Platensimycin: a promising antimicrobial targeting fatty acid synthesis.

Platensimycin was recently discovered by Merck Research Laboratories and has created considerable interest given its potent antibacterial activity and mode of action. The use of RNA gene-silencing techniques and screening libraries of natural products allowed Merck to find this antibiotic which may have otherwise been missed using conventional methods. Interestingly, platensimycin has shown good activity against a panel of Gram positive organisms which included various resistant strains. Platensimycin works by inhibiting beta-ketoacyl synthases I/II (FabF/B) which are key enzymes in the production of fatty acids required for bacterial cell membranes. So far, a number of groups have explored synthetic strategies for platensimycin and this work has subsequently lead to the synthesis of active analogues. Given its mode of action, it is intriguing as to why Merck themselves patented only a single compound and have not apparently sought to generate further libraries. This review will discuss the origins of platensimycin, its mechanism of action, synthetic schemes and where the future may take us following this fascinating discovery.

The cost and distribution of firefighter injuries in a large Canadian Fire Department.

BACKGROUND: There is limited data available regarding the cost of firefighter injuries. This information is necessary to develop targeted injury prevention strategies. OBJECTIVE: To categorize the cost of injuries filed in 2012 by firefighters from a from a large department by job duty, injury type, body part affected, and the general motion pattern employed at the time of injury. METHODS: Data were taken from reports filed by CFD personnel and claims filed with the Workers' Compensation Board (WCB) of Alberta between January 1, 2012 and December 31, 2012. RESULTS: Of the 244 injuries reported, 65% were categorized as sprains and strains, the most frequent of which affected the back (32%). The total cost of all claims was $555,955; 77% were sprain/strain-related. Knee and back injuries were most costly ($157,383 and $100,459). Categorized by job duty, most sprains/strains (31%) were sustained while attending to fire station responsibilities, although physical training was associated with the highest costs (34%). Fireground operations were attributed to 18% of sprains/strains and 16% of costs. Lifting injuries were more frequent (23%) and costly (20%) than all injuries. CONCLUSIONS: The most common and costly injuries occurred while attending to fire station-related responsibilities and during physical training.

Prospective assessment of regional myocardial perfusion before and after coronary revascularization surgery by quantitative thallium-201 scintigraphy.

Because thallium-201 uptake relates directly to the amount of viable myocardium and nutrient blood flow, the potential for exercise scintigraphy to predict response to coronary revascularization surgery was investigated in 47 consecutive patients. All patients underwent thallium-201 scintigraphy and coronary angiography at a mean (+/- standard deviation) of 4.3 +/- 3.1 weeks before and 7.5 +/- 1.6 weeks after surgery. Thallium uptake and washout were computer-quantified and each of six segments was defined as normal, showing total or partial redistribution or a persistent defect. Persistent defects were further classified according to the percent reduction in regional thallium activity; PD25-50 denoted a 25 to 50% constant reduction in relative thallium activity and PD greater than 50 denoted a greater than 50% reduction. Of 82 segments with total redistribution before surgery, 76 (93%) showed normal thallium uptake and washout postoperatively, versus only 16 (73%) of 22 with partial redistribution (probability [p] = 0.01). Preoperative ventriculography revealed that 95% of the segments with total redistribution had preserved wall motion, versus only 74% of those with partial redistribution (p = 0.01). Of 42 persistent defects thought to represent myocardial scar before surgery, 19 (45%) demonstrated normal perfusion postoperatively. Of the persistent defects that showed improved thallium perfusion postoperatively, 75% had normal or hypokinetic wall motion before surgery, versus only 14% of those without improvement (p less than 0.001). Whereas 57% of the persistent defects that showed a 25 to 50% decrease in myocardial activity demonstrated normal thallium uptake and washout postoperatively, only 21% of the persistent defects with a decrease in myocardial activity greater than 50% demonstrated improved perfusion after surgery (p = 0.02). Thus, preoperative quantitative thallium-201 scintigraphy appears useful in predicting response to revascularization surgery, and some persistent defects may revert to normal thallium uptake after surgery. Importantly, the preoperative distinction between viable and nonviable myocardium can be reasonably established by quantitating the amount of persistent reduction in thallium uptake and correlating this with preoperative wall motion.

Firefighter injuries are not just a fireground problem.

BACKGROUND: Linking firefighter injury reporting to general motion patterns may provide insight into potential injury mechanisms and the development of prevention strategies. OBJECTIVE: To characterize the injuries sustained by members of a large Canadian metropolitan fire department over a 5-year span. METHODS: Data were taken from injury reports filed by career firefighters between 2007 and 2011. Injuries were described by job duty, type, body part affected, and the general motion pattern employed at the time of injury (e.g. lifting). RESULTS: Of the 1311 injuries reported, 64% were categorized as sprains and strains (musculoskeletal disorders -MSDs), the most frequent of which affected the back (32%). Categorized by job duty, 65% of MSDs were sustained while working at the fire station or during physical training-related activities. Only 15% were attributed to fireground operations. Furthermore, the associated job duty could not differentiate the types of injuries sustained; back injuries occurred primarily while lifting, knee injuries while stepping, and shoulder injuries during pushing/pulling-related activities. CONCLUSIONS: Firefighter injuries are not just a fireground problem. Injury causation may be better understood by linking the injury location and type with motion patterns rather than job duties. This information could assist in developing general prevention strategies for the fire service.

Schizophrenia: genesis, receptorology and current therapeutics.

Schizophrenia is a debilitating mental disease affecting approximately 1% of the population worldwide. Since the discovery of the first modern treatment for schizophrenia, chlorpromazine, in 1952 there have been many new structures investigated, only a small fraction of which have resulted in clinically useful drugs. Of these, haloperidol may be regarded as the drug for first line treatment. Since then, clozapine has emerged as the benchmark therapeutic ameliorating positive and negative symptoms and devoid of movement disorders, with its greatest feature being improvement of treatment-resistant patients. However, a major, potential lethal side-effect of clozapine is the induction of agranulocytosis, a blood disorder with unknown mechanism that results in lowered white-blood cell counts and consequent susceptibility to infections. In the 50 years of antipsychotic drug development, several novel theories have evolved that focus on receptor sub-types (serotonin 5-HTsub>2A, dopamine D(2) and D(4)) and the degree to which they need to be selectively attenuated by the drugs. Also of significance is the location of these receptors in the brain in relation to the disease state, the myriad of side-effects associated with antipsychotics and physicochemical properties of antipsychotic molecules relative to models of the drugs and the GPCR receptors involved. The techniques for investigation have shown increasing sophistication and refinement over this period, involving cloned receptors and PET scanning for determination of receptor location, density and binding, and rate constants at receptors. Knowledge of receptor structure, although in its infancy since no membrane bound CNS-receptor has yet been crystallized, is likely to benefit substantially with advances in computer-aided modelling. Overall, these new techniques have resulted in a number of novel antipsychotics such as risperidone, sertindole, olanzapine, seroquel, zotepine and ziprasidone, whose design, synthesis and testing has benefited enormously from the accumulated knowledge base of the past 50 years. In this review, we will provide a comprehensive update of the theories of action and clinical profiles of the latest drugs listed. The following appraisal of the literature will provide the practising medicinal chemist interested in this critical area of research with sufficient insight and understanding, to embark on productive investigations into the design and development of new therapeutic agents devoid of clinically limiting side-effects.

Determinants of reperfusion cardiac electrical activity after cold cardioplegic arrest during coronary bypass surgery.

In a prospective study of 99 patients with coronary artery disease, reperfusion of the heart after a period of ischemia (protected by contemporary techniques of myocardial preservation) resulted in spontaneous resumption of cardiac electrical activity in 53%, spontaneous defibrillation in 10%, reperfusion ventricular fibrillation (VF) in 32% and indeterminate rhythm in 5%. In hearts spontaneously developing rhythms excluding VF (as opposed to hearts requiring direct-current shock), factors significantly associated were a higher plasma potassium concentration (5.2 vs 4.8 mEq/liter), shorter reperfusion time (1 vs 4 minutes), higher plasma magnesium concentration (1.36 vs 1.25 mg/dl) and a lower myocardial temperature (27 vs 32 degrees C). The duration of ischemia, arterial blood gas levels, plasma catecholamine levels, plasma ionized calcium levels, volume of cardioplegia and mean arterial pressure did not relate to occurrence of spontaneous episodes. However, VF developed in 39 of 52 patients (75%) with spontaneous resumption of electrical activity. This event was associated with lower myocardial temperature. Thus, direct-current shocks were ultimately required in 77 of the 99 patients (78%). Although certain thermal, biochemical and hemodynamic variables facilitate spontaneous resumption of cardiac rhythm, the development of VF may negate the potential benefit of this event in the prevention of myocardial damage from direct-current defibrillation.

Influence of magnesium ion on human ventricular defibrillation after aortocoronary bypass surgery.

The administration of magnesium ion (Mg++) has been reported to defibrillate the ventricles and to decrease the incidence of arrhythmias after cardiopulmonary bypass. In a prospective study of 76 randomly selected patients undergoing coronary artery bypass grafting, patients received either no Mg++, 0.25 mEq/kg of Mg++ during cardiopulmonary bypass with the aorta clamped, or 0.375 mEq/kg of Mg++ before cardiopulmonary bypass. Spontaneous resumption of a cardiac rhythm or spontaneous defibrillation during reperfusion was not significantly affected by Mg++ administration. However, the number of shocks to initial and to sustained defibrillation and the energy required for the last direct-current shock was greatest in patients who received Mg++ before bypass and in those whose plasma Mg++ was greater than 2.26 mg/dl. Thus, the administration of Mg++ may have adverse effects on the heart if intraoperative plasma Mg++ exceeds 2.26 mg/dl.

Early operative intervention for complications of acute myocardial infarction.

Cardiac operations were performed on 21 patients for treatment of complications of acute myocardial infarction unresponsive to vigorous drug therapy. There were six hospital deaths (28.5 per cent) and 15 survivors 3 to 50 months postoperatively. Fourteen of the 15 survivors are asymptomatic (Class I N.Y.H.A.); one patient remains in Class III. The average time from infarction to operation was 7 days; operative mortality rate was unrelated to the time from infarction to operation. Five of six deaths were in patients with preoperative cardiogenic shock who were not supported by an external cardiac assistance device. The two survivors of cardiogenic shock, treated preoperatively with the intraaortic balloon pump (IABP), are now asymptomatic. Early operative intervention is recommended to decrease the mortality rate in patients with complications of acute myocardial infarction unresponsive to conventional medical therapy. Preoperative treatment with the IABP is advised for the patient in cardiogenic shock.

Total occlusion of left coronary artery. Incidence and management.

From July 1, 1972, to Jan. 1, 1978, 527 patients underwent coronary revascularization. In four (0.76%) of these patients arteriography demonstrated total occlusion of the left main coronary artery. The incidence of acquired occlusion of the left coronary artery encountered in the cardiac catheterization laboratory during the same period was 0.17% in patients undergoing coronary arteriography. Literature review reveals 13 patients with total occlusion of the left coronary artery, and only seven of these were treated operatively, some with suboptimal results. With an average of three grafts per patient, all four of our patients are in Class I of the New York Association an average of 23 months postoperatively. These patients were dramatically symptomatic preoperatively, and their clinical management in terms of pharmacologic or mechanical intraoperative support was no different from that of patients with critical stenosis of the left main coronary artery. This report documents the incidence of left coronary artery occlusion encountered in clinical practice. This incidence should not be as rare as the literature review suggests.

Resection of acute posterior ventricular aneurysm with repair of ventricular septal defect after acute myocardial infarction.

Three patients with true posterior myocardial infarctions and ventricular septal defects were treated by posterior infarctectomy, closure of the defect, and appropriate combinations of mitral valve replacement and coronary grafting. Aortic balloon pumping was not used. The technique of infarctectomy and ventricular septal defect closure is illustrated. Two of the 3 patients have excellent long-term results.

Who manages the postoperative cardiac patient?

Information on the role of the intensivist in postoperative cardiovascular patient care was obtained from a national survey of cardiac surgeons. The cardiac surgeon today retains overall responsibility for patient care. However, when intensivists are present, they significantly reduce the involvement of the cardiac surgeon in most aspects of patient care, particular ventilatory support. Intensivists are less likely to practice in nonteaching hospitals and less likely to be present in those cardiac surgical units that are not combined with other services. Because of the preponderance of intensivists in training programs, the surgical resident's role in patient care may be reduced in the future.

A decade of experience with the Model 103 and 104 Beall valve prostheses.

Mitral or tricuspid valve replacement with the Beall Model 103 or 104 prosthesis has been associated with a high incidence of late prosthetic malfunction which has necessitated reoperation. Between 1972 and 1975, 57 patients underwent single valve replacement (55 mitral and two tricuspid) with Beall Model 103 or 104 valvular prostheses and survived at least 2 years. The mean follow-up time was 73.7 months (range 24 to 119 months). Of these patients, 22 required explantation of the prosthesis; there was an operative mortality of 27%. Major prosthetic malfunction occurred in four patients: Two occluders were embolized and two occluders were fixed in the open position. All four patients required urgent operation, and two of them died. The development of symptoms of congestive heart failure, systolic murmur, or hemolysis were the reasons for cardiac catheterizations and possible reoperation. Nineteen patients had cardiac catheterization. Fifteen of these subsequently underwent reoperation, with a mortality of 26%. Three patients were considered inoperable. Cardiac catheterization data revealed significant prosthetic regurgitation in all patients: pulmonary capillary pressure 29.9 mm Hg +/- 6.7 (standard deviation); V wave 31.5 mm Hg +/- 12.0; left ventricular end-diastolic pressure 18.0 mm Hg +/- 7.8. Comparison of hemolysis indicators in this group to those of asymptomatic patients revealed that the former had a significant elevation in lactic dehydrogenase (p = 0.038) and a lowered hematocrit value (p = 0.017). Waiting for severe symptomatic deterioration to justify reoperation risks the development of left ventricular dysfunction and possible emergency reoperation with a high operative mortality.

Emergency carotid endarterectomy for fluctuating neurologic deficits.

The merit of emergency carotid endarterectomy for patients with fluctuating neurologic deficits remains controversial. Twenty-four patients with fluctuating neurologic deficits underwent emergency carotid endarterectomy and were compared to 31 patients managed nonoperatively. Both groups were similar in age and sex distribution, indicence of hypertension (50%), myocardial infarction (16%), and diabetes mellitus (12%). The two groups were subdivided into patients with crescendo transient ischemic attack (CTIA) and patients with stroke in evolution (SIE). Within the operative CTIA group, all seven patients recovered completely. Among the five nonoperative CTIA patients, one recovered, three sustained moderate or severe neurologic deficits, and one died. Within the operative SIE group of 17 patients, none had a worsening of the deficit, four remained unchanged (24%), and 12 patients (70%) had complete recovery or only a mild deficit. One patient (6%) died postoperatively. Among 26 nonoperative SIE patients, five recovered or sustained mild deficits (19%), 17 had moderate or severe deficits (66%), and four died (15%). The 12 patients with complete or near recovery of neurologic function represented more than a threefold improvement (P less than 0.01) in the quality of life with endarterectomy. When compared with the natural history of fluctuating neurologic deficits, these data suggest that immediate operative intervention will result in better salvage.

Mycotic aneurysm of the ascending aorta following coronary revascularization.

A large mycotic aneurysm of the ascending aorta that appeared two years, three months after triple coronary revascularization is described. Hypothermia and total circulatory arrest were used in excising the aneurysm, and sterilization of the mediastinum was achieved with systemic and local antibiotic therapy. Follow-up at eight months showed a satisfactory postoperative course and no recurrence of mediastinal infection.

The lesser saphenous vein. An alternative graft for coronary revascularization.

In patients with surgically removed or varicose greater saphenous veins and atherosclerotic or small internal mammary arteries, or in patients requiring three or more coronary bypasses, the lesser saphenous vein can be considered for aortocoronary revascularization procedures. Its suitability can be demonstrated preoperatively by careful clinical examination and by venography. This report describes the successful use of the lesser saphenous vein in 3 patients, with long-term follow-up.

Rupture of postcoarctation mycotic aneurysms of the aorta.

Sudden and usually fatal rupture is a common complication of postcoarctation mycotic aneurysms. Prompt operative treatment is always indicated, and can be performed using one of three techniques depending on the adequacy of the collateral circulation and the presence or absence of active bacterial infection. Renal dysfunction commonly is associated with bacterial endarteritis and is secondary to an immune-complex glomerulonephritis. The patient reported here was treated successfully by the placement of an emergency axillofemoral bypass graft, removal of the infected portion of the descending thoracic aorta, and delayed intrathoracic reconstruction.

Anterolateral thoracotomy as an alternative to repeat median sternotomy for replacement of the mitral valve.

Median sternotomy is the most common approach for repeat cardiac surgery despite the potential complications of cardiac injury. Right anterolateral thoracotomy has been recommended as an alternative for patients undergoing mitral valve replacement, but data supporting one approach over the other do not exist. To compare these procedures, the records of 43 patients who had had a previous median sternotomy and who underwent mitral valve replacement were reviewed. No statistically significant differences between patients undergoing repeat median sternotomy (33 patients) and those undergoing right anterolateral thoracotomy (10 patients) were demonstrable when compared for age, gender, New York Heart Association Functional Class, other diseased valves, urgency of operation, indication for operation, type of valve removed, type of valve implanted, length of postoperative hospitalization, length of operation, days of ventilatory support, length of intensive care unit stay, and survival (90% for thoracotomy group; 76% for median sternotomy group; p, NS). Significant differences between the two groups, favoring right anterolateral thoracotomy, were apparent when comparisons were made for length of perfusion (means, 94.8 min, thoracotomy group; 121.4 min, sternotomy group; p = .03), incidence of reexploration (0%, thoracotomy group; 13%, sternotomy group; p = .001), and blood transfusion (means, 5.3 units, thoracotomy group; 11.4 units, sternotomy group; p = .003). Right anterolateral thoracotomy is an effective alternative to repeat median sternotomy for replacement of the mitral valve in patients who have had a previous median sternotomy.

Unanticipated postoperative ventricular tachyarrhythmias.

Eighteen (1.4%) of 1,251 patients who underwent cardiac operations during a three-year period had new sustained ventricular tachycardia (12 patients) or ventricular fibrillation (6 patients) not caused by but resulting in hemodynamic compromise. In 13 patients, the initial arrhythmia occurred in the first 48 hours postoperatively. Lidocaine was being administered to 10 of these patients for suppression of previously noted ventricular ectopy, but it did not prevent the occurrence of the arrhythmia. The initial episode was fatal for 5 patients. Two of these deaths were directly related to the adverse effects of the antiarrhythmic agents used to suppress ventricular tachycardia or fibrillation. Five of 10 survivors underwent electrophysiological studies after initial resuscitation. In all 5, programmed ventricular stimulation reproduced the clinical arrhythmia. There have been 2 late sudden deaths in patients who either did not undergo or remained uncontrolled at electrophysiological study during serial drug trials. Our experience suggests that a cardiac operation may unmask or induce potentially lethal arrhythmias that previously had not been apparent. Pharmacological suppression of ventricular ectopy does not necessarily prevent ventricular tachycardia or ventricular fibrillation in the early postoperative period. Electrophysiological study may be helpful in determining the appropriate prophylactic therapy in such patients.

Aortic dissection: surgical and nonsurgical treatments compared. An analysis of seventy-four cases at the University of Virginia.

During the eleven year period from 1965 to 1976, aortic dissection was diagnosed in seventy-eight patients treated at the University of Virginia Medical Center. The seventy-four cases that comprise the present report were confirmed by aortography, surgery, or autopsy. Forty patients (54 per cent) were surgically treated by interruption of the origin of dissection and insertion of a Dacron prosthesis. The remaining thirty-four (46 per cent) were treated according to the Wheat regimen or by nonspecific supportive measures. The overall survival at one year was 28 per cent. One year survival for patients with type I dissections treated surgically was 19 per cent compared with 8 per cent one year survival for nonsurgically treated patients. Sixty per cent of patients with type II dissections treated surgically were alive at the end of one year, whereas no patients with type II dissection treated nonsurgically survived beyond one year. Half the patients with type III dissections treated surgically were alive at one year compared with 35 per cent of those nonsurgically treated. These data suggest that surgery is the treatment of choice for all types of aortic dissections, but particularly for type II. Patients with type I dissections have a very poor prognosis regardless of therapy.

Effects of coronary grafting technique upon reperfusion cardiac rhythm, ventricular function, and other variables.

The effects of different techniques of aortocoronary bypass grafting on reperfusion cardiac rhythm and ventricular function have not been systematically evaluated for possible advantages or disadvantages. The placement of proximal anastomoses before cardiopulmonary bypass and sequential coronary grafting with reperfusion via both the grafts and the native circulation were prospectively compared to traditional grafting and reperfusion via native arteries. More than 40 biochemical, thermal, temporal, hemodynamic, and other variables, including arrhythmias and myocardial failure, were measured intraoperatively and postoperatively. Spontaneous resumption of a cardiac rhythm occurred more frequently with traditional grafting technique in association with a larger cardioplegia volume and a higher serum potassium. However, the disadvantage of the traditional technique was a higher incidence of cardiac failure postoperatively and greater use of isoproterenol after discontinuation of bypass. While cardiac rhythm resumed spontaneously more often with the traditional technique, the increased incidence of cardiac failure postoperatively has serious implications. Thus, placement of proximal anastomoses before cardiopulmonary bypass seems warranted.