The complement system: an old story or target of new therapeutic approaches?

The complement system is a multifactorial protein cascade system which is essentially involved in the early unspecific immune response. Its major function is the activation of cellular defense mechanisms, opsonisation of foreign particles and the destruction of target cells. While the impact of the different complement components for bacterial elimination still remains controversial, overwhelming activation of the complement cascade, however, can induce life threatening tissue damage due to the effective cytotoxic properties. In the last years a variety of studies demonstrated beneficial, organ protective effects of complement modulation in models of severe inflammation. Attempts to control the complement system include the application of endogenous complement inhibitors e.g. C1-inhibitor (C1-INH) or the administration of recombinant complement receptors such as the soluble complement receptor 1 (rsCR1). Moreover antibodies against key proteins (C3, C5), against their activation products (C5a) or against complement receptor 3 (CR3, CD18/11b) mediated adhesion of leukocytes to the vascular endothelium, represent effective options of complement modulation. Besides this, insertion of membrane bound human complement regulators (DAF- CD55, MCP- CD46 or CD59) into xenogenic donor organs has proven effectiveness to prevent xenograft rejection. The described interventions protected from severe organ damage in various animal models of sepsis, myocardial and intestinal ischaemia-reperfusion injury, ARDS, nephritis, and xenograft rejection. With respect to recent clinical data, complement inhibition could represent a useful therapeutic strategy to control overwhelming inflammation. Own experiments demonstrated protective effects of complement modulation with C1 INH and rsCR1 in a model of complement induced pulmonary injury. With respect to sufficient host defense, however, the use of complement inhibitors must be considered carefully.     

Sepsis‐related acute kidney injury: a protective effect of drotrecogin alfa (activated) treatment?

Background: Drotrecogin alfa activated (DrotAA) is licensed for treatment of patients with severe sepsis and organ failure. Among the latter, acute kidney injury (AKI), defined as the persistence of oligo‐anuria following adequate resuscitation, is one of the most apprehended. We conducted a prospective, observational, and controlled study to test the hypothesis that DrotAA beneficially affected the evolution and outcome of AKI, complicating acute sepsis‐induced cardiopulmonary failure. Methods: Forty‐six patients were studied. Thirty subjects received standard treatment for sepsis without DrotAA. In the remaining 16 patients, DrotAA was added as a continuous infusion of 24 μg/kg/h for 96 h. Results: Mean age, causes of sepsis, and severity/organ failure scores were comparable between patients treated with or without DrotAA. Mortality at 28 days was high and comparable between both treatment groups (56% vs. 69%, DrotAA vs. no DrotAA; P=0.5). When oligo‐anuria was present at the start of the study, it persisted during treatment in all patients, with no significant difference between groups. Both treatment groups presented with baseline mean daily fractional excretion of sodium values >2% that remained high during the observation period, regardless of whether DrotAA was given or not. Kidney histology showed a preserved renal architecture with tubular necrosis in all specimens. Similar glomerular, tubulo‐interstitial, and vascular alterations were present in both treatment groups. Conclusion: In this small cohort of patients with severe sepsis who received adjuvant DrotAA treatment, no effect on urine output, tubular function, or mortality could be demonstrated.     

Gauze packing of open surgical wounds: empirical or evidence-based practice?

INTRODUCTION: Most surgical wounds are closed primarily, but some are allowed to heal by secondary intention. This usually involves repeated packing and dressing of the raw wound surfaces. Although the long-term care of such wounds has devolved to the care of nurses in the community or out-patient setting, the initial wound dressing or cavity packing is done by the surgeon in the operating theatre. Many surgeons are unaware of the growth of the discipline of wound care, and still use traditional soaked gauze for dressing and packing open surgical wounds and cavities. RESULTS: This review summarises the some of the modern alternatives available and the evidence--or the lack of it--for their use in both the acute and chronic setting.     

Australian haemodialysis patients on intravenous epoetin alfa or intravenous darbepoetin alfa: How do they compare?

AIM: The purpose of the present study was to determine whether Australian haemodialysis patients receiving intravenous epoetin alfa are comparable to those receiving darbepoetin alfa with respect to a range of demographic and clinical characteristics. METHODS: Data on haemodialysis patients were extracted from the Renal Anaemia Management database for the period from July 2003 to March 2004. RESULTS: Patients on haemodialysis were more likely to receive epoetin alfa than to receive darbepoetin alfa (n = 1898 vs n = 603, respectively). Patients receiving epoetin alfa were marginally older than patients receiving darbepoetin alfa (61 +/- 15 vs 59 +/- 15, mean +/- SD; P < 0.05). Patients were similar in terms of proportion of males, incidence of diabetes, and angiotensin-converting enzyme inhibitor and antihypertensive use. However, patients receiving epoetin alfa had higher haemoglobin (116 +/- 13 g/L vs 113 +/- 15 g/L), serum ferritin (582 +/- 414 mug/L vs 461 +/- 350 mug/L) and transferrin saturation levels (29 +/- 13% vs 26 +/- 14%), and better dialysis adequacy test results, as measured by urea reduction ratio (URR) or Kt/V, than patients on darbepoetin alfa (P < 0.001 in all cases). The frequency of dosing was higher in the epoetin alfa group (1.7 +/- 0.7 doses/week vs 1.0 +/- 0.4 doses/week, P < 0.001). Using the 240:1 dose ratio recommended in the Australian prescribing information for darbepoetin alfa, epoetin alfa was administered at a lower dose compared with darbepoetin alfa (164 +/- 116 IU/kg per week vs 192 +/- 152 IU/kg per week, P < 0.001). CONCLUSION: This cross-sectional sample of Australian clinical practice suggests that there are differences in the haematological parameters of patients receiving epoetin alfa compared with patients receiving darbepoetin alfa.     

The future of surgery: autonomy or employment?

History has shown that the professions of medicine and surgery have been in constant evolution. Physicians, including the historical barber surgeons, often remained focused only on medical practice and patient care. As a result, the medical profession had a reactionary response to the financial and political circumstances that developed over time. Subsequently, physicians have worked in environments designed by nonphysicians lacking the benefit of medical insight. The most poignant example of this in the U.S. was the rapid development of private insurance and Medicare. Due to the surrounding financial and political forces, these programs rapidly changed the practice environment of medicine. Physicians found that they needed to participate in these programs to remain financially solvent. Various countries around the world have faced similar challenges of increasing health care cost. As populations expand, the need for care increases, but is limited by available resources. These global experiences can lend insight into the effects of different models and how variations may or may not work within the U.S. The effects of those systems demonstrate the importance of physician input into the development of new models. A long-standing unwritten rule in medicine has taught generations of physicians to avoid discussing reimbursement and health care politics. Yet, in order to recruit the brightest minds with a compassionate bedside manner, excellent judgment, and high vigilance toward patient care, medical professionals need to discuss topics related to reimbursement. The government, insurance company administrations, and other lobby interest groups freely express their interests in these issues. Physicians must engage in health care politics to ensure an adequate physician pool in the future to take care of patients. By influencing the structure of the health care system, including physician reimbursement, all patient care can be positively influenced.     

The Delivery of Aesthetic Medicine: Illegal or Not?

The field of aesthetic facial surgery is dynamic and may be driven by new technology and market trends. It is important that we respond to these pressures as small business persons, but only in the context of our obligations to our state regulatory boards, the Hippocratic Oath, and our patients' best interests. Regulations with regard to the scope of practice of aesthetic medicine and the corporate practice of medicine have the greatest potential to affect facial plastic surgeons. This article provides basic information regarding these medicolegal issues and resources to examine physician compliance. There may be an opportunity for the American Academy of Facial Plastic and Reconstructive Surgery to provide its membership with basic guidelines for scope of practice and corporate practice of medicine in an effort to optimize patient care.     

Chronic renal failure from lead: myth or evidence-based fact?

In this mini review, we would like to challenge the well-established 'fact' that lead exposure causes chronic renal failure (CRF). Even though only scarce evidence exists of the relationship between lead and renal failure, a World Health Organization Environmental Health Criteria document summarizes that 'Lead has been a very common cause of acute or chronic renal failure'. It is also written and cited in textbooks and numerous publications that chronic lead nephropathy causes a slowly progressive interstitial nephritis manifested by a reduced glomerular filtration rate, and that there is a growing consensus that lead contributes to hypertension in the general population. We will argue that, when published reports are carefully scrutinized, such statements on lead and CRF are not evidence based but are rather founded on a few narrative reports on lead-exposed individuals and statistical associations between lead and serum creatinine (or urea) in a few population studies. We will, however, not argue that lead is not toxic and that lead does not cause other types of severe health effects where the evidence is unquestionable, but we do not believe that the kidneys are an early victim after lead exposure.     

The aerodynamics of running socks: Reality or rhetoric?

Aim

The primary objective of this study was to test the aerodynamic properties of a selection of running and general sports socks.

Methods and procedures

Eleven pairs of socks were tested in a specially constructed rig which was inserted into a fully calibrated wind tunnel. Wind test speeds included 3, 4, 5, 6, 12 and 45 m/s.

Results

There was no significant difference between any of the socks tested for their aerodynamic properties. The drag coefficients calculated for each sock varied proportionally with the Reynolds number. No particular sock was more aerodynamic than any of the socks tested.

Conclusion

There is no evidence that a sock that is “aerodynamically designed” will help an athlete go faster. This may be more product rhetoric than reality, and further work is justified if such claims are being made.     

The individual patient and evidence-based medicine – a conflict?

The doctor–patient relationship is characterised by clinical situations that reflect different degrees of impairment of the patient’s quality of life on the one hand and different degrees of threat to the patient’s life on the other. Typical patterns of these situations from absent or minimal to severe impairment of well being or threat to life are described. With regard to this, the doctor–patient communication is still suffering from considerable deficits. For the latter, a possible philosophical framework and reason is given. The potential of evidence-based medicine to ease this conflict by bringing into the game the current best-available scientific evidence is discussed, and some inherent serious limitations of evidence-based medicine are shown. Besides these drawbacks, doctors are usually very reluctant and lazy to integrate evidence-based results into their daily practice. In the author’s view, evidence-based medicine is a reasonably new tool. However, it should not yet be overestimated in its potential to influence and improve daily clinical practice. Received: 9 March 1999 Accepted: 2 September 1999     

The acute mesenteric ischemia - not understood or incurable?

PURPOSE: Despite surgical research and progress, the high mortality of acute intestinal ischemia seems to be improved insignificantly over the past fifty years. In this study we analyzed the specific diagnostic and therapeutic problems of the disease in order to improve further management of acute mesenteric ischemia. Methods: From 1979 until 2000 64 patients (female 31, male 33) with a mean age of 64 (30-89) years underwent operation for primary intestinal ischemia at our institution. All medical and surgical records and imaging studies were reviewed retrospectively. Follow up consisted of clinical examination and duplex sonography. RESULTS: Only in 26 patients (41 %) a preoperative diagnostic work-up including angiography 12 and CT 14 was performed, whereas in 42 cases the intestinal ischemia was diagnosed during surgical exploration. Intestine malperfusion was caused primarily by venous thrombosis in 9 cases (14 %) and by arterial occlusive disease in 55 cases (86 %). Arterial disorders consisted of arterial thrombosis in 19 cases (30 %), arterial embolism in 18 cases (28 %), aortic or mesenteric artery dissection in 10 cases (15 %), non occlusive disease (NOD) in 5 cases (8 %), trauma 3 cases (5 %). Five different therapeutic strategies were applied: group I: Intestinal resection: 24 patients, anastomotic insufficiency 5 (39 %), mortality 11 (46 %), group II: intestinal artery revascularization: 5 patients, secondary patency rate 80 %, mortality 40 %, GROUP III: Intestinal artery revacularization and perfusion with Ringer's solution: 11 patients, mortality 8 (73 %), group IV intestinal artery revascularization and intestinal resection: 3 patients, mortality 100 %, group V intestinal artery revascularization and perfusion and intestinal resection: 3 patients, mortality 33 %. A second look operation was performed in 29 cases (40 %) and displayed malperfusion in 72 %. Only 21 of 64 patients survived the acute intestinal ischemia (in hospital mortality was 67 %). Delayed diagnostic and operation caused higher mortality (interval 10 hours: mortality 59 %, interval 37 hours mortality; 71 %, p = 0,06). Follow up after 61 (4-72) months of 21 patients (100 %) could be achieved. Ten patients (48 %) had meanwhile died, 5 patients (50) % as consequence of mesenteric ischemia, the others of unrelated reasons. Eleven patients are still alive without clinical signs of intestinal ischemia. CONCLUSIONS: Early diagnosis before hospitalisation and in-hospital (arteriography) and operation are essential to improve the outcome of patients with acute intestinal ischemia. To avoid short bowel syndrome bowel resection should be combined with mesenteric revascularization. Resection of malperfused bowel should be done cautiously and should be followed automatically by second look operations. Special expertise and good team work of visceral and vascular surgeons are required to achieve better therapeutic results.     

Why evidence-based medicine?

This chapter considers briefly what counts as ‘evidence’ and describes three historical strands, in medical science generally, in epidemiology and in clinical trials, that have converged to give rise to the concept of evidence-based medicine. It then returns to the randomized controlled trial as the fundamental building block of evidence-based practice. Finally, through considering whether all trials are equally useful, it demonstrates that discerning what is the best way to proceed in the clinical management of individual patients and problems is not necessarily a simple matter.     

The Declining Phase of Lactation: Peripheral or Central,Programmed or Pathological?

In most species the functional activity of the mammary gland during lactation follows a biphasic developmental pattern. This pattern starts with a rapid increase in milk output that occurs with secretory activation and continues with a more gradual increase until the point of peak lactation is reached. Following this gain-of-function phase, the ability of the gland to produce milk decreases. This decrease occurs even if the lactation is prolonged by the presence of continued suckling stimulus and complete milk removal. This review describes the current state of our knowledge concerning the factors that regulate milk synthesis capacity by the mammary gland during the lactation cycle. The review describes four potential alternatives as mechanisms governing the process, which we refer to as secretory diminution. These alternatives are not presented as mutually exclusive of each other or other possible mechanisms, but are proposed as potential contributing mechanisms.