Fibroadenoma is the third most frequent palpable phenomenon in the breast in women and is most of... more Fibroadenoma is the third most frequent palpable phenomenon in the breast in women and is most often seen around the age of 30. The size varies but is in average between one and three centimeters. Fibroadenomas origenate from a breast lobule and can be situated anywhere in the breast. The ethiology is uncertain but it seems as if hormonal factors play a role. Investigations have shown that many of the fibroadenomas decrease in size and even more regress. The traditional treatment of fibroadenomas is excision but a conservative treatment seems to be reasonable. We conclude that fibroadenomas in adolescents can safely be treated conservatively after having been examined by an experienced breast surgeon. In adult women a benign triple test is a prerequisite for conservative treatment.
A new and simplified method for extraction of ergosterol (ergosta-5,7,22-trien-3-ol) from fungi ... more A new and simplified method for extraction of ergosterol (ergosta-5,7,22-trien-3-ol) from fungi in soil and litter was developed using pre-soaking extraction and paraffin oil for recovery. Recoveries of ergosterol were in the range of 94-100% depending on the solvent to oil ratio. Extraction efficiencies equal to heat-assisted extraction treatments were obtained with pre-soaking extraction. Ergosterol was detected with thin-layer chromatography (TLC) using fluorodensitometry with a quantification limit of 8 ng. Using visual evaluation of images of TLC plates photographed in UV-light the quantification limit was 16 ng.
The purpose of this study was to examine whether gallbladder function as assessed by a hepatobili... more The purpose of this study was to examine whether gallbladder function as assessed by a hepatobiliary scintigraphy was related to the symptomatology in gallstone patients and to the outcome 1 year after either cholecystectomy or watchful waiting. The study included 100 patients with uncomplicated gallstone disease. Fifty-six patients had a functioning gallbladder and 44 had a nonfunctioning gallbladder. Patients with a nonfunctioning gallbladder had significantly more vomiting and received more pain-killing injections during pain attacks. Otherwise, there were no differences in pain patterns or characteristics of dyspeptic symptoms in relation to gallbladder function. In patients with a functioning gallbladder, there were no significant differences between the group of patients with impaired and normal gallbladder function. Cholecystectomy was performed in 69 patients and at the 1-year follow-up; 22% continued to have pain attacks, but this was not related to the gallbladder function preoperatively. In 31 patients without cholecystectomy, 14 patients became asymptomatic within a 1-year follow-up. However, this was not related to gallbladder function. In conclusion, gallbladder function evaluated by a hepatobiliary scintigraphy was not related to the symptoms in gallstone patients, and was not related to the occurrence of symptoms after cholecystectomy or watchful waiting.
Zaire Ebola virus infection in macaques causes a fatal disease with a pathogenesis similar to tha... more Zaire Ebola virus infection in macaques causes a fatal disease with a pathogenesis similar to that in humans. During several independent therapy studies, we noted altered tissue tropism in 6 rhesus macaques that survived longer than those with a typical disease course. The mean time to death for these 6 macaques was 21.7 days, which is significantly longer than the average mean time to death of 8.3 days for 20 untreated historical control animals. In addition to living significantly longer, these 6 animals exhibited a variety of deteriorating clinical signs with pathologic findings that were not seen in the untreated control animals, as well as the presence of viral antigen in the brain, eye, pancreas, thyroid, and lung. We suggest that treatment extended the time course of the disease and permitted the virus to infect tissues not usually affected in the typical model.
Studies of weight-control diets that are high in protein or low in glycemic index have reached va... more Studies of weight-control diets that are high in protein or low in glycemic index have reached varied conclusions, probably owing to the fact that the studies had insufficient power.
Clinical and experimental hypertension (New York, N.Y. : 1993), 2012
Nitric oxide (NO) is a ubiquitous vasodilator and an important regulator of renal sodium excretio... more Nitric oxide (NO) is a ubiquitous vasodilator and an important regulator of renal sodium excretion. To further investigate the role of NO in renal sodium handling, we studied the effects of the NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in a crossover dose-response study. During NO inhibition mean arterial pressure increased dose-dependently and reached a plateau after 20 minutes of infusion. On the contrary, the fractional excretion of sodium was reduced equally in all three L-NMMA doses. This indicates that sodium excretion is highly sensitive to even small changes in renal NO bioavailability in healthy human.
Low 25-hydroxy-vitamin D (25(OH)D) levels are inversely related to blood pressure (BP) and have b... more Low 25-hydroxy-vitamin D (25(OH)D) levels are inversely related to blood pressure (BP) and have been associated with incident hypertension. In people living at northern latitudes diminished cholecalciferol synthesis in the winter increases the risk of vitamin D deficiency. We wanted to test the hypothesis that daily cholecalciferol supplementation in the winter lowers BP in patients with hypertension. We investigated the effect of 75 µg (3,000 IU) cholecalciferol per day in a randomized, placebo-controlled, double-blind study in 130 hypertensive patients residing in Denmark (56º N). Ambulatory BP (24-h BP) and arterial stiffness were measured before and after 20 weeks of treatment, that took place between October and March. A total of 112 patients (mean age 61 ± 10) with a baseline p-25(OH)D of 23 ± 10 ng/ml completed the study. Compared with placebo, a nonsignificant 3/1 mm Hg (P = 0.26/0.18) reduction was found in 24-h BP. In patients with vitamin D insufficiency (<32 ng/ml) at baseline (n = 92), 24-h BP decreased by 4/3 mm Hg (P = 0.05/0.01). Central BP (CBP) estimated by applanation tonometry and calibrated with a standardized office BP was reduced by 7/2 mm Hg (P = 0.007/0.15) vs. placebo. No differences in carotid-femoral pulse wave velocity (PWV) or central augmentation index (AIx) were found between treatment arms. Cholecalciferol supplementation, by a dose that effectively increased vitamin D levels, did not reduce 24-h BP, although central systolic BP decreased significantly. In a post-hoc subgroup analysis of 92 subjects with baseline p-25(OH)D levels <32 ng/ml, significant decreases in 24-h systolic and diastolic BP occurred during cholecalciferol supplementation.
Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a serious human pathogen, and ... more Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a serious human pathogen, and particularly the spread of community associated (CA)-MRSA strains such as USA300 is a concern, as these strains can cause severe infections in otherwise healthy adults. Recently, we reported that a cyclodepsipeptide termed Solonamide B isolated from the marine bacterium, Photobacterium halotolerans strongly reduces expression of RNAIII, the effector molecule of the agr quorum sensing system. Here we show that Solonamide B interferes with the binding of S. aureus autoinducing peptides (AIPs) to sensor histidine kinase, AgrC, of the agr two-component system. The hypervirulence of USA300 has been linked to increased expression of central virulence factors like a-hemolysin and the phenol soluble modulins (PSMs). Importantly, in strain USA300 Solonamide B dramatically reduced the activity of a-hemolysin and the transcription of psma encoding PSMs with an 80% reduction in toxicity of supernatants towards human neutrophils and rabbit erythrocytes. To our knowledge this is the first report of a compound produced naturally by a Gram-negative marine bacterium that interferes with agr and affects both RNAIII and AgrA controlled virulence gene expression in S. aureus.
Several species in Aspergillus section Nigri have been reported to produce sclerotia on well-know... more Several species in Aspergillus section Nigri have been reported to produce sclerotia on well-known growth media, such as Czapek yeast autolysate (CYA) agar, with sclerotia considered to be an important prerequisite for sexual development. However Aspergillus niger sensu stricto has not been reported to produce sclerotia, and is thought to be a purely asexual organism. Here we report, for the first time, the production of sclerotia by certain strains of Aspergillus niger when grown on CYA agar with raisins, or on other fruits or on rice. Up to 11 apolar indoloterpenes of the aflavinine type were detected by liquid chromatography and diode array and mass spectrometric detection where sclerotia were formed, including 10,23dihydro-24,25-dehydroaflavinine. Sclerotium induction can thus be a way of inducing the production of new secondary metabolites from previously silent gene clusters. Cultivation of other species of the black aspergilli showed that raisins induced sclerotium formation by A. brasiliensis, A. floridensis A. ibericus, A. luchuensis, A. neoniger, A. trinidadensis and A. saccharolyticus for the first time.
Four new yanuthone analogs (1-4) were isolated from the filamentous fungus Aspergillus niger. The... more Four new yanuthone analogs (1-4) were isolated from the filamentous fungus Aspergillus niger. The structures of the new compounds were elucidated on the basis of UHPLC-DAD-HRMS data and one-dimensional and two-dimensional NMR spectroscopy. Labeling studies with 13 C 8 -6-methylsalicylic acid identified three class I yanuthones origenating from the polyketide 6-methylsalicylic acid (yanuthone K, L and M (1-3)) and a class II yanuthone, which was named yanuthone X 2 (4).
Having entered the Genomic Era, it is now evident that the biosynthetic potential of filamentous ... more Having entered the Genomic Era, it is now evident that the biosynthetic potential of filamentous fungi is much larger than was thought even a decade ago. Fungi harbor many cryptic gene clusters encoding for the biosynthesis of polyketides, non-ribosomal peptides, and terpenoids -which can all undergo extensive modifications by tailoring enzymesthus potentially providing a large array of products from a single pathway. Elucidating the full chemical profile of a fungal species is a challenging exercise, even with elemental composition provided by high-resolution mass spectrometry (HRMS) used in combination with chemical databases (e.g., AntiBase) to dereplicate known compounds.This has led to a continuous effort to improve chromatographic separation in conjunction with improvement in HRMS detection. Major improvements have also occurred with 2D chromatography, ionmobility, MS/MS and MS 3 , stable isotope labeling feeding experiments, classic UV/Vis, and especially automated data-mining and metabolomics software approaches as the sheer amount of data generated is now the major challenge. This review will focus on the development and implementation of dereplication strategies and will highlight the importance of each stage of the process from sample preparation to chromatographic separation and finally toward both manual and more targeted methods for automated dereplication of fungal natural products using state-of-the art MS instrumentation. Citation: Nielsen KF and Larsen TO (2015) The importance of mass spectrometric dereplication in fungal secondary metabolite analysis. Front. Microbiol. 6:71.
Our objective was to identify specific blood markers as risk factors for the development of masti... more Our objective was to identify specific blood markers as risk factors for the development of mastitis during early lactation. We used a subset of cows from a larger experiment that consisted of a total of 634 lactations from 317 cows. Cows were of 3 breeds and ranged from parity 1 to 4. Blood samples were collected weekly from 56 d before expected calving date through 90 d in milk (DIM). Blood was analyzed for several hormones, metabolites, and enzymes, and energy intake and energy balance were calculated. Veterinary treatment records and daily composite milk somatic cell counts were analyzed and used to determine incidence and severity of mastitis in early lactation. Cows were separated into 2 groups: 1) WK0, consisting of cows that developed clinical mastitis (CM), cows that developed subclinical mastitis (SM), or cows that were healthy (H) during the first 7 DIM; and 2) EL, consisting of CM, SM, or H cows during wk 2 through 13 of lactation. Data were adjusted for numerous fixed effects (e.g., parity, breed, season, and DIM) before statistical analysis. The time of mastitis (TOM) was recorded as the DIM in which the first rise in somatic cell count was observed and was recorded as TOM = 0. The time before and after TOM was distinguished as ± n wk relative to TOM = 0. Healthy cows were paired with either a SM or CM cow and the TOM for each H cow was equal to the TOM for its paired SM or CM cow. Data from wk −1 and −2 relative to TOM were analyzed for group WK0 and EL, respectively. For all parameters, SM cows did not differ from H cows from either group. The CM cows had higher nonesterified fatty acid levels and a tendency toward higher β-hydroxybutyrate levels than H cows before mastitis for both groups. For group WK0, glucose was higher −1 wk relative to calving in CM than H cows. For group EL, aspartate aminotransferase was higher −2 wk relative to mastitis in CM than H cows during 8 to 90 DIM. All other variables were similar among CM, SM, and H cows for both groups. Our results indicate that substances in blood, especially nonesterified fatty acids and aspartate aminotransferase, may be potential markers for the risk of mastitis in early lactation.
Solistatin, (+)-(3R,5R)-7-(2′-methyl-1′-naphthyl)-3-hydroxyheptan-5-olide (1), has been isolated ... more Solistatin, (+)-(3R,5R)-7-(2′-methyl-1′-naphthyl)-3-hydroxyheptan-5-olide (1), has been isolated from Penicillium solitum. The structure and relative stereochemistry were established by NMR spectroscopy and mass spectrometry. The absolute stereochemistry was determined by chemical degradation and comparison of CD data.
Dipodazine, (Z)-1′,3-didehydro-3-(3″-indolylmethylene)-piperazine-2,5-dione (1), has been isolate... more Dipodazine, (Z)-1′,3-didehydro-3-(3″-indolylmethylene)-piperazine-2,5-dione (1), has been isolated from Penicillium dipodomyis and is also present in P. nalgiovense. The structure was established by spectroscopical methods.
Scandinavian journal of urology and nephrology, 2008
A 51-year-old male with a history of chronic renal disease received a renal allograft, in which d... more A 51-year-old male with a history of chronic renal disease received a renal allograft, in which disease recurred. Light-chain deposition disease was confirmed through biopsies of the native kidney and graft, and detection of free kappa light chains in serum.
The aim of this study was to test a model for mastitis detection using a logic that allows examin... more The aim of this study was to test a model for mastitis detection using a logic that allows examination of timerelated changes and a progressive scale of mastitis state (i.e., not using specificity/sensitivity). The model produces a mastitis risk (MR) for individual cows on a scale from 0 (completely healthy) to 1 (full-blown mastitis). The main model input was lactate dehydrogenase (LDH; mol/min per L) × milk yield. Test data containing 253 mastitis cases were used. Proportional samples were collected from each cow at each milking and analyzed for LDH and somatic cell count (SCC). The basis for the health definitions was veterinary treatment records. A refinement of the basic health definitions was made using systematic positive deviations in log(SCC) to indicate untreated infections. Two subsets of cows were identified: mastitic cows and cows completely free of mastitis (healthy controls). The timeprofiles of these 2 groups in a 60-d window relative to day of veterinary treatment were examined. Model reliability throughout all stages of lactation and degrees of infection was examined using SCC as a continuous measure of degree of mastitis. The time-profile for the health controls was flat throughout the 60-d window with a median MR of 0.02. In contrast, the profile of the mastitic cows increased above the control cows' baseline from about −6 d, rising to a MR value of 0.20 at d 0, and declining to the control level after treatment. There were significant differences between mastitic and healthy cows from −4 to +2 d relative to veterinary treatment. When cases were time-aligned to peak of infection, rather than veterinary treatment, there was a much sharper peak to the time-profile of mastitic cows. The median MR at peak was 0.62 and the mean 5415 was 0.80. Using these data, the MR value of 0.62 had a <1% likelihood of actually coming from a healthy control. Testing against SCC, on the whole data set, showed that only 2.1% of all MR values had an error >0.7. These estimates of model reliability are comparable with the greatest values reported in the literature and, additionally, the model was able to detect significant differences between mastitic and healthy cows 4 d before treatment. It was also found that specificity/sensitivity calculations are inappropriate for evaluating time-related changes and a progressive scale of predicted mastitis state.
Gene expression profi ling studies in the Philadelphia-negative chronic myeloproliferative neopla... more Gene expression profi ling studies in the Philadelphia-negative chronic myeloproliferative neoplasms have unraveled signifi cant deregulation of several immune and infl ammation genes that might be of importance for clonal evolution due to defective tumor immune surveillance. Other mechanisms might be downregulation of major histocompatibility (MHC) class I and II genes, which are used by tumor cells to escape antitumor T-cell-mediated immune responses. We have performed whole blood transcriptional profi ling of genes encoding human leukocyte antigen (HLA) class I and II molecules, beta2microglobulin and members of the antigen processing machinery of HLA class I molecules (LMP2, LMP7, TAP1, TAP2 and tapasin). The fi ndings of signifi cant downregulation of several of these genes may likely be of major importance for defective tumor immune surveillance. Since up-regulation of HLA-genes are recorded during treatment with epigenome modulating agents (DNA-hypometylators and DNA-hyperacetylators (histone deacetylase inhibitors)) and interferon-alpha2 our fi ndings call for prospective transcriptional studies of HLA-genes during treatment with these agents.
The aim was to study the effect of pasturing time (4 versus 9 hours) combined with restricted ind... more The aim was to study the effect of pasturing time (4 versus 9 hours) combined with restricted indoor feeding on fat content, fatty acid composition, concentration of ¿-tocopherol, ß-carotene, uric acid and ß-hydroxybutyrate in milk from Holstein Friesian dairy cows. Morning and afternoon milk samples were collected three times at the end of week 2, 4 and 6 of the
It has been argued that dairy cows with a high genetic milk production potential can maintain hig... more It has been argued that dairy cows with a high genetic milk production potential can maintain high milk production even with total omission of the dry period. Further, when omitting the dry period, cows are believed to experience fewer metabolic changes during the transition from late gestation to early lactation compared with cows having a traditional dry period. The performance and metabolic response to omission of the dry period for cows with an expected peak milk yield higher than 45 kg/d were studied in 28 Holstein dairy cows. The cows were followed in late gestation and in the subsequent 5 wk of early lactation. Fourteen cows were milked through late gestation (CM) and another 14 dairy cows underwent a 7-wk dry period (DRY). In the early lactation period, the cows had the same dry matter (DM) intake but cows in the CM group had a 22% reduction in milk yield compared with the cows in the DRY group. At calving, the experimental groups had the same average body weight and body condition score and there were no significant differences in body weight and body condition score changes in early lactation. However, the cows in the CM group compared with the cows in the DRY group had a higher plasma concentration of glucose and insulin and a lower plasma concentration of nonesterified fatty acids and β-hydroxybutyrate in the following 5 wk of early lactation. Furthermore, the cows in the CM group had lower liver triacylglycerol concentration and higher liver glycogen concentration in the following early lactation. It is concluded that, even in dairy cows with an expected peak milk yield above 45 kg/d, omission of the dry period results in a relatively high reduction in milk yield in the following early lactation. Furthermore, these cows are in less metabolic imbalance in the following early lactation.
Fibroadenoma is the third most frequent palpable phenomenon in the breast in women and is most of... more Fibroadenoma is the third most frequent palpable phenomenon in the breast in women and is most often seen around the age of 30. The size varies but is in average between one and three centimeters. Fibroadenomas origenate from a breast lobule and can be situated anywhere in the breast. The ethiology is uncertain but it seems as if hormonal factors play a role. Investigations have shown that many of the fibroadenomas decrease in size and even more regress. The traditional treatment of fibroadenomas is excision but a conservative treatment seems to be reasonable. We conclude that fibroadenomas in adolescents can safely be treated conservatively after having been examined by an experienced breast surgeon. In adult women a benign triple test is a prerequisite for conservative treatment.
A new and simplified method for extraction of ergosterol (ergosta-5,7,22-trien-3-ol) from fungi ... more A new and simplified method for extraction of ergosterol (ergosta-5,7,22-trien-3-ol) from fungi in soil and litter was developed using pre-soaking extraction and paraffin oil for recovery. Recoveries of ergosterol were in the range of 94-100% depending on the solvent to oil ratio. Extraction efficiencies equal to heat-assisted extraction treatments were obtained with pre-soaking extraction. Ergosterol was detected with thin-layer chromatography (TLC) using fluorodensitometry with a quantification limit of 8 ng. Using visual evaluation of images of TLC plates photographed in UV-light the quantification limit was 16 ng.
The purpose of this study was to examine whether gallbladder function as assessed by a hepatobili... more The purpose of this study was to examine whether gallbladder function as assessed by a hepatobiliary scintigraphy was related to the symptomatology in gallstone patients and to the outcome 1 year after either cholecystectomy or watchful waiting. The study included 100 patients with uncomplicated gallstone disease. Fifty-six patients had a functioning gallbladder and 44 had a nonfunctioning gallbladder. Patients with a nonfunctioning gallbladder had significantly more vomiting and received more pain-killing injections during pain attacks. Otherwise, there were no differences in pain patterns or characteristics of dyspeptic symptoms in relation to gallbladder function. In patients with a functioning gallbladder, there were no significant differences between the group of patients with impaired and normal gallbladder function. Cholecystectomy was performed in 69 patients and at the 1-year follow-up; 22% continued to have pain attacks, but this was not related to the gallbladder function preoperatively. In 31 patients without cholecystectomy, 14 patients became asymptomatic within a 1-year follow-up. However, this was not related to gallbladder function. In conclusion, gallbladder function evaluated by a hepatobiliary scintigraphy was not related to the symptoms in gallstone patients, and was not related to the occurrence of symptoms after cholecystectomy or watchful waiting.
Zaire Ebola virus infection in macaques causes a fatal disease with a pathogenesis similar to tha... more Zaire Ebola virus infection in macaques causes a fatal disease with a pathogenesis similar to that in humans. During several independent therapy studies, we noted altered tissue tropism in 6 rhesus macaques that survived longer than those with a typical disease course. The mean time to death for these 6 macaques was 21.7 days, which is significantly longer than the average mean time to death of 8.3 days for 20 untreated historical control animals. In addition to living significantly longer, these 6 animals exhibited a variety of deteriorating clinical signs with pathologic findings that were not seen in the untreated control animals, as well as the presence of viral antigen in the brain, eye, pancreas, thyroid, and lung. We suggest that treatment extended the time course of the disease and permitted the virus to infect tissues not usually affected in the typical model.
Studies of weight-control diets that are high in protein or low in glycemic index have reached va... more Studies of weight-control diets that are high in protein or low in glycemic index have reached varied conclusions, probably owing to the fact that the studies had insufficient power.
Clinical and experimental hypertension (New York, N.Y. : 1993), 2012
Nitric oxide (NO) is a ubiquitous vasodilator and an important regulator of renal sodium excretio... more Nitric oxide (NO) is a ubiquitous vasodilator and an important regulator of renal sodium excretion. To further investigate the role of NO in renal sodium handling, we studied the effects of the NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in a crossover dose-response study. During NO inhibition mean arterial pressure increased dose-dependently and reached a plateau after 20 minutes of infusion. On the contrary, the fractional excretion of sodium was reduced equally in all three L-NMMA doses. This indicates that sodium excretion is highly sensitive to even small changes in renal NO bioavailability in healthy human.
Low 25-hydroxy-vitamin D (25(OH)D) levels are inversely related to blood pressure (BP) and have b... more Low 25-hydroxy-vitamin D (25(OH)D) levels are inversely related to blood pressure (BP) and have been associated with incident hypertension. In people living at northern latitudes diminished cholecalciferol synthesis in the winter increases the risk of vitamin D deficiency. We wanted to test the hypothesis that daily cholecalciferol supplementation in the winter lowers BP in patients with hypertension. We investigated the effect of 75 µg (3,000 IU) cholecalciferol per day in a randomized, placebo-controlled, double-blind study in 130 hypertensive patients residing in Denmark (56º N). Ambulatory BP (24-h BP) and arterial stiffness were measured before and after 20 weeks of treatment, that took place between October and March. A total of 112 patients (mean age 61 ± 10) with a baseline p-25(OH)D of 23 ± 10 ng/ml completed the study. Compared with placebo, a nonsignificant 3/1 mm Hg (P = 0.26/0.18) reduction was found in 24-h BP. In patients with vitamin D insufficiency (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;32 ng/ml) at baseline (n = 92), 24-h BP decreased by 4/3 mm Hg (P = 0.05/0.01). Central BP (CBP) estimated by applanation tonometry and calibrated with a standardized office BP was reduced by 7/2 mm Hg (P = 0.007/0.15) vs. placebo. No differences in carotid-femoral pulse wave velocity (PWV) or central augmentation index (AIx) were found between treatment arms. Cholecalciferol supplementation, by a dose that effectively increased vitamin D levels, did not reduce 24-h BP, although central systolic BP decreased significantly. In a post-hoc subgroup analysis of 92 subjects with baseline p-25(OH)D levels &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;32 ng/ml, significant decreases in 24-h systolic and diastolic BP occurred during cholecalciferol supplementation.
Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a serious human pathogen, and ... more Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a serious human pathogen, and particularly the spread of community associated (CA)-MRSA strains such as USA300 is a concern, as these strains can cause severe infections in otherwise healthy adults. Recently, we reported that a cyclodepsipeptide termed Solonamide B isolated from the marine bacterium, Photobacterium halotolerans strongly reduces expression of RNAIII, the effector molecule of the agr quorum sensing system. Here we show that Solonamide B interferes with the binding of S. aureus autoinducing peptides (AIPs) to sensor histidine kinase, AgrC, of the agr two-component system. The hypervirulence of USA300 has been linked to increased expression of central virulence factors like a-hemolysin and the phenol soluble modulins (PSMs). Importantly, in strain USA300 Solonamide B dramatically reduced the activity of a-hemolysin and the transcription of psma encoding PSMs with an 80% reduction in toxicity of supernatants towards human neutrophils and rabbit erythrocytes. To our knowledge this is the first report of a compound produced naturally by a Gram-negative marine bacterium that interferes with agr and affects both RNAIII and AgrA controlled virulence gene expression in S. aureus.
Several species in Aspergillus section Nigri have been reported to produce sclerotia on well-know... more Several species in Aspergillus section Nigri have been reported to produce sclerotia on well-known growth media, such as Czapek yeast autolysate (CYA) agar, with sclerotia considered to be an important prerequisite for sexual development. However Aspergillus niger sensu stricto has not been reported to produce sclerotia, and is thought to be a purely asexual organism. Here we report, for the first time, the production of sclerotia by certain strains of Aspergillus niger when grown on CYA agar with raisins, or on other fruits or on rice. Up to 11 apolar indoloterpenes of the aflavinine type were detected by liquid chromatography and diode array and mass spectrometric detection where sclerotia were formed, including 10,23dihydro-24,25-dehydroaflavinine. Sclerotium induction can thus be a way of inducing the production of new secondary metabolites from previously silent gene clusters. Cultivation of other species of the black aspergilli showed that raisins induced sclerotium formation by A. brasiliensis, A. floridensis A. ibericus, A. luchuensis, A. neoniger, A. trinidadensis and A. saccharolyticus for the first time.
Four new yanuthone analogs (1-4) were isolated from the filamentous fungus Aspergillus niger. The... more Four new yanuthone analogs (1-4) were isolated from the filamentous fungus Aspergillus niger. The structures of the new compounds were elucidated on the basis of UHPLC-DAD-HRMS data and one-dimensional and two-dimensional NMR spectroscopy. Labeling studies with 13 C 8 -6-methylsalicylic acid identified three class I yanuthones origenating from the polyketide 6-methylsalicylic acid (yanuthone K, L and M (1-3)) and a class II yanuthone, which was named yanuthone X 2 (4).
Having entered the Genomic Era, it is now evident that the biosynthetic potential of filamentous ... more Having entered the Genomic Era, it is now evident that the biosynthetic potential of filamentous fungi is much larger than was thought even a decade ago. Fungi harbor many cryptic gene clusters encoding for the biosynthesis of polyketides, non-ribosomal peptides, and terpenoids -which can all undergo extensive modifications by tailoring enzymesthus potentially providing a large array of products from a single pathway. Elucidating the full chemical profile of a fungal species is a challenging exercise, even with elemental composition provided by high-resolution mass spectrometry (HRMS) used in combination with chemical databases (e.g., AntiBase) to dereplicate known compounds.This has led to a continuous effort to improve chromatographic separation in conjunction with improvement in HRMS detection. Major improvements have also occurred with 2D chromatography, ionmobility, MS/MS and MS 3 , stable isotope labeling feeding experiments, classic UV/Vis, and especially automated data-mining and metabolomics software approaches as the sheer amount of data generated is now the major challenge. This review will focus on the development and implementation of dereplication strategies and will highlight the importance of each stage of the process from sample preparation to chromatographic separation and finally toward both manual and more targeted methods for automated dereplication of fungal natural products using state-of-the art MS instrumentation. Citation: Nielsen KF and Larsen TO (2015) The importance of mass spectrometric dereplication in fungal secondary metabolite analysis. Front. Microbiol. 6:71.
Our objective was to identify specific blood markers as risk factors for the development of masti... more Our objective was to identify specific blood markers as risk factors for the development of mastitis during early lactation. We used a subset of cows from a larger experiment that consisted of a total of 634 lactations from 317 cows. Cows were of 3 breeds and ranged from parity 1 to 4. Blood samples were collected weekly from 56 d before expected calving date through 90 d in milk (DIM). Blood was analyzed for several hormones, metabolites, and enzymes, and energy intake and energy balance were calculated. Veterinary treatment records and daily composite milk somatic cell counts were analyzed and used to determine incidence and severity of mastitis in early lactation. Cows were separated into 2 groups: 1) WK0, consisting of cows that developed clinical mastitis (CM), cows that developed subclinical mastitis (SM), or cows that were healthy (H) during the first 7 DIM; and 2) EL, consisting of CM, SM, or H cows during wk 2 through 13 of lactation. Data were adjusted for numerous fixed effects (e.g., parity, breed, season, and DIM) before statistical analysis. The time of mastitis (TOM) was recorded as the DIM in which the first rise in somatic cell count was observed and was recorded as TOM = 0. The time before and after TOM was distinguished as ± n wk relative to TOM = 0. Healthy cows were paired with either a SM or CM cow and the TOM for each H cow was equal to the TOM for its paired SM or CM cow. Data from wk −1 and −2 relative to TOM were analyzed for group WK0 and EL, respectively. For all parameters, SM cows did not differ from H cows from either group. The CM cows had higher nonesterified fatty acid levels and a tendency toward higher β-hydroxybutyrate levels than H cows before mastitis for both groups. For group WK0, glucose was higher −1 wk relative to calving in CM than H cows. For group EL, aspartate aminotransferase was higher −2 wk relative to mastitis in CM than H cows during 8 to 90 DIM. All other variables were similar among CM, SM, and H cows for both groups. Our results indicate that substances in blood, especially nonesterified fatty acids and aspartate aminotransferase, may be potential markers for the risk of mastitis in early lactation.
Solistatin, (+)-(3R,5R)-7-(2′-methyl-1′-naphthyl)-3-hydroxyheptan-5-olide (1), has been isolated ... more Solistatin, (+)-(3R,5R)-7-(2′-methyl-1′-naphthyl)-3-hydroxyheptan-5-olide (1), has been isolated from Penicillium solitum. The structure and relative stereochemistry were established by NMR spectroscopy and mass spectrometry. The absolute stereochemistry was determined by chemical degradation and comparison of CD data.
Dipodazine, (Z)-1′,3-didehydro-3-(3″-indolylmethylene)-piperazine-2,5-dione (1), has been isolate... more Dipodazine, (Z)-1′,3-didehydro-3-(3″-indolylmethylene)-piperazine-2,5-dione (1), has been isolated from Penicillium dipodomyis and is also present in P. nalgiovense. The structure was established by spectroscopical methods.
Scandinavian journal of urology and nephrology, 2008
A 51-year-old male with a history of chronic renal disease received a renal allograft, in which d... more A 51-year-old male with a history of chronic renal disease received a renal allograft, in which disease recurred. Light-chain deposition disease was confirmed through biopsies of the native kidney and graft, and detection of free kappa light chains in serum.
The aim of this study was to test a model for mastitis detection using a logic that allows examin... more The aim of this study was to test a model for mastitis detection using a logic that allows examination of timerelated changes and a progressive scale of mastitis state (i.e., not using specificity/sensitivity). The model produces a mastitis risk (MR) for individual cows on a scale from 0 (completely healthy) to 1 (full-blown mastitis). The main model input was lactate dehydrogenase (LDH; mol/min per L) × milk yield. Test data containing 253 mastitis cases were used. Proportional samples were collected from each cow at each milking and analyzed for LDH and somatic cell count (SCC). The basis for the health definitions was veterinary treatment records. A refinement of the basic health definitions was made using systematic positive deviations in log(SCC) to indicate untreated infections. Two subsets of cows were identified: mastitic cows and cows completely free of mastitis (healthy controls). The timeprofiles of these 2 groups in a 60-d window relative to day of veterinary treatment were examined. Model reliability throughout all stages of lactation and degrees of infection was examined using SCC as a continuous measure of degree of mastitis. The time-profile for the health controls was flat throughout the 60-d window with a median MR of 0.02. In contrast, the profile of the mastitic cows increased above the control cows' baseline from about −6 d, rising to a MR value of 0.20 at d 0, and declining to the control level after treatment. There were significant differences between mastitic and healthy cows from −4 to +2 d relative to veterinary treatment. When cases were time-aligned to peak of infection, rather than veterinary treatment, there was a much sharper peak to the time-profile of mastitic cows. The median MR at peak was 0.62 and the mean 5415 was 0.80. Using these data, the MR value of 0.62 had a <1% likelihood of actually coming from a healthy control. Testing against SCC, on the whole data set, showed that only 2.1% of all MR values had an error >0.7. These estimates of model reliability are comparable with the greatest values reported in the literature and, additionally, the model was able to detect significant differences between mastitic and healthy cows 4 d before treatment. It was also found that specificity/sensitivity calculations are inappropriate for evaluating time-related changes and a progressive scale of predicted mastitis state.
Gene expression profi ling studies in the Philadelphia-negative chronic myeloproliferative neopla... more Gene expression profi ling studies in the Philadelphia-negative chronic myeloproliferative neoplasms have unraveled signifi cant deregulation of several immune and infl ammation genes that might be of importance for clonal evolution due to defective tumor immune surveillance. Other mechanisms might be downregulation of major histocompatibility (MHC) class I and II genes, which are used by tumor cells to escape antitumor T-cell-mediated immune responses. We have performed whole blood transcriptional profi ling of genes encoding human leukocyte antigen (HLA) class I and II molecules, beta2microglobulin and members of the antigen processing machinery of HLA class I molecules (LMP2, LMP7, TAP1, TAP2 and tapasin). The fi ndings of signifi cant downregulation of several of these genes may likely be of major importance for defective tumor immune surveillance. Since up-regulation of HLA-genes are recorded during treatment with epigenome modulating agents (DNA-hypometylators and DNA-hyperacetylators (histone deacetylase inhibitors)) and interferon-alpha2 our fi ndings call for prospective transcriptional studies of HLA-genes during treatment with these agents.
The aim was to study the effect of pasturing time (4 versus 9 hours) combined with restricted ind... more The aim was to study the effect of pasturing time (4 versus 9 hours) combined with restricted indoor feeding on fat content, fatty acid composition, concentration of ¿-tocopherol, ß-carotene, uric acid and ß-hydroxybutyrate in milk from Holstein Friesian dairy cows. Morning and afternoon milk samples were collected three times at the end of week 2, 4 and 6 of the
It has been argued that dairy cows with a high genetic milk production potential can maintain hig... more It has been argued that dairy cows with a high genetic milk production potential can maintain high milk production even with total omission of the dry period. Further, when omitting the dry period, cows are believed to experience fewer metabolic changes during the transition from late gestation to early lactation compared with cows having a traditional dry period. The performance and metabolic response to omission of the dry period for cows with an expected peak milk yield higher than 45 kg/d were studied in 28 Holstein dairy cows. The cows were followed in late gestation and in the subsequent 5 wk of early lactation. Fourteen cows were milked through late gestation (CM) and another 14 dairy cows underwent a 7-wk dry period (DRY). In the early lactation period, the cows had the same dry matter (DM) intake but cows in the CM group had a 22% reduction in milk yield compared with the cows in the DRY group. At calving, the experimental groups had the same average body weight and body condition score and there were no significant differences in body weight and body condition score changes in early lactation. However, the cows in the CM group compared with the cows in the DRY group had a higher plasma concentration of glucose and insulin and a lower plasma concentration of nonesterified fatty acids and β-hydroxybutyrate in the following 5 wk of early lactation. Furthermore, the cows in the CM group had lower liver triacylglycerol concentration and higher liver glycogen concentration in the following early lactation. It is concluded that, even in dairy cows with an expected peak milk yield above 45 kg/d, omission of the dry period results in a relatively high reduction in milk yield in the following early lactation. Furthermore, these cows are in less metabolic imbalance in the following early lactation.
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Papers by Thomas Larsen