Effect of preoperative injection of superparamagnetic iron oxide particles on rates of sentinel lymph node dissection in women undergoing surgery for ductal carcinoma in situ (SentiNot study).

BACKGROUND: One-fifth of patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS) have invasive breast cancer (IBC) on definitive histology. Sentinel lymph node dissection (SLND) is performed in almost half of women having surgery for DCIS in Sweden. The aim of the present study was to try to minimize unnecessary SLND by injecting superparamagnetic iron oxide (SPIO) nanoparticles at the time of primary breast surgery, enabling SLND to be performed later, if IBC is found in the primary specimen. METHODS: Women with DCIS at high risk for the presence of invasion undergoing breast conservation, and patients with DCIS undergoing mastectomy were included. The primary outcome was whether this technique could reduce SLND. Secondary outcomes were number of SLNDs avoided, detection rate and procedure-related costs. RESULTS: This was a preplanned interim analysis of 189 procedures. IBC was found in 47 and a secondary SLND was performed in 41 women. Thus, 78·3 per cent of patients avoided SLND (P < 0·001). At reoperation, SPIO plus blue dye outperformed isotope and blue dye in detection of the sentinel node (40 of 40 versus 26 of 40 women; P < 0·001). Costs were reduced by a mean of 24·5 per cent in women without IBC (€3990 versus 5286; P < 0·001). CONCLUSION: Marking the sentinel node with SPIO in women having surgery for DCIS was effective at avoiding unnecessary SLND in this study. Registration number: ISRCTN18430240 (http://www.isrctn.com).

Progranulin inhibits platelet aggregation and prolongs bleeding time in rats.

OBJECTIVE: Several adipokines secreted by adipose tissue have an anti-thrombotic and anti-atherosclerotic function. Recently identified adipokine progranulin was found to play a protective role in atherosclerosis. Bearing in mind the central role of platelets in inflammation and atherosclerosis, we aimed, in this study, to examine the effect of progranulin on platelet function and coagulation profile in rats. MATERIALS AND METHODS: Healthy male albino Wistar rats weighing (250-300 g) were divided into 4 groups. Three groups were given increasing doses of progranulin (0.001 µg, 0.01 µg, and 0.1 µg) intraperitoneally, while the control group received phosphate-buffered saline (PBS). Bleeding time, prothrombin time, activated partial thromboplastin time and platelet aggregation responses to adenosine diphosphate and arachidonic acid were assessed. RESULTS: Administration of progranulin resulted in a significant inhibition of platelet aggregation in response to both adenosine diphosphate, and arachidonic acid. Bleeding time, prothrombin time and activated partial thromboplastin time were significantly prolonged in all groups that received progranulin, in particular, the 0.1 µg dose, in comparison to the control group. CONCLUSIONS: This preliminary data is first suggesting that the antiplatelet and anticoagulant action of progranulin could have a physiological protective function against thrombotic disorders associated with obesity and atherosclerosis. However, these results merit further exploration.

In-hospital complications and 1-year outcome of acute coronary syndrome in patients with hypertension: findings from the 2nd Gulf Registry of Acute Cardiac Events.

Using data from the 2nd Gulf Registry of Acute Coronary Events (Gulf RACE-2) in 2008-09 we investigated the in-hospital complications and 1-year outcome of acute coronary syndrome (ACS) in patients with systemic hypertension from 6 Gulf countries. Of 7847 consecutive patients admitted with ACS, 3746 (47.7%) had hypertension. Hypertension was more prevalent in women, in Arabs than non-Arabs and in older age groups. Patients with hypertension were more likely than those without hypertension to present with dyspnoea and advanced Killip class. Among hypertensive patients, the mortality rate was higher only among those admitted with ST-elevation myocardial infarction. After adjustment for baseline variables, hypertension was an independent predictive factor for heart failure (OR = 1.31) and stroke (OR = 2.47). here were no significant differences in mortality in hypertensive ACS patients when stratified by sex, age or ethnicity.

In-hospital complications and 1-year outcome of acute coronary syndrome in patients with hypertension: findings from the 2nd Gulf registry of acute cardiac events

Using data from the 2nd Gulf Registry of Acute Coronary Events [Gulf RACE-2] in 2008-09 we investigated the in-hospital complications and 1-year outcome of acute coronary syndrome [ACS] in patients with systemic hypertension from 6 Gulf countries. Of 7847 consecutive patients admitted with ACS, 3746 [47.7%] had hypertension. Hypertension was more prevalent in women, in Arabs than non-Arabs and in older age groups. Patients with hypertension were more likely than those without hypertension to present with dyspnoea and advanced Killip class. Among hypertensive patients, the mortality rate was higher only among those admitted with ST-elevation myocardial infarction. After adjustment for baseline variables, hypertension was an independent predictive factor for heart failure [OR = 1.31] and stroke [OR = 2.47]. There were no significant differences in mortality in hypertensive ACS patients when stratified by sex, age or ethnicity

Management of atrial fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. It is common in the elderly and those with structural heart disease. Clinical classification can be helpful in treatment decisions and the most widely accepted classification scheme (first episode, recurrent paroxysmal, recurrent persistent, permanent) is found in the ACC/AHA/ESC guidelines. The pathophysiology of AF remains unclear at this time. It is unlikely that a single pathophysiology is operative in all or even a majority of cases. Therapies to be considered for AF include prevention of thromboembolism, rate control, and restoration and maintenance of sinus rhythm. These therapies and specific treatments for these purposes are discussed under these headings, including a section on the relative merits of the rate control and rhythm control strategies. Risk stratification is a fundamental part of the treatment for thromboembolism. When risk warrants treatment, prevention of thromboembolism is achieved either pharmacologically with aspirin, or with warfarin or new agents like ximelagatran, or by nonpharmacological approaches. Schema to assist in risk stratification and selection of appropriate antithrombotic therapy are provided. Recent trials comparing the strategy of rate control to the strategy of rhythm control failed to demonstrate that the rhythm control approach is superior to the rate control approach in patients and therapies studied so far. Rate control is an acceptable primary line of therapy in many patients, particularly the elderly with persistent AF who are not highly symptomatic. However, the risk and benefit of each treatment modality should be individualized according to the patient circumstances and comorbidity. Algorithms to help individualize which of the two strategies to use are provided. There are a number of pharmacologic and nonpharmacologic therapies available for rhythm management of AF. Pharmacologic cardioversion is an alternative to electrical cardioversion for recent onset AF but the latter is preferred for persistent AF. Current drug therapy to maintain sinus rhythm is neither highly effective nor completely safe. An algorithm to guide selection of the most appropriate antiarrhythmic drug for an individual patient is provided. Nonpharmacologic therapies for maintenance of sinus rhythm include surgery, radiofrequency ablation, devices, and hybrid (combination) therapies. Much remains to be learned about the role and application of such therapies. Pharmacologic heart rate control can be achieved for most patients with available agents and, when it cannot, there are effective nonpharmacologic therapies. A few specific situations in which AF occurs and for which there are some special considerations are described.

Does the discharge ECG provide additional prognostic insight(s) in non-ST elevation ACS patients from that acquired on admission?

BACKGROUND: Although the prognostic value of admission ST changes in patients with non-ST elevation acute coronary syndrome (ACS) is established, the utility of the discharge ECG is unknown. Accordingly, using the PARAGON-B Troponin substudy, we assessed the prevalence of ST depression on both admission and discharge ECG, the likelihood of developing new Q-waves at discharge and the additional prognostic value of these changes. METHODS AND RESULTS: Nine hundred and eighteen patients were studied; 542 patients (59%) had admission ST downward arrow > or =1mm and 376 patients (41%) did not and their 6-month mortality was 4.4 vs 0.8%, P=0.002, respectively. Of patients with ST downward arrow on admission, 320 (59%) normalized their ST segment at discharge. Of patients without ST downward arrow on admission, 35 (9.3%) developed new ST downward arrow at discharge. Patients with persistent ST downward arrow on discharge had a higher 6-month mortality (6.0 vs 0.9%), (re)MI (16.3 vs 7.4%), and death/(re)MI (20.0 vs 8.3%) than those who never had ST downward arrow (all P< or =0.002). Two hundred and fifty-six patients had Q-waves on admission whereas by discharge 320 had Q-waves. Patients with Q-waves on discharge vs those without had a higher mortality (4.8 vs 1.9%), (re)MI (13.8 vs 8.3%), and death/(re)MI (16.4 vs 9.6%) at 6 months (all P< or =0.021). CONCLUSIONS: This study highlights that the dynamic ECG changes which occur between admission and discharge in non-ST elevation ACS patients allows further risk stratification in determining the likelihood of 6-month death and/or re(MI).

Dopamine D-5 receptor modulates hippocampal acetylcholine release.

Dopamine is intimately involved in cognitive processes in the brain. Of the several subtypes of dopamine receptors, the possible role of dopamine D1-like receptors in brain functions, especially in learning and memory, has recently generated much interest. However, molecularly the D1-like receptors are comprised of at least two subtypes, namely D-1 and D-5, and it has not been possible to ascertain which of these two receptor classes is responsible for these functions due to the lack of selective ligands. In the present study, utilizing a combined antisense-in vivo dialysis approach, we show that the D-5 subtype is the dopamine D1-like receptor involved in modulating hippocampal acetylcholine (ACh) release, a transmitter implicated in a variety of cognitive processes. This is one of the first evidence for a functional role for the D-5 receptor.

Multidrug-resistant tuberculosis in Alberta and British Columbia, 1989 to 1998.

OBJECTIVE: To describe the extent of the problem of multidrug-resistant tuberculosis (MDR-TB) in Alberta and British Columbia from 1989 to 1998. DESIGN: A retrospective, population-based descriptive study of all notified MDR-TB cases in the context of all notified TB cases, all notified culture-positive TB cases and all notified drug-resistant TB cases. SETTING: Provinces of Alberta and British Columbia, and their TB registries. PATIENTS: All people with TB reported to the TB registries of Alberta and British Columbia between January 1, 1989 and June 30, 1998. MAIN OUTCOME MEASURES: Drug susceptibility testing was performed in all cases of culture-positive TB. Demographic, clinical and laboratory data on all cases of MDR-TB were recorded. RESULTS: Of 4606 notified cases of TB, 3553 (77.1%) were culture positive. Of these, 365 (10.3%) were drug resistant; of the drug-resistant cases, 24 (6.6%) were MDR. Most MDR-TB patients were foreign-born; of the four Canadian-born patients, two were infected while travelling abroad. Although foreign-born patients were significantly more likely to harbour drug-resistant strains, 14.3% versus 4.8%, respectively (P<0.001), among those who were harbouring a drug-resistant strain, the proportion of Canadian-born versus foreign-born patients with an MDR strain was the same (6.7% versus 6. 6%, respectively). From 1994 to 1998 versus 1989 to 1993, the proportion of all drug-resistant strains that were MDR was greater (9.0% versus 4.3%, respectively), but the difference was not statistically significant. Isolates from 16 of the 24 MDR-TB cases had been archived. Each of these was fingerprinted and found to be unique. Most MDR-TB cases (88%) were respiratory. Of those tested for human immunodeficiency virus (n=17), only one was seropositive. MDR-TB was 'acquired' in 67% and 'primary' in 33% of cases. Eight (33%) of the MDR-TB cases received curative courses of treatment, six (25%) are still being treated, and the remainder have either died (five, 21%), transferred out (four, 17%) or become 'chronic' (one, 4%). No secondary case of MDR-TB has been identified in Alberta and British Columbia. CONCLUSIONS: Most MDR-TB in Alberta and British Columbia is imported. The proportion of all drug-resistant cases that are MDR appears to be increasing, but not because of disease acquired from recent contact with MDR-TB in Canada.

Dopamine D1 receptor ligands modulate cognitive performance and hippocampal acetylcholine release in memory-impaired aged rats.

The possible modulation by D1 drugs of learning abilities of a population of aged memory-impaired animals was investigated in the present study. The level of D1/[3H]SCH 23390 receptors was first examined by quantitative autoradiography to ascertain if cognitive deficits seen in these animals could be related to alterations in the levels of these receptors. No significant differences in [3H]SCH 23390 binding were observed in any of the brain areas examined between young, and aged memory-unimpaired and aged memory-impaired animals. However, the cognitive deficits of the aged-impaired rats were modulated by D1 drugs. The D1 agonists SKF 38393 and SKF 81297 (3.0 mg/kg, i.p.) significantly reduced the latency period to find a hidden platform in the Morris Water Maze, reflecting improved cognitive functions, while the D1 antagonist SCH 23390 (0.05 mg/kg, i.p.) had no overall significant effect. Moreover, the D1 agonist SKF 38393 increased, whereas the antagonist inhibited, in vivo hippocampal acetylcholine release. Taken together, these results suggest that functional hippocampal acetylcholine-dopamine interactions exist in aged memory-impaired rats. More importantly, the cognitive deficits seen in the aged-impaired rats can be attenuated by stimulations of D1 receptors, hence suggesting an alternative approach to alleviate the cognitive deficits seen in the aged brain.

Local modulation of hippocampal acetylcholine release by dopamine D1 receptors: a combined receptor autoradiography and in vivo dialysis study.

The modulation of in vivo hippocampal ACh release by dopaminergic D1 and D2 receptors was examined in this study. Additionally, in an attempt to ascertain the location of these receptors in relation to hippocampal cholinergic terminals, fimbriaectomy and quantitative autoradiography were used. Following unilateral fimbriaectomy, whereby at least 50% of hippocampal cholineacetyltransferase (ChAT) activity was lost, a significant ipsilateral decrease in D1/3H SCH23390 binding was observed in the molecular layer of the dentate gyrus while hippocampal D2/3H raclopride binding was unaffected. The effects of prototypical D1 and D2 receptor agonists and antagonists on hippocampal ACh release were examined next using in vivo dialysis in freely moving rats. The D1 agonist SKF 38393 (10 microM to 100 microM) administered directly into the hippocampus via the dialysis probe stimulated ACh release in a concentration dependent manner. The effect of the agonist was blocked by the coadministration of the D1 receptor antagonist SCH 23390 (1 microM), which by itself failed to modulate ACh release. In contrast, neither the D2 agonist quinpirole (1-10 microM) nor the D2 antagonist sulpiride (1-10 microM) had any direct effect on hippocampal ACh release. Additionally, the infusion of these D1 and D2 drugs in the septal area failed to affect hippocampal ACh release. Taken together, these results suggest that a proportion of hippocampal D1 receptors are located on cholinergic nerve terminals and that dopamine, acting via D1 receptors, can locally stimulate hippocampal ACh release.