Intravenous cidofovir treatment for recalcitrant warts in the setting of a patient with myelodysplastic syndrome

Cidofovir is an acyclic nucleoside phosphonate with broad-spectrum activity against DNA viruses, including human papilloma virus (HPV). However, data on the efficacy of cidofovir in an immunosuppressive setting remain contradictory. We report for the first time on the promotion of the healing of recalcitrant warts in a patient with myelodysplastic syndrome with intravenous cidofovir treatment.     

Effect of fibreoptic bronchoscopy on pulmonary function.

Several studies have shown that after fibreoptic bronchoscopy there may be a deterioration in lung function but it is not known whether this is due to the premedication, the topical anaesthetic, or the obstruction produced by the bronchoscope. The effects of each part of the procedure on spirometric measurements were studied in patients with lung disease and in normal non-smokers. Measurements were made after premedication (papaveretum and atropine) in seven patients and after topical anaesthesia of the bronchial tree (340 mg lignocaine) with and without the bronchoscope in the trachea in 21 patients and 10 control subjects. Premedication had no effect. In the normal subjects lignocaine produced significant falls in FEV1, forced vital capacity (FVC), peak expiratory flow (PEF), and peak inspiratory flow (PIF), and insertion of the bronchoscope caused further falls that were also significant. In the patients, however, although anaesthesia produced significant falls in FEV1, FVC, PEF, and PIF of similar magnitude to those found in the normal subjects, there was no further important decrease when the bronchoscope was inserted. It is concluded that the major effect of bronchoscopy on lung function is due to topical lignocaine in the airways, and in patients with lung disease (excluding asthma or a central obstructing carcinoma) the insertion of the bronchoscope causes little additional obstruction.     

Optimal timing of a single dose of zoledronic acid to increase strength in rat fracture repair.

We hypothesized that ZA treatment would bolster fracture repair. In a rat model for closed fracture healing, a single dose of ZA at 0, 1, or 2 wk after fracture significantly increased BMC and strength of the healed fracture. Delaying the dose (1 or 2 wk after fracture) displayed superior results compared with dosing at the time of fracture. INTRODUCTION: Bisphosphonates are known to increase bone strength and thus the resistance to fracture by decreasing osteoclastic bone resorption. These properties may enable bisphosphonates to also increase the strength of fracture repair. Zoledronic acid (ZA) is a potent bisphosphonate with a high affinity for bone mineral, allowing bolus intravenous dosing in a range of indications. In this study, we examined the application of bolus dose ZA in endochondral fracture repair. MATERIALS AND METHODS: Carbon-14 labeled ZA was used in a closed rat fracture model. Rats were divided into five treatment groups (n = 25 per group): saline control, local ZA (0.01 mg/kg), and three systemic bolus ZA groups (0.1 mg/kg) with different administration times: at fracture, 1 wk after fracture, and 2 wk after fracture. Rats were killed 6 wk postoperatively. Postmortem analyses included radiography, QCT, microCT, biomechanical testing, scintillation counting, autoradiography, and histology. RESULTS: Single-dose systemic ZA administration significantly increased callus volume, callus BMC, and mechanical strength. Perioperative treatment increased mechanical strength by 30% compared with controls (p < 0.05). Administering the systemic dose at 1 or 2 wk after fracture further increased mechanical strength compared with controls by 44% and 50%, respectively (p < 0.05). No significant differences in mechanical parameters were seen with local injection at the dose studied. Autoradiographic analysis indicated that ZA binds significantly to bone that is present at the time of administration. ZA quantification indicated that delayed administration significantly increased the uptake efficiency in the callus. Histological and microCT analysis showed that ZA treated calluses had a distinctive internal structure consisting of an intricate network of retained trabecular bone. CONCLUSIONS: The timing of a single systemic dose of ZA plays an important role in the modulation of callus properties in this rat fracture model; delaying the single dose produces a larger and stronger callus.     

Epidural test dose and intravascular injection in obstetrics: sensitivity, specificity, and lowest effective dose.

The authors studied the sensitivity and specificity of several epidural test doses as markers of intravascular injection in laboring patients in a prospective double-blind, randomized study. Fifty-nine parturients were assigned randomly to receive an intravenous injection of either normal saline solution (3 mL, NS group) or 1.5% lidocaine with epinephrine 1:200,000 (1 mL, EPI-5 group; 2 mL, EPI-10 group; or 3 mL, EPI-15 group). The EPI-5 and EPI-10 doses were diluted to 3 mL volume with normal saline solution. All injections were given during uterine diastole. Maternal heart rate was monitored with a pulse oximeter. An observer who was unaware of the study treatment recorded the baseline and the peak maternal heart rate within the first minute after the injection and questioned the patient about tinnitus, dizziness, metallic taste, and palpitations. He then recorded his opinion as to whether the patient had received the saline or the test solution. Analysis of the maternal heart rate showed an average increase (baseline-to-peak criterion) of 8 +/- 10 beats/min (mean +/- SD) in the NS group. In the other groups, the increase was 21 +/- 8 (EPI-5 group), 31.5 +/- 13 (EPI-10 group), and 29 +/- 9 beats/min (EPI-15 group). A baseline-to-peak criterion of greater than 10 beats/min identified all intravascular injections in the EPI-15 (by design) and EPI-10 groups (15 of 15 and 14 of 14, respectively) with a sensitivity of 100%. Specificity was 73% (11 of 15 true negatives).(ABSTRACT TRUNCATED AT 250 WORDS)     

Examining the range of normal intraindividual variability in neuropsychological test performance.

Neuropsychologists often diagnose cerebral dysfunction based, in part, on marked variation in an individual's cognitive test performance. However, little is known about what constitutes the normal range of intraindividual variation. In this study, after excluding 54 individuals with significant health problems, we derived 32 z-transformed scores from 15 tests administered to 197 adult participants in a study of normal aging. The difference between each person's highest and lowest scores was computed to assess his or her maximum discrepancy (MD). The resulting MD values ranged from 1.6 to 6.1 meaning that the smallest MD shown by any person was 1.6 standard deviations (SDs) and the largest MD shown by any person was 6.1 SDs. Sixty-six percent of participants produced MD values that exceeded 3 SDs. Eliminating each person's highest and lowest test scores decreased their MDs, but 27% of the participants still produced MD values exceeding 3. Although MD values appeared to increase with age, adjusting test scores for age, which is standard in clinical practice, did not correct for this. These data reveal that marked intraindividual variability is very common in normal adults, and underscore the need to base diagnostic inferences on clinically recognizable patterns rather than psychometric variability alone.     

Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation

The receptor tyrosine kinase (RTK) Ret is activated by the formation of a complex consisting of ligands such as glial cell line-derived neurotrophic factor (GDNF) and glycerophosphatidylinositol-anchored coreceptors termed GFRalphas. During activation, Ret translocates into lipid rafts, which is critical for functional responses to GDNF. We found that Ret was rapidly ubiquitinated and degraded in sympathetic neurons when activated with GDNF, but, unlike other RTKs that are trafficked to lysosomes for degradation, Ret was degraded predominantly by the proteasome. After GDNF stimulation, the majority of ubiquitinated Ret was located outside of lipid rafts and Ret was lost predominantly from nonraft membrane domains. Consistent with the predominance of Ret degradation outside of rafts, disruption of lipid rafts in neurons did not alter either the GDNF-dependent ubiquitination or degradation of Ret. GDNF-mediated survival of sympathetic neurons was inhibited by lipid raft depletion, and this inhibitory effect of raft disruption on GDNF-mediated survival was reversed if Ret degradation was blocked via proteasome inhibition. Therefore, lipid rafts sequester Ret away from the degradation machinery located in nonraft membrane domains, such as Cbl family E3 ligases, thereby sustaining Ret signaling.     

Late side-effects with cosmetic relevance following soft X-ray therapy of cutaneous neoplasias

Background Cosmetic changes are to be expected after radiotherapy for skin tumours. Objectives This study aimed to answer the questions: How frequent are cosmetic changes after soft X‐ray therapy? Do treatment parameters, tumour thickness, localization and size of the irradiated field have a major influence? Were patients irritated by the visual appearance of the irradiated field? Methods In total, 2474 examinations of 1149 irradiated fields were performed. Results Hypopigmentation was found in 64.7% of examinations more than 90 days after therapy, teleangiectases in 43.1%, erythema in 24.8%, and hyperpigmentation in 16.8%. The frequency of hypopigmentation, teleangiectases and hyperpigmentation increased with time from X‐ray exposure; more than 4 years after therapy hypopigmentation was diagnosed in 91.8% and teleangiectases in 82.2% of examinations. Total dose, the time–dose–fractionation factor (TDF), field size and dose per fraction were significantly related to the frequency of cosmetic changes. Incidence rates of cosmetic changes differed by less than 15% if different treatment conditions were compared: thicker vs. thinner tumours, larger vs. smaller fields, higher vs. lower total doses, doses per fraction, and TDF. Frequencies of hypopigmentation, teleangiectases, erythema and hyperpigmentation differed by more than 15% between some localizations on the head. Women reported irritation by the visual appearance of the irradiated field in 12.6% of 1116 interviews, and men in 4.4% of 1284 interviews. Conclusions Cosmetic changes after soft X‐ray therapy are relatively frequent. Treatment parameters, tumour thickness and field size have only a minor influence. Few patients, but more women than men, were irritated by the visual appearance of the irradiated field.