Pseudoporphyria and sunbeds

Five cases of pseudoporphyria with recurrent blistering and skin fragility especially of the hands are described. Porphyrin studies were normal. The histopathological investigations in three of these cases showed subepidermal bullae consistent with porphyria cutanea tarda. All patients had considerable sunbed exposure before symptoms appeared. One patient was taking naproxen, a weak photosensitizer.     

Cefazolin as empiric therapy in hemodialysis-related infections: efficacy and blood concentrations

Concern about the increasing incidence of vancomycin-resistant organisms has tempered the enthusiasm for indiscriminate vancomycin use. Cefazolin has an antibacterial activity profile similar to vancomycin against most pathogens encountered in the hemodialysis (HD) population. We evaluated the clinical efficacy and serum concentrations that were achieved during empiric cefazolin use. Fifteen consecutive HD patients (five, conventional HD; five, high-efficiency HD; and five, high-flux HD) with suspected or documented infections warranting antibiotic intervention, including access-related, respiratory tract, urinary tract, or wound infections, were enrolled. Each patient received intravenous cefazolin (20 mg/kg actual body weight rounded to the nearest 500-mg increment [range, 1 to 2 g]) after each dialysis treatment for at least three doses. Cefazolin concentrations were obtained before and immediately after the next three consecutive dialysis treatments. Thirteen patients were evaluated for efficacy and all 15 were evaluated for toxicity and cefazolin blood concentrations. All patients showed at least a short-term (3-week) clinical resolution of infection with cefazolin treatment. No central nervous system toxicities were noted and no other adverse events were expressed by the patients during the course of cefazolin treatment. Predialysis cefazolin concentrations, as determined by high-performance liquid chromatography, were 70.2 +/- 42.7 (conventional HD), 45.6 +/- 18.9 (high-efficiency HD), and 41.6 +/- 23.9 mg/L (high-flux HD) over the three dialysis sessions. Cefazolin at doses of approximately 20 mg/kg administered post-HD appears to be a safe and effective empiric therapy and yields predialysis cefazolin concentrations of 2.5 times or greater than those considered to be the minimum inhibitory concentration breakpoint (16 mg/L) for susceptible organisms. These data support the broader use of cefazolin for empiric treatment in the HD population, allowing vancomycin to be reserved for confirmed resistant organisms.     

Effect of estrogen and antiestrogens on the estrogen receptor content in the cochlea of ovariectomized rats

Older women in the normal population tend to develop less severe hearing loss as compared to males in the same age. In Turner syndrome (45,X), estrogen deficiency is one of the predominant problems. Ear and hearing problems are common among these patients. Does estrogen have an impact on the hearing organ? Twenty-four rats were ovariectomized and treated with vehicle (controls), estradiol or selective estrogen receptor modulators such as tamoxifen and ICI182780, in order to study the effects on the estrogen receptor levels and distribution in the inner ear. The cochleas were stained immunohistochemically using antibodies against estrogen receptor alpha and beta. No major difference in estrogen receptor content in the cochleas was observed among groups. There was however a potential down regulation of estrogen receptor alpha in the marginal cells of stria vascularis in the rats that were substituted with ICI182780 (pure antiestrogen) as compared to those given estradiol or tamoxifen. When investigating the tissues with light microscopy no change in inner ear anatomy could be observed.     

Effect of local anaesthesia on neuronal c-fos expression in the spinal dorsal horn and hypothalamic paraventricular nucleus after surgery in rats

The surgical stress response is the neurophysiologic reflex response to surgery, which involves activation of the hypothalamic-pituitary-adrenal axis and is regulated by the hypothalamic paraventricular nucleus. The effect of pre-operative use of local anaesthetics on activation of neurones in the paraventricular nucleus during surgery was studied by quantification of the neuronal expression of the c-fos-gene after a standardized plantar incision in rats. Furthermore, c-fos expression in the spinal dorsal horn was used as a measure of spinal nociception. Six halothane-anaesthetized animals underwent surgery following infiltration with lidocaine and bupivacaine, six animals were operated without local anaesthetics, and six control animals were subjected to the anaesthetic procedures. After two hours, the animals were perfused with 4% formaldehyde and the spinal cords and brains were collected and processed by immunohistochemistry for stereological quantification of the number of neurones with Fos-like immunoreactivity. Furthermore, brain and spinal cord were sampled from nine control animals right after induction of halothane anaesthesia. Surgery without local anaesthetics caused a significant increased number of neurones with Fos-like immunoreactivity in the spinal cord (4258+/-1710; mean+/-S.D.; P<0.01) compared to the anaesthesia control group (1204+/-436). Local anaesthetics reduced this number to 2029+/-919 (P<0.05), which was not significantly different from the anaesthesia control group. After surgery, the number of neurones with Fos-like immunoreactivity in paraventricular nucleus increased from 2948+/-1365 in the anaesthetized control group to 5550+/-3875 and 5191+/-1558 in the surgery and local anaesthetics plus surgery group, respectively, although significance was only reached for the group receiving local anaesthetics (P<0.05). In conclusion, preoperative local anaesthetic infiltration did not reduce the surgery-induced c-fos expression in paraventricular nucleus after paw surgery in rats, although spinal nociception was reduced.     

Differences in the catalytic efficiencies of allelic variants of glutathione transferase P1-1 towards carcinogenic diol epoxides of polycyclic aromatic hydrocarbons

Previous studies have identified allelic variants of the human glutathione transferase (GST) Pi gene and showed that the two different encoded proteins with isoleucine (GSTP1-1/I-105) or valine (GSTP1-1/V- 105) at position 105, respectively, differ significantly in their catalytic activities with model substrates. Moreover, recent epidemiological studies have demonstrated that individuals differing in the expression of these allelic variants also differ in susceptibility to tumour formation in certain organs, including such in which polycyclic aromatic hydrocarbons (PAH) may be etiological factors. In the present study the catalytic efficiencies (kcat/Km) of these GSTP1-1 variants were determined with a number of stereoisomeric bay-region diol epoxides, known as the ultimate mutagenic and carcinogenic metabolites of PAH, including those from chrysene, benzo[a]pyrene and dibenz[a,h]anthracene. In addition, GSTP1-1 mutants in which amino residue 105 is alanine (GSTP1-1/A-105) or tryptophan (GSTP1-1/W-105) have been constructed and characterized. GSTP1-1/V-105 was found to be more active than GSTP1-1/I-105 in conjugation reactions with the bulky diol epoxides of PAH, being up to 3-fold as active towards the anti- and syn-diol epoxide enantiomers with R-absolute configuration at the benzylic oxiranyl carbon. Comparing the four enzyme variants, GSTP1-1/A- 105 generally demonstrated the highest kcat/Km value and GSTP1-1/W-105 the lowest with the anti-diol epoxides. A close correlation was observed between the volume occupied by the amino acid residue at position 105 and the value of kcat/Km. With the syn-diol epoxides, such a correlation was observed with alanine, valine and isoleucine, whereas tryptophan was associated with increased kcat/Km values. The mutational replacement of isoleucine with alanine or tryptophan at position 105 did not alter the enantio selectivity of the GSTP1-1 variants compared with the naturally occurring allelic variants GSTP1-1/I-105 and GSTP1- 1/V-105. Since the amino acid at position 105 forms part of the substrate binding site (H-site) the effect of increasing bulkiness is expected to cause restricted access of the diol epoxide and proper alignment of the two reactants for efficient glutathionylation. In conclusion, the present study indicates that individuals who are homozygous for the allele GSTP1* B (coding for GSTP1-1/V-105) display a higher susceptibility to malignancy because of other factors than a decreased catalytic efficiency of GSTP1-1/V-105 in the detoxication of carcinogenic diol epoxides of benzo[a]pyrene or structurally related PAH.      

Wilms tumor in children: abdominal CT and US evaluation

Computed tomographic (CT) scans and sonograms of 13 children with Wilms tumor were reviewed to determine the ability of each imaging test to characterize the tumor and determine its extent. The findings of this review were correlated with diagnoses based on surgical and pathologic evidence. Tumor necrosis and a pseudocapsule were detected more often using CT scans than sonograms. CT scanning also was more sensitive in assessing perinephric extension, lymph node involvement, and bilateral tumors. Overall, CT scans allowed better determination of the extent of a suspected tumor, enabling correct diagnosis in 77% of patients, while US study was correct in only 23%.     

Haemodynamic studies on the antihypertensive effect of guancydine

Summary Guancydine, a new antihypertensive agent, was given orally in divided doses up to 1000 mg a day, to five male in-patients with severe arterial hypertension. Haemodynamic parameters were determined at rest and during standardized exercise before and after seven to fourteen days of treatment. In the second study significant reductions in the systemic vascular resistance were found which paralleled the lower brachial artery blood pressure. The circulation was hyperkinetic and the cardiac output was increased. Also, during exercise the blood pressure remained much lower despite a relatively greater cardiac output, resulting in significantly lower levels of vascular resistance. Sodium retention occurred in one patient, and central nervous system symptoms were reported by two men during treatment with guancydine. However, these findings should encourage further studies to establish the clinical usefulness of guancydine, as they suggest it to have a peripheral site of action, perhaps directly on blood vessel walls.     

Incorporation into nucleic acids of the antiherpes guanosine analog buciclovir, and effects on DNA and protein synthesis

Using cells expressing herpes simplex virus (HSV) thymidine kinase, we investigated the metabolism of the acyclic antiherpes guanosine analog buciclovir, in relation to the effects of the drug on viral DNA and protein synthesis. In these cells the predominant metabolite of buciclovir was its triphosphate, as in the HSV-1 infected Vero cells investigated in parallel. Further metabolism of buciclovir led to incorporation into RNA and DNA. Buciclovir inhibited DNA synthesis, not RNA synthesis, and prevented an increase in the size of newly synthesized DNA. To study the relative effects of BCV on cellular and viral DNA synthesis, human TK-cells transformed to a TK+ phenotype with HSV-2 DNA, were infected with HSV-1. In these HSV-1 infected cells buciclovir-triphosphate caused a preferential inhibition of viral DNA synthesis. Despite incorporation of buciclovir into RNA, and the presence of buciclovir-triphosphate from the time of infection onwards, no effect was observed on the synthesis of the beta proteins ICP-6 and ICP-8. Presumably as a consequence of inhibition of viral DNA synthesis, the synthesis of a beta gamma protein (gD) and a gamma protein (gC) were inhibited, and synthesis of the beta proteins (ICP-6 and ICP-8) was not shut-off. Glycosylation of gC that was still synthesized, was not inhibited. Thus, the biological effects of buciclovir can be explained by its inhibition of DNA synthesis.