Patient tolerability during office cystoscopy and bladder tumor cauterization: a multivariate analysis of risk factors.

OBJECTIVE: Cystoscopy and cauterization performed in the operating room is expensive and exposes patients to anesthesia risks. Patient tolerability during office cystoscopy and cauterization is critical to the office management of bladder cancer (BC) and other urologic diseases. We evaluated the risk factors for pain of flexible cystoscopy in the office-setting with emphasis on a sub-group of BC patients who underwent cauterization. MATERIALS AND METHODS: Retrospective analyses of 110 anonymous patient surveys completed after cystoscopy and/or cauterization. Survey information included age, gender, indication for cystoscopy, number of prior cystoscopies, number of prior office-based cauterizations, anxiety prior/during cystoscopy, and pain during cystoscopy and/or cauterization. Univariate/multivariate and linear-regression analyses were performed to evaluate the association of pain with clinical parameters. RESULTS: Average pain during cystoscopy (1.75 ±â€¯1.331) was not significantly different when cauterization was also performed (2.37 ±â€¯2.214) (p < 0.001) (p = 0.2840). Patients in the lower age group (<66 years) indicated higher anxiety levels (p = 0.0005), more pain at cystoscopy (P = 0.004) and cauterization (p < 0.001). Although the patients' overall anxiety level was low (1-3/10), it was associated with some pain during cystoscopy (p = 0.0005) and cauterization (p < 0.000). In multivariate analysis, anxiety was the only independent predictor of pain during cystoscopy (p = 0.03, OR: 6.52,95% CI: 1.2-35.6) and cauterization (p = 0.0012, OR: 3.4, 95%CI: 1.6-7.0). In BC patients, pain scores during cystoscopy and cauterization were not significantly different (p = 0.4772) but associated with anxiety. CONCLUSION: Office-based cystoscopy and cauterization are tolerable with minimal pain. Higher pain levels during cystoscopy were associated with procedure anxiety, and pain during cauterization was associated with procedure anxiety and younger age. Younger and more anxious patients may need more counseling before cystoscopy.

Surveillance and office management of low-grade Ta bladder tumors.

OBJECTIVE: Patients with low-grade (LG), grade 1-2, Ta bladder cancer (BC) will frequently have a "recurrence". However, they rarely progress in stage. Although current guidelines mention surveillance and office management for these new or recurrent tumors, transurethral resection (TURBT) is the most common treatment. The purpose of this study is to determine if surveillance and/or office cautery is safe. MATERIALS AND METHODS: This study was conducted as a retrospective case series analysis of 45 patients who had recurrent LG Ta appearing bladder cancer (BC) and were managed primarily with surveillance and/or office cautery. Patients with carcinoma in-situ were excluded. The primary outcome was stage progression. RESULTS: Median follow up was 62 months. 41 (91%) patients did not progress in stage. Three patients recurred with HG T1 BC; one is receiving systemic immunotherapy. One patient developed HG T2 BC and was treated with a bladder preservation protocol. 40 (89%) patients underwent office cauterization. Eleven received BCG and 26 received post-cautery intravesical chemotherapy. Five (11%) patients developed HG BC during follow up. No patients died. None of the 17 (38%) Hispanic patients had progression. CONCLUSIONS: Active surveillance and/or office cautery for patients with small recurrent LG Ta bladder tumors is safe, reduces cost and improves quality of life by avoiding TURBTs.

FV-162 is a novel, orally bioavailable, irreversible proteasome inhibitor with improved pharmacokinetics displaying preclinical efficacy with continuous daily dosing.

Approved proteasome inhibitors have advanced the treatment of multiple myeloma but are associated with serious toxicities, poor pharmacokinetics, and most with the inconvenience of intravenous administration. We therefore sought to identify novel orally bioavailable proteasome inhibitors with a continuous daily dosing schedule and improved therapeutic window using a unique drug discovery platform. We employed a fluorine-based medicinal chemistry technology to synthesize 14 novel analogs of epoxyketone-based proteasome inhibitors and screened them for their stability, ability to inhibit the chymotrypsin-like proteasome, and antimyeloma activity in vitro. The tolerability, pharmacokinetics, pharmacodynamic activity, and antimyeloma efficacy of our lead candidate were examined in NOD/SCID mice. We identified a tripeptide epoxyketone, FV-162, as a metabolically stable, potent proteasome inhibitor cytotoxic to human myeloma cell lines and primary myeloma cells. FV-162 had limited toxicity and was well tolerated on a continuous daily dosing schedule. Compared with the benchmark oral irreversible proteasome inhibitor, ONX-0192, FV-162 had a lower peak plasma concentration and longer half-life, resulting in a larger area under the curve (AUC). Oral FV-162 treatment induced rapid, irreversible inhibition of chymotrypsin-like proteasome activity in murine red blood cells and inhibited tumor growth in a myeloma xenograft model. Our data suggest that oral FV-162 with continuous daily dosing schedule displays a favorable safety, efficacy, and pharmacokinetic profile in vivo, identifying it as a promising lead for clinical evaluation in myeloma therapy.

Mutant Rab7 causes the accumulation of cathepsin D and cation-independent mannose 6-phosphate receptor in an early endocytic compartment.

Stable BHK cell lines inducibly expressing wild-type or dominant negative mutant forms of the rab7 GTPase were isolated and used to analyze the role of a rab7-regulated pathway in lysosome biogenesis. Expression of mutant rab7N125I protein induced a dramatic redistribution of cation-independent mannose 6-phosphate receptor (CI-MPR) from its normal perinuclear localization to large peripheral endosomes. Under these circumstances approximately 50% of the total receptor and several lysosomal hydrolases cofractionated with light membranes containing early endosome and Golgi markers. Late endosomes and lysosomes were contained exclusively in well-separated, denser gradient fractions. Newly synthesized CI-MPR and cathepsin D were shown to traverse through an early endocytic compartment, and functional rab7 was crucial for delivery to later compartments. This observation was evidenced by the fact that 2 h after synthesis, both markers were more prevalent in fractions containing light membranes. In addition, both were sensitive to HRP-DAB- mediated cross-linking of early endosomal proteins, and the late endosomal processing of cathepsin D was impaired. Using similar criteria, the lysosomal membrane glycoprotein 120 was not found accumulated in an early endocytic compartment. The data are indicative of a post-Golgi divergence in the routes followed by different lysosome-directed molecules.

Management of the suicidal child or adolescent in the emergency department.

The pediatrician may be called on either as the primary physician or as a consultant to see a suicidal child or adolescent in the emergency department. Psychiatric consultation may not be available immediately. The pediatrician will then play a pivotal role in the evaluation and disposition of the patient. We discuss the epidemiology, initial approach to evaluation, and a rational plan for deciding when it is safe to discharge the patient from the emergency department.

B cell antigen receptor signaling links biochemical changes in the class II peptide-loading compartment to enhanced processing.

In B cells, processing of antigens in the context of MHC class II molecules is initiated by the binding of antigen to the B cell antigen receptor (BCR). BCR-mediated processing is highly efficient, as a consequence of the BCR's linked roles of delivering antigen to the class II peptide-loading compartment and of signaling for increased antigen-processing activity. Evidence is emerging that receptor signaling regulates intracellular transport through the activities of kinases. These in turn have been implicated in the regulation of small mol. wt GTPases which govern membrane transport. Therefore, we investigated the changes in the phosphoprotein and GTPase profiles associated with the class II peptide-loading compartment following BCR cross-linking. We first show that protein kinase inhibitors, known to block BCR signal transduction, inhibit BCR-enhanced antigen processing, demonstrating the critical dependence of enhanced processing on the signaling activity of the BCR. Consistent with this observation, the phosphoprotein profile of the class II peptide-loading compartment underwent rapid and transient changes following BCR cross-linking. We also observed a marked increase in the low mol. wt GTPases associated with the class II peptide-loading compartment within 5 min of BCR cross-linking. The observed changes in both the phosphoprotein and GTPase profiles associated with the peptide-loading compartment were blocked by kinase inhibitors and were not accompanied by overall gross changes in the protein composition of the subcellular compartments. Thus, signal cascades initiated by BCR cross-linking at the plasma membrane are translated into changes in specific subsets of regulatory proteins associated with the peptide-loading compartment.

Parenchymal cytokine expression precedes clinically observed ischemia in dorsal flaps in the rat.

Cytokines have been implicated as pivotal mediators of the wound-healing process. An understanding of the production and interaction of cytokines may lead to a better appreciation of the complex mechanisms of flap ischemia. The potential would then exist for novel diagnostic and therapeutic approaches to prevent and reverse damage to the endangered flap. The goal of this study was to determine the expression of parenchymal cytokines at various time points during flap ischemia. Punch biopsies were obtained from McFarlane dorsal flaps in the Sprague-Dawley murine model. We examined cytokine mRNA profiles for interleukin 1 alpha (IL-1 alpha), IL-2, IL-6, basic fibroblast growth factor (b-FGF), gamma-interferon (gamma IFN), transforming growth factor beta (TGF-beta), and platelet-derived growth factor A chain (PDGF-alpha) using in situ hybridization. Samples were taken from 0 to 48 hours postoperatively, with n = 3 for each time point. Eight hours postoperatively there was an abrupt peak of parenchymal cytokine expression at the bases of the flaps. Clinically at this time the flaps appeared completely viable without evidence of ischemic change. Leukocyte cytokine production peaked at 16 hours, when distal flap ischemia was evident clinically. These findings demonstrate an early peak of cytokine expression prior to clinical evidence of ischemia.

Rab 7: an important regulator of late endocytic membrane traffic.

Rab5 and rab7 proteins belong to a superfamily of small molecular weight GTPases known to be associated with early and late endosomes, respectively. The rab5 protein plays an important regulatory role in early endocytosis, yet the function of rab7 protein was previously uncharacterized. This question was addressed by comparing the kinetics of vesicular stomatitis virus (VSV) G protein internalization in baby hamster kidney cells overexpressing wild-type or dominant negative mutant forms of the rab7 protein (rab7N125I and rab7T22N). Overexpression of wild-type rab7 protein allowed normal transport to late endosomes (mannose 6-phosphate receptor positive), while the rab7N125I mutant caused the VSV G protein to accumulate specifically in early (transferrin receptor positive) endosomes. Horseradish peroxidase and paramyxovirus SV5 hemagglutinin-neuraminidase (HN) were used in quantitative biochemical assays to further demonstrate that rab7 function was not required for early internalization events, but was crucial in downstream degradative events. The characteristic cleavage of SV5 HN in the late endosome distinguishes internalization from transport to later stages of the endocytic pathway. Mutant rab7N125I or rab7T22N proteins had no effect on the internalization of either horseradish peroxidase or SV5 HN protein. In contrast, the mutant proteins markedly inhibited the subsequent cleavage of the SV5 HN protein. Taken together, these data support a key role for rab7, downstream of rab5, in regulating membrane transport leading from early to late endosomes. We compare our findings to those obtained for the yeast homologues Ypt51p, Ypt52p, Ypt53p, and Ypt7p.

Scarless wound healing: implications for the aesthetic surgeon.

Recent developments in surgery and basic science research offer aesthetic surgeons the prospect of scarless repair. Studies in fetal wound healing provide both cellular and molecular models of optimal tissue healing without scar formation. Furthermore, craniofacial surgeons may one day operate on cleft lip, cleft palate, and other congenital malformations in utero. Cytokine research has begun to unravel possibilities for modulating the wound-healing inflammatory response in hopes of limiting scar formation. This article presents research on these developments and comments on their possible applications to aesthetic surgery.

Association of down-regulation of cytokine activity with rat hind limb allograft survival.

Cytokines are short-acting protein modulators of many physiologic processes including graft rejection. An understanding of the production, action, and interaction of cytokines may lead to better appreciation of the complex mechanism of graft rejection. The potential would then exist for more selective and less-toxic means of modulating the immune response. A rat hind limb allograft model with major immunohistoincompatibility was used to study the local mRNA expression of IL-1 alpha, IL-2, IL-6, gamma interferon (gamma INF), platelet-derived growth factor-alpha (PDGF-alpha), basic fibroblast growth factor (FGF), and transforming growth factor-beta (TGF-beta) during acute allograft rejection. A 14-day postoperative course of immunosuppressive therapy with FK506 or rapamycin was administered. In situ hybridization was performed on serial full-thickness skin punch biopsies of the untreated rejecting limb allograft and compared with tissue from treated allografts, isografts, and to normal limb tissue. A sequential pattern of cytokine mRNA expression was demonstrated which progressed in a time-dependent manner and paralleled observed clinical rejection. Maximal cytokine mRNA expression correlated with peak graft rejection. Cellular expression of IL-1 alpha, IL-2, IL-6, gamma-INF, FGF, and TGF-beta mRNA was suppressed with FK506 to below isograft levels, and clinical rejection was not observed with the doses, routes, and schedules used. Rapamycin was ineffective in suppressing cytokine expression, and allograft rejection was not prevented. Isografts demonstrated no evidence of rejection. The in situ hybridization technique demonstrates a time-dependent, selective expression of cytokines within rejecting allograft tissue, and the modification of this response with immunosuppressive therapy. Down-regulation of cytokine expression is associated with clinical allograft survival.

Reduction mammaplasty for gigantomastia using inferiorly based pedicle and free nipple transplantation.

Patients with gigantomastia have severely distorted anatomical breast structures. Reduction mammaplasty in such cases using the inferiorly based pedicle containing the nipple-areola complex can be technically difficult, yield poor results, and cause postoperative complications such as nipple necrosis and loss. Alternative traditional methods such as amputation mammaplasty with free nipple-areola transplantation usually results in a flattened, nonaesthetic breast with poor projection. This unacceptable result is due to the lack of central breast tissue required for normal anatomical projection. Herein, we describe a method of reduction mammaplasty for gigantomastia combining free nipple transplantation and an inferiorly based pyramidal parenchymal flap for augmentation of breast fullness and nipple projection.

Light microscopic and immunohistochemical features in serial biopsies of epidermal versus dermal allografts.

The local immune response to allograft dermis and epidermis was studied in a rat skin-graft model. Biopsies taken at varying times after transplantation were analyzed using routine light microscopy and a panel of monoclonal antibodies. The dermis appeared to be spared by the rejection process, whereas the epithelium and adnexal elements of the dermis were destroyed. The persistence of dermis transplanted across major histoincompatibilities may allow it to be useful in reconstructing large skin losses.

Efficacy of rapamycin and FK 506 in prolonging rat hind limb allograft survival.

OBJECTIVE: Graft rejection and the toxicity of current immunosuppressive regimens preclude the application of microsurgical advances to transplantation of limbs or other nonessential parts. If limb transplantation is to become a clinical reality, newer, safer, more effective immunosuppressive agents are needed. SUMMARY BACKGROUND DATA: Rapamycin (RPM) and FK 506 are fungal macrolide antibiotics with effective immunosuppressive properties demonstrated in several animal models. RPM is more potent and effective than is FK 506 in rat cardiac allografts and has demonstrated synergy with cyclosporine (CsA) in limb allograft models. METHODS: An orthotopic rat hind limb allograft model (Brown-Norway [RT-1n] to Lewis [RT-1(1)] rats was used. RPM (doses, 3.0, 4.5, and 6.0 mg/kg/day) was administered intraperitoneally on postoperative days 1 to 14. FK 506 (6 mg/kg/day) was administered orally on postoperative 1 to 14 and 1 to 90 and at rejection onset (10 mg/kg/day for salvage). CsA with RPM (postoperative days 1 to 14) was used to assess synergy, with CsA alone serving as the control. Other controls included untreated and placebo-treated allografted animals. The permutation test and Mann-Whitney test were applied to the data. RESULTS: The mean survival times were assessed as follows: (1) control (placebo, untreated), 5 days; (2) RPM groups, 9.5, 10.6, and 8.7 days; (3) 14-day FK 506, 28 days; (4) 90-day FK 506, > 90 days; (5) CsA, 17.3 days; and (6) CsA with RPM, 19.3 days. FK 506 significantly prolonged graft survival compared with RPM (Permutation Test, p < 0.001 and Mann-Whitney Test, p < 0.05). FK 506 salvage reversed early rejection. High-dose RPM produced significant toxicity. Synergy between CsA and RPM was not demonstrated. CONCLUSIONS: FK 506 prolongs allograft survival, reverses early rejection, and prevents rejection without clinical toxicity when given continually. RPM does not prevent rejection in this model and produces significant toxicity at high doses. FK 506 may be a first step in making limb transplantation a clinical reality in reconstructive surgery.

Successful treatment of coccidioidomycosis osteomyelitis in an infant.

A 10-month-old Hispanic male infant with expansile lesions of the third metacarpal and proximal phalanx positively diagnosed as Coccidioides immitis osteomyelitis is presented. Treatment consisted of combined surgical debridement and systemic antifungal therapy and resulted in complete resolution of the lesions. Treatment was guided by clinical response and complement fixation titers. Osteomyelitis is a relatively infrequent manifestation of disseminated coccidioidomycosis. Neonates and infants appear to be more susceptible to the development of dissemination, but less likely to develop toxicity due to systemic therapy. Current therapy consists of concomitant surgical excision of involved lesions and systemic antifungal therapy. Complement fixation titers correlate closely with clinical response to therapy and are useful in detecting subclinical recurrences.

Outpatient or short-stay skin grafting with early ambulation for lower-extremity burns.

Lower-extremity burns and skin grafts to these wounds have traditionally required extended hospitalization. We have used early tangential excision of the burn wounds and application of an Unna boot to fresh skin grafts in an attempt to shorten the hospitalization for such patients. Over a six-month period, 9 patients were treated with Unna boots to fresh skin grafts on the lower extremity. The average hospital stay was 0.9 days (range, 0 to 3 days). Graft take was 85% to 100%; no regrafting was required. Ambulation was begun 24 hours postoperatively. The technique described is a safe, effective, and inexpensive alternative to prolonged immobilization and hospitalization in patients with lower-extremity skin grafts.