protein expression. There was no difference in colorectal cancer-free or overall survival between patients with high (score 2) and low (score 1) COX-2 scores (Kaplan-Meier survival analysis and log rank test, both P = 0.97). Multivariate Cox regression analysis identified age, incomplete resection and presence of extra-hepatic disease as independent predictors of disease-free and overall survival following surgery. COX-2 protein was also localized to a subset of stromal fibroblasts and mononuclear cells within metastases as well as hepatocytes from resection specimens. COX-2 protein was expressed by cancer cells in all human colorectal cancer liver metastases which were studied. Investigation of the effect of selective COX-2 inhibition on metastasis growth and metastasis cancer cell proliferation/apoptosis in vivo are warranted.

Impact of Protocol Deviations in Acute Ischemic Stroke Treated With Intravenous rt-PA Within 4.5 Hours After Symptom Onset.

BACKGROUND: There is limited experience in the community with intravenous tissue plasminogen activator (rt-PA) administered 3 to 4.5 hours after acute ischemic stroke (AIS) onset. Many patients do not meet entry criteria of pivotal clinical trials because of severe stroke, age >80, severe hypertension (sHTN), or history of previous stroke and diabetes. Whether rt-PA benefits these patients is unclear. Thus, we investigated the outcomes of stroke patients treated with rt-PA with or without these adverse clinical characteristics. METHODS: Chart review of patients with AIS treated with intravenous rt-PA at a single institution. Outcomes at discharge were compared between patients with severe stroke, age >80, sHTN, or previous stroke/diabetes and those without these characteristics. Good outcome was defined as modified Rankin score (mRS) of 0 to 1. Analysis of variance and t tests were used to compare the outcomes. RESULTS: Of the 118 cases analyzed, 103 (87%) were treated ≤3 hours and 15 (13%) between 3 and 4.5 hours. Sixty-three (53%) patients had severe stroke, age >80, sHTN, or previous stroke/diabetes, whereas 55 (47%) did not. Compared to controls, patients with these adverse characteristics were less likely to have good outcomes (35% vs 56%, p = .02). No patients treated within the 3- to 4.5-hour window experienced symptomatic intracranial hemorrhage (sICH). Eight patients treated between 3 and 4.5 hours had severe stroke, age >80, sHTN, or previous stroke/diabetes. Of these, 6 had poor outcomes. CONCLUSIONS: In a highly selected group of patients treated with intravenous rt-PA, lack of adherence to current guidelines did not improve stroke outcomes. This was related to more severe strokes at baseline, not sICH. Prospective studies of this patient group are needed.

Clinical and endorectal ultrasound staging of circumferential rectal cancers.

Circumferential rectal cancers present at a more advanced stage than those located in a single quadrant. Although accurate staging is an important aspect of the preoperative management of the patient with a rectal cancer, the clinical and radiological staging of this subgroup of rectal cancer patients has been poorly studied. All patients with a rectal cancer were assessed clinically (by digital rectal examination and rigid sigmoidoscopy) before the radiological assessment by endorectal ultrasound (ERUS). Data collected included tumour height (distance from anal verge in centimetre) and tumour type (circumferential or non-circumferential). Radiological tumour staging was with the TNM system. Fifty-nine subjects (33 men, 26 women; median age 65 years (range 38-86 years)) were identified with a circumferential rectal cancer. Mean height of the cancer was 8 +/- 0.4 cm (standard error of the mean; range 2-13 cm). Forty-two cancers were palpable, and 17 cancers were impalpable. All cancers assessed clinically as circumferential were confirmed as circumferential on ERUS scanning. Tumour stage as assessed by ERUS was either T3 (n = 57) or T4 (n = 2). Nodal status was N0 (n = 29) and N1 (n = 30). All rectal cancers assessed as circumferential on clinical examination have an ERUS stage of T3 or greater.

Pneumothorax, pneumomediastinum, pneumoperitoneum, pneumoretroperitoneum and subcutaneous emphysema following diagnostic colonoscopy.

Colonic perforation is an unusual complication of colonoscopy. We present a case of pneumothorax, pneumomediastinum, pneumoperitoneum and extensive subcutaneous emphysema resulting from a diagnostic colonoscopy. To our knowledge, only two such cases have been described previously.

Cyclooxygenase-2 expression and its association with increased angiogenesis in human abdominal aortic aneurysms.

Although the mechanism whereby non-steroidal anti-inflammatory drugs may reduce abdominal aortic aneurysm (AAA) development is unknown, one potential route is via inhibition of the cyclooxygenase (COX) enzyme. Despite the fact that evidence from animal models suggests a role for the COX-2 isoform in promotion of AAA development, only very limited data exist on COX-2 expression in human AAAs. Semiquantitative immunohistochemistry for COX-2 was performed on a series of formalin-fixed, paraffin-embedded human AAAs (n = 49). Associated clinicopathological data, including the degree of inflammatory cell infiltration and neorevascularization, were obtained. COX-2 protein was detected in 46 of 49 (94%) human AAAs. Expression of COX-2 protein varied widely between AAAs. COX-2 protein localized to cells in the inflammatory infiltrate with a morphology characteristic of macrophages. COX-2 expression increased with the extent of inflammatory cell infiltration (P < 0.001) and with the degree of AAA neorevascularization (P < 0.001). Logistic regression analysis identified neorevascularization (P < 0.001) as the only significant independent predictor of COX-2 positivity in human AAAs. COX-2 protein is present at increased levels in the majority of human AAAs and is expressed by mononuclear cells in the inflammatory cell infiltrate. Promotion of angiogenesis by COX-2 may play a role in AAA development.

Zanamivir in the treatment and prevention of influenza.

OBJECTIVE: To evaluate the efficacy of zanamivir in the prevention and treatment of influenza. DATA SOURCES: Medical literature was accessed through MEDLINE (1966-June 1999). Key search terms included zanamivir, GG167, and influenza. Additional information was obtained from GlaxoWellcome, Inc. DATA SYNTHESIS: Zanamivir is the first in a new class of drugs to be developed for the treatment of influenza. An evaluation of clinical trials using inhaled zanamivir was conducted to determine its efficacy. CONCLUSIONS: Zanamivir appears to shorten the median duration of influenza symptoms by up to 2.5 days when compared with placebo. It was well tolerated in clinical trials, with mild adverse effects occurring in a small percentage of subjects.

Traumatic abscess of pectoralis major.

Pectoralis major rupture is a well-recognised but uncommon injury that rarely leads to complications. We present an unusual case where the resultant haematoma following a partial rupture became infected and caused problems with diagnosis. We are only aware of one previous report of this.

Prognostic value of magnetic resonance imaging in the management of fistula-in-ano.

PURPOSE: Magnetic resonance imaging of fistula-in-ano has been shown to predict surgical anatomy accurately and identify complex features. In addition, fistula complexity has been correlated with poor outcome after surgical intervention. We investigated whether preoperative magnetic resonance imaging could predict clinical outcome after surgery for fistulous disease better than clinical examination under anesthetic. METHODS: Seventy patients with clinically suspected fistula-in-ano underwent preoperative dynamic contrast-enhanced magnetic resonance imaging before surgical exploration. Outcome was assessed at a minimum of one year after surgical exploration and correlated in a blinded fashion with the surgical and magnetic resonance grading of the severity of the fistulous disease. RESULTS: Of 70 patients, 12 were not operated on and 6 were lost to follow-up, making 52 patients eligible for analysis. Assessment by dynamic contrast-enhanced magnetic resonance imaging more accurately predicted outcome than the findings at initial surgical exploration. Dynamic contrast-enhanced magnetic resonance imaging had a sensitivity of 81 percent, specificity of 73 percent, and positive predictive value of 75 percent; surgery had a sensitivity of 77 percent, specificity of 46 percent, and positive predictive value of 59 percent. Surgical assessment of apparent disease severity bore no relation to final outcome. Dynamic contrast-enhanced magnetic resonance imaging could accurately predict whether patients were likely to have a satisfactory or unsatisfactory outcome after surgery. CONCLUSION: Dynamic contrast-enhanced magnetic resonance imaging better predicts clinical outcome of patients with fistula-in-ano than initial surgical exploration.

Outcome after surgery for perianal fistula: predictive value of MR imaging.

OBJECTIVE: The purpose of this study was to determine if MR findings are predictive of long-term outcome in a cohort of patients whose initial surgery was performed without access to the findings of MR imaging. SUBJECTS AND METHODS: Forty patients with surgically proven perianal fistulas underwent preoperative dynamic contrast-enhanced MR imaging. The MR and surgical findings were independently recorded on an identical anatomic form. Three patients were subsequently lost to follow-up. The outcome for the remaining 37 patients was determined from surgical review, case notes, and questionnaires. Minimum follow-up period was 14 months (range, 14-39 months). Outcome was determined by one observer who was unaware of the initial MR grading and had not been present during surgery. Outcome was considered unsatisfactory if further surgery was required. RESULTS: MR imaging was better than surgical exploration in predicting outcome (for MR imaging: positive predictive value, 73%; negative predictive value, 87%; sensitivity, 89%; and specificity, 68%; for surgical exploration: positive predictive value, 57%; negative predictive value, 64%; sensitivity, 73%; and specificity, 47%). MR classification of fistulas was significantly associated with outcome (p = .0004), and surgical classification was not significantly associated with outcome (p = .22, chi-square test). Also MR grades differed significantly for patients with satisfactory and unsatisfactory outcomes (p < .001, Mann-Whitney U test). CONCLUSION: MR imaging is valuable in the management of patients with perianal fistulas. MR imaging accurately reveals surgical anatomy and can be used to make better predictions regarding patient outcome than surgical findings.

Localization of cyclooxygenase-2 in human sporadic colorectal adenomas.

A putative target for the anti-colorectal cancer action of nonsteroidal anti-inflammatory drugs is the inducible isoform of cyclooxygenase (COX), COX-2. COX-2 is expressed within intestinal adenomas in murine polyposis models, but expression has been poorly characterized in human colorectal neoplasms. Therefore, we investigated the localization of the COX-2 protein in human sporadic colorectal adenomas. Immunohistochemistry for COX-2 and CD68 (a tissue macrophage marker) was performed on formalin-fixed, paraffin-embedded (n = 52) and frozen, acetone-fixed (n = 6) sections of human sporadic colorectal adenomas. Forty of 52 (77%) formalin-fixed adenomas expressed immunoreactive COX-2. COX-2 was localized to superficial interstitial macrophages in 39 cases (75%) and to deep interstitial macrophages in 9 cases (17%). COX-2 staining of dysplastic epithelial cells was observed in 15 cases (29%). A logistic regression analysis identified the adenoma site (P = 0.012) and histological type (P = 0.001) as independent predictors of superficial macrophage COX-2 expression. There was no relationship between the number of macrophages within an adenoma and macrophage COX-2 expression. These results indicate that COX-2 is expressed predominantly by interstitial macrophages within human sporadic colorectal adenomas. If COX-2 does indeed play a role in the early stages of colorectal carcinogenesis in man, these data suggest COX-2-mediated paracrine signaling between the macrophages and epithelial cells within adenomas.