Effects of treatments with alpha-difluoromethylornithine and hyperthermia on the growth and polyamine metabolism of Harding-Passey murine melanoma

The oral administration of alpha-difluoromethylornithine (DFMO), an enzyme-activated inhibitor of ornithine decarboxylase (ODC), produced a marked decrease in the rate of growth of amelanotic Harding-Passey melanoma transplanted in mice. The half-life of this compound in Harding-Pasey melanoma was 30 min. A combined treatment of DFMO and hyperthermia did not show any synergistic effect on the inhibition of tumor growth, and no differences in the levels of tumor ODC, S-Adenosylmethionine decarboxylase (SAMDC) and polyamines were observed between single and combination treatments. DFMO-treatment alone produced a decrease of about 80% in spermidine concentration in melanoma, while in other tissues such as kidney, the diminution of spermidine was only moderate. ODC activity was reduced greatly in the kidney and moderately in melanoma. However, the activity of SAMDC increased up to 30-fold in DFMO-treated melanoma, while only a moderate increase was observed in the renal enzyme. Melanoma tyrosinase activity did not increase with the treatment with DFMO. These results indicate that the inhibition of amelanotic Harding-Passey melanoma growth by DFMO is not caused by the stimulation of cell differentiation, and that in this system polyamine depletion caused by this drug does not produce an enhancement in the heat-induced cytotoxicity.     

The pathogenesis of Alport syndrome involves type IV collagen molecules containing the alpha 3(IV) chain: evidence from anti-GBM nephritis after renal transplantation.

Mutations in the COL4A5 collagen gene have been implicated as the primary defect in Alport syndrome, a heritable disorder characterized by sensorineural deafness and glomerulonephritis that progresses to end-stage renal failure. In the present study, the molecular nature of the defect in Alport glomerular basement membrane (GBM) was explored using anti-GBM alloantibodies (tissue-bound and circulating) produced in three Alport patients subsequent to renal transplantation. The alloantibodies bound to the alpha 3(IV)NC1 domain of type IV collagen and not to any other basement membrane component. In tissue sections, the alloantibodies bound specifically to peripheral GBM in normal kidney and the affected renal transplant but not to that of Alport kidney. These results establish that: the alpha 3 chain in type IV collagen molecules, the Goodpasture autoantigen, is the target alloantigen in post-transplant anti-GBM nephritis in patients with Alport syndrome, and that a molecular commonality exists in the pathogenesis of anti-GBM nephritis causing loss of renal allografts in patients with Alport syndrome and renal failure in patients with Goodpasture syndrome. These findings implicate: (1) defective assembly of type IV collagen molecules containing the alpha 3(IV) chain in Alport GBM; and (2) the existence of a mechanism linking the assembly of molecules containing the alpha 3(IV) chain with those containing the alpha 5(IV) chain.     

Airborne particulate matter and premature deaths in urban Europe: the new WHO guidelines and the challenge ahead as illustrated by Spain

Twenty first century epidemiological publications on urban air pollution are confirming that inhalation of fine, airborne particulate matter (PM) has serious chronic human health effects and is a major cause of premature death worldwide. Recently updated recommendations by WHO identify three “Interim Targets” for the stepped reduction in PM levels within world cities in the quest to achieve an annual mean Air Quality Guideline (AQG) concentration of 20 μg/m³ for particles less than 10 microns in size (PM₁₀). In this paper we offer a perspective from Spain, a country with the longest record of reporting pollution data from large numbers of urban traffic sites to a central European database (AIRBASE). We can demonstrate that average annual PM concentrations at urban traffic monitoring stations in many European cities continue to be 50–100% above the WHO AQG, a situation exacerbated by high urban PM_2.5/10 ratios which indicate a dominance of finer, more deeply inhalable particles potentially more detrimental to health. Given that WHO has estimated in 2000 there were well over 250,000 premature deaths in Europe attributable to PM inhalation, such continuing high urban pollution levels are placing a huge burden on European medical resources.     

FN14 and GRP94 expression are prognostic/predictive biomarkers of brain metastasis outcome that open up new therapeutic strategies

Brain metastasis is a devastating problem in patients with breast, lung and melanoma tumors. GRP94 and FN14 are predictive biomarkers over-expressed in primary breast carcinomas that metastasized in brain. To further validate these brain metastasis biomarkers, we performed a multicenter study including 318 patients with breast carcinomas. Among these patients, there were 138 patients with metastasis, of whom 84 had brain metastasis. The likelihood of developing brain metastasis increased by 5.24-fold (95%CI 2.83–9.71) and 2.55- (95%CI 1.52–4.3) in the presence of FN14 and GRP94, respectively. Moreover, FN14 was more sensitive than ErbB2 (38.27 vs. 24.68) with similar specificity (89.43 vs. 89.55) to predict brain metastasis and had identical prognostic value than triple negative patients (p < 0.0001). Furthermore, we used GRP94 and FN14 pathways and GUILD, a network-based disease-gene prioritization program, to pinpoint the genes likely to be therapeutic targets, which resulted in FN14 as the main modulator and thalidomide as the best scored drug. The treatment of mice with brain metastasis improves survival decreasing reactive astrocytes and angiogenesis, and down-regulate FN14 and its ligand TWEAK. In conclusion our results indicate that FN14 and GRP94 are prediction/prognosis markers which open up new possibilities for preventing/treating brain metastasis.     

Anorectal symptoms before and after laparoscopic sacrocolpoperineopexy for pelvic organ prolapse

Introduction and hypothesis

To evaluate changes in anorectal symptoms before and after pelvic organ prolapse (POP) surgery, using laparoscopic sacrocolpoperineopexy.

Methods

Preoperative and postoperative anorectal symptoms, colorectal–anal distress inventory (CRADI) and colorectal–anal impact questionnaire (CRAIQ) scores were prospectively compared from 90 consecutive women undergoing laparoscopic sacrocolpoperineopexy.

Results

After a median follow-up of 30.7?months, laparoscopic surgery significantly worsened CRADI (p?=?0.02) with no effect on CRAIQ (p?=?0.37) scores. Post-operative and de novo straining (27%) and the need for digital assistance (17%) were the most frequent anorectal symptoms. No correlation was found between laparoscopic surgery and anorectal symptoms after multivariate analysis (OR?=?2.45[95% confidence interval 0.99–6.05], p?=?0.05).

Conclusion

Anorectal symptoms are not improved after POP surgery by laparoscopic sacrocolpoperineopexy.     

Prevalence of exposure to occupational risks during pregnancy in Spain

Objectives

We describe reported exposures to main categories of occupational agents and conditions in Spanish pregnant workers.

Methods

Women were recruited at 12th week of pregnancy from main public gynaecological consults to be included in the INMA Spanish cohorts study (n?=?2,058). Through personal interviews with structured questionnaires, information on working situation and working conditions during pregnancy was obtained.

Results

Fifty percent of the women reported frequent exposure to physical load (standing, heavy lifting) and 45?% reported exposure to three or more indicators of job strain. Exposure to at least one physical agent (noise, vibrations, etc.) affected 25?% of the women. Exposure to chemicals was reported by 20?% of the women, mostly including solvents and cleaning products. Eight percent of the women worked at night shifts. Job strain was more prevalent in office workers and industrial operators. Industrial workers showed the highest prevalence of exposure to chemical and physical pollutants.

Conclusions

Our data suggest that working conditions of pregnant women may need increased control in Spain.