Spinal Cord Injury-Induced Osteoporosis: Pathogenesis and Emerging Therapies

Spinal cord injury causes rapid, severe osteoporosis with increased fracture risk. Mechanical unloading after paralysis results in increased osteocyte expression of sclerostin, suppressed bone formation, and indirect stimulation of bone resorption. At this time, there are no clinical guidelines to prevent bone loss after SCI, and fractures are common. More research is required to define the pathophysiology and epidemiology of SCI-induced osteoporosis. This review summarizes emerging therapeutics including anti-sclerostin antibodies, mechanical loading of the lower extremity with electrical stimulation, and mechanical stimulation via vibration therapy.     

Adjuvant hepatic arterial chemotherapy following metastasectomy in patients with isolated liver metastases

OBJECTIVE: To examine survival and toxicity by querying a single-institutional experience with adjuvant hepatic arterial infusional (HAI) chemotherapy. SUMMARY BACKGROUND DATA: Three randomized series in the literature have examined adjuvant HAI after complete resection of liver metastases. Only one of these trials showed an overall survival benefit at 2 years but not over the entire time period of the study. Previous studies in patients with unresectable disease were plagued by high rates of biliary toxicity. METHODS: A retrospective review of a prospectively maintained database was performed. Hepatic arterial pumps were placed in the standard fashion. Patients received floxuridine at doses previously demonstrated as safe in the literature. Standard statistical methods were used. RESULTS: Twenty-one of 92 patients underwent placement of hepatic arterial pumps at the time of liver resection. The HAI group was similar in all demographic measures to the non-HAI group, with the exception that the HAI patients were significantly younger. No differences were seen between the groups in either disease-free or overall survival, although a trend toward improved hepatic progression-free survival was noted. Significant biliary sclerosis developed in six patients in the HAI group, requiring chronic indwelling stents in four patients. One patient died of progressive liver failure associated with this toxicity. CONCLUSIONS: Biliary toxicity is an important potential side effect of hepatic arterial chemotherapy. Although larger randomized studies and this one suggest significant improvements in hepatic recurrences, these have not reliably translated into overall survival benefit. This fact, in light of the potential toxicity, would argue for a larger confirmatory trial of HAI in the adjuvant setting, incorporating recent advances in systemic therapy and careful attention to hepatotoxicity.     

Significance of Histological Response to Preoperative Chemoradiotherapy for Pancreatic Cancer

Background Neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer offers theoretical advantages over the standard approach of surgery followed by adjuvant CRT. We hypothesized that histological responses to CRT would be significant prognostic factors in patients undergoing neoadjuvant CRT followed by resection. Methods Since 1994, 193 patients with biopsy-proven pancreatic adenocarcinoma have completed neoadjuvant CRT, and 70 patients have undergone resection. Specimens were retrospectively examined by an individual pathologist for histological responses (tumor necrosis, tumor fibrosis, and residual tumor load) and immunohistochemical staining for p53 and epidermal growth factor receptor. Factors influencing overall survival were analyzed with the Kaplan-Meier (univariate) and Cox proportional hazards (multivariate) methods.Results The estimated overall survival (median±SE) in the entire group of patients undergoing resection was 23±4.2 months, with an estimated 3-year survival of 37%±6.6% and a median follow-up of 28 months. Complete histological responses occurred in 6% of patients. Overexpression of p53 was more common in patients with large residual tumor loads. Tumor necrosis was an independent negative prognostic factor, as were positive lymph nodes, a large residual tumor load, and poor tumor differentiation.Conclusions Histological response to neoadjuvant CRT—as measured by residual tumor load—may be useful as a surrogate marker for treatment efficacy. Characterization of the tumor cells that survive neoadjuvant CRT may help us to identify new or more appropriate targets for systemic therapy.     

The clinical and pathological characteristics of Chinese patients with pauci-immune crescent golmerulonephritis

Objective　To investigate the clinical and pathological characteristics of pauci-immune crescent glomerulo～nephritis (PICGN) in Chinese patients. Methods　During 13 years (1985-1998), 6400 patients underwent non-transplanting renal biopsy. Twenty-four patients were diagnosed as PICGN. All clinical and laboratory data of these patients were collected from the patients’ records and used for detailed analysis. The diagnosis is based on clinico-pathologic findings. Results　Of the 24 patients, 16 were females and 8 were males, with median age of 33 years (ranged 10-76 years). Microscopic polyarteritis (MPA) (33.3%) and systemic vasculitis (8.3%) were the secondary diseases. The incidence of PICGN was 0.38% in renal biopsies and 22.9% in crescentic glomerulonephritis. Clinically, most patients (75.0%) showed rapidly progressive nephritis with enlarged kidneys. At onset, gross hematuria was noted in 58.3% of patients, hypertension in 45.8%, nephrotic syndrome in 41.7%, and oliguria in 25.0%. However, systemic symptoms were rare except for anemia. Pathologically, necrosis of glomerular capillaries (62.5%), infiltration of monocytes and neutrophil cells in glomeruli (66.7%), and vasculitis in the interstitium (53.3%) were observed. In addition, glomerulosclerosis was noted in 45.8%, severe tubular atrophy in 83.3% and interstitial fibrosis in 75.0%. Anti-neutrophil cytoplasmic antibodies (ANCAs) were positive in 52.2%. All patients except two received intensively immunosuppressive therapy. Sixteen patients were available for long-term follow up (median 29.8 months, range 8-92 months). Twelve of them had life-sustaining renal function, four had normal serum creatinine (<124?μmol/L) and only 4 patients were dialysis-dependent. Conclusion　PICGN is not rare in China. Early diagnosis and administration of immunosuppressive therapy, particularly in patients with rapidly progressive glomerulonephritis (RPGN), are important for good prognosis.     

Gonococcal urethritis diagnosed from enzyme immunoassay of urine sediment

First-catch urine specimens were obtained before clinical examination from 101 sexually active men who attended a sexually transmitted diseases clinic with a complaint of urethral discharge. Urethral swab specimens were used for preparation of smears and were then cultured on Martin-Lewis medium. Enzyme immunoassay (EIA) tests were performed on (1) uncentrifuged urine, (2) urine sediment, and (3) urine sediment diluted 1:6 with detergent buffer. Urethral cultures from 65 (64%) of the 101 men were positive for N. gonorrhoeae. EIA performed on urine sediment diluted 1:6 yielded the highest sensitivity: 98.5% (64/65). Sensitivity of EIA for uncentrifuged urine was only 66% (43/65). Specificity of all samples tested exceeded 97.2%. Overall agreement between results of EIA on diluted urine sediment and culture was 98% (99/101). Discordant culture and EIA results were unrelated to urine volume, time since prior urination, quantity of gonococcal growth on Martin-Lewis medium, duration of urine storage (less than 72 hours) before testing, or immunotype. EIA tests using urine sediment are highly sensitive and specific, and they offer an alternative means of diagnosing gonorrhea in men who refuse urethral manipulation. They also provide a means of screening men at high risk for gonorrhea who have submitted a urine specimen for other reasons.     

Surgical repair of cytomegalovirus-related retinal detachment without silicone oil in patients with AIDS.

PURPOSE: To analyze visual and anatomic results following surgical repair of cytomegalovirus (CMV)-related retinal detachment (RD) without silicone oil permanent tamponade. METHODS: We analyzed five consecutive patients (six eyes) with acquired immunodeficiency syndrome and CMV-related RD that were repaired with pars plana vitrectomy with peeling of the posterior hyaloid, laser photocoagulation, encircling scleral buckle, and intraocular gas tamponade. RESULTS: Preoperative vision ranged from 20/40 to hand motion. Total retinal reattachment was achieved in five of six eyes (83%). Macular reattachment was achieved in all eyes. Mean postoperative visual acuity was 20/40 (range 20/30-20/60). Mean postoperative follow-up was 12 months (range 7-19 months). All patients in this series presented with low preoperative CD4+ T-lymphocyte counts (mean, 24 cells per microL) and received highly active antiretroviral therapy. One retina (Patient 1) redetached 7 months after initial repair and was successfully reattached without using silicone oil. Postoperatively, visual acuity remains 20/30, and total retinal reattachment has been maintained for 16 months. CONCLUSION: Good anatomic and visual success can be achieved and maintained in CMV-related RD without the use of silicone oil.     

Consistency of Recall of Sexual and Drug-Using Behaviors for Homeless Persons with Dual Diagnosis

In this paper we present data from a study of the consistency of recall of several sexual and drug-using behaviors gathered from face-to-face interviews with homeless persons who have dual diagnosis (severe mental illness plus a substance use disorder). Factors associated with inconsistent reporting are also examined. One hundred and thirty-three individuals participating in a longitudinal study of HIV risk behaviors were recruited for a retrospective recall study. Participants were completing monthly interviews that included assessments of sexual behaviors and drug use. Participants completed an additional interview using the same instruments and were randomly assigned to a 3- or 6-month recall condition; the data from the additional interview were correlated with the regular, monthly interviews. Results indicated that reports of sexual and substance-using behaviors were generally reported consistently for both 3- and 6-month recall periods; however, coefficients for the 3-month interval were generally better than those for the 6-month interval. One exception was that protected intercourse was generally not reported consistently. Inconsistent reporting of sexual and drug-using behaviors was associated with the severity of substance abuse; inconsistent reporting of sexual behaviors was also associated with African-American race. Our data suggest that a 3-month recall interval is generally superior to a 6-month interval for persons with severe mental illness.     

A subset of human monocyte-derived dendritic cells expresses high levels of interleukin-12 in response to combined CD40 ligand and interferon-gamma treatment

Dendritic cells (DCs) may arise from multiple lineages and progress through a series of intermediate stages until fully mature, at which time they are capable of optimal antigen presentation and T-cell activation. High cell surface expression of CD83 is presumed to correlate with full maturation of DCs, and a number of agents have been shown to increase CD83 expression on DCs. We hypothesized that interleukin 12 (IL-12) expression would be a more accurate marker of functionally mature DCs capable of activating antigen-specific T cells. We used combinations of signaling through CD40, using CD40 ligand trimer (CD40L), and interferon gamma to demonstrate that CD83 expression is necessary but not sufficient for optimal production of IL-12 by DCs. Phenotypically mature DCs could be induced to produce high levels of IL-12 p70 only when provided 2 simultaneous stimulatory signals. By intracellular cytokine detection, we determined that only a subset of cells that express high levels of CD80 and CD83 generate large amounts of IL-12. DCs matured with both signals are superior to DCs stimulated with the individual agents in activating antigen-specific T cell in vitro. These findings have important implications regarding the identification, characterization, and clinical application of functionally mature DCs.