Comparative Study of foF2 Measurements with IRI-2007 Model Predictions During Extended Solar Minimum

The unusually deep and extended solar minimum of cycle 2324 made it very difficult to predict the solar indices 1 or 2 years into the future. Most of the predictions were proven wrong by the actual observed indices. IRI gets its solar, magnetic, and ionospheric indices from an indices file that is updated twice a year. In recent years, due to the unusual solar minimum, predictions had to be corrected downward with every new indices update. In this paper we analyse how much the uncertainties in the predictability of solar activity indices affect the IRI outcome and how the IRI values calculated with predicted and observed indices compared to the actual measurements.Monthly median values of F2 layer critical frequency (foF2) derived from the ionosonde measurements at the mid-latitude ionospheric station Juliusruh were compared with the International Reference Ionosphere (IRI-2007) model predictions. The analysis found that IRIprovides reliable results that compare well with actual measurements, when the definite (observed and adjusted) indices of solar activityare used, while IRI values based on earlier predictions of these indices noticeably overestimated the measurements during the solar minimum.One of the principal objectives of this paper is to direct attention of IRI users to update their solar activity indices files regularly.Use of an older index file can lead to serious IRI overestimations of F-region electron density during the recent extended solar minimum

Augmenter of liver regeneration enhances the success rate of fetal pancreas transplantation in rodents

Background. Treatment of fetal pancreas (FP) isografts with insulin- like growth factor-I greatly improves the rate of conversion to euglycemia in diabetic rats. Complete knowledge of other factors that may facilitate the engraftment and function of FP in vivo is still embryonic. Augmenter of liver regeneration (ALR) is a newly described polypeptide growth factor found in weanling rat livers. ALR has trophic effects on regenerating liver. We studied the effects of in situ administration of this agent on FP isografts in rats. Methods. Streptozotocin-diabetic Lewis rats (blood glucose >300 mg/dl) received 16 FP isografts transplanted intramuscularly. ALR was delivered from day 1 through day 14, in doses of 40 or 400 ng/kg/d. Animals were followed for 3 months with serial weights and blood glucose monitoring. These animals were compared with those treated with vehicle alone. Results. Of the group treated with ALR at 40 ng/kg/day for 14 days, 89% (eight of nine) were euglycemic (P=0.0003). Of the group treated with ALR at 400 ng/kg/day for 14 days, 88% (seven of eight) were euglycemic (P=0.0007). Of the group treated with vehicle alone, none of the six were euglycemic. Euglycemia is defined here as glucose<200 mg/dl for 3 days. Pathology of the intramuscular transplant site showed patches of islet tissue embedded in fat. These patches demonstrated insulin immunoreactivity. Conclusions. Diabetes was reversed in a significantly greater proportion of FP + ALR-treated recipients than those animals treated with vehicle alone. Local delivery of growth factors my be used as an adjunct to FP transplantation to improve the rate of success. This in situ model may be useful to further evaluate other soluble factors

Distribution of plantar pressure in healthy controls and patients with type 1 and 2 diabetes

WSTĘP. Celem pracy jest ocena rozkładu podeszwowych nacisków w grupie osób zdrowych i chorych na cukrzycę typu 1 i 2 przy obecności lub braku neuropatii ruchowo-czuciowej. Opisane badania stanowią wstęp do opracowania pierwszego polskiego obuwia profilaktycznego, uwzględniającego odciążenie miejsc wysokiego ryzyka owrzodzenia na stopie. MATERIAŁ I METODY. Przebadano grupę 215 zdrowych osób, 56 osób chorych na cukrzycę typu 1, 61 chorych na cukrzycę typu 2. Badano zaawansowanie przewlekłych powikłań cukrzycy, szczególnie neuropatii, którą oceniano na podstawie skali NDS, NSS i przewodnictwa nerwowego. Pomiar nacisku [N/cm2] wykonano za pomocą systemu Emed-SF V2.1. WYNIKI BADAŃ. Wśród osób zdrowych stwierdzono największe naciski pod 2 (38,8 N/cm2) i 3 głową (33,4 N/cm2) kości śródstopia. Podobne wyniki uzyskano w populacji osób chorych na cukrzycę typu 1. U chorych na cukrzycę typu 2 ciśnienie pod 2 (45,5 N/cm2), 3 (39,6 N/cm2), 4 (31,8 N/cm2) głową kości śródstopia było statystycznie istotnie wyższe w porównaniu z populacją zdrowych osób. Podobnie wysokie ciśnienie stwierdzono pod 3 i 4 głową kości śródstopia w cukrzycy typu 2 powikłanej neuropatią. WNIOSKI. 1. Miejscami największego nacisku u osób zdrowych są: paluch, pięta, 2 i 3 głowa kości śródstopia. 2. U chorych na cukrzycę typu 2 naciski na 2, 3, 4 i 5 głowie kości śródstopia są istotnie statystycznie większe niż u osób zdrowych i chorych na cukrzycę typu 1. 3. U chorych na cukrzycę typu 2 powikłaną neuropatią ruchową i czuciową najwyższe naciski występują na 3 i 4 głowie kości śródstopia i różnią się one istotnie statystycznie od grupy osób zdrowych. 4. Szczególnych zabiegów prewencyjnych w postaci odciążenia główek kości śródstopia wymagają chorzy na cukrzycę typu 2, zwłaszcza powikłaną neuropatią ruchowo-czuciową.OBJECTIVE. To investigate the distribution of plantar pressures in healthy subjects and in patients with type 1 and 2 diabetes with or without sensorimotor neuropathy (SMN). The paper opens a series of studies aiming at the construction of the first Polish prophylactic footwear, which would offload the sites at high risk of plantar foot ulceration. MATERIAL AND METHODS. We studied 215 healthy subjects, 56 patients with type 1 diabetes, and 61 patients with type 2 diabetes. Chronic complications of diabetes were evaluated, especially neuropathy based upon NDS score, NSS score and neural conduction. We used the Emed-SF V2.1 system to measure plantar pressures [N/cm2]. RESULTS. Among the healthy individuals the highest pressures were observed below the second and the third metatarsal head (38,8 N/cm2 and 33,4 N/cm2, respectively). Similar results were found in the group of type 1 diabetes patients. However, the patients with type 2 diabetes mellitus had statistically significant higher pressures below the second, the third, and the fourth metatarsal head when compared with non-diabetic controls (45,5 N/cm2, 39,6 N/cm2, 31,8 N/cm2, respectively). Similar results below the third and fourth metatarsal head were observed in the group of type 2 diabetes patients complicated by diabetic neuropathy. CONCLUSIONS. 1. The highest pressures in healthy subjects were identified under great toe, the second and third metatarsal head. 2. Patients with type 2 diabetes have significantly higher pressures under the second through fifth metatarsal heads as compared with healthy subjects and type 1 diabetics. 3. In patients with type 2 diabetes complicated by SMN the highest pressures are found under the third and fourth metatarsal head, being significantly different from healthy subjects. 4. Special preventive procedures i.e. offloading metatarsal heads are necessary in patients with type 2 diabetes, especially those with concomitant SMN

The effect of insulin and sulodexide (Vessel Due F) on diabetic foot syndrome. Pilot study in elderly patients

Celem pracy była ocena skuteczności stosowania insuliny wraz z sulodeksydem (mieszanina 80% pochodnych heparyny i 20% siarczanu dermatanu) w leczeniu owrzodzeń stóp oraz określenie ich wpływu na mikrokrążenie skórne i neuropatię cukrzycową. Chorzy z zaawansowaną neuropatią cukrzycową i owrzodzeniem stopy losowo przydzielono do grupy leczonej insuliną (I) z sulodeksydem (S) (n = 12) lub do grupy kontrolnej leczonej insuliną z placebo (P) (n = 6) przez 10 tygodni. Za pomocą metody dopplerowskiego lasera oceniano skórny przepływ krwi w stopach (LDF, laser doppler flow) w spoczynku oraz po 30- i 60-sekundowym niedokrwieniu. Ocenie poddano również przewodnictwo nerwowe na podstawie czuciowych i ruchowych potencjałów wywołanych. U chorych na cukrzycę skórny przepływ po niedokrwieniu był 2,5 raza krótszy w kończynie z owrzodzeniem niż w stopie zdrowej. Obserwowano znamienny wzrost przepływów skórnych po 30- i 60-sekundowym niedokrwieniu po zakończeniu terapii (grupa IS, owrzodzenie stopy, LDF - 60 s; od 99,1 &plusmn; 14,3 do 218,6 &plusmn; 28,6 PU, p < 0,001, grupa od 110,5 &plusmn; 13,0 do 164,8 &plusmn; 15,4 PU, p < 0,05). Czas przekrwienia reaktywnego uległ wydłużeniu w grupie IS (IS: od 30,3 &plusmn; 2,9 do 43,9 &plusmn; 2,2 s, p < 0,001; IP: od 28,7 &plusmn; 3,0 do 33,3 &plusmn; 3,3 s, NS). W grupie IS 92% owrzodzeń stóp uległo zagojeniu w ciągu 46,4 dnia, natomiast w grupie IP 83% w ciągu 63,0 dnia. Badania przewodnictwa nerwowego nie wykazały różnic nasilenia neuropatii w obrębie grup i pomiędzy grupami. W stopach z owrzodzeniami sulodeksyd i insulina poprawiają przepływ skórny w odpowiedzi na niedokrwienie, nie wpływając na przewodnictwo nerwowe. Kliniczne efekty działania sulodeksydu, sumując się z działaniami insuliny, mogą istotnie skracać czas niezbędny do całkowitego wyleczenia owrzodzenia. Ostateczne potwierdzenie przedstawionych wstępnych wyników wymaga dalszych badań klinicznych.To assess the efficacy of insulin plus sulodexide (a mixture of 80% heparin-like substances and 20% dermatan sulphate) on diabetic ulcers, and its influence on foot skin microcirculation and diabetic neuropathy. Two groups of diabetic patients, suffering from severe neuropathy and ulceration, were randomly assigned to insulin (I) plus sulodexide (S) (n = 12) or insulin plus placebo (P) (n = 6) therapy, for 10 weeks. Laser Doppler assessment of foot skin flow (LDF), at rest and 30 or 60 s after arterial occlusion, and nerve conduction tests (sensorial evoked and motoric conduction potentials) have been evaluated in both groups. Postischaemic flow was 2.5 times shorter in ulcerated vs. non-ulcerated feet in diabetic patients. A significant increase in flows after 30 and 60 s ischaemia was detected in both groups at the end of therapy (IS group, ulcerated foot, LDF = 60 s: from 99.1 &#177; 14.3 to 218.6 &#177; 28.6 PU, P < 0.001. IP group = from 110.5 &#177; 13.0 to 164.8 &#177; 15.4 PU, P < 0.05). The length of reactive hyperaemia was higher in IS vs. IP group (IS: from 30.3 &#177; 2.9 to 43.9 &#177; 2.2 s, P < 0.001; IP: from 28.7 &#177; 3.0 to 33.3 &#177; 3.3 s, ns). Ninety-two percent of ulcers heals in a mean time of 46.4 days (IS group) vs. 83% and 63.0 days, respectively, in IP group. Nerve conduction studies have not demonstrated within- and between-group differences. Sulodexide and insulin improve the postischaemic skin flow in ulcerated feet, without affecting nerve conduction tests. The effect of sulodexide results additive to insulin; it is clinically relevant, in the view of the possibility of reducing the time needed to completely heal ulcers. The ultimate validation of these preliminary results requires extensive trials

Genetic Pathway in Acquisition and Loss of Vancomycin Resistance in a Methicillin Resistant Staphylococcus aureus (MRSA) Strain of Clonal Type USA300

An isolate of the methicillin-resistant Staphylococcus aureus (MRSA) clone USA300 with reduced susceptibility to vancomycin (SG-R) (i.e, vancomycin-intermediate S. aureus, VISA) and its susceptible “parental” strain (SG-S) were recovered from a patient at the end and at the beginning of an unsuccessful vancomycin therapy. The VISA phenotype was unstable in vitro generating a susceptible revertant strain (SG-rev). The availability of these 3 isogenic strains allowed us to explore genetic correlates of antibiotic resistance as it emerged in vivo. Compared to the susceptible isolate, both the VISA and revertant strains carried the same point mutations in yycH, vraG, yvqF and lspA genes and a substantial deletion within an intergenic region. The revertant strain carried a single additional frameshift mutation in vraS which is part of two component regulatory system VraSR. VISA isolate SG-R showed complex alterations in phenotype: decreased susceptibility to other antibiotics, slow autolysis, abnormal cell division and increased thickness of cell wall. There was also altered expression of 239 genes including down-regulation of major virulence determinants. All phenotypic properties and gene expression profile returned to parental levels in the revertant strain. Introduction of wild type yvqF on a multicopy plasmid into the VISA strain caused loss of resistance along with loss of all the associated phenotypic changes. Introduction of the wild type vraSR into the revertant strain caused recovery of VISA type resistance. The yvqF/vraSR operon seems to function as an on/off switch: mutation in yvqF in strain SG-R turns on the vraSR system, which leads to increase in vancomycin resistance and down-regulation of virulence determinants. Mutation in vraS in the revertant strain turns off this regulatory system accompanied by loss of resistance and normal expression of virulence genes. Down-regulation of virulence genes may provide VISA strains with a “stealth” strategy to evade detection by the host immune system

Evolution of Multidrug Resistance during Staphylococcus aureus Infection Involves Mutation of the Essential Two Component Regulator WalKR

Antimicrobial resistance in Staphylococcus aureus is a major public health threat, compounded by emergence of strains with resistance to vancomycin and daptomycin, both last line antimicrobials. Here we have performed high throughput DNA sequencing and comparative genomics for five clinical pairs of vancomycin-susceptible (VSSA) and vancomycin-intermediate ST239 S. aureus (VISA); each pair isolated before and after vancomycin treatment failure. These comparisons revealed a frequent pattern of mutation among the VISA strains within the essential walKR two-component regulatory locus involved in control of cell wall metabolism. We then conducted bi-directional allelic exchange experiments in our clinical VSSA and VISA strains and showed that single nucleotide substitutions within either walK or walR lead to co-resistance to vancomycin and daptomycin, and caused the typical cell wall thickening observed in resistant clinical isolates. Ion Torrent genome sequencing confirmed no additional regulatory mutations had been introduced into either the walR or walK VISA mutants during the allelic exchange process. However, two potential compensatory mutations were detected within putative transport genes for the walK mutant. The minimal genetic changes in either walK or walR also attenuated virulence, reduced biofilm formation, and led to consistent transcriptional changes that suggest an important role for this regulator in control of central metabolism. This study highlights the dramatic impacts of single mutations that arise during persistent S. aureus infections and demonstrates the role played by walKR to increase drug resistance, control metabolism and alter the virulence potential of this pathogen

Whole Genome Sequencing and Complete Genetic Analysis Reveals Novel Pathways to Glycopeptide Resistance in Staphylococcus aureus

The precise mechanisms leading to the emergence of low-level glycopeptide resistance in Staphylococcus aureus are poorly understood. In this study, we used whole genome deep sequencing to detect differences between two isogenic strains: a parental strain and a stable derivative selected stepwise for survival on 4 µg/ml teicoplanin, but which grows at higher drug concentrations (MIC 8 µg/ml). We uncovered only three single nucleotide changes in the selected strain. Nonsense mutations occurred in stp1, encoding a serine/threonine phosphatase, and in yjbH, encoding a post-transcriptional negative regulator of the redox/thiol stress sensor and global transcriptional regulator, Spx. A missense mutation (G45R) occurred in the histidine kinase sensor of cell wall stress, VraS. Using genetic methods, all single, pairwise combinations, and a fully reconstructed triple mutant were evaluated for their contribution to low-level glycopeptide resistance. We found a synergistic cooperation between dual phospho-signalling systems and a subtle contribution from YjbH, suggesting the activation of oxidative stress defences via Spx. To our knowledge, this is the first genetic demonstration of multiple sensor and stress pathways contributing simultaneously to glycopeptide resistance development. The multifactorial nature of glycopeptide resistance in this strain suggests a complex reprogramming of cell physiology to survive in the face of drug challenge