The genome of bacteriophage phiKMV,a T7-like virus infecting Pseudomonas aeruginosa

The complete DNA sequence of a new lytic T7-like bacteriophage phiKMV is presented. It is the first genome sequence of a member of the Podoviridae that infects Pseudomonas aeruginosa. The linear G + C-rich (62.3%) double-stranded DNA genome of 42,519 bp has direct terminal repeats of 414 bp and contains 48 open reading frames that are all transcribed from the same strand. Despite absence of homology at the DNA level, 11 of the 48 phiKMV-encoded putative proteins show sequence similarity to known T7-type phage proteins. Eighteen open reading frame products have been assigned, including an RNA polymerase, proteins involved in DNA replication, as well as structural, phage maturation, and lysis proteins. Surprisingly, the major capsid protein completely lacks sequence homology to any known protein. Also, the strong virulence toward many clinical P. aeruginosa isolates and a short replication time make phiKMV attractive for phage therapy or a potential source for antimicrobial proteins.     

The impact of underweight and obesity on outcomes in anticoagulated patients with atrial fibrillation: A systematic review and meta‐analysis on the obesity paradox

Although obesity is associated with the development and progression of atrial fibrillation (AF), an obesity paradox may be present, illustrated by seemingly protective effects of obesity on AF‐related outcomes. Body mass index (BMI) has an impact on outcomes in AF patients using oral anticoagulants. After searching Medline and Embase, meta‐analysis of results of four randomized and five observational studies demonstrated significantly lower risks of stroke or systemic embolism (RR 0.80, 95%CI [0.73–0.87]; RR 0.63, 95%CI [0.57–0.70]; and RR 0.42, 95%CI [0.31–0.57], respectively) and all‐cause mortality (RR 0.73, 95%CI [0.64–0.83]; RR 0.61, 95%CI [0.52–0.71]; and RR 0.56, 95%CI [0.47–0.66], respectively) in overweight, obese and morbidly obese anticoagulated AF patients (BMI 25 to <30, ≥30 and ≥40 kg/m², respectively) compared to normal BMI anticoagulated AF patients (BMI 18.5 to <25 kg/m²). In contrast, thromboembolic (RR 1.92, 95%CI [1.28–2.90]) and mortality (RR 3.57, 95%CI [2.50–5.11]) risks were significantly increased in underweight anticoagulated AF patients (BMI <18.5 kg/m²). In overweight and obese anticoagulated AF patients, the risks of major bleeding (RR 0.86, 95%CI [0.76–0.99]; and RR 0.88, 95%CI [0.79–0.98], respectively) and intracranial bleeding (RR 0.75, 95%CI [0.58–0.97]; and RR 0.57, 95%CI [0.40–0.80], respectively) were also significantly lower compared to normal BMI patients, while similar risks were observed in underweight and morbidly obese patients. This meta‐analysis demonstrated lower thromboembolic and mortality risks with increasing BMI. However, as this paradox was driven by results from randomized studies, while observational studies rendered more conflicting results, these seemingly protective effects should still be interpreted with caution.     

Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) Versus Warfarin in Patients with Atrial Fibrillation and (Morbid) Obesity or Low Body Weight: a Systematic Review and Meta-Analysis

Cardiovascular Drugs and Therapy - Oral anticoagulants are crucial for preventing systemic thromboembolism in atrial fibrillation (AF), with guidelines preferring non-vitamin K antagonist oral...     

Vitamin D metabolites in childhood nephrotic syndrome

We measured serum levels of total and ionised calcium, phosphate, intact parathyroid hormone, 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)₂D] and the vitamin D binding protein (DBP) in 14 children with idiopathic nephrotic syndrome and 10 healthy, age-matched controls. In all nephrotics serum DBP levels were below the normal range. Serum 25(OH)D was below 7 ng/ml in 10 of 14 nephrotic children and in the low normal range in the remaining 4 patients. The average serum 1,25(OH)₂D levels were lower in the nephrotic patients than in the controls. However, free 1,25(OH)₂D levels were normal in the nephrotic patients. Both serum 25(OH)D and 1,25(OH)₂D correlated positively with the concentration of DBP There was a significant negative correlation between serum DBP levels and the urinary protein excretion and a significant positive correlation between the urinary excretions of DBP and albumin. From this study it can be concluded that the nephrotic child is capable of maintaining appropriate serum concentrations of free calcitriol despite important urinary losses of both substrate and bound calcitriol.     

Verbal fluency in dementia of frontal lobe type and dementia of Alzheimer type.

This study compares semantic (category) and letter-initial verbal fluency performance in dementia of frontal lobe type, dementia of Alzheimer type, and control subjects matched for age, sex, and level of education. As well as demographic characteristics, patients were matched for severity of dementia as estimated by the mini mental scale (23.2 (SD 4.9)). All patients with dementia of frontal lobe type had a frontal hypoperfusion on single photon emission computed tomography whereas patients with dementia of Alzheimer type showed mainly posterior deficits. Patients had significantly lower verbal fluency than controls but those with dementia of frontal lobe type did not differ from those with dementia of Alzheimer type in the number of words generated, intrusions, or preservations. Category fluency was more impaired than letter fluency in both dementias. No correlation between frontal index, frontal/parietal index, and fluency was found. Verbal fluency tests are sensitive tools for detecting dementia but do not seem useful in distinguishing between patients with dementia of Alzheimer type and those with dementia of frontal lobe type in early disease.     

Efficacy of Artilysin Art-175 against Resistant and Persistent Acinetobacter baumannii

Bacteriophage-encoded endolysins have shown promise as a novel class of antibacterials with a unique mode of action, i.e., peptidoglycan degradation. However, Gram-negative pathogens are generally not susceptible due to their protective outer membrane. Artilysins overcome this barrier. Artilysins are optimized, engineered fusions of selected endolysins with specific outer membrane-destabilizing peptides. Artilysin Art-175 comprises a modified variant of endolysin KZ144 with an N-terminal fusion to SMAP-29. Previously, we have shown the high susceptibility of Pseudomonas aeruginosa to Art-175. Here, we report that Art-175 is highly bactericidal against stationary-phase cells of multidrug-resistant Acinetobacter baumannii, even resulting in a complete elimination of large inocula (≥10⁸ CFU/ml). Besides actively dividing cells, Art-175 also kills persisters. Instantaneous killing of A. baumannii upon contact with Art-175 could be visualized after immobilization of the bacteria in a microfluidic flow cell. Effective killing of a cell takes place through osmotic lysis after peptidoglycan degradation. The killing rate is enhanced by the addition of 0.5 mM EDTA. No development of resistance to Art-175 under selection pressure and no cross-resistance with existing resistance mechanisms could be observed. In conclusion, Art-175 represents a highly active Artilysin against both A. baumannii and P. aeruginosa, two of the most life-threatening pathogens of the order Pseudomonadales.     

Art-175 Is a Highly Efficient Antibacterial against Multidrug-Resistant Strains and Persisters of Pseudomonas aeruginosa

Artilysins constitute a novel class of efficient enzyme-based antibacterials. Specifically, they covalently combine a bacteriophage-encoded endolysin, which degrades the peptidoglycan, with a targeting peptide that transports the endolysin through the outer membrane of Gram-negative bacteria. Art-085, as well as Art-175, its optimized homolog with increased thermostability, are each composed of the sheep myeloid 29-amino acid (SMAP-29) peptide fused to the KZ144 endolysin. In contrast to KZ144, Art-085 and Art-175 pass the outer membrane and kill Pseudomonas aeruginosa, including multidrug-resistant strains, in a rapid and efficient (∼5 log units) manner. Time-lapse microscopy confirms that Art-175 punctures the peptidoglycan layer within 1 min, inducing a bulging membrane and complete lysis. Art-175 is highly refractory to resistance development by naturally occurring mutations. In addition, the resistance mechanisms against 21 therapeutically used antibiotics do not show cross-resistance to Art-175. Since Art-175 does not require an active metabolism for its activity, it has a superior bactericidal effect against P. aeruginosa persisters (up to >4 log units compared to that of the untreated controls). In summary, Art-175 is a novel antibacterial that is well suited for a broad range of applications in hygiene and veterinary and human medicine, with a unique potential to target persister-driven chronic infections.     

Disseminated BCG in HIV infection.

A boy, born to a mother with AIDS related complex, was immunised with BCG on the 10th day of life. At the age of 4 months he presented with a local enlarged lymph node, fever, hypotonia, and diarrhoea. Mycobacterium bovis, BCG strain, was grown from the lymph node and cerebrospinal fluid; this proved dissemination.     

Memory impairment differs in frontotemporal dementia and Alzheimer's disease

The aim of this study was to assess short-term and long-term explicit memory and implicit memory in frontotemporal dementia (FTD; frontal variant) and to compare FTD and Alzheimer's disease (AD) patients with similar severity of dementia. Fifteen FTD patients [mean age: 68 years; Mini-Mental State (MMS): 24], 30 probable AD patients (mean age: 72 years; MMS: 23) and 12 healthy subjects participated in the study. The three groups were comparable in terms of gender and educational level. Short-term memory was assessed with the digit span and Corsi block-tapping tests. Explicit verbal memory was assessed with the Grober and Buschke test, and implicit memory with a verbal priming task and a fragmented picture test. FTD patients demonstrated a genuine memory deficit with impaired digit span, encoding deficit and retrieval strategy difficulties, but preserved implicit verbal and visual priming. Memory patterns differed in AD and FTD: short-term memory and free recall were similarly decreased in FTD and AD but cues provided more benefit to FTD than to AD; encoding was more impaired and the forgetting rate was faster in AD than in FTD; priming was lower in AD than in FTD. AD patients with clinical and imaging frontal lobe dysfunction tended to have lower memory performance and to differ even more from FTD patients than AD patients without frontal lobe dysfunction.