Clinical landscape of LAG-3-targeted therapy.

Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed.

Lead accumulation in photosynthetic Euglena gracilis depends on polyphosphates and calcium.

Worldwide increasing levels of lead in water systems require the search for efficient ecologically friendly strategies to remove it. Hence, lead accumulation by the free-living algae-like Euglena gracilis and its effects on cellular growth, respiration, photosynthesis, chlorophyll, calcium, and levels of thiol- and phosphate-molecules were analyzed. Photosynthetic cells were able to accumulate 4627 mg lead/kgDW after 5 days of culture with 200 µM Pb2+. Nevertheless, exposure to 50, 100 and 200 µM Pb2+ for up to 8 days did not modify growth, viability, chlorophyll content and oxygen consumption/production. Enhanced biosynthesis of thiol molecules and polyphosphates, i.e. the two canonical metal ion chelation mechanisms in E. gracilis, was not induced under such conditions. However, in cells cultured in the absence of phosphate, lead accumulation and polyphosphate content markedly decreased, while culturing in the absence of sulfate did not modify the accumulation of this metal. In turn, the total amount of intracellular calcium slightly increased as the amount of intracellular lead increased, whereas under Ca2+ deficiency lead accumulation doubled. Therefore, the results indicated that E. gracilis is highly resistant to lead through mechanisms mediated by polyphosphates and Ca2+ and can in fact be classified as a lead hyperaccumulator microorganism.

Risk factors for invasive mold diseases in allogeneic hematopoietic cell transplant recipients.

BACKGROUND: The epidemiology of and risk factors for invasive mold disease (IMD) among allogeneic hematopoietic cell transplant (HCT) recipients may vary according to the region. In this study, we sought to evaluate risk factors for IMD in our patient population. METHODS: Between May 2007 and July 2009, all HCT recipients from 8 Brazilian centers were followed prospectively until 1 year post transplant. Cases of IMD were classified as early (before day +40) or late (after day +40). Patients with IMD (cases) were compared with controls (patients without IMD) using univariate and multivariate Cox regression analysis. RESULTS: Among 345 HCT recipients, 28 IMDs were diagnosed. Risk factors for early IMD were acute myeloid leukemia (hazard ratio [HR] 2.95, 95% confidence interval [95% CI] 1.13-7.68, P = 0.03) and transplant with a human leukocyte antigen-mismatched donor (HR 3.38, 95% CI 1.18-9.68, P = 0.02), and for late IMD risk factors were lymphoma (HR 8.49, 95% CI 2.35-30.68, P = 0.001), cytomegalovirus reactivation (HR 5.51, 95% CI 1.15-26.47, P = 0.03), and neutropenia (HR 3.49, 95% CI 1.01-12.13, P = 0.049). CONCLUSION: The variables identified in this study may help to define risk groups, and to tailor special preventive measures to patients at higher risk to develop IMD.

Isolation, molecular characterization and antimicrobial susceptibilities of isolates of Mycoplasma agalactiae from bulk tank milk in an endemic area of Spain.

AIM: To isolate and characterize strains of Mycoplasma agalactiae from bulk tank and silo ewes' milk. METHODS AND RESULTS: Thirteen mycoplasma isolates were obtained from samples of sheep milk taken from bulk tank and large silos and identified as Myc. agalactiae by PCR-DGGE. The isolates were typed by pulsed field gel electrophoresis (PFGE), SDS-PAGE and immunoblot. The in vitro activity of 13 antimicrobials of veterinary interest was tested against these isolates. Results showed that the most effective compounds against Myc. agalactiae in vitro were clindamycin, an antibiotic not previously described as a suitable contagious agalactia (CA) treatment, with Minimum Inhibitory Concentration (MIC) values of <0·12 µg ml(-1) , and quinolones, with MIC values <0·12-0·5 µg ml(-1) , which are used as standard treatments against CA. CONCLUSIONS: Based on the in vitro assay, clindamycin, quinolones, tylosin and tilmicosin would be appropriate antimicrobials for CA treatment. The isolates were mostly resistant to erythromycin, indicating that it would not be a suitable choice for therapy. The isolates showed common molecular and protein profiles by PFGE and SDS-PAGE, with minor differences observed by immunoblot analysis, suggesting a clonal relationship among them. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated the importance of the appropriate selection of antimicrobials for treatment of CA.

Epidemiology of candidemia in patients with hematologic malignancies and solid tumours in Brazil.

Candidemia in cancer patients may differ according to the type of cancer. To characterise the epidemiology and outcome of candidemia in cancer patients from Brazilian hospitals, we compared the characteristics of patients with hematologic malignancies (HM) and solid tumours (ST). A retrospective study was performed, based on data collected from laboratory-based surveillance studies in 18 tertiary care hospitals between March/2003 and December/2007. The characteristics of patients with HM (n = 117) were compared with patients with ST (n = 248). Predictors of 30-day mortality were identified by uni- and multivariate analyses. Candidemia in HM was more likely to occur in the setting of chemotherapy, corticosteroids, neutropenia, mucositis and tunnelled central venous catheter (CVC), whereas surgery, intensive care unit admission and invasive procedures (mechanical ventilation, parenteral nutrition and CVC) were more frequent in ST. The 30-day mortality rate was higher in the ST group (65% vs. 46%, P = 0.001). Factors significantly associated with 30-day mortality were older age and intensive care unit admission. Important differences in the epidemiology and outcome of candidemia in HM and ST were observed. The characterisation of the epidemiology is important to drive preventive measures and to select appropriate therapies.

Invasive fungal diseases in haematopoietic cell transplant recipients and in patients with acute myeloid leukaemia or myelodysplasia in Brazil.

Invasive fungal disease (IFD) shows distinct regional incidence patterns and epidemiological features depending on the geographic region. We conducted a prospective survey in eight centres in Brazil from May 2007 to July 2009. All haematopoietic cell transplant (HCT) recipients and patients with acute myeloid leukaemia (AML) or myelodysplasia (MDS) were followed from admission until 1 year (HCT) or end of consolidation therapy (AML/MDS). The 12-month cumulative incidence (CI) of proven or probable IFD was calculated, and curves were compared using the Grey test. Among 237 AML/MDS patients and 700 HCT recipients (378 allogeneic, 322 autologous), the 1-year CI of IFD in AML/MDS, allogeneic HCT and autologous HCT was 18.7%, 11.3% and 1.9% (p <0.001), respectively. Fusariosis (23 episodes), aspergillosis (20 episodes) and candidiasis (11 episodes) were the most frequent IFD. The 1-year CI of aspergillosis and fusariosis in AML/MDS, allogeneic HCT and autologous HCT were 13.4%, 2.3% and 0% (p <0.001), and 5.2%, 3.8% and 0.6% (p 0.01), respectively. The 6-week probability of survival was 53%, and was lower in cases of fusariosis (41%). We observed a high burden of IFD and a high incidence and mortality for fusariosis in this first multicentre epidemiological study of IFD in haematological patients in Brazil.

Relationship among specific bacterial counts and total bacterial and somatic cell counts and factors influencing their variation in ovine bulk tank milk.

To analyze the relationship among the counts of different organisms and total bacterial count (BTTBC) and somatic cell count (BTSCC) as determined in dairy laboratories in ovine bulk tank milk, 751 bulk tank milk samples from 205 dairy sheep flocks belonging to Consortium for Ovine Promotion (CPO) were collected between January and December 2011. Four samplings were carried out in each flock, once per season, throughout 1 yr. Variables analyzed were bulk tank counts of thermoduric, psychrotrophic, coliform, and gram-positive catalase-negative cocci (GPCNC) bacterial groups. Thermoduric, psychrotrophic, and coliform species were significantly related to BTTBC, whereas GPCNC were correlated with both BTTBC and BTSCC variables. Highest counts were for psychrotroph and coliform groups, and a moderate to high correlation (r=0.51) was found between both variables, indicating that poor cleaning practices in the flocks tend to select for less-resistant organisms, such as gram-negative rods. In addition, BTTBC correlated with BTSCC (r=0.42). Some variation factors for specific bacterial counts, such as breed, season, milking type, dry therapy, and milk yield, were also analyzed. Flock information was collected from flock books, annual audits, and the CPO traceability system. Psychrotrophs and coliforms had elevated counts in winter, whereas GPCNC were higher in summer and in hand-milked flocks. Dry therapy contributed to the reduction in psychrotrophic bacteria; therefore, some strains of mammary pathogens could also be psychrotrophic bacteria. Results of this study would be helpful for troubleshooting milk quality problems and developing premium payment systems in dairy sheep.

Leiomiomatosis benigna metastatizante: a propósito de un caso / Benign metastasizing leiomyomatosis: apropos of a case

Se presenta el caso de una paciente con neumotórax bilaterales de repetición secundarios a una leiomiomatosis benigna metastatizante. Se intentó el control de su enfermedad con tratamiento médico, siendo necesario proceder a tratamiento radical mediante histerectomía más doble anexectomía ante la escasa respuesta a los procedimientos conservadores (AU)

We report the case of a patient with recurrent bilateral pneumothorax secondary to benign metastasizing leiomyomatosis. Medical treatment was administered but surgery with hysterectomy plus double annexectomy was required due to the lack of response to conservative procedures (AU)

Role of dispersion forces in the structure of graphene monolayers on Ru surfaces.

Elaborate density functional theory (DFT) calculations that include the effect of van der Waals (vdW) interactions have been carried out for graphene epitaxially grown on Ru(0001). The calculations predict a reduction of structural corrugation in the observed moiré pattern of about 25% (∼0.4 Å) with respect to DFT calculations without vdW corrections. The simulated STM topographies are close to the experimental ones in a wide range of bias voltage around the Fermi level.

Multilocus sequence typing of Mycoplasma agalactiae.

Mycoplasma agalactiae is the main cause of contagious agalactia, a serious disease of sheep and goats, which has major clinical and economic impacts. We have developed a multilocus sequence typing (MLST) scheme using the sequenced genomes of the M. agalactiae strains PG2 and 5632. An MLST scheme based on the genes gltX, metS, gyrB, tufA and dnaA was designed and in total 3468 bp of sequence were analysed for each strain. MLST offers a highly discriminatory typing method for M. agalactiae and was capable of subdividing 53 strains into 17 distinct sequence types, largely according to geographical origin. MLST detected unexpected diversity in recent isolates from Spain, identifying two novel outliers, and enabled typing of novel Mongolian isolates for the first time. Genetic diversity in the sequenced regions was largely due to mutation, with recombination playing a much smaller role. A web-accessible database has been set up for this MLST scheme for M. agalactiae: http://pubmlst.org/magalactiae/. MLST offers a robust, objective molecular epidemiological tool for M. agalactiae that that enables interlaboratory comparison of data.

Influence of storage and preservation on microbiological quality of silo ovine milk.

This study was designed to analyze the effects of the storage and preservation conditions on counts of mesophilic, thermoduric, psychotrophic, coliform, Escherichia coli, Streptococcus agalactiae, and Staphylococcus aureus organisms in silo ovine milk. A total of 910 analytical determinations were conducted from aliquots of 10 silo ovine milks. The conditions tested were unpreserved and azidiol-preserved milk stored at 4°C, and unpreserved milk stored at -20°C. Milk aged 2, 24, 48, 72, and 96 h post-collection for refrigerated aliquots, and 7, 15, and 30 d post-collection for frozen aliquots. The factors silo and storage conditions significantly contributed to variation of all microbiological variables, although milk age effect within storage was only significant for mesophilic, psychrotrophic, and coliform bacteria counts. In refrigerated raw milk, mesophile, psychrotroph, and coliform counts significantly increased over 96 h post-collection, whereas the other groups and bacteria species tested maintained their initial concentration. In all cases, azidiol preservation maintained the initial bacterial concentration in raw sheep milk under refrigeration throughout 96 h. Thus, azidiol was a suitable preservative for microbiological studies in sheep milk. Smallest counts were registered for frozen samples, particularly for coliforms, E. coli, Strep. agalactiae and Staph. aureus. Estimates of mesophilic, thermoduric and psychrotrophic organisms showed similar values on both azidiol-preserved and frozen milk samples. Coliforms and E. coli counts significantly decrease over time after freezing. Consequently, freezing at -20°C could also be appropriate for analysis of mesophilic, thermoduric, and psychrotrophic bacterial groups, but not for coliforms or mammary pathogens.

Potential energy landscape for hot electrons in periodically nanostructured graphene.

We explore the spatial variations of the unoccupied electronic states of graphene epitaxially grown on Ru(0001) and observed three unexpected features: the first graphene image state is split in energy; unlike all other image states, the split state does not follow the local work function modulation, and a new interfacial state at +3 eV appears on some areas of the surface. First-principles calculations explain the observations and permit us to conclude that the system behaves as a self-organized periodic array of quantum dots.

Factors associated with bacteremia due to multidrug-resistant Gram-negative bacilli in hematopoietic stem cell transplant recipients.

The epidemiology of bacteremia developing during neutropenia has changed in the past decade, with the re-emergence of Gram-negative (GN) bacteria and the development of multidrug resistance (MDR) among GN bacteria. We conducted a case-control study in order to identify factors associated with bacteremia due to multidrug-resistant Gram-negative (MDRGN) isolates in hematopoietic stem cell transplant recipients. Ten patients with MDRGN bacteremia were compared with 44 patients with GN bacteremia without MDR. Bacteremia due to Burkholderia or Stenotrophomonas sp was excluded from analysis (3 cases), because the possibility of intrinsical resistance. Infection due to MDRGN bacteria occurred in 2.9% of 342 hematopoietic stem cell transplant recipients. Klebsiella pneumoniae was the most frequent MDRGN (4 isolates), followed by Pseudomonas aeruginosa (3 isolates). Among non-MDRGN, P. aeruginosa was the most frequent agent (34%), followed by Escherichia coli (30%). The development of GN bacteremia during the empirical treatment of febrile neutropenia (breakthrough bacteremia) was associated with MDR (P < 0.001, odds ratio = 32, 95% confidence interval = 5_190) by multivariate analysis. Bacteremia due to MDRGN bacteria was associated with a higher death rate by univariate analysis (40 vs 9%; P = 0.03). We were unable to identify risk factors on admission or at the time of the first fever, but the occurrence of breakthrough bacteremia was strongly associated with MDRGN bacteria. An immediate change in the antibiotic regimen in such circumstances may improve the prognosis of these patients.

Factors associated with bacteremia due to multidrug-resistant Gram-negative bacilli in hematopoietic stem cell transplant recipients

The epidemiology of bacteremia developing during neutropenia has changed in the past decade, with the re-emergence of Gram-negative (GN) bacteria and the development of multidrug resistance (MDR) among GN bacteria. We conducted a case-control study in order to identify factors associated with bacteremia due to multidrug-resistant Gram-negative (MDRGN) isolates in hematopoietic stem cell transplant recipients. Ten patients with MDRGN bacteremia were compared with 44 patients with GN bacteremia without MDR. Bacteremia due to Burkholderia or Stenotrophomonas sp was excluded from analysis (3 cases), because the possibility of intrinsical resistance. Infection due to MDRGN bacteria occurred in 2.9 percent of 342 hematopoietic stem cell transplant recipients. Klebsiella pneumoniae was the most frequent MDRGN (4 isolates), followed by Pseudomonas aeruginosa (3 isolates). Among non-MDRGN, P. aeruginosa was the most frequent agent (34 percent), followed by Escherichia coli (30 percent). The development of GN bacteremia during the empirical treatment of febrile neutropenia (breakthrough bacteremia) was associated with MDR (P < 0.001, odds ratio = 32, 95 percent confidence interval = 5_190) by multivariate analysis. Bacteremia due to MDRGN bacteria was associated with a higher death rate by univariate analysis (40 vs 9 percent; P = 0.03). We were unable to identify risk factors on admission or at the time of the first fever, but the occurrence of breakthrough bacteremia was strongly associated with MDRGN bacteria. An immediate change in the antibiotic regimen in such circumstances may improve the prognosis of these patients.

[Cost-benefit of the pharmacologic treatment of cerebral palsy with spasticity in Mexico]. / Coste-beneficio del tratamiento farmacológico de la parálisis cerebral con espasticidad en México.

BACKGROUND: Cerebral palsy involving spasticity is a highly handicapping illness, especially among children, the treatment of which is limited to reducing the handicaps involved without any full cure. There is a drug treatment which affords the possibility of providing patients with a better quality of life, regarding which a cost effectiveness analysis is made, note being made of the individual achievements and social benefits. METHODS: This analysis is based on nationwide information from Mexico which was obtained from secondary sources. The base data is set out within the framework of trends in the growth of this health problem, and the calculations affording the possibility of sizing up this problem are employed in order to ascertain the benefits thereof based on the following indicators: relative impact of this disease and years of healthy life lost and gained, based on which the social and economic benefit entailed in the drug treatment under analysis is estimated. RESULTS: The data reveals that the drug treatment in question is directly beneficial, because it lowers the relative impact of this disease from 0.92 to 0.40. At the individual level, the greatest benefit takes the form of the improved quality of life among the afflicted children within the 6-12 age range, they having gone from 0.08 years to 0.60 years of life in terms of quality. At the nationwide level, the 595,817 years of healthy life which would be lost without any treatment would be recouped. The monetary value involved in this treatment is that of 2,725.00 Mexican pesos (US $283.00) for administering the drug over a one-year period to each child suffering from this disability. CONCLUSIONS: This is a low-cost treatment, because it is currently impossible to reverse the neurological and physiological processes of cerebral palsy, this treatment therefore improving the quality of life of the children afflicted with this disease is the best possible benefit. The cost effectiveness analysis taking into account these indicators reveals a clear-cut relationship between the monetary values and the health benefits.

Decline in sexually transmitted disease prevalence in female Bolivian sex workers: impact of an HIV prevention project.

OBJECTIVE: To implement an HIV prevention intervention among female commercial sex workers (CSW), and to monitor key outcomes using routinely collected clinical and laboratory data. DESIGN: Cross-sectional and longitudinal analysis of data from an open-enrollment cohort. SETTING: One public sexually transmitted disease (STD) clinic and about 25 brothels in La Paz, Bolivia. PARTICIPANTS: A total of 508 female CSW who work at brothels and attend a public STD clinic. INTERVENTION: Improved STD clinical care, supported by periodic laboratory testing, and behavioral interventions performed by a local non-governmental organization. MAIN OUTCOME MEASURES: Prevalence of gonorrhea, syphilis (reactive plasma reagin titer > or = 1 : 16), genital ulcer disease, chlamydial infection, and trichomoniasis; self-reported condom use in the previous month; and HIV seroprevalence. RESULTS: From 1992 through 1995, prevalence of gonorrhea among CSW declined from 25.8 to 9.9% (P < 0.001), syphilis from 14.9 to 8.7% (P = 0.02), and genital ulcer disease from 5.7 to 1.3% (P = 0.006); trends in prevalence of chlamydial infection and trichomoniasis were not significant. Self-reported condom use during vaginal sex in the past month increased from 36.3 to 72.5% (P < 0.001). In a multivariate analysis, condom use was inversely associated with gonorrhea [odds ratio (OR), 0.63; 95% confidence interval (Cl), 0.41-0.97], syphilis (OR, 0.39; 95% Cl, 0.23-0.64), and trichomoniasis (OR, 0.44; 95% Cl, 0.32-0.71). In 1995, HIV seroprevalence among CSW was 0.1%. CONCLUSION: Effective prevention interventions for female CSW can be implemented through public services and non-governmental organizations while HIV rates are still low, and key outcomes can be monitored using data obtained from periodic screening examinations.

[Lactation and weaning patterns in Mexico. 1986 National Health Survey]. / Patrones de lactancia y ablactación en México. Encuesta nacional de salud 1986.

In the process of nutrition, breastfeeding is fundamentally important, due to the nutritional and immunological value of the mother's milk. Within its beneficial effects, it is found that it improves weight and size in children. Another stage in the child's feeding that should be considered during the first year of life is the weaning that complements, at certain age of the breastfeeder, the nutrition given by breastmilk. The decrease or abandonment of breastfeeding is alarming in the developing countries, where this natural product is more available, economical and nutritious. There is evidence that within the health institutions, artificial feeding is encouraged. The National Health Survey collected basic information on sociodemographic variables risk factors, demand and use of health services. It also included questions on breastfeeding and weaning for the population under one year of age. It was found that 19.9 percent was never breastfed. Another important fact is that 42.4 percent of children received breastmilk for just three months or less. This view suggests that breastfeeding in our country is changing, due to various factors, among which we can mention the differences in life styles, education and economical development among states. The results of this study show interesting data that oblige us to consider more detailed and specific analyses in the future.