Interactions of human antibodies,epitope exposure,antibody binding and neutralization of primary isolate HIV-1 virions

OBJECTIVE: Development of an effective HIV vaccine has been limited because of the inherent structural properties of the HIV envelope on native virions and the failure of the immune system to respond in an effective manner. Identification of the interactions of human antibodies with virions resulting in neutralization will facilitate vaccine design. DESIGN: Combinations of human monoclonal antibodies (hMAb) were studied for binding to and neutralization of primary isolate virions. METHODS: Virion binding and neutralization were measured using primary isolate virions. RESULTS: Antibodies and combinations of antibodies to epitopes exposed upon CD4 binding (CD4i) and V3 loop antibodies resulted in additive binding and neutralization of R5X4 virus. Antibodies did not bind to or neutralize R5 virus as well. The combination of V3 loop antibody with 2G12 resulted in enhanced neutralization and binding to the R5X4 isolate but not the R5 isolate. Preincubation of the R5X4 isolate with F240, a non-neutralizing anti-gp41 antibody, significantly enhanced binding and neutralization by CD4i hMAb and 2F5. F240 also enhanced the binding of 2F5 to the R5 isolate and the neutralization of the R5 isolate mediated by 2G12. CONCLUSIONS: Neutralizing epitopes are obscured on intact primary isolate virions and are dynamically exposed upon ligand (CD4) interactions. Interestingly, a non-neutralizing antibody to gp41 also increased binding and neutralizing activity of some hMAb that poorly neutralized R5 virus. These data suggest that non-neutralizing epitopes may be appropriate targets for vaccine design and epitope exposure should be considered in the development of immunotherapeutic strategies for HIV.     

Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis

OBJECTIVE: To review the effect of calcitonin on bone density and fractures in postmenopausal women. DATA SOURCE: We searched MEDLINE and EMBASE from 1966 to 2000 and examined citations of relevant articles and the proceedings of international osteoporosis meetings. We contacted osteoporosis investigators to identify additional studies and primary authors for unpublished data. STUDY SELECTION: We included 30 studies that randomized women to calcitonin or an alternative (placebo or calcium and/or vitamin D) and measured bone density or fracture incidence for at least 1 yr. DATA EXTRACTION: For each trial, three independent reviewers assessed the methodological quality and abstracted data. DATA SYNTHESIS: Calcitonin reduced the incidence of vertebral fractures, with a pooled relative risk (RR) of 0.46 [95% confidence interval (CI) 0.25-0.87, P = 0.02, n = 1404, 4 trials]. However, the RR from the one relatively large randomized controlled trial (RCT) was 0.79 (95% CI 0.62-1.00, P = 0.05, n = 1108). For nonvertebral fractures, the pooled RR was 0.52 (95% CI 0.22-1.23, P = 0.14, n = 1481, 3 trials). Once again, the single large trial showed a less impressive effect than the smaller trials (RR 0.80, 95% CI 0.59-1.09, P = 0.16, n = 1245). For bone density of the lumbar spine, the pooled weekly dose of 250 to 2800 IU per week resulted in significant increase in the weighted mean difference (WMD) of 3.74 (2.04-5.43, P < 0.01, n = 2260, 24 trials). The combined forearm showed a similar effect, with a WMD of 3.02 (95% CI 0.98-5.07, P < 0.01, n = 468, 9 trials). At the femoral neck, the pooled weighted mean difference showed a nonsignificant trend toward benefit, WMD 3.80 (95% CI -0.32-7.91, P = 0.07, 9 trials, n = 513). Methodologically weaker studies tended to show greater effects on bone density, and the lumbar spine results suggested the possibility of publication bias. CONCLUSIONS: Calcitonin likely increases bone density in postmenopausal women predominantly at the lumbar spine and forearm for weekly doses of greater than 250 IU, although the true effect may be smaller than the pooled estimate would suggest. Calcitonin likely reduces the risk of vertebral fracture; its effect on nonvertebral fracture remains uncertain.     

Preoperative and early postoperative magnetic resonance imaging in two cases of childhood choroid plexus carcinoma

We present and illustrate the MRI appearances of two children with choroid plexus carcinoma. The MRI characteristics of these rare tumours are reviewed. Since total surgical resection is a significant prognostic factor, early postoperative MRI was performed in both cases to ensure surgical clearance. In one case a complete resection was documented and this patient remains well at short-term follow-up. Residual tumour was noted in the second case, but despite "second look" surgery there was subsequent local relapse.     

How to detect hepatocellular carcinoma in cirrhosis

Cirrhosis predisposes to hepatocellular carcinoma (HCC) which develops by sequential steps of de-differentiation of hepatocytes from regenerative nodules via borderline (dysplastic) nodules to frankly malignant HCC. Effective treatment depends on early recognition of HCC, so the key tasks for imaging are firstly recognising the presence of a suspicious lesion, and secondly differentiating between benign, borderline and malignant nodules. Screening of high-risk cirrhotic patients with sonography and measurement of alpha fetoprotein (AFP) is helpful but will not reliably differentiate small HCC from benign or dysplastic nodules. Large HCCs can usually be recognised by their characteristic morphology on imaging, but the appearances of smaller benign and malignant nodules show considerable overlap on unenhanced sonography, CT and MRI. Increasing degrees of histological malignancy are associated with increasing arterialisation and loss of portal blood supply, so the recognition of HCC requires the use of dynamic imaging with contrast-enhanced CT or T1-weighted MRI with gadolinium enhancement. Sonography with microbubble contrast media now offers another method for detecting arterialised nodules; however, some non-malignant nodules show arterial hypervascularity and a minority of HCCs are hypovascular, so the assessment of perfusion does not conclusively distinguish benign from malignant lesions. Kupffer cell function is another attribute of liver tissue which can be explored using MRI with superparamagnetic iron oxide particles (SPIO). Experience thus far suggests that uptake of SPIO is an effective discriminator between benign and malignant nodules. The combination of SPIO with gadolinium-enhanced MRI offers the opportunity for imaging characterisation of cirrhotic nodules by cellular function as well as by blood supply, and this approach is now proposed as the examination of choice for detecting HCC in cirrhosis.     

Energy intake deficit and physical performance at altitude

BACKGROUND: Physical performance of sea-level (SL) residents acutely exposed to altitude (ALT) is diminished and may improve somewhat with ALT acclimatization. HYPOTHESIS: A large reduction in lean body mass (LBM), due to severe energy intake deficit during the first 21 d of ALT (4300 m) acclimatization, will adversely affect performance. METHODS: At ALT, 10 men received a deficit (DEF) of 1500 kcal x d(-1) below body weight (BW) maintenance requirements and 7 men received adequate (ADQ) kcal x d(-1) to maintain BW. Performance was assessed by: 1) maximal oxygen uptake (VO2max); 2) time to complete 50 cycles of a lift and carry task (L+C); 3) number of one-arm elbow flexions (10% BW at 22 flexions x min(-1); and 4) adductor pollicis (AP) muscle strength and endurance time (repeated 5-s static contractions at 50% of maximal force followed by 5-s rest, to exhaustion). Performance and body composition (using BW and circumference measures) were determined at SL and at ALT on days 2 through 21. RESULTS: At SL, there were no between-group differences (p > 0.05) for any of the performance measures. From SL to day 21 at ALT, BW and LBM declined by 6.6 +/- 3 kg and 4.6 kg, respectively, for the DEF group (both p < 0.01), but did not change (both p > 0.05) for the ADQ group. Performance changes from day 2 or 3 to day 20 or 21 at ALT were as follows (values are means +/- SD): VO2max (ml x min(-1)): DEF = +97 +/- 237, ADQ = +159 +/- 156; L + C (s): DEF = -62 +/- 35*, ADQ = -35 +/- 20* (*p < 0.05; improved from day 3); arm flex (reps): DEF = -2 +/- 7, ADQ = +2 +/- 8; AP endurance (min): DEF = +1.4 +/- 2, ADQ = + 1.9 +/- 2; AP strength (kg): DEF = -0.7 +/- 4, ADQ = -1.2 +/- 2. There were no differences in performance between groups. CONCLUSIONS: A significant BW and LBM loss due to underfeeding during the first 21 d of ALT acclimatization does not impair physical performance at ALT.     

Incidence of symptomatic thrombosis in a stable population of 650,000: travel and other risk factors

Despite recent intensive media interest, the incidence of traveler's thrombosis is unknown. We have undertaken a study of all symptomatic cases of venous thrombosis, presenting to a hospital, in a fixed population of 650,000. There were 1,250 cases of venous thromboembolism diagnosed over a 2-yr period. Of these, only 47 (3.8%) answered positively to the question" did you make a journey of more than 100 mi in the 4 wk prior to diagnosis?" Among the travelers, 60% had traveled by air, 36% by road, and the remainder by rail. At least one medical risk factor for venous thrombosis was present in all but three of our cohort. We conclude that, taking into consideration the enormous number of passengers who travel, the relative risk of traveler's thrombosis is likely to be low. The incidence of this complication in the North East of England is 1 per 27,660 of the whole population.     

Transient bone oedema of the tibia mimicking a tumorous process

The authors describe a distinct clinical entity consisting of bony tenderness, increased isotope uptake along the metaphyses and/or diaphyses and magnetic resonance changes simulating a bone marrow-replacing lesion. Bone biopsies indicate the presence of bone marrow fibrosis and some new bone formation. Nine such cases were prospectively evaluated according to a standardized protocol including clinical examination, x-rays, bone scan and CT scan as well as MRI scans including contrast medium injection. All patients presented with tibial tenderness. In one case the bone was noticeably thicker as compared to the other side. The ages ranged from 6 years to 64 years and 6 of the patients were female. Xrays were normal in 6/9 patients; the rest had minimal periosteal reaction, and mild intramedullary sclerosis. Uniform imaging findings were longitudinal increased uptake along the metadiaphysis of the tibia on bone scans, and increased bone marrow density on CAT scans without a fracture line. A magnetic resonance study indicated bone marrow replacement as demonstrated by an area of low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Some enhancement of signal was observed following gadolinium injection. This clinical entity, which the authors attribute to be a medullary stress reaction, is self-limited, and pain resolves within 3 months. However the radiographic changes appear to be permanent. A biopsy is not required provided no cortical penetration or soft tissue mass is demonstrated by MRI scan.     

Discrepancies in frozen section mucosal margin tissue in laryngeal squamous cell carcinoma

BACKGROUND: Head and neck surgeons commonly request frozen sections. Practice patterns vary from laboratory to laboratory on how the tissue is used in performing the frozen section. Some pathologists wish to see all the material submitted by consuming it completely during frozen section, whereas others reserve some for permanent section. We wished to determine whether knowledge of margin status was initially inaccurate because of reserving tissue for permanent section. METHODS: Sixty-five laryngectomies (total and partial) with margin assessment enhanced by frozen section evaluation were studied. Forty-five laryngectomy specimens, generating 249 frozen sections in which a permanent section was prepared from tissue remaining from frozen section examination, were studied. RESULTS: Five of the 249 frozen sections contained a discrepancy between the frozen section and permanent section because of insufficient leveling of the frozen section block. These five discrepancies were called negative on frozen section, but permanent section revealed dysplasia (two cases of mild dysplasia, one case with moderate dysplasia, and one case with severe dysplasia) or carcinoma in situ (one case). Twenty laryngectomies in which the frozen section tissue was consumed at the time of frozen section generated 103 frozen sections. In eight of the frozen sections involving six cases, the diagnostic tissue was not present on one or two of the frozen section levels examined. CONCLUSIONS: We conclude that in examining margins for laryngeal squamous cell carcinoma the frozen section tissue should be completely sampled by examining several levels at the time of frozen section. This requires consuming or exhausting the frozen section tissue rather than reserving any remaining frozen tissue for a paraffin-embedded permanent section.     

Presentation, treatment, and outcome of oral cavity cancer: a National Cancer Data Base report

BACKGROUND: Oral cancer has been identified as a significant public health threat. Systematic evaluation of the impact of this disease on the US population is of great importance to health care providers and policy makers. METHODS: This study used the National Cancer Data Base (NCDB) to evaluate associations between demographic and disease characteristics, treatment, and survival for patients with oral cavity cancer in the United States. Of patients diagnosed between 1985 and 1996, 58,976 were extracted from the NCDB. ANOVAs were performed on selected cross-tabulations, and relative survival was used to calculate outcome. RESULTS: Median age of patients was 64.0 years. Men made up 60.2% of patients. Pathologic diagnosis was squamous cell carcinoma (SCC) in 86.3% of cases. Younger patients had a much higher frequency of non-SCC, and this was related to survival in these patients. African-Americans (independent of income), lower income patients, and patients with higher grade disease were seen more frequently with advanced-stage SCC. Five-year relative survival for SCC cases was lower for older patients, men, and African-Americans. CONCLUSIONS: This study addressed many issues related to oral cancer that have been previously discussed in the literature. The demographic, site, stage, histologic, and survival data available for this large number of cases in the NCDB allowed an accurate characterization of the contemporary status of oral cancer in the United States.     

Prioritizing patients for elective surgery: clinical judgement summarized by a Linear Analogue Scale

Background: The New Zealand health reforms have resulted in the requirement that surgeons utilize Clinical Priority Access Criteria (CPAC) to ration patient access to elective surgery. The validity of the tools used as CPAC has been challenged. An alter­native tool, the Linear Analogue Scale (LAS), is therefore used in our institution. Our objectives were to determine the variables that influence the priority score generated using the LAS, and the length of time waited by patients awaiting general surgical procedures. Methods: A cohort of 918 patients who were listed for elective general surgical procedures at Auckland Hospital, Auckland, New Zealand between 1 July 1998 and 31 March 1999 were studied. Patients were given a priority score generated using the LAS. For each patient, the time from assessment until his or her procedure was documented. Linear and logistic regression models were used to investigate variables (age, gender, diagnosis and surgical team) that influence priority score. Cox proportional hazards models were used to investigate variables (priority score, age, gender, and diagnosis) that influence the length of time waited. Results: Graphical presentation showed a pattern of priority scores falling into ‘bands’ for different diagnoses. Diagnosis, and to a lesser extent surgical team, influenced priority score. Survival analysis showed ‘time waited’ to be influenced by priority score, diagnosis, and patient age and gender. Conclusion: The LAS may have a useful role in the difficult sphere of patient prioritization. Its strength lies in its simplicity. Further investigation of reliability and effect on patient outcomes is required.