Resistance-minimizing strategies for introducing a novel antibiotic for gonorrhea treatment: a mathematical modeling study.

Background: Gonorrhea is a highly prevalent sexually transmitted infection and an urgent public health concern due to increasing antibiotic resistance. Only ceftriaxone remains as the recommended treatment in the U.S. The prospect of approval of new anti-gonococcal antibiotics raises the question of how to deploy a new drug to maximize its clinically useful lifespan. Methods: We used a compartmental model of gonorrhea transmission in the U.S. population of men who have sex with men to compare strategies for introducing a new antibiotic for gonorrhea treatment. The strategies tested included holding the new antibiotic in reserve until the current therapy reached a threshold prevalence of resistance; using either drug, considering immediate and gradual introduction of the new drug; and combination therapy. The primary outcome of interest was the time until 5% prevalence of resistance to both the novel drug and to the current first-line drug (ceftriaxone). Findings: The reserve strategy was consistently inferior for mitigating antibiotic resistance under the parameter space explored. The reserve strategy was increasingly outperformed by the other strategies as the probability of de novo resistance emergence decreased and as the fitness costs associated with resistance increased. Combination therapy tended to prolong the development of antibiotic resistance and minimize the number of annual gonococcal infections. Interpretation: Our study argues for rapid introduction of new anti-gonococcal antibiotics, recognizing that the feasibility of each strategy must incorporate cost, safety, and other practical concerns. The analyses should be revisited once robust estimates of key parameters-likelihood of emergence of resistance and fitness costs of resistance for the new antibiotic-are available. Funding: U.S. Centers for Disease Control and Prevention (CDC), National Institute of Allergy and Infectious Diseases.

Methoxyl stable isotopic constraints on the origins and limits of coal-bed methane.

Microbial coal-bed methane is an important economic resource and source of a potent greenhouse gas, but controls on its formation are poorly understood. To test whether the microbial degradability of coal limits microbial methane, we monitored methoxyl group demethylation­a reaction that feeds methanogenesis­in a global sample suite ranging in maturity from wood to bituminous coal. Carbon isotopic compositions of residual methoxyl groups were inconsistent with a thermal reaction, instead implying a substrate-limited biologic process. This suggests that deep biosphere communities participated in transforming plant matter to coal on geologic time scales and that methoxyl abundance influences coal-bed methane yield. Carbon isotopic enrichments resulting from microbial methylotrophy also explain an enigmatic offset in the carbon-13 content of microbial methane from coals and conventional hydrocarbon deposits.

'Candidatus Liberibacter solanacearum' Is Tightly Associated with Carrot Yellows Symptoms in Israel and Transmitted by the Prevalent Psyllid Vector Bactericera trigonica.

Carrot yellows disease has been associated for many years with the Gram-positive, insect-vectored bacteria, 'Candidatus Phytoplasma' and Spiroplasma citri. However, reports in the last decade also link carrot yellows symptoms with a different, Gram-negative, insect-vectored bacterium, 'Ca. Liberibacter solanacearum'. Our study shows that to date 'Ca. L. solanacearum' is tightly associated with carrot yellows symptoms across Israel. The genetic variant found in Israel is most similar to haplotype D, found around the Mediterranean Basin. We further show that the psyllid vector of 'Ca. L. solanacearum', Bactericera trigonica, is highly abundant in Israel and is an efficient vector for this pathogen. A survey conducted comparing conventional and organic carrot fields showed a marked reduction in psyllid numbers and disease incidence in the field practicing chemical control. Fluorescent in situ hybridization and scanning electron microscopy analyses further support the association of 'Ca. L. solanacearum' with disease symptoms and show that the pathogen is located in phloem sieve elements. Seed transmission experiments revealed that while approximately 30% of the tested carrot seed lots are positive for 'Ca. L. solanacearum', disease transmission was not observed. Possible scenarios that may have led to the change in association of the disease etiological agent with carrot yellows are discussed. [Formula: see text] Copyright © 2018 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

DEEP BIOSPHERE. Exploring deep microbial life in coal-bearing sediment down to ~2.5 km below the ocean floor.

Microbial life inhabits deeply buried marine sediments, but the extent of this vast ecosystem remains poorly constrained. Here we provide evidence for the existence of microbial communities in ~40° to 60°C sediment associated with lignite coal beds at ~1.5 to 2.5 km below the seafloor in the Pacific Ocean off Japan. Microbial methanogenesis was indicated by the isotopic compositions of methane and carbon dioxide, biomarkers, cultivation data, and gas compositions. Concentrations of indigenous microbial cells below 1.5 km ranged from <10 to ~10(4) cells cm(-3). Peak concentrations occurred in lignite layers, where communities differed markedly from shallower subseafloor communities and instead resembled organotrophic communities in forest soils. This suggests that terrigenous sediments retain indigenous community members tens of millions of years after burial in the seabed.

Diacylglycerol kinase n modualtes oncogenic properties of lung cancer cells

PURPOSE: Lung cancer is a leading cause of cancer deaths and efforts are underway to identify novel therapies to treat these tumors. Diacylglycerol kinase η (DGKη), an enzyme that phosphorylates diacylglycerol to form phosphatidic acid, has been shown to modulate MAPK signaling downstream of EGFR, which is an oncogenic driver in some lung cancers. Since mutations in EGFR and K-Ras are common in lung cancer, we hypothesized that limiting the function of DGKη would attenuate oncogenic properties of lung cancer cells. METHODS: We determined the expression levels of DGKη in a mouse models of mutant EGFR and K-Ras lung cancer and in human lung cancer cell lines with activating mutations in either EGFR or K-Ras. We also tested the effects of shRNA-mediated depletion of DGKη in lung cancer cells and tested if DGKη depletion augmented the effects of afatinib, a new generation EGFR inhibitor. RESULTS: DGKη was expressed in malignant epithelium from mice with mutant EGFR or K-Ras lung cancer. It was also expressed in human lung cancer cell lines with EGFR or K-Ras mutations. Depleting DGKη in lung cancer cell lines, harboring mutant EGFR, reduced their growth on plastic and in soft agar and also augmented the effects of afatinib, an EGFR inhibitor. DGKη depletion also reduced growth of one of two lung cancer cell lines that harbored mutant K-Ras. CONCLUSIONS: Our data indicate that DGKη is a potential therapeutic target in lung cancers, especially those harboring EGFR mutations. Our findings warrant further studies to examine the effects of limiting its function in vivo (AU)

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Diacylglycerol kinase η modulates oncogenic properties of lung cancer cells.

PURPOSE: Lung cancer is a leading cause of cancer deaths and efforts are underway to identify novel therapies to treat these tumors. Diacylglycerol kinase η (DGKη), an enzyme that phosphorylates diacylglycerol to form phosphatidic acid, has been shown to modulate MAPK signaling downstream of EGFR, which is an oncogenic driver in some lung cancers. Since mutations in EGFR and K-Ras are common in lung cancer, we hypothesized that limiting the function of DGKη would attenuate oncogenic properties of lung cancer cells. METHODS: We determined the expression levels of DGKη in a mouse models of mutant EGFR and K-Ras lung cancer and in human lung cancer cell lines with activating mutations in either EGFR or K-Ras. We also tested the effects of shRNA-mediated depletion of DGKη in lung cancer cells and tested if DGKη depletion augmented the effects of afatinib, a new generation EGFR inhibitor. RESULTS: DGKη was expressed in malignant epithelium from mice with mutant EGFR or K-Ras lung cancer. It was also expressed in human lung cancer cell lines with EGFR or K-Ras mutations. Depleting DGKη in lung cancer cell lines, harboring mutant EGFR, reduced their growth on plastic and in soft agar and also augmented the effects of afatinib, an EGFR inhibitor. DGKη depletion also reduced growth of one of two lung cancer cell lines that harbored mutant K-Ras. CONCLUSIONS: Our data indicate that DGKη is a potential therapeutic target in lung cancers, especially those harboring EGFR mutations. Our findings warrant further studies to examine the effects of limiting its function in vivo.

Prenatal allergen exposures prevent allergen-induced sensitization and airway inflammation in young mice.

BACKGROUND: Immune-modulation such as tolerance induction appears to be an upcoming concept to prevent development of atopic diseases. Pregnancy might present a critical period for preventing allergic sensitization of the progeny. We investigated the effect of maternal allergen exposures during pregnancy on allergen-induced sensitization and airway inflammation in the offspring in a murine model. METHODS: BALB/c mice were exposed to aerosolized ovalbumin (OVA) three times per week from day 7 of pregnancy until delivery (day 0). Offspring were systemically sensitized by six intraperitoneal injections with OVA between postnatal days 21 and 35, prior to airway allergen challenges on days 48, 49, and 50. Analyses were performed on day 52. To examine long-lasting effects of maternal OVA exposures some offspring were sensitized between days 115 and 129; analyses took place on day 147. RESULTS: Compared to maternal placebo exposures, maternal OVA exposures suppressed OVA-specific IgE serum levels and inhibited development of allergen-induced airway inflammation in the OVA-sensitized offspring on both days 52 and 147. This protective effect was associated with a shift from a predominant Th2 immune response toward a predominant production of the cytokines IFN-γ and IL-10. Further, maternal OVA exposures were associated with development of CD25(+) Foxp3(+) regulatory T cells (T(regs)) in the OVA-sensitized offspring. Depletion of T(regs) or neutralization of IL-10 prior to allergen sensitization re-established OVA-induced sensitization and eosinophilic airway inflammation in the OVA-sensitized offspring. CONCLUSIONS: In our model, maternal allergen exposures during pregnancy prevented later allergen-mediated sensitization and airway inflammation by allergen-specific tolerance induction in the offspring.

[Nephropathia epidemica caused by Puumala hantavirus infection: a case report from the outpatient sector]. / Nephropathia epidemica durch Hantavirus-Infektion vom Puumala-Typ: Ein Fallbericht aus dem ambulanten Sektor.

HISTORY AND ADMISSION FINDINGS: A 42-year-old man without pre-existing health problems presented to his family practitioner in Baden-Württemberg with fever (up to 39˚ C for two days), headache, abdominal pain, back pain and aching limbs. Ten days before, he had done heavy gardening work. He felt diffuse pain on abdominal palpation. The physical examination of the skin, lymph nodes, the heart, the lungs and the oral mucosa was unremarkable. INVESTIGATIONS AND DIAGNOSIS: Erythrocytes, leukocytes and sporadic bacteria were found in the urine. Urine test strip analysis gave a threefold positive result for protein. The blood test revealed in an elevated C-reactive protein, leukocytosis, elevated creatinine and thrombocytopenia. Enlarged kidneys and an enlarged spleen were found on ultra sound examination. IgG and IgM tested for Hantavirus infection were detected by IFA (Immunofluorescence antibody assay) and by ELISA (enzyme-linked immunosorbent assay). TREATMENT AND COURSE: The blood tests had returned to normal by 15 days after onset of the fever which had persisted for 7 days. Oliguria and/or anuria did not occur. After three weeks of illness, the blood pressure was found to be at hypertensive levels and the patient was treated with antihypertensive drugs. CONCLUSION: A history of gardening work (exposure to rodents) and nonspecific symptoms (like headache and fever), in combination with elevated serum creatinine and thrombocytopenia, should raise the suspicion of nephropathia epidemica (hemorrhagic fever with renal syndrome) caused by hantavirus infection. As sequelae of hantavirus infection may persist, patients should subsequently be followed for clinical and laboratory evidence of renal disease. Hospitalization is not generally warranted.

Multiple enzyme activities of flavivirus proteins.

Dengue viruses (DENV) have 5'-capped RNA genomes of (+) polarity and encode a single polyprotein precursor that is processed into mature viral proteins. NS2B, NS3 and NS5 proteins catalyse/activate enzyme activities that are required for key processes in the virus life cycle. The heterodimeric NS2B/NS3 is a serine protease required for processing. Using a high-throughput protease assay, we screened a small molecule chemical library and identified -200 compounds having > or = 50% inhibition. Moreover, NS3 exhibits RNA-stimulated NTPase, RNA helicase and the 5'-RNA triphosphatase activities. The NTPase and the 5'-RTPase activities of NS3 are stimulated by interaction with NS5. Moreover, the conserved, positively charged motif in DENV-2 NS3, 184RKRK, is required for RNA binding and modulates the RNA-dependent enzyme activities of NS3. To study viral replication, a variety of methods are used such as the in vitro RNA-dependent RNA polymerase assays that utilize lysates from DENV-2-infected mosquito or mammalian cells or the purified NS5 along with exogenous short subgenomic viral RNAs or the replicative intracellular membrane-bound viral RNAs as templates. In addition, a cell-based DENV-2 replicon RNA encoding a luciferase reporter is also used to examine the role of cis-acting elements within the 3' UTR and the RKRK motif in viral replication.

International conferences on violence against women.

Violence against women has been written about as an international health issue. Since 1975 international conferences and organizations have addressed the problems. The resulting resolutions requested that measures be taken to eliminate violence against women.

Significant enhanced superoxide anion (O2-) production in vitro by peripheral blood monocytes of lepromatous leprosy patients stimulated with liposome and suppression by C-reactive protein (CRP).

Peripheral blood monocytes (PBM) from normal individuals, infectious mononucleosis (IM) and leprosy patients were stimulated with liposome. The mean and standard error of superoxide anion (O2-) generated in nm/1.5 X 10(5) PBM/well for 5 normal subjects and 3 IM patients was 2.9 +/- 0.5 and 3.1 +/- 0.2, respectively. Monocytes stimulated with 100 ng C-reactive protein (CRP) incorporated into liposome gave values of 3.3 +/- 0.3 and 2.7 +/- 0.1 nm O-2/1.5 X 10(5) PBM/well for normals and IM, respectively. No significant differences in O2- production between liposome and liposome with incorporated CRP were shown. PBM from lepromatous patients demonstrated a significant (p less than 0.01) increase in O2- production with liposome alone compared with tuberculoid patients (3.5 +/- 0.4 vs 1.8 +/- 0.3). The most dramatic suppression of O2- shown when purified CRP was added to the mixtures in all groups examined [0.4 +/- 0.1 (500 ng), 0.3 +/- 0.0 (500 ng), 1.5 +/- 0.1 (100 ng), and 1.3 +/- 0.6 (100 ng) nm O2-/1.5 X 10(5) PBM/well for normals, IM, lepromatous, and tuberculoid, respectively]. Results of O2- formation with incorporation of CRP into liposome as compared with liposome alone had no significant effect on PBM of lepromatous or tuberculoid patients. It is suggested that CRP may play a significant role in regulation of oxygen free radicals formed during acute and chronic inflammatory episides.

Relationship of sodium bicarbonate to intraventricular hemorrhage in premature infants with respiratory distress syndrome.

It has been suggested that hypertonic loads of saline built up in the administration of sodium bicarbonate to correct acidosis in infants with respiratory distress syndrome (IRDS) can precipitate intraventricular hemorrhage (IVH). Therefore, from medical records we noted the daily intake of sodium of 36 babies with IRDS who were on mechanical respirators. Eighteen of the infants developed IVH, and for these infants total sodium intake 24 hours prior to IVH was also recorded. The mean was 5.83 +/- 4.22 mEq/kg per day, a dose substantially less than the recommended limit of 8 mEq/kg per day. The difference between means was not significant (p = .071), but the variance was significant (p = .016). The results indicated that the total sodium dose, particularly that taken in during the sodium bicarbonate administration, did not regularly contribute to the development of IVH, when given under controlled conditions, that is, conservative doses, dilution, and slow injection to minimize the hypertonic load.

Clinical findings in workers exposed to pentachlorophenol.

Comparative findings are presented on the health and exposure status of groups of individuals in Hawaii with and without occupational exposure to pentachlorophenol (PCP). Occupational exposure to PCP occurred through employment at firms engaged in the treatment of wood with either PCP alone or PCP plus other compounds as preservative chemicals. Mean serum levels were 0.32 ppm for 32 control individuals, 1.72 ppm for 24 workers exposed to PCP and other wood preservative chemicals, and 3.78 ppm for 22 workers exposed to PCP as the sole preservative chemical. Age-standardized prevalence rates were significantly higher among the PCP-exposed than among the controls for low-grade infections or inflammations of the skin and subcutaneous tissue, protective membrane of the eyes and the mucosa membrane of the upper respiratory tract. Strong to moderate statistical associations were observed between PCP exposure and increased occurrence of bands (immature leucocytes) and basophils, increased plasma cholinesterase, alkaline phosphatase, gamma globulin and uric acid, and decreased serum calcium. Despite these statistical associations, laboratory values considered to be clinically abnormal were few and not significantly greater in occurrence among the PCP-exposed individuals.

Five cases of intentional ingestion of 25 percent diazinon with treatment and recovery.

The use of atropine to block the effects of acetylcholine and pralidoxime chloride to restore cholinesterase in the blood, along with supportative therapy, intravenous fluids, and oxygen, prevented death in five cases of intentional ingestion of 25% diazinon. Treatment of such cases must be tailored to the condition of the patient, and all residual poison in the stomach must be removed as rapidly as possible with gastric lavage to prevent absorption of the poison.

[Type distribution of hyperlipoproteinemias in 645 diabetics]. / Die Typenverteilung der Hyperlipoproteinämien bei 645 Diabetikern.

On 645 diabetics of the treatment-groups diet (n = 180), sulfonylurea therapy (n = 250), biguanide therapy (n = 50), and insulin therapy (n = 165) the concentrations of cholesterol and triglyceride were determined and the lipoprotein electrophoresis was carried out. 29% of the diabetics showed hyperliproteinaemias, males and females in the same frequency. In about 54% the type IV was observed most frequently, then followed the types IIb with 25% and the type IIa with about 13%. The dependence of triglycerides on the metabolic situation and the body weight was proved in diabetics. The cholesterol values were independent on form of therapy, body weight and metabolic situation. In the group with sulfonylurea in about 49%, in the group with insulin in about 37% and in the group with diet and buformin only in about 32% a hyperlipoproteinaemia was proved. The opinion is represented that the high percentage of hyperlipoproteinaemia in diabetics and the connected with this additionally increased risk for vascular complications should lead to the introduction of diagnostics and therapy of hyperlipoproteinaemia into the programme of the diabetes dispensaries of the GDR. For the treatment of diabetes the principle should be taken into consideration that a diabetes is optimally regulated only then, when apart from the blood sugar values also the blood fats are within the normal.

Results of the single-radial-diffusion test with formaldehyde-treated influenza virus.

We found reduced values for formaldehyde-treated influenza virus in the single-radial-diffusion test by comparison with non-treated virus. The reduction correlates with the formaldehyde concentration. Hemagglutination and neuraminidase activities were not affected by the same treatment. We therefore suggest that this reduction is not based on antigen destruction.

Association between renal function tests and pentachlorophenol exposure.

Data are presented and renal function tests and Pcp measurements on consecutive blood and urine samples collected from 18 workers at a wood treatment plant before, during, and after a 20-day vacation. Pcp concentrations in blood averaging 5.1 ppm before vacation fell to 2.2 ppm during vacation but with a temporary rise early in this nonexposure period, suggesting a body tissues store of Pcp which was mobilized in response to a negative Pcp balance. Urine Pcp concentrations showed similar but less marked variations. Creatinine clearance and phosphorus reabsorption values were depressed before vacation but showed significant improvement during vacation, suggesting that Pcp exposure reduced both glomerular filtration rate and tubular function, with recovery following a nonexposure period.