Economic evaluation of vaccination: capturing the full benefits, with an application to human papillomavirus.

Vaccination has been among the greatest contributors to the past century's dramatic improvements in health and life expectancy. Recent advances in vaccinology have resulted in new vaccines that will likely lead to substantial future health gains. However, the high cost of these new vaccines, such as the human papillomavirus (HPV) vaccine, poses an obstacle to their widespread adoption in many countries. Economic evaluation can help to determine if investment in vaccine introduction is worthwhile. However, existing economic evaluations usually focus on a narrow set of vaccination-mediated benefits-most notably avoided medical-care costs-and fail to account for several categories of potentially important gains. We consider three sources of such benefit and discuss them with respect to HPV vaccination: (i) outcome-related productivity gains, (ii) behaviour-related productivity gains, and (iii) externalities. We also highlight that HPV vaccination protects against more than just cervical cancer and that these other health gains should be taken into account. Failing to account for these broader benefits of HPV vaccination could result in substantial underestimation of the value of HPV vaccination, thereby leading to ill-founded decisions regarding its introduction into national immunization programmes.

Immunosensing platforms using spontaneously adsorbed antibody fragments on gold.

This paper describes the construction and characterization of miniaturized antigenic immunosurfaces composed of spontaneously adsorbed Fab'-SH fragments on gold. Rabbit Fab'-SH fragments contain a free sulfhydryl group that forms a thiolate bond with a gold substrate as detailed by X-ray photoelectron spectroscopy. This approach creates surfaces of higher epitope density, a factor critical to the early detection of disease, than surfaces composed of adsorbed whole molecule IgG on gold. The viability and specificity of antigenic Fab'-SH immunosurfaces is demonstrated using atomic force microscopy and confocal fluorescence microscopy, and possible explanations for the larger epitope density are discussed.

Sentinel lymph node biopsy for melanoma.

BACKGROUND: The most powerful predictor of survival for patients with melanoma is the status of the regional lymph nodes. Sentinel lymph node biopsy may provide improved staging accuracy without the morbidity of elective lymph node dissection (ELND). METHODS: Sixty-eight patients with intermediate thickness melanoma underwent gamma probe guided sentinel node biopsy without ELND and were followed up over a mean of 22 months. RESULTS: A sentinel node was found in all patients. Six patients (9%) had positive sentinel nodes; all underwent complete lymphadenectomy. Two patients (3%) with negative sentinel nodes developed nodal recurrence; 1 of these patients was found to have microscopic disease on reexamination of the sentinel node. Two patients (3%) developed systemic disease. CONCLUSION: Gamma probe guided sentinel node biopsy can be performed with a high rate of technical success. It provides accurate pathological staging with a low incidence of nodal basin failure.

Microelectrode control of surface-bound enzymatic activity.

Microelectrodes have been used to control the microscopically local reaction environment of surface-bound alcohol dehydrogenase (ADH). A surface comprised of agarose beads coated with immobilized ADH was prepared on a microscope slide and exhibited maximum activity toward the oxidation of ethanol, in the presence of nicotinamide adenine dinucleotide (NAD(+)), at a pH of 9.0. Microelectrode control of activity was achieved by submerging the slide in a solution of pH 6.0, well below the optimum value, and generating hydroxide at the microelectrode tip through the reduction of oxygen or water. An alkaline "sphere of influence" was set up around the microelectrode tip that, when positioned in close proximity to the enzyme surface, created a favorable reaction environment. The increased enzymatic activity was monitored by observing fluorescence of the reduced cofactor, NADH, using a fluorescence microscope equipped with an imaging camera. The fluorescent sphere diameter was characterized as a function of time, potential, and solution buffer strength. Optimum spatial resolution for enzymatic control was 7-12 µm.

Examination of four 123I-labeled piperidine-based sigma receptor ligands as potential melanoma imaging agents: initial studies in mouse tumor models.

The development of sigma (sigma) receptor radioligands has become the focus of research over the past few years due to their potential uses in nuclear medicine. It has been shown that a wide variety of human tumor cell lines express sigma receptors, including malignant melanoma and tumors of the colon, lung, brain, breast and testes. To provide potential probes for the in vivo SPECT examination of sigma receptor densities, we have synthesized a series of halogenated 4-(phenoxymethyl)piperidines and related compounds as high affinity sigma receptor ligands. Four of these have been labeled with I-123 and evaluated in vivo in mouse tumor models. All four radioligands were synthesized no-carrier-added using oxidative radioiododestannylation methods and specific activities > 74,000 MBq/mumol were obtained. Radiochemical yields were 55-83% EOS and radiochemical purities were > 98%. All four tracers were initially screened in vivo using distribution studies in nude mice with B16 melanoma tumors (8-12 mm diameter in the flank). In all four studies, high uptake (up to 0.90 +/- 0.42 %ID, 12.99 +/- 4.28 %ID/g at 48 h) and excellent retention of radioactivity in tumor tissues was exhibited for as long as 48 h post-injection (PI). In the B16 melanoma model, the most promising results were obtained with [123I]-1-(2-hydroxyethyl)-4-(iodophenoxymethyl)piperidine (123I-3), for which tumor/tissue ratios were significantly > 1.0 by 4 h PI for most organs and increased thereafter. Tumor/tissue ratios at 48 h were as follows: blood, 68.4; muscle 31.7; brain, 7.4; lung, 6.3; liver, 1.3. In subsequent studies, 123I-3 was evaluated in nude mice with A375 human malignant melanoma. As in the B16 model, high uptake and prolonged retention of radioactivity in tumor tissues was noted. These results indicate that 123I-3 shows promise as a SPECT ligand for the detection of malignant melanoma.

Surgical management of thyroid cancer invading the airway.

BACKGROUND: Locally advanced thyroid cancer invading the tracheal cartilage represents a difficult treatment dilemma during thyroidectomy. METHODS: A retrospective chart review was performed to determine the results of laryngotracheal resection or tracheal cartilage shave with adjuvant radiotherapy in patients with locally advanced thyroid cancer invading the upper airway. RESULTS: Of 597 patients undergoing thyroidectomy for thyroid cancer, 40 were found to have laryngotracheal invasion. Thirty-five patients with superficial invasion underwent cartilage shave procedures with adjuvant radiotherapy; five with full-thickness invasion underwent radical resection, including tracheal sleeve resection (n = 3) or total laryngectomy (n = 2). Histologic subtypes included papillary (n = 32), follicular (n = 2), Hurthle cell (n = 1), medullary (n = 3), and anaplastic (n = 2). Of the cartilage shave group, 25 are currently alive with no evidence of disease at a mean follow-up of 81 months (range 1-290). Six developed isolated local/regional recurrence and were managed with total laryngectomy (n = 1), tracheal resection (n = 1), cervical lymphadenectomy (n = 1), or repeat radiotherapy (n = 3). All six patients remain free of disease at a mean follow-up of 5 years. Of those who underwent initial laryngotracheal resection, four remain free of disease at a mean follow-up of 5 years. The rates of 10-year disease-free survival and overall survival for all patients were 47.9% (95% confidence interval [CI] 24.8, 71.0) and 83.9% (95% CI 70.3, 97.5), respectively. CONCLUSIONS: These data suggest that adequate management of thyroid cancer with laryngotracheal invasion can be achieved with a more conservative surgical approach and adjuvant radiotherapy, reserving more radical resections for extensive primary lesions or locally recurrent disease.

Halogenated 4-(phenoxymethyl)piperidines as potential radiolabeled probes for sigma-1 receptors: in vivo evaluation of [123I]-1-(iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl]pip eri dine.

Several halogenated 4-(4-phenoxymethyl)piperidines were synthesized as potential sigma receptor ligands. The affinity and selectivity of these compounds were determined using in vitro receptor binding assays, and their log P values were estimated using HPLC analysis. The effect of various N-substituents on the sigma-1 and sigma-2 dissociation constants was examined. These substituents included fluoroalkyl, hydroxyalkyl, iodopropenyl, and selected ortho-, meta-, and para-substituted benzyl groups. Also determined were the effects of various moieties on the phenoxy ring; specifically 4-iodo, 4-bromo, 4-nitro, 4-cyano, 3-bromo, and pentafluoro substituents were examined. The ranges in the dissociation constants of these compounds for sigma-1 and sigma-2 receptors were 0.38-24.3 and 3.9-361 nM, respectively. The ratio of Ki (sigma-2/sigma-1) ranged from 1.19 to 121. One of the most promising of the iodinated ligands, 1-(trans-iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl]piperidi ne (4), was labeled with 123I and studied in vivo in adult male rats. High uptake and good retention of radioactivity was observed in the brain and many other organs known to possess sigma receptors. Blocking studies revealed high specific binding of [123I]-4 to sigma receptors in the brain, lung, kidney, heart, muscle, and other organs known to possess these sites. These results indicate that [123I]-4 and other halogenated 4-(phenoxymethyl)piperidines of this series may provide useful probes for in vivo tomographic studies of sigma receptors.

What is a stent and where can you get one.

The development of the word stent as we use it today refers to a material to hold tissues in position or to make tissues patent. Dr. Charles Thomas Stent, a 19th century London dentist, created a compound for dental impressions that was used to hold skin grafts in place by later plastic surgeons, presaging its present usage.

Synthesis and preliminary evaluation of [123I]1-(4-cyanobenzyl)-4-[[(trans-iodopropen-2-yl)oxy]meth yl]piperidin e: a novel high affinity sigma receptor radioligand for SPECT.

1-(4-Cyanobenzyl)-4-[[(trans-iodopropen-2-yl)oxy]methyl]pipe ridine (2) has been synthesized as a novel iodinated ligand for sigma receptors. This new compound exhibited high affinity (Ki = 0.38 nM) for the sigma-1 receptor and selectivity for sigma-1 vs. sigma-2 receptors (Ki sigma-1/sigma-2 = 0.02) using in vitro receptor binding assays. Moderate affinity for muscarinic M1 (Ki = 322 nM) and M2 (Ki = 178 nM) receptors and low affinity (Ki = 1,460 nM) for dopamine D2 receptors was also noted. The lipophilicity of 2 (log P7.5 = 3.24) is moderate, indicating that the ligand should readily cross the blood/brain barrier. The corresponding radioiodinated ligand, 123I-2, was synthesized from the appropriate trans vinyl tributylstannane precursor under acidic conditions using oxidative iododestannylation methods. HPLC purification provided the radioligand in yields ranging between 63 and 75% EOS (n = 5) and with > 99% radiochemical purity and a specific activity > 77,000 MBq/mumol. Preliminary in vivo distribution and pharmacological blocking studies using 123I-2 were performed in male Australian Albino Wistar rats. 123I-2 exhibited good brain uptake (1.11 +/- 0.14% ID at 20 min PI) with no significant loss of radioactivity from the brain over the course of the study (4 h). The gross regional brain distribution of the radioligand showed highest uptake in the posterior cortex and frontal cortex, with slightly lower uptake in other brain regions examined. Most of the uptake of radioactivity in the brain, lung, heart, muscle, and kidney was prevented by pre-administration of compounds with affinity for sigma receptors, indicating the in vivo specificity of the ligand. In view of these results, 123I-2 shows promise for the in vivo tomographic evaluation of sigma receptor densities.

Ultrastructural effects of T-2 mycotoxin on rat hepatocytes in vitro.

Cultured rat hepatocytes were treated with several doses of T-2 mycotoxin for either 1 or 12 hr and with or without a 12 hr recovery period. Inhibition of protein synthesis and release of lactate dehydrogenase were measured and correlated with ultrastructural changes, as assessed by transmission electron microscopy. Results indicated that at a dose of 0.01 microgram/ml protein synthesis was inhibited 75% within 1 hr, but recovered to near control levels with or without the continual presence of toxin. At the higher toxin dose of 1.0 microgram/ml hepatocytes were able to recover from a 1 hr, but not a 12 hr, exposure. Cell damage, as assessed by release of lactate dehydrogenase, lagged behind inhibition of protein synthesis. Only at a T-2 concentration of 1.0 microgram/ml for 12 hr followed by a 12 hr recovery period was release of lactate dehydrogenase significantly elevated over control values. Under the same parameters, protein synthesis was inhibited 94%. The ultrastructural appearance of the cell membrane, nucleus, lysosomes, peroxisomes and smooth endoplasmic reticulum remained unchanged. The two organelles which appeared altered by T-2 exposure were the rough endoplasmic reticulum and the mitochondria. Endoplasmic reticulum changes were limited to degranulation of attached ribosomes without dilation of the cisternae. Alterations were seen as early as 1 hr at a T-2 dose of 0.01 microgram/ml. After a dose of 1.0 microgram/ml T-2 for 12 hr some mitochondria displayed one or more non-membrane-bound translucent foci, some of which contained electron-dense cores.

Depression in young women who have attempted suicide. An international replication study.

In accord with a recent Australian study, a greater proportion of young women who attempted suicide in 4 centres in Australia, Canada and New Zealand were designated as manifesting a depressive syndrome by a depression questionnaire than would have been anticipated on the basis of previous clinical reports. Furthermore, on the basis of a decision-rule applied to the questionnaire responses, one-third of subjects in each centre were allocated to the "endogenous' category of depression.