Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses.

The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.

Metachronous bilateral adrenal metastases following curative treatment for colorectal carcinoma.

A delayed, metachronous presentation of bilateral adrenal metastases following colorectal cancer has never previously been reported. We describe the case of a 68-year-old man who underwent curative surgery and adjuvant chemotherapy for a locally invasive sigmoid adenocarcinoma, only to be diagnosed with metachronous bilateral adrenal metastasis necessitating further resection and chemotherapy. We discuss the literature surrounding this pathology and highlight the importance of continual, vigilant radiological surveillance of the adrenal glands after curative treatment of colorectal carcinoma with or without subsequent adrenal metastasis.

Polymyositis in African HIV-infected subjects.

Polymyositis in HIV-infected subjects, clinically and pathologically resemble polymyositis in non-HIV-infected subjects. We report 14 consecutive HIV-associated polymyositis cases and compare specific features with 25 polymyositis cases seen over the same 6.5 year period. The HIV-polymyositis cases were all female and compared to the polymyositis cases were younger (median age 33 years, interquartile range (IQR) 29; 37 vs. 46 years, IQR 38; 52, p=0.002), and with 4-fold lower serum creatine kinase (CK) values (median 1158 vs. 5153IU/l; p=0.019). A definite clinical improvement on prednisone therapy was documented in eight HIV-polymyositis cases and one improved with anti-retroviral therapy alone. The recognition of HIV-polymyositis which is treatable, but may present with serum CK elevations less than twofolds above normal, is clinically relevant in sub-Saharan Africa where electromyography and muscle biopsies are not readily available.

Hypothalamic-pituitary-adrenal axis function in patients with chronic depression.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis function in patients with chronic depression has previously been shown to be normal when measured using the dexamethasone suppression test (DST). We examined patients with chronic depression using the sensitive dexamethasone/corticotropin releasing hormone (dex/CRH) test and the dexamethasone suppression test (DST) to establish whether HPA axis abnormalities are present in this group. We also compared the sensitivity of the two tests and compared the results with previous studies in depression that have not specifically selected chronic patients. METHOD: Twenty-nine patients with the chronic subtype of major depressive disorder and 28 matched controls underwent examination of HPA axis function. RESULTS: Neither the cortisol response to the DST or the dex/CRH test differed significantly between the patient and control groups. There was a trend in favour of more patients than controls having an abnormal response to the dex/CRH test (P = 0.052). Neither the patients with an abnormally enhanced response, nor the magnitude of response could be predicted by any illness or demographic variable. CONCLUSION: The HPA axis is not overtly abnormal in chronic depression. This contrasts with previous findings in acute depression and bipolar disorder and may suggest that the HPA axis abnormalities present in acute depression resolve, but are not accompanied by symptom resolution. Alternatively, a subgroup of depressives with less HPA dysfunction may progress to chronicity. This has implications for treatment and prognosis. The dex/CRH is a more sensitive test of HPA axis function than the DST in patients with chronic depression.

Cervical SNAGs: a biomechanical analysis.

A sustained natural apophyseal glide (SNAG) is a mobilization technique commonly used in the treatment of painful movement restrictions of the cervical spine. In the manual therapy literature, the biological basis and empirical efficacy of cervical SNAGs have received scant attention. In particular, an examination of their potential biological basis in order to stimulate informed discussion seems overdue. This paper discusses the likely biomechanical effects of both the accessory and physiological movement components of a unilateral cervical SNAG applied ipsilateral to the side of pain when treating painfully restricted cervical rotation. The use of flexion and extension SNAGS, and rotation SNAGS performed contralateral to the side of pain are not considered. Although a cervical SNAG may clinically be able to resolve painfully restricted cervical spine movement, it is difficult to explain biomechanically why a technique which first distracts (opens) and then compresses (closes) the zygapophyseal joint ipsilateral to the side of pain, and perhaps slightly distracts the uncovertebral cleft, would be superior to a technique which distracts the articular surfaces with both accessory and physiological movement components. Therefore, the reported clinical efficacy of cervical SNAGs cannot be explained purely on the basis of the resultant biomechanical effects in the cervical spine.

Kinetic analysis of product inhibition in human manganese superoxide dismutase.

Manganese superoxide dismutase (MnSOD) cycles between the Mn(II) and Mn(III) states during the catalyzed disproportionation of O(2)(*-), a catalysis that is limited at micromolar levels of superoxide by a peroxide-inhibited complex with the metal. We have investigated the role in catalysis and inhibition of the conserved residue Trp161 which forms a hydrophobic side of the active site cavity of MnSOD. Crystal structures of mutants of human MnSOD in which Trp161 was replaced with Ala or Phe showed significant conformational changes on adjacent residues near the active site, particularly Gln143 and Tyr34 which in wild-type MnSOD participate in a hydrogen bond network believed to support proton transfer during catalysis. Using pulse radiolysis and observing the UV absorbance of superoxide, we have determined rate constants for the catalytic dismutation of superoxide. In addition, the rates of formation and dissociation of the product-inhibited complex of these mutants were determined by direct observation of the characteristic visible absorption of the oxidized and inhibited states. Catalysis by W161A and W161F MnSOD was associated with a decrease of at least 100-fold in the catalytic rate of reduction of superoxide, which then promotes a competing pathway leading to product inhibition. The structural changes caused by the mutations at position 161 led to small changes, at most a 6-fold decrease, in the rate constant for formation of the inhibited complex. Solvent hydrogen isotope effects support a mechanism in which formation of this complex, presumably the peroxide dianion bound to the manganese, involves no rate-contributing proton transfer; however, the dissociation of the complex requires proton transfer to generate HO(2)(-) or H2O2.

Attitudes to evidence-based practice in urology: results of a survey.

BACKGROUND: The advantages of promoting evidence-based care through implementation of clinical guidelines are well established. Clinical practice guidelines have been developed for lower urinary tract symptoms (LUTS) and prostate cancer screening. Aspects of the delivery of care by urologists or specialist registrars relevant to the guidelines were assessed. METHODS: A questionnaire was distributed at the 1999 meeting of the Urological Society of Australasia, which was attended by 187 Australasian and 33 foreign delegates. Questions addressed access to resources for evidence-based medicine; perceived need; preferred sources of information; and then presented four clinical scenarios. These were: (i) treatment recommendations in early stage prostate cancer; (ii) the same scenario if the respondent was the patient; (iii) treatment recommendations after radical prostatectomy when there was a positive resection margin; and (iv) clinical investigations for mild to moderate LUTS. RESULTS: Of 220 possible responses, 132 were received, a response rate of 60%. Urologists overwhelmingly (100%) endorsed the need for access to evidence-based reviews, although 28% claimed such access was non-existent to poor. Clinical guidelines were the preferred source of evidence-based information. For early stage prostate cancer in a 55-year-old man, radical prostatectomy was recommended by 93.2% of respondents, but this dropped to 83% when the respondent was the patient (P < 0.05), and a wider range of treatments was recommended. Pelvic radiotherapy and hormone therapy were equally recommended for biochemical progression following radical prostatectomy where there was a positive surgical margin. Investigations for LUTS included serum prostate-specific antigen (PSA) testing (78.0%) and voided flow studies (77.3%). CONCLUSIONS: Urologists express a need for evidence-based practice resources, in particular clinical guidelines. Nevertheless their clinical approach is not necessarily consistent with existing guidelines, particularly for LUTS. An alteration in the recommendation when the respondent is the patient of interest and endorses the recommendation that patients with prostate cancer should be involved in treatment decisions.

Rupture of the abdominal aorta in patients with Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome (EDS) is a heterogeneous inherited disorder of collagen synthesis. Type IV is frequently associated with major vascular catastrophes and challenges the vascular surgeon with its varied clinical presentation and the difficulty of vascular repair. Rupture of the abdominal aorta is one of the most serious complications and is associated with nearly 100% mortality rate. We describe here three patients with type IV EDS.

Role of tryptophan 161 in catalysis by human manganese superoxide dismutase.

Tryptophan 161 is a highly conserved residue that forms a hydrophobic side of the active site cavity of manganese superoxide dismutase (MnSOD), with its indole ring adjacent to and about 5 A from the manganese. We have made a mutant containing the conservative replacement Trp 161 --> Phe in human MnSOD (W161F MnSOD), determined its crystal structure, and measured the catalysis of the resulting mutant using pulse radiolysis to produce O(2)(*)(-). In the structure of W161F MnSOD the phenyl side chain of Phe 161 superimposes on the indole ring of Trp 161 in the wild type. However, in the mutant, the hydroxyl side chain of Tyr 34 is 3.9 A from the manganese, closer by 1.2 A than in the wild type. The tryptophan in MnSOD is not essential for the half-cycle of catalytic activity involving reduction of the manganese; the mutant W161F MnSOD had k(cat)/K(m) at 2.5 x 10(8) M(-)(1) s(-)(1), reduced only 3-fold compared with wild type. However, this mutant exhibited a strong product inhibition with a zero-order region of superoxide decay slower by 10-fold compared with wild type. The visible absorption spectrum of W161F MnSOD in the inhibited state was very similar to that observed for the inhibited wild-type enzyme. The appearance of the inhibited form required reaction of 2 molar equiv of O(2)(*)(-) with W161F Mn(III)SOD, one to form the reduced state of the metal and the second to form the inhibited complex, confirming that the inhibited complex requires reaction of O(2)(*)(-) with the reduced form of the enzyme. This work suggests that a significant role of Trp 161 in the active site is to promote the dissociation of product peroxide, perhaps in part through its effect on the orientation of Tyr 34.

Characterization of the product-inhibited complex in catalysis by human manganese superoxide dismutase.

The reduction with excess H(2)O(2) of human Mn(III) superoxide dismutase (SOD) and the active-site mutant Y34F Mn(III)SOD was measured by scanning stopped-flow spectrophotometry and revealed the presence of an intermediate in the reduction of the manganese. The visible absorption spectrum of this intermediate closely resembled that of the enzyme in the inhibited, zero-order phase of the catalyzed disproportionation of superoxide. The decay of the visible spectrum of this intermediate was 2-fold faster for the wild-type compared with the mutant Y34F Mn-SOD. This correlates with the enhanced product inhibition of Y34F during the catalysis of O-(2) dismutation. The visible spectrum of the product-inhibited complex resembles that of the azide-Mn-SOD complex, suggesting that the inhibited complex has expanded geometry about the metal to octahedral. This study shows that the inhibited complex responsible for the zero-order phase in the catalysis by Mn-SOD of superoxide dismutation can be reached through both the forward (O-(2)) and reverse (H(2)O(2)) reactions, supporting a mechanism in which the zero-order phase results from product inhibition.

Evaluation of lidocaine as an analgesic when added to hypertonic saline for sclerotherapy.

PURPOSE: The efficacy of sclerosing agents for the treatment of telangiectasias and reticular veins is well established. The injection of these agents is often associated with pain, and it is not uncommon for sclerotherapists to include lidocaine with the sclerosants in an attempt to reduce the pain associated with treatment. However, there are concerns that this may reduce the overall efficacy of the treatment because of dilution of the sclerosant. Patient comfort and overall outcome associated with treatment using HS with lidocaine (LIDO) versus that using HS alone was compared. METHODS: Forty-two patients were prospectively entered into the study and randomized blindly to sclerotherapy with 23.4% HS or 19% LIDO. Study subjects and treating physicians were blinded to the injection solution used. Injection sites were chosen for veins ranging in size from 0.1 to 3 mm. Photographs of the area to be treated were taken, and the patients rated their pain. They were then observed at regular intervals for four months, and clinical data was collected. Thirty-five subjects completed the full follow-up period, and photographs of the injected area were taken again. Three investigators blinded to the treatment assignment then evaluated the photographs and scored the treatment efficacy according to a standardized system. RESULTS: In the HS group, 61.9% (13 of 21) patients rated their pain as none or mild, whereas 90.5% (19 of 21) of patients in the LIDO group had no or mild discomfort. This difference is significant, with a P value of.034. There was no difference in the overall efficacy of treatment between the two groups. The groups had similar rates of vein thrombosis and skin necrosis. CONCLUSION: Although lidocaine is often used with sclerosing agents, there are no previous reports in the literature to evaluate its effectiveness in reducing the pain experienced by the patient. In this study, patients receiving LIDO experienced significantly less discomfort at the time of injection than patients who received HS alone. There were no differences in the effectiveness of treatment or in the incidence of complications between the two groups.

Endovascular stent infection with delayed bacterial challenge.

BACKGROUND: Reports of endovascular stent infection have recently been described. The purpose of this study was to determine if intravascular metallic stents in a swine model could become infected following a bacterial challenge given remote from the time of stent placement. METHODS: Balloon expandable metallic stents (Palmaz) were implanted in the iliac arteries of 14 swine. An angioplasty, without stent placement, was also performed in the contralateral iliac artery. An intravenous bacterial challenge with Staphylococcus aureus was given 4 weeks after stent placement. Euthanasia was performed 72 hours after the bacterial challenge. At the time of euthanasia, the iliac artery/stent complex and the contralateral angioplastied iliac artery were harvested and sent for microbiologic and pathologic analysis. RESULTS: Seven of the 14 stent/artery complexes were culture positive for S aureus whereas only one of the 14 angioplastied arteries was positive for S aureus (P = 0.03). On histologic examination, 6 of the 14 stent/artery complexes had evidence of acute inflammatory changes in the arterial wall. This compares with only 1 of 14 angioplastied arteries having evidence of inflammatory infiltrate in the arterial wall (P = 0.07). All 6 of the stent/artery complexes with inflammatory infiltrate were culture positive. CONCLUSION: In the swine model, intravascular metallic stents have the potential to become infected when a bacterial challenge is given 4 weeks after stent placement. Further studies evaluating the incidence of stent infections in humans are needed.

Lessons learned from the DIASTAT vascular access graft.

BACKGROUND: The vascular community continues to search for the ideal vascular access graft that will allow early cannulation and avoid temporary central venous catheters. METHODS: This is a review of the Cranley Surgical Associates' experience with the use of the Gore-Tex DIASTAT (W.L. Gore & Associates, Inc., Flagstaff, Arizona) vascular access graft in 20 patients compared with 20 control patients matched for age, sex and risk factors. RESULTS: Although the DIASTAT graft is touted for early accessibility and decreased need for central venous access, that was not found to be the case as 14 patients in the DIASTAT group received temporary access catheters. There was significantly more edema in the DIASTAT patients (P = 0.0048). Comparing the time to the first thrombosis or to revision revealed an average of 18 weeks for the DIASTAT group and 56 weeks for the control group. The length of time to thrombosis or revision was significantly longer in the control group (P = 0.0058). Comparison of the number of weeks of function and serviceability of the grafts revealed the average DIASTAT graft functioned for 34 weeks and that of the control group for an average of 70 weeks (P = 0.0131). Comparison of the two groups showed a significant increase in early thrombotic events (< 90 days) in the DIASTAT grafts (P = 0.0013). CONCLUSIONS: The DIASTAT vascular access graft does not appear to be the ideal hemodialysis access graft.

Analysis of autogenous vein femoral-infrapopliteal bypass for limb salvage in the elderly.

The hypothesis that older patients undergoing femoral-infrapopliteal bypass have a similar outcome as a matched younger group of patients undergoing the same operation was tested. Seventy-six femoral-infrapopliteal autogenous saphenous vein bypasses for critical limb ischemia were performed from 1985 to 1990. By using the life-table method, the primary and secondary patency, limb salvage and survival rates are analyzed and compared for older and younger age groups. Forty cases (53%) were performed in an elderly group, defined as age 70 or older. At 4 years, there was no significant difference between age groups in limb salvage and patency rates. However, operative mortality for the older age group was 12%, compared with 0% in the younger group (P = 0.0004). Thus, femoral-infrapopliteal autogenous vein bypass can be performed with comparable limb salvage and patency rates for an older age group, but the risk of operative mortality appears to be increased with age.

Utilization management advancement system: a career ladder for nonclinical nursing.

This article describes a utilization management advancement system at the authors' facility that recognizes the staff members' levels of utilization management expertise and links them with the annual performance appraisal. After 2 years of brainstorming, analysis, discussion, and research, the utilization management nurses were able to define their practice in terms of functional domains that reflect levels of experience and competencies. The process of developing these levels and the performance appraisal standards is addressed.

Management options for hepatic artery aneurysms.

A 70-year-old woman underwent an elective sigmoid resection for chronic diverticulitis. On the third postoperative day she suddenly developed abdominal pain and hypotension after a coughing episode. Radiologic evaluation demonstrated the presence of a hemoperitoneum. A celiac arteriogram was obtained in an effort to determine the cause of the hemorrhage. Four aneurysms of the intrahepatic portions of the left and right hepatic arteries were found. These aneurysms were successfully treated using steel coil embolization. Surgery has traditionally been the "gold standard" treatment of this rare entity. Recent reports have demonstrated the utility of embolization in treating aneurysms of the hepatic arteries. This report reviews the current treatment options available in the management of hepatic artery aneurysms. Embolization of the aneurysms is recommended.