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.     

Applying the neoadjuvant paradigm to ductal carcinoma in situ

Local treatment options for ductal carcinoma in situ (DCIS) are virtually identical to those for early invasive breast cancer, despite the fact that the survival from this condition is much higher. Our ability to more appropriately tailor therapy for DCIS is hampered by a lack of understanding of the natural history of DCIS, our limited ability to predict the rate of progression to invasive cancer and the response to therapy, and the absence of tools to follow patients who have not had invasive treatments. Neoadjuvant therapy, which has been proven to be both safe and effective in tailoring treatments for invasive cancer, could be ideally suited to DCIS. However, neoadjuvant therapy requires that doctors and patients delay surgical treatment that has known benefits. In order to successfully introduce this approach into clinical practice, risk assessment and decision support tools will be needed to help physicians and patients feel comfortable that they are not being exposed to unnecessary or excessive risk. In addition, we need better imaging to track extent and progression of disease. Among the possible benefits of the neoadjuvant approach, we may discover that many lesions are responsive and some even reversible, leaving us with treatments that might be tailored to biology and with important clues for breast cancer prevention in high-risk women.     

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.     

HYPOKALEMIA IN THE ELDERLY: IS IT ALWAYS DIURETIC-INDUCED?

SUMMARY Serum potassium was measured within 24 hours in 156 patients (48 male, 108 female) with an average age of 81.9 years admitted to the unit with acute illness. Of the 156 patients, 88 (56.4%) were taking diuretics (none was on ACE inhibitors); 20 patients (12.8%) were also on digoxin therapy. In all, 24 patients (16%) had hypokalaemia and 3 (2%) hyperkalaemia. Hypokalaemia was seen in patients associated with acute illness. There was no significant difference between the diuretic and non-diuretic groups. Monitoring of serum potassium is not routinely indicated to detect hypokalaemia in patients on diuretic therapy except in those with severe hepatic or renal impairment or those on digoxin.     

DNA polymorphism among isolates from multiple sites of a patient with chronic herpes simplex virus, type 1 infection

DNA polymorphisms among independent isolates of herpes simplex virus (HSV) type 1 were studied from a 7-year-old male patient with recurrent infections of the skin and internal organs. In the patient's serum, HSV antibodies could not be detected by complement fixation, enzyme-linked immunosorbent assay (ELISA), or neutralization tests. ELISA tests for the presence of antibodies to human immunodeficiency virus were also negative. One HSV isolate was obtained from mesenteric nodes biopsied in 1983; one from skin in 1984; and three (postmortem) from brain, lungs, and liver in 1985. Restriction enzymes Eco RI, Bgl II, Hind III, Kpn I, and Bam H1 digestion patterns of the five isolates were similar. However, Sal I digests of isolates from skin, mesenteric nodes, lungs, and liver showed variations that were distinct from that of the brain isolate. Although Sal I digests of skin, mesenteric nodes, lungs, and liver isolates share a common variation in lacking F and G, the liver isolate can be further differentiated because of the gain of a restriction site on the H fragment. Thus, the three distinct variants observed were the isolates from brain (variant 1); from skin, mesenteric nodes, and lungs (variant 2); and from liver (variant 3). The fragments involved in variations among these isolates (presence or absence of Sal, G and H) are from the unique short and long regions (invariable regions) of the genome and therefore do not show heterogeneity in size. The extent of variation among these isolates is less than that seen among epidemiologically unrelated strains, suggesting that they originated from a single infecting strain, probably the brain isolate.     

Homozygosity mapping of achromatopsia to chromosome 2 using DNA pooling

Achromatopsia is an autosomal recessive disease of the retina, characterized clinically by an inability to distinguish colors, impaired visual acuity, nystagmus and photophobia. A genome-wide search for linkage was performed using an inbred Jewish kindred from Iran. To facilitate the genome-wide search, we utilized a DNA pooling strategy which takes advantage of the likelihood that the disease in this inbred kindred is inherited by all affected individuals from a common founder. Equal molar amounts of DNA from all affected individuals were pooled and used as the PCR template for short tandem repeat polymorphic markers (STRPs). Pooled DNA from unaffected members of the kindred was used as a control. A reduction in the number of alleles in the affected versus control pool was observed at several loci. Upon genotyping of individual family members, significant linkage was established between the disease phenotype and markers localized on chromosome 2. The highest LOD score observed was 5.4 (theta = 0). When four additional small unrelated families were genotyped, the combined peak LOD score was 8.2. Analysis of recombinant chromosomes revealed that the disease gene lies within a 30 cM interval which spans the centromere. Additional fine-mapping studies identified a region of homozygosity in all affected individuals, narrowing the region to 14 cM. A candidate gene for achromatopsia was excluded from this disease interval by radiation hybrid mapping. Linkage of achromatopsia to chromosome 2 is an essential first step in the identification of the disease-causing gene.