Differentiation and stromal-induced growth promotion of murine prostatic tumors

BACKGROUND: We have derived a panel of p53-null prostatic "basal" and "luminal" epithelial cell lines and their ras transformed counterparts to study stromal/epithelial interactions and the properties of tumors arising from "basal" and "luminal" cells. METHODS: Previously derived normal murine prostatic "basal" epithelial (PE-B-1) and "luminal" epithelial (PE-L-1) cell lines were transformed with N-Ras. These lines and a spontaneously transformed "luminal" cell line were inoculated subcutaneously or orthotopically into athymic mice, alone or in combination with normal prostatic smooth muscle cells (SMC). RESULTS: All transformed lines formed subcutaneous tumors. SMC significantly enhanced the growth rate of the tumors arising from the "basal" and one of the "luminal" cell lines. The transformed "basal" line gave rise to tumors expressing both "basal" and "luminal" cytokeratins. CONCLUSIONS: Prostatic SMC promote the growth of transformed epithelial cells, suggesting that prostatic stroma may promote tumor development. Furthermore, transformed "basal" cells give rise to tumors containing "luminal" cells, suggesting that although most human tumors have a "luminal" phenotype, they may originate from transformed "basal" cells.     

Neuroleptic malignant syndrome and mivacurium: a safe alternative to succinylcholine?

Neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH) may have a common pathogenic mechanism; therefore, it has been suggested that known triggering agents for MH (such as succinylcholine) should be avoided in patients with NMS. Electroconvulsive therapy (ECT) continues to play a major therapeutic role in contemporary psychiatry, and succinylcholine has been the muscle relaxant of choice in attenuating violent muscle contractions induced by ECT. Mivacurium is a nondepolarizing muscle relaxant with a relatively rapid onset and a short duration of action, and to date it has been proved safe in MH- susceptible patients. In this case report, following succinylcholine use during ECT, a patient with NMS developed an increase in temperature and serum creatine kinase (CK) level, possibly due to an MH reaction. Since the patient’s mental status necessitated further ECT, mivacurium was administered during subsequent treatments and resulted in effective attenuation of muscle contractions without elevation of patient temperature or CK levels. In addition, there was no marked prolongation of the anaesthetic. Mivacurium is a suitable agent for patients with NMS undergoing ECT, as it has not been associated with precipitation of an MH response.     

Phaeochromocytoma presenting as acute hyperamylasaemia and multiple organ failure

Phaeochromocytoma may present in many different ways. We report an unusual presentation of phaeochromocytoma in a man with hyperamylasaemia and multiple organ failure thought to be due to acute relapsing pancreatitis. Abdominal ultrasound and computerised tomography (CT) examinations revealed a mass at the tail of the pancreas. Fine needle biopsy of the mass precipitated headache, intense vasoconstriction and labile blood pressure. He proceeded to laparotomy, at which an 8 × 9 cm mass was found to be replacing the left adrenal gland. Histological examination revealed a phaeochromocytoma. This case illustrates that hyperamylasaemia and multiple organ failure may be unusual presentations of phaeochromocytoma and phaeochromocytoma should be considered in the differential diagnosis of a peripancreatic mass found by ultrasound or CT.     

Clinicopathological and immunohistochemical studies on carcinoma of the papilla of Vater]

The non-invasive adenomatous component (nac) was observed in 44% of 32 resected specimens of carcinoma of the papilla of Vater. Incidence of the "nac" positive carcinoma declined with cancer staging, but there was no significant relationship between the "nac" and tumor size. The "nac" positive rates in "tumor forming", "ulcerating" and "mixed" types were 65, 0 and 38%, respectively. The "nac" negative carcinoma metastasized more frequently to the lymph nodes, duodenum, pancreas and veins. The five year survival rates of the patients with the "nac" positive and negative carcinoma were 78 and 22%, respectively. Immunohistochemically, the "nac" positive carcinoma mostly showed partial distribution of CA19-9, while the "nac" negative carcinoma, carcinoma of the pancreas and bile duct mostly showed diffuse distribution. The intact mucosa of the common channel and orifice of the papilla almost showed partial distribution, and duodenal mucosa showed negative distribution. The pancreatic and bile duct almost indicated diffuse distribution. The "nac" may be precancerous condition and the "nac" positive carcinoma may arise from the common channel or the orifice of the papilla or the duodenum. But the "nac" negative carcinoma may belong primarily to carcinoma of the pancreas and bile duct as de-novo carcinoma.     

Mechanisms of inhibition of endothelium-dependent relaxation by halothane,isoflurane, and sevoflurane

Volatile anaesthetics inhibit endothelium-dependent relaxation, but the underlying mechanism(s) have not been clarified. In an attempt to elucidate the mechanism(s), we determined the effects of halothane, isoflurane and sevoflurane on relaxation induced by acetylcholine and sodium nitro-prusside (SNP) and the cGMP formation elicited by exogenous nitric oxide (NO) and SNP in rat aortas. Acetylcholine (10^?7?10^?5M) - induced relaxation was attenuated by halothane (2%), isoflurane (2%) and sevoflurane (4%). SNP (10^?8 M) - induced relaxation was reduced by halothane (2%), but not by isoflurane (2%) or sevoflurane (4%). The cGMP level of NO-stimulated aorta was reduced by halothane (2%) and sevoflurane (4%), but not by isoflurane (2%). The cGMP level of SNP (10^?7 M) - stimulated aorta was reduced by halothane (2%), but not by isoflurane (2%) and sevoflurane (4%). We conclude that the mechanisms responsible for the inhibition of endothelium-dependent relaxation differ among anaesthetics. Isoflurane inhibits the relaxation mainly by inhibiting the formation of NO in the endothelium. In contrast, the effect of halothane on endotheliumdependent relaxation may be largely due to the inhibition of action of NO in the vascular smooth muscle and the effect of sevoflurane may be to inactivate NO or to inhibit the action of NO.     

Clinicopathological evaluation of angiograms in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) was classified into the three types of expansive type "Exp", mixed type "Mix" and infiltrative type "Inf" according to the preoperative angiographic characteristics, referred to clinicopathological features. "Exp" type had less incidence of accompanied portal venous invasion and daughter nodules in comparison to "Inf" type. And "Exp" type had a better prognosis in the cumulative survival rate than "Inf" type (p less than 0.001). Thus, the present typing essentially classified by tumor vascular architecture represents "malignancy grade" of HCC. In addition, "Inf" type may be recommended more extensive resection or multidisciplinary therapy (for example TAE) for better prognosis.     

Absorptiometry and “osteoporosis”: problems

connecting the dots between diverse clinical and other matters and an updated bone physiology reveals relationships that could modify some ideas about the roles and uses of absorptiometry in osteoporosis work. Herein, absorptiometry means that part of clinical densitometry that depends on X-ray absorption by bone and other tissues, thus excluding ultrasound methods and magnetic resonance imaging. The modifications concern, in part, some limitations of bone mineral density data, the kinds of physiological information that absorptiometry can and cannot provide, the relative importance of bone mass and whole-bone strength, how to define and study bone health and osteoporosis, and two kinds of osteoporotic fractures. As those modifications concern important national health care issues, they deserve answers based on hard evidence. Identifying those modifications might help others to evaluate them.     

Anesthesia, department of anesthesiology and anesthesiology--why has anesthesiology not been accepted socially in Japan?

An incorrect Japanese terminology of "Masuigaku [symbol: see text]" has been used widely to express "anesthesiology" or "anaesthetics" [symbol: see text] since the first Department of Anesthesiology was established in Tokyo University in 1952. The reason why the nomenclature "Masui-gaku" is wrong is as follows: Japanese nomenclatures for clinical medical sciences should include a Chinese character "Ka [symbol: see text]" such as "nai-ka-gaku" for internal medicine, "ge-ka-gaku" for surgery and "gan-ka-gaku" for ophthalmology. Accordingly the name "Masui-gaku" is erroneous to mean "Anesthesiology" and it should be "Masui-ka-gaku" [symbol: see text]. Thus a big confusion has occurred among lay people as well as many physicians in medical field. "Ma-sui" is etymologically a Japanese word which Dr Seikei Sugita coined when he translated a Dutch edition of J. Schlesinger's monograph on ether anesthesia in 1850. "Ma [symbol: see text]" means analgesia or loss of regional sensation and "Sui [symbol: see text]" means loss of consciousness. Most people consider that "Ma [symbol: see text]" is originated from "[symbol: see text] (Hemp, Asa)" or "[symbol: see text] (Marihuana, Taima)", however, this is definitely incorrect and "Ma [symbol: see text]" of "Ma-sui" has no direct relation with the pharmacological effect of hemp. Thus the misuse of "Masui-ga-ku" might have caused serious academic and social confusions, such as misunderstanding of anesthesiologists as comedical technicians, leading to a poor social acceptance of anesthesiology and anesthesiologists for these fifty years in Japan. To correct this confused situation I would like to ask our colleagues to use correctly these nomenclatures.     

Adjuvant propofol enables better control of nausea and emesis secondary to chemotherapy for breast cancer

We investigated the prophylactic antiemetic effect of added lowdose infusion of propofol in patients exhibiting nausea and vomiting refractory to dexamethasone and serotonin antagonist during non-cisplatin chemotherapy for breast cancer. In a prospective open longitudinal study, 117 patients who had more than five episodes of nausea and vomiting in their first chemotherapy cycle during the first 24 hr completed the study. They received in addition to the usual prophylactic antiemetic regimen a continuous intravenous infusion of 1 mg · kg^?1 · hr^?1 propofol started four hours before chemotherapy and continued up to 24 hr for the two subsequent cycles. The number of vomiting / nausea episodes, level of sedation, patient activity, appetite and preference for future chemotherapy cycles were assessed. In the propofol supplemented cycles 90 and 80% of patients, during the 1st and 2nd propofol-assisted cycle respectively, were free of nausea and vomiting during the first 24 hr after chemotherapy. Patients were more frequently active and had more appetite during the propofol-assisted cycles. No propofol-associated side effects were observed. We conclude that the addition of a subhypnotic infusion of propofol enables better control of nausea and vomiting caused by non-cisplatin chemotherapy in the first 24 hr post-treatment.     

The opening of maitotoxin-sensitive calcium channels induces the acrosome reaction in human spermatozoa： differences from the zona pellucida

The acrosome reaction (AR), an absolute requirement for spermatozoa and egg fusion, requires the influx of Ca²⁺ into the spermatozoa through voltage-dependent Ca²⁺ channels and store-operated channels. Maitotoxin (MTx), a Ca²⁺-mobilizing agent, has been shown to be a potent inducer of the mouse sperm AR, with a pharmacology similar to that of the zona pellucida (ZP), possibly suggesting a common pathway for both inducers. Using recombinant human ZP3 (rhZP3), mouse ZP and two MTx channel blockers ({"type":"entrez-nucleotide","attrs":{"text":"U73122","term_id":"4098075","term_text":"U73122"}}U73122 and {"type":"entrez-nucleotide","attrs":{"text":"U73343","term_id":"1688125"}}U73343), we investigated and compared the MTx- and ZP-induced ARs in human and mouse spermatozoa. Herein, we report that MTx induced AR and elevated intracellular Ca²⁺ ([Ca²⁺]_i) in human spermatozoa, both of which were blocked by {"type":"entrez-nucleotide","attrs":{"text":"U73122","term_id":"4098075","term_text":"U73122"}}U73122 and {"type":"entrez-nucleotide","attrs":{"text":"U73343","term_id":"1688125"}}U73343. These two compounds also inhibited the MTx-induced AR in mouse spermatozoa. In disagreement with our previous proposal, the AR triggered by rhZP3 or mouse ZP was not blocked by {"type":"entrez-nucleotide","attrs":{"text":"U73343","term_id":"1688125"}}U73343, indicating that in human and mouse spermatozoa, the AR induction by the physiological ligands or by MTx occurred through distinct pathways. {"type":"entrez-nucleotide","attrs":{"text":"U73122","term_id":"4098075","term_text":"U73122"}}U73122, but not {"type":"entrez-nucleotide","attrs":{"text":"U73343","term_id":"1688125"}}U73343 (inactive analogue), can block phospholipase C (PLC). Another PLC inhibitor, edelfosine, also blocked the rhZP3- and ZP-induced ARs. These findings confirmed the participation of a PLC-dependent signalling pathway in human and mouse zona protein-induced AR. Notably, edelfosine also inhibited the MTx-induced mouse sperm AR but not that of the human, suggesting that toxin-induced AR is PLC-dependent in mice and PLC-independent in humans.     

Locking plate osteosynthesis in displaced 4-part fractures of the proximal humerus

Background and purpose

There is considerable uncertainty about the optimal treatment of displaced 4-part fractures of the proximal humerus. Within the last decade, locking plate technology has been considered a breakthrough in the treatment of these complex injuries.

Methods

We systematically identified and reviewed clinical studies on the benefits and harms after osteosynthesis with locking plates in displaced 4-part fractures.

Results

We included 14 studies with 374 four-part fractures. There were 10 case series, 3 retrospective observational comparative studies, 1 prospective observational comparative study, and no randomized trials. Small studies with a high risk of bias precluded reliable estimates of functional outcome. High rates of complications (16–64%) and reoperations (11–27%) were reported.

Interpretation

The empirical foundation for the value of locking plates in displaced 4-part fractures of the proximal humerus is weak. We emphasize the need for well-conducted randomized trials and observational studies.There is considerable uncertainty about the optimal treatment of displaced 4-part fractures of the proximal humerus (Misra et al. 2001, Handoll et al. 2003, Bhandari et al. 2004, Lanting et al. 2008). Only 2 small inconclusive randomized trials have been published (Stableforth 1984, Hoellen et al. 1997). A large number of interventions are used routinely, ranging from a non-operative approach to open reduction and internal fixation (ORIF), and primary hemiarthroplasty (HA).In the last decade, locking plate technology has been developed and has been heralded as a breakthrough in the treatment of fractures in osteoporotic bone (Gautier and Sommer 2003, Sommer et al. 2003, Haidukewych 2004, Miranda 2007). Locking plate technique is based on the elimination of friction between the plate and cortex, and relies on stability between the subchondral bone and screws. Multiple multidirectional convergent and divergent locking screws enhance the angular stability of the osteosynthesis, possibly resulting in better postoperative function with reduced pain. Reported complications include screw cut-out, varus fracture collapse, tuberosity re-displacement, humeral head necrosis, plate impingement, and plate or screw breakage (Hall et al. 2006, Tolat et al. 2006, van Rooyen et al. 2006, Agudelo et al. 2007, Gardner et al. 2007, Khunda et al. 2007, Ring 2007, Smith et al. 2007, Voigt et al. 2007, Egol et al. 2008, Kirchhoff et al. 2008, Owsley and Gorczyca 2008, Brunner et al. 2009, Micic et al. 2009, Sudkamp et al. 2009). The balance between the benefit and harms of the intervention seems delicate.Several authors of narrative reviews and clinical series have strongly recommended fixation of displaced 4-part fractures of the humerus with locking plates (Bjorkenheim et al. 2004, Hente et al. 2004, Hessler et al. 2006, Koukakis et al. 2006, Kilic et al. 2008, Korkmaz et al. 2008, Shahid et al. 2008, Papadopoulos et al. 2009, Ricchetti et al. 2009) and producers of implants unsurprisingly strongly advocate them (aap Implantate 2010, Stryker 2010, Synthes 2010, Zimmer 2010). Despite the increasing use of locking plates (Illert et al. 2008, Ricchetti et al. 2009), we have been unable to identify systematic reviews on the benefits and harms of this new technology in displaced 4-part fractures. Thus, we systematically identified and reviewed clinical studies on the benefits and harms after osteosynthesis with locking plates in displaced 4-part fractures of the proximal humerus.     

Opisthotonos following propofol: A nonepileptic perspective and treatment strategy

In this report of opisthotonos during recovery from propofol anaesthesia, we relate clinical observations with scientific considerations, and propose a strategy for treatment of this rare side effect. Following a brief operative procedure, a healthy 29-yr-old woman developed recurrent opisthotonos while recovering from anaesthesia with alfentanil, propofol, and nitrous oxide. In contrast to accumulating reports, the patient remained conscious during each episode of back extension and retrocollis. The preservation of consciousness and similarities to strychnine-induced opisthotonos suggest to us that the mechanism may have a brainstem and spinal origin. Recent investigations show that propofol potentiates the inhibitory transmitters glycine and γ-aminobutyric acid (GABA) which would enhance spinal inhibition during anaesthesia. Postanaesthetic opisthotonos, however, may be due to a propofol-induced tolerance to inhibitory transmitters. This rebound phenomenon would lead to an acute, enduring refractoriness in inhibitory pathways of the brainstem and spinal cord, resulting in increased activity of extensor motoneurons. We recommend a therapeutic strategy that restores inhibition by glycine and GABA at multiple sites; the preferred therapeutic agents would be diazepam and physostigmine. The episodes are usually short-lived, but two of the reviewed 17 patients developed recurrent retrocollis for four and 23 days following antiepileptic drug therapy. Since high doses of phenytoin and carbamazepine can result in opisthotonos, we recommend that anticonvulsants be reserved for post-anaesthetic patients with electroencephalographic evidence of seizure activity.     

Perioperative mortality after hemiarthroplasty related to fixation method

Background and purpose

The appropriate fixation method for hemiarthroplasty of the hip as it relates to implant survivorship and patient mortality is a matter of ongoing debate. We examined the influence of fixation method on revision rate and mortality.

Methods

We analyzed approximately 25,000 hemiarthroplasty cases from the AOA National Joint Replacement Registry. Deaths at 1 day, 1 week, 1 month, and 1 year were compared for all patients and among subgroups based on implant type.

Results

Patients treated with cemented monoblock hemiarthroplasty had a 1.7-times higher day-1 mortality compared to uncemented monoblock components (p < 0.001). This finding was reversed by 1 week, 1 month, and 1 year after surgery (p < 0.001). Modular hemiarthroplasties did not reveal a difference in mortality between fixation methods at any time point.

Interpretation

This study shows lower (or similar) overall mortality with cemented hemiarthroplasty of the hip.The frequency of hip fractures is increasing with our ageing population, with an annual incidence of between 1.4 and 5 per 103 per year (Lonnroos et al. 2006, Icks et al. 2008, Varez-Nebreda et al. 2008). Health model projections have estimated that 6.3 million hip fractures will occur annually worldwide within the next 40 years (Cooper et al. 1992), imposing a significant economic health burden. There is a large reported perioperative mortality rate in this population, ranging from 2.4% to 8.2% at 1 month (Parvizi et al. 2001, Radcliff et al. 2008) and over 25% at 1 year (Elliott et al. 2003, Jiang et al. 2005). Furthermore, it was recently reported that the current mortality rate is higher now than 25 years ago (Vestergaard et al. 2007a). Today, it is generally accepted that displaced intracapsular fractures are best treated with arthroplasty rather than internal fixation (Keating et al. 2006, Leighton et al. 2007). In the at-risk population, however, multiple comorbidities are common and the best form of component fixation is in question.Bone cement implantation syndrome is a well-described complication of cemented hip arthroplasty. It is characterized by a systemic drop in systolic blood pressure, hypoxemia, pulmonary hypertension, cardiac dysrhythmias, and occasionally cardiac arrest and death (Rinecker 1980, Orsini et al. 1987, Parvizi et al. 1999). The prevailing theory to explain the pathophysiology of this phenomenon is embolism of fat, marrow contents, bone, and to some degree methylmethacrylate to the lung (Rinecker 1980, Elmaraghy et al. 1998, Parvizi et al. 1999, Koessler et al. 2001). An increased degree of pulmonary insult with fat microemboli has been demonstrated (mostly in randomized controlled trials) during insertion of a cemented femoral stem rather than an uncemented implant (Orsini et al. 1987, Ries et al. 1993, Christie et al. 1994, Pitto et al. 1999), presumably due to increased intramedullary femoral canal pressures in the cemented group (Kallos et al. 1974, Orsini et al. 1987). These pressures can be reduced by the use of distal venting holes in the femur during stem insertion (Engesæter et al. 1984). It has been shown previously by single-institutional review that patients undergoing cemented hip arthroplasty have a higher intraoperative mortality rate relative to uncemented arthroplasty, presumably due to a reduced incidence of fat embolism in the latter group (Parvizi et al. 1999). The increased mortality risk was also present at 30 days in the treatment of acute fractures with cemented arthroplasty, also from a single-institutional review (Parvizi et al. 2004). Although cement-related mortality is rare (Dearborn and Harris 1998, Parvizi et al. 1999, 2001, 2004, Weinrauch et al. 2006), it is a devastating complication—often reported through observational studies or literature reviews. Proponents of uncemented hip arthroplasty often cite this concern to support their reluctance to use cemented hip arthroplasty in both elective procedures and fracture management. However, many different types of studies have been unable to identify any increased mortality risk with the use of cement (Lausten and Vedel 1982 (observational), Emery et al. 1991 (RCT), Lo et al. 1994 (observational), Khan et al. 2002a,b (literature review), Parker and Gurusamy 2004 (literature review)) and others have shown a decrease in mortality at 30 days when cement is used (Foster et al. 2005).Cemented hip hemiarthroplasty appears to offer improved rate of return to baseline function, reduced postoperative pain, and superior long-term survivorship relative to uncemented arthroplasty (Khan et al. 2002a, b, Parker and Gurusamy 2004). We reasoned that failure to return to baseline function after hemiarthroplasty may be another risk factor for perioperative mortality (Hannan et al. 2001, Braithwaite et al. 2003). Lower revision rates for cemented prostheses and increased mortality at revision surgery contribute further to reducing the overall mortality risk. We evaluated the relationship between the method of fixation of hip arthroplasty and perioperative mortality using a large national joint replacement registry.     

Terminology and definition of the main concepts in the surgery of injuries]

Based upon the 20-years experience of the clinic of field surgery of the Military Medical Academy with treatment of critical mechanical injuries the authors propose to differentiate concepts "injury" and "trauma" and hence the ideas of "severity of injury", "severity of the state" and "severity of trauma". It is expedient to use concepts of "isolated", "multiple", "associated" traumas instead of non concrete ideas of "polytrauma" which is correct but for determination of critical associated traumas. Definitions of such concepts as "consequences of trauma" and "complications of trauma", "trauma disease" and "trauma shock" are given.     

Predictors of blood loss after coronary artery bypass grafting

To assess the predictive value of variables possibly associated with blood loss after coronary artery bypass grafting (CABG). A prospective study. A university hospital. Eighty-nine patients scheduled for elective CABG. Blood samples were drawn before and after surgery. Chest tube drainage was measured hourly until removal of drains. Activation of coagulation and fibrinolysis, routine clotting tests, and expression of platelet surface antigens were analyzed using flow cytometry. A significant correlation was found among blood loss and activated partial thromboplastin time, fibrinogen, prothrombin fragment 1 + 2, D-dimers, platelet count, GPlb and P-selectin expression on platelets, use of internal thoracic artery, cross-clamp time, and thrombin-antithrombin III complex. In a multiple regression model, glycoprotein (GP) Ib expression on platelets, platelet count, use of internal thoracic artery, and D-dimers were significantly associated with blood loss. Logistic regression analysis showed that GPIb and D-dimers predicted an increased blood loss with a positive predictive value of 73% and a negative predictive value of 91%. Postoperative D-dimers and GPIb expression may be useful to exclude nonsurgical causes in bleeding patients after CABG.     

Cost-Effectiveness of Aliskiren in Type 2 Diabetes,Hypertension, and Albuminuria

The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial demonstrated that adding aliskiren, an oral direct renin inhibitor, at a dosage of 300 mg/d to the highest approved dosage of losartan and optimal antihypertensive therapy reduces albuminuria over 6 mo among patients with type 2 diabetes, hypertension, and albuminuria. The cost-effectiveness of this therapy, however, is unknown. Here, we used a Markov model to project progression to ESRD, life years, quality-adjusted life years, and lifetime costs for aliskiren plus losartan versus losartan. We used data from the AVOID study and the Irbesartan in Diabetic Nephropathy Trial (IDNT) to estimate probabilities of progression of renal disease. We estimated probabilities of mortality for ESRD and other comorbidities using data from the US Renal Data System, US Vital Statistics, and published studies. We based pharmacy costs on wholesale acquisition costs and based costs of ESRD and transplantation on data from the US Renal Data System. We found that adding aliskiren to losartan increased time free of ESRD, life expectancy, and quality-adjusted life expectancy by 0.1772, 0.1021, and 0.0967 yr, respectively. Total expected lifetime health care costs increased by $2952, reflecting the higher pharmacy costs of aliskiren and losartan ($7769), which were partially offset by savings in costs of ESRD ($4860). We estimated the cost-effectiveness of aliskiren to be $30,500 per quality-adjusted life year gained. In conclusion, adding aliskiren to losartan and optimal therapy in patients with type 2 diabetes, hypertension, and albuminuria may be cost-effective from a US health care system perspective.Recent clinical trials have shown that reductions in albuminuria with agents that inhibit the renin-angiotensin-aldosterone system (RAAS; e.g., angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), as defined by a urinary albumin-creatinine ratio (UACR) or urinary albumin excretion rate (UAER), can delay progression of renal disease in patients with hypertension and type 2 diabetes.^1–5 Albuminuria is associated with fatal and nonfatal cardiovascular events and progression toward ESRD,^1,2,6 and reductions in albuminuria have been widely used as surrogate markers of renoprotection.^7,8The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial was a multicenter, randomized, double-blind study to assess the efficacy and safety of adding aliskiren, an oral direct renin inhibitor, at a dosage of 300 mg/d to the highest approved dosage of losartan (100 mg/d) and optimal antihypertensive therapy in patients with type 2 diabetes, hypertension, and albuminuria.⁹ At the end of 6 mo of follow-up, aliskiren 300 mg/d significantly reduced mean UACR by 20% (P = 0.0009) and overnight UAER by 18% versus placebo (P = 0.009). Although the AVOID trial demonstrated that adjunctive treatment with aliskiren 300 mg/d reduces albuminuria during 6 mo in these patients, it did not examine the potential long-term clinical and economic consequences of such treatment.The objective of this study was to evaluate, from the US health care system perspective, the potential cost-effectiveness of lifetime treatment with aliskiren 300 mg/d plus losartan 100 mg/d and optimal antihypertensive therapy (aliskiren plus losartan) versus lifetime treatment with losartan 100 mg/d and optimal antihypertensive therapy alone (losartan only) in patients with type 2 diabetes, hypertension, and albuminuria. We evaluated cost-effectiveness using a Markov model (Figure 1).¹⁰ The initial distribution of the population across disease states and probabilities of progression from microalbuminuria (MA) and early overt nephropathy (EON) to advanced overt nephropathy (AON) were from the AVOID trial (11Open in a separate windowFigure 1.Markov state transition model. Ovals represent health states. Patients are assumed to transition among states every 6 mo on the basis of transition probabilities in

A Practical Approach to Monitoring Patients on Biological Agents for the Treatment of Psoriasis

Psoriasis is a chronic, systemic, inflammatory skin condition that manifests predominantly as well-demarcated, erythematous, scaly plaques on the elbows, knees, and scalp. While mild cases (minimal body surface) often respond to various topical treatments and light therapy, patients with extensive disease (larger body surface and possibly joint involvement) may require systemic medications for remission. The development of biological agents provides dermatologists valuable ways to help treat psoriatic disease quite efficiently, but literature regarding the monitoring of patients on biological treatments is sparse. Clinical practice varies widely since there is modest strong evidence to recommend or refute most tests currently recommended by the United States Food and Drug Administration. The purpose of this article is to present a practical approach to monitoring patients on biological therapy based on the most up-to-date literature.The use of biological treatments has grown significantly since their introduction and now account for a significant proportion of the systemic therapies used for the treatment of psoriasis. Biological therapies target precise segments of the immune system, offering the advantage of being less immunosuppressive compared to the traditional systemic therapies that broadly cause immunosuppression. Currently, five biological agents (e.g., alefacept, etanercept, infliximab, adalimumab, and ustekinumab) are approved by the United States Food and Drug Administration (FDA) for the treatment of psoriasis, and other newer agents (e.g., ABT-874) are in various stages of development and clinical trials (1–6 The biologicals at present are divided into either tumor necrosis factor alpha (TNF-α) or T-cell lymphocyte inhibitors. Recently, CD4+ T helper (Th) 17 cells and interleukins (IL)-12 and IL-23 have been important in the pathogenesis of T-cell mediated disorders, such as psoriasis, and have influenced the development of medications that specifically target these key immunological players. Both IL-12 and IL-23 stimulate differentiation of naive T-cells into Th1 and Th17 cells, key cells that regulate the production of other pro-inflammatory cytokines significant in the pathogenesis of psoriasis.^7,8 Understanding of these immune cascade complexities has divulged this new class of biological agents that target cytokines (e.g., ustekinumab) important in the pathogenesis of inflammatory skin disease. Each drug class that is used in the treatment of psoriasis works by blocking different steps along the same immune-dysregulation pathway leading to psoriatic disease.

Table 1

Currently approved biological medications for the treatment of psoriasis^1–4,6