Vaccination strategies for measles control and elimination: time to strengthen local initiatives.

BACKGROUND: Through a combination of strong routine immunization (RI), strategic supplemental immunization activities (SIA) and robust surveillance, numerous countries have been able to approach or achieve measles elimination. The fragility of these achievements has been shown, however, by the resurgence of measles since 2016. We describe trends in routine measles vaccine coverage at national and district level, SIA performance and demographic changes in the three regions with the highest measles burden. FINDINGS: WHO-UNICEF estimates of immunization coverage show that global coverage of the first dose of measles vaccine has stabilized at 85% from 2015 to 19. In 2000, 17 countries in the WHO African and Eastern Mediterranean regions had measles vaccine coverage below 50%, and although all increased coverage by 2019, at a median of 60%, it remained far below levels needed for elimination. Geospatial estimates show many low coverage districts across Africa and much of the Eastern Mediterranean and southeast Asian regions. A large proportion of children unvaccinated for MCV live in conflict-affected areas with remote rural areas and some urban areas also at risk. Countries with low RI coverage use SIAs frequently, yet the ideal timing and target age range for SIAs vary within countries, and the impact of SIAs has often been mitigated by delays or disruptions. SIAs have not been sufficient to achieve or sustain measles elimination in the countries with weakest routine systems. Demographic changes also affect measles transmission, and their variation between and within countries should be incorporated into strategic planning. CONCLUSIONS: Rebuilding services after the COVID-19 pandemic provides a need and an opportunity to increase community engagement in planning and monitoring services. A broader suite of interventions is needed beyond SIAs. Improved methods for tracking coverage at the individual and community level are needed together with enhanced surveillance. Decision-making needs to be decentralized to develop locally-driven, sustainable strategies for measles control and elimination.

Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program.

BACKGROUND: EGFR mutations cause inconsistent response to EGFR tyrosine-kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR-mutated non-small-cell lung cancer collected in the Biomarkers France database. PATIENTS AND METHODS: Of 17 664 patients, 1837 (11%) with EGFR-mutated non-small-cell lung cancer were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 stage IV patients. RESULTS: EGFR exon 18, 19, 20 and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%) and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7 months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type {exon 19: hazard ratio (HR)=0.51 [95% confidence interval (CI): 0.41-0.64], P < 0.0001; exon 21: HR = 0.76 (95% CI: 0.61-0.95), P = 0.002; exon 20: HR = 1.56 (95% CI: 1.02-2.38), P = 0.004}. EGFR mutation type was prognostic of progression-free survival versus wild-type [exon 19: HR = 0.62 (95% CI: 0.49-0.78), P < 0.0001; exon 20: HR = 1.46 (95% CI: 0.96-2.21), P = 0.07]. First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved progression-free survival versus chemotherapy [HR = 0.67 (95% CI: 0.53-0.85), P = 0.001]. OS was longer for del19 versus L858R, which was associated with better OS compared with other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients. CONCLUSION: EGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.

Prognostic and predictive values of oncogenic BRAF, NRAS, c-KIT and MITF in cutaneous and mucous melanoma.

BACKGROUND: Mutations of BRAF, NRAS and c-KIT oncogenes are preferentially described in certain histological subtypes of melanoma and linked to specific histopathological features. BRAF-, MEK- and KIT-inhibitors led to improvement in overall survival of patients harbouring mutated metastatic melanoma. OBJECTIVES: To assess the prevalence and types of BRAF, NRAS, c-KIT and MITF mutations in cutaneous and mucous melanoma and to correlate mutation status with clinicopathological features and outcome. METHODS: Clinicopathological features and mutation status of 108 samples and of 98 consecutive patients were, respectively, assessed in one retrospective and one prospective study. Clinicopathological features were correlated with mutation status and the predictive value of these mutations was studied. RESULTS: This work identified significant correlations between BRAF mutations and melanoma occurring on non-chronic sun-damaged skin and superficial spreading melanoma (P < 0.05) on one hand, and between NRAS mutations and nodular melanoma (P < 0.05) on the other hand. Younger age (P < 0.05), microscopic (P < 0.05) and macroscopic (P < 0.05) lymphatic involvement at diagnosis of primary melanoma were significantly linked to BRAF mutations. A mutated status was a positive predictive factor of a response to BRAF inhibitors (OR = 3.44). Mutated melanoma showed a significantly (P = 0.038) higher objective response rate to cytotoxic chemotherapy (26.3%) than wild-type tumours (6.7%). CONCLUSION: Clinical and pathological characteristics of the primary melanoma differed between wild-type and BRAF- or NRAS-mutated tumours. Patients with BRAF-mutated tumours were younger at diagnosis of primary melanoma. Patients carrying mutations showed better responses better to specific kinase inhibitors and interestingly also to systemic cytotoxic chemotherapy.

Iron excess limits HHIPL-2 gene expression and decreases osteoblastic activity in human MG-63 cells.

UNLABELLED: In order to understand mechanisms involved in osteoporosis observed during iron overload diseases, we analyzed the impact of iron on a human osteoblast-like cell line. Iron exposure decreases osteoblast phenotype. HHIPL-2 is an iron-modulated gene which could contribute to these alterations. Our results suggest osteoblast impairment in iron-related osteoporosis. INTRODUCTION: Iron overload may cause osteoporosis. An iron-related decrease in osteoblast activity has been suggested. METHODS: We investigated the effect of iron exposure on human osteoblast cells (MG-63) by analyzing the impact of ferric ammonium citrate (FAC) and iron citrate (FeCi) on the expression of genes involved in iron metabolism or associated with osteoblast phenotype. A transcriptomic analysis was performed to identify iron-modulated genes. RESULTS: FAC and FeCi exposure modulated cellular iron status with a decrease in TFRC mRNA level and an increase in intracellular ferritin level. FAC increased ROS level and caspase 3 activity. Ferroportin, HFE and TFR2 mRNAs were expressed in MG-63 cells under basal conditions. The level of ferroportin mRNA was increased by iron, whereas HFE mRNA level was decreased. The level of mRNA alpha 1 collagen type I chain, osteocalcin and the transcriptional factor RUNX2 were decreased by iron. Transcriptomic analysis revealed that the mRNA level of HedgeHog Interacting Protein Like-2 (HHIPL-2) gene, encoding an inhibitor of the hedgehog signaling pathway, was decreased in the presence of FAC. Specific inhibition of HHIPL-2 expression decreased osteoblast marker mRNA levels. Purmorphamine, hedgehog pathway activator, increased the mRNA level of GLI1, a target gene for the hedgehog pathway, and decreased osteoblast marker levels. GLI1 mRNA level was increased under iron exposure. CONCLUSION: We showed that in human MG-63 cells, iron exposure impacts iron metabolism and osteoblast gene expression. HHIPL-2 gene expression modulation may contribute to these alterations. Our results support a role of osteoblast impairment in iron-related osteoporosis.

Polychlorinated biphenyls and DDT alter species composition in mixed cultures of algae.

Either DDT or polychlorinated biphenyls were added to mixed cultures containing a marine diatom and a marine green alga that were sensitive and resistant, respectively, to these organochlorine compounds. The diatom grew faster and was therefore dominant in control cultures, but its dominance diminished in treated cultures, even at concentrations of chlorinated hydrocarbons that had no apparent effect in pure cultures. Such stable pollutants could disrupt the species composition of phytoplankton communities, thereby affecting whole eco-systems.

Bacterial origin of sulfuric Acid in geothermal habitats.

Natural populations of Sulfolobus, a new genus of bacteria occurring in sulfur-rich, acid hot springs and soils, were found to oxidize large amounts of sulfur to sulfuric acid at temperatures up to 85 degrees C. These bacteria are important high-temperature geochemical agents in solfatara soils.

Polychlorinated biphenyls: toxicity to certain phytoplankters.

The growth rates of two species of marine diatoms were reduced by polychlorinated biphenyls (PCB's), widespread pollutants of the marine environment, at concentrations as low as 10 to 25 parts per billion. In contrast, a marine green alga and two species of freshwater algae were not inhibited at these or higher concentrations. The sensitivity of these species to PCB's paralleled their sensitivity to DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane].

Dose-related effect of moxisylyte on maximal urethral closing pressure in patients with spinal cord injuries.

The effects of single intravenous doses of 0.25, 0.50, and 0.75 mg/kg moxisylyte on maximum urethral closure pressure were evaluated in a placebo-controlled double-blind experiment in 20 patients with spinal cord injuries. Pharmacodynamic testing was performed until 30 minutes, and blood pressure was assessed until 60 minutes. Our findings showed a dose-dependent decrease in maximum urethral closure pressure. At each individual time point, the three doses differed significantly from placebo. Ten minutes after dose administration the maximum effect (48% decrease) was obtained with 0.75 mg/kg. A significant difference in favor of the highest dose was shown from 15 to 20 minutes after administration. According to these findings and because 0.75 mg/kg was as well tolerated as the two other doses, such a drop in pressure indicates that the alpha-blocking agent moxisylyte may be an effective means of decreasing urethral resistance, with obvious implications for the management of urinary obstruction.

The protein coded by the X-adrenoleukodystrophy gene is a peroxisomal integral membrane protein.

The gene for adrenoleukodystrophy (X-ALD), a peroxisomal disease characterized by excessive accumulation of very long-chain (VLC) fatty acids (> C22:0), has recently been identified by positional cloning, and it is predicted to encode a protein (ALD-P) of 745 amino acids [(1993) Nature 361, 726]. Using Western blot analysis of subcellular organelles purified by isopycnic density gradient centrifugation from X-ALD and control fibroblasts, we show that the monoclonal antibodies directed against ALD-P cross-react with a 75 kDa protein in intact peroxisomes and that ALD-P is an integral component of the peroxisomal membrane. Moreover, no signal for ALD-P was detected in peroxisomes from X-ALD patients with deletion of the ALD gene.

Adrenoleukodystrophy gene: unexpected homology to a protein involved in peroxisome biogenesis.

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder characterized by a progressive demyelination of the central nervous system and adrenal insufficiency. Clinical phenotypes of different severity are frequently observed within the same kindred. ALD is characterized biochemically by the accumulation of very-long-chain fatty acids (VLCFA) due to an impairment in the beta-oxidation of these fatty acids in peroxisome. From the observation that oxidation of VLCFA-CoA is normal in fibroblasts from patients with ALD, it was concluded that the gene coding for VLCFA-CoA synthetase was a candidate gene for ALD. Using positional cloning strategies, we have identified a gene which was found partially deleted in 7% of 85 independent patients with ALD. The predicted protein (ALDP) sequence shows significant homology to the 70-kDa peroxisomal membrane protein which is involved in peroxisome biogenesis and belongs to the 'ATP binding' superfamily of transporters. ALDP thus encodes a putative peroxisomal transporter molecule which may be involved in the import or anchoring of VLCFA-CoA synthetase.

Update from the SENIC project. Hospital infection control: recent progress and opportunities under prospective payment.

From a survey of all U.S. hospitals in 1976 and of a random sample in 1983, we found that the intensity of infection surveillance and control activities greatly increased, and the percentage of hospitals with an infection control nurse per 250 beds increased from 22% to 57%. The percentage with a physician trained in infection control remained low (15%), and there was a drop in the percentages of hospitals doing surgical wound infection surveillance (from 90% down to 79%) and reporting surgeon-specific rates to surgeons (from 19% down to 13%). There was an increase in the percentage of hospitals with programs shown to be effective in preventing urinary tract infections, bacteremias, and pneumonias, but not surgical wound infections. The percentage of nosocomial infections being prevented nationwide appears to have increased from 6% to only 9%, whereas 32% could be prevented if all hospitals adopted the most effective programs.

[3H]ramiprilat binding to the angiotensin-converting enzyme in rat renal brush-border membranes: the effect of chloride.

The [3H]ramiprilat binding to the angiotensin-converting enzyme (ACE) in rat renal brush-border membranes was studied. At pH 7.9, and in the presence of 50 mM NaCl, specific binding of [3H]ramiprilat was saturable with a dissociation constant KD = 5.05 nM and maximum number of binding sites of 1.52 pmol/mg prot. [3H]Ramiprilat binding was completely inhibited by specific inhibitors of ACE: ramiprilat, ramipril, enalaprilat, enalapril and captopril. [3H]Ramiprilat binding was Zn2(+)- and Cl(-)-dependent. In the presence of EGTA, which chelates Zn2+ ions, ramiprilat binding was inhibited, but the addition of Zn2+ restored the initial binding. Binding was maximum in the presence of 10 mM NaCl while higher NaCl concentrations decreased the binding, corresponding to a decrease in affinity. The association and dissociation kinetics were also NaCl-dependent. In the absence of NaCl, association and dissociation kinetics were rapid and monophasic. Two-step dissociation kinetics appeared in the presence of 10, 50 and 300 mM NaCl and dissociation time increased with the NaCl concentration. These results confirmed the role of Cl- in the isomerisation and the stability of the membrane-associated ACE-inhibitor complex.

X-linked adrenoleukodystrophy gene: identification of a candidate gene by positional cloning.

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder characterized by a progressive demyelination of the central nervous system, adrenal insufficiency and impaired capacity to o-oxidase very long chain fatty acids, a metabolic process that normally takes place in peroxisomes. The ALD locus has been mapped to Xq28 and we have recently identified a patient with ALD who has a complex rearrangement in the 5' end of the red/green color pigment genes in Xq28. This rearrangement comprises two deletions separated by a large inversion. The second deletion of this key ALD patient extends 19 kb into the 3' region of an expressed gene which was found partially deleted in six of 85 independent patients with ALD. This segment thus constitutes a candidate region for the ALD gene.

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous and intracavernous administration.

The concentration-time profiles of metabolites of moxisylyte, an alpha-adrenergic receptor blocking agent, in the plasma of 12 healthy volunteers were investigated after intravenous (iv) and intracavernous (ic) administrations. The study was conducted in open, randomized, Latin Squares. Plasma levels of moxisylyte and its biotransformation products were assayed by a specific high-performance liquid chromatography method with fluorescence detection. Three metabolites, unconjugated desacetylmoxisylyte (DAM), conjugated DAM, and conjugated monodesmethylated DAM (MDAM), were found in plasma. After iv administration, unconjugated DAM appeared in plasma in < 5 min; the formation of this metabolite is slightly lower after ic administration (half-life, 6.08 +/- 2.33 min). Maximum plasma levels (57.2 +/- 29.4 ng/mL) and area under the curve of concentration versus time (43.3 +/- 11.4 micrograms.h/L) were significantly lower after ic administration than after iv administration (352.8 +/- 287.6 ng/mL and 152.6 +/- 0.247 micrograms.h/L, respectively). For conjugated DAM, the time to reach the maximum concentration is significantly increased after ic administration (0.9 h instead of 0.46 h) and the maximum concentration is significantly decreased (163.5 ng/mL instead of 203.4 ng/mL). The other pharmacokinetic parameters show no change between the two routes of administration. The pharmacokinetic parameters computed for MDAM are in the same range after iv and ic administrations, and there are no significant statistical differences.

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous and oral administration.

The concentration-time profiles of metabolites of moxisylyte, an alpha-blocking agent, in the plasma and urine of 12 healthy volunteers were investigated after intravenous (iv) and oral (two formulations) administration. The study was conducted with an open, randomized Latin squares design. Plasma and urine levels of moxisylyte and its biotransformation products were assayed by a specific HPLC method with fluorescence detection. Plasma levels declined in a monophasic or biphasic pattern depending on the subject. Two metabolites, conjugated desacetylmoxisylyte (DAM) and conjugated monodesmethylated DAM (MDAM), were found in plasma and urine. Unconjugated DAM was found in plasma only after iv administration. The apparent elimination half-lives of unconjugated DAM, conjugated DAM, and MDAM were 0.86, 1.7, and 3 h, respectively. The total amounts of metabolites (expressed as the equivalent of DAM) excreted in the urine were 75% after i.v. administration and 68 and 69% after oral administration of the two formulations. Oral absorption appeared to be complete for the two treatments. There was no statistical difference between the two oral formulations studied.

Multiple-dose pharmacokinetics of moxisylyte after oral administration to healthy volunteers.

The pharmacokinetics of moxisylyte in plasma and urine was investigated after oral administration. Twelve subjects were treated orally, twice daily with 240 mg of the drug for 6 days; on day 7, the subjects received a last dose of 240 mg of moxisylyte. Moxisylyte was assayed in plasma and urine by a specific HPLC method with fluorimetric detection. Moxisylyte was absorbed rapidly and changed to its metabolites immediately after drug administration; unchanged moxisylyte was not found in plasma. Two metabolites were found in plasma and urine: conjugated desacetylmoxisylyte (DAM) and the conjugate of desmethylated DAM (MDAM). The pharmacokinetic parameters determined after the first oral administration were not modified on multiple dosing. The apparent elimination half-lives of conjugated DAM and MDAM were 2.3 and 3.5 h, respectively. Elimination of these two metabolites in urine averaged 50 and 10%, respectively.

Serum kinetics of doxycycline polyphosphate in dogs.

Serum kinetics of Doxycycline polyphosphate (DPP) have been studied in dogs after oral administration of 10 mg.kg-1 by measurement of total serum concentration (Ct) of tetracycline derivatives by a chemical assay and active concentration (Ca) by a microbiological method. Kinetics have been studied using a one compartment open model with absorption by oral route. DPP is rapidly absorbed, the peak serum level is reached three hours after absorption and slowly eliminated (elimination half-life = 12 hours). The main differences observed between Ct and Ca kinetics are in the values of the areas under the curves (AUC) and the peak serum level. The values obtained for these parameters for Ca kinetics were found to be 50% of those obtained for Ct, the volumes of distribution being in inverse proportion. These results are in a good agreement with the correlation and linear regression observed between Ca and Ct showing that 55% of total serum Doxycycline possesses immediate antibacterial activity. It is postulated that this difference between Ct and Ca kinetics is essentially a reflection of the ratios of bound and free drug. Similar results were obtained with the finished pharmaceutical form except for a 15% increase of AUC indicating improvement of the bioavailability of the drug.