Slow release theophylline in patients with airways obstruction with particular reference to the effects of food upon serum levels

Eighteen patients with airways obstruction were given slow release theophylline and were then investigated to determine the influence of a standard meal upon the serum levels achieved over the ensuing 12-hour period. After food the peak to trough differences were decreased and the serum levels were significantly lower over the first 6 hours. In this study, the patients were given 10 mg/kg/day of slow release theophylline and none subsequently was found to have toxic levels, therefore this was considered to be a reasonable dose with which to initiate therapy in adults with uncomplicated airflow limitation. However even under the strictly controlled conditions of the study there were wide variations between individuals in the blood levels achieved and serum monitoring is necessary to use theophylline in an optimal fashion.     

Nucleotide excision repair by dual incisions in plants

Plants use light for photosynthesis and for various signaling purposes. The UV wavelengths in sunlight also introduce DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts [(6-4)PPs] that must be repaired for the survival of the plant. Genome sequencing has revealed the presence of genes for both CPD and (6-4)PP photolyases, as well as genes for nucleotide excision repair in plants, such as Arabidopsis and rice. Plant photolyases have been purified, characterized, and have been shown to play an important role in plant survival. In contrast, even though nucleotide excision repair gene homologs have been found in plants, the mechanism of nucleotide excision repair has not been investigated. Here we used the in vivo excision repair assay developed in our laboratory to demonstrate that Arabidopsis removes CPDs and (6-4)PPs by a dual-incision mechanism that is essentially identical to the mechanism of dual incisions in humans and other eukaryotes, in which oligonucleotides with a mean length of 26–27 nucleotides are removed by incising ∼20 phosphodiester bonds 5′ and 5 phosphodiester bonds 3′ to the photoproduct.Plants and other organisms that depend on photosynthesis are, by necessity, exposed to more sunlight than other organisms that are chemotrophs or heterotrophs. Hence, plants are expected to receive more exposure to UV wavelengths of light than other organisms. The genotoxic effects of UV are somewhat mitigated by the reflection of UV by the waxy leaf surface and absorbance of UV by the intracellular pigments that are present at high concentration in plant cells, including carotenoids and flavonoids. Nevertheless, plants still receive considerable amounts of DNA-damaging UV radiation and therefore must have the means to cope with the damage to ensure their survival. Indeed, DNA sequencing has revealed that plant genomes contain genes that are homologous to the genes of all major DNA repair pathways, including photoreactivation, nucleotide excision repair, base excision repair, and recombination/double-strand break repair (1–6).However, biochemical studies of these DNA repair mechanisms have been limited. Of significance, Arabidopsis photolyases have been expressed in heterologous systems, purified, and characterized (7–9). Similarly, some of the enzymes of the base excision repair and recombination/double-strand break repair systems have been studied. In contrast, there have been no mechanistic studies on plant nucleotide excision repair, although it is known that plants can remove cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts [(6-4)PPs] in a photolyase-independent manner (6, 10, 11), presumably by nucleotide excision repair. Here, we have used an Arabidopsis cell line and the in vivo excision assay recently developed in our laboratory (12–14) to demonstrate that Arabidopsis removes these photoproducts by dual incisions in a manner that is virtually identical to human nucleotide excision repair.     

Autoantibodies as Diagnostic and Predictive Markers of Vitiligo

Genetic and environmental factors are believed to influence development of systemic lupus erythematosus (SLE). Endogenous retroviruses (ERV) correspond to the integrated proviral form of infectious retroviruses, which are trapped within the genome due to mutations. ERV represent a key molecular link between the host genome and infectious viral particles. ERV-encoded proteins are recognized by antiviral immune responses and become targets of autoreactivity. Alternatively, ERV protein may influence cellular processes and the life cycle of infectious viruses. As examples, the HRES-1 human ERV encodes a 28-kDa nuclear autoantigen and a 24-kDa small GTP-ase, termed HRES-1/Rab4. HRES-1/p28 is a nuclear autoantigen recognized by cross-reactive antiviral antibodies, while HRES-1/Rab4 regulates surface expression of CD4 and the transferrin receptor (TFR) through endosome recycling. Expression of HRES-1/Rab4 is induced by the tat gene of HIV-1, which in turn down-regulates expression of CD4 and susceptibility to re-infection by HIV-1. CD4 and the TFR play essential roles in formation of the immunological synapse (IS) during normal T-cell activation by a cognate MHC class II peptide complex. The key intracellular transducer of T-cell activation, Lck, is brought to the IS via binding to CD4. T-cell receptorζ (TCRζ) chain binds to the TFR. Abnormal T-cell responses in SLE have been associated with reduced lck and TCRζ chain levels. HRES-1 is centrally located on chromosome 1 at q42 relative to lupus-linked microsatellite markers and polymorphic HRES-1 alleles have been linked to the development of SLE. 1q42 is one of the three most common fragile sites in the human genome, and is inducible by DNA demethylation, a known mechanism of retroviral gene activation. Molecular mimicry and immunomodulation by a ERV, such as HRES-1, may contribute to self-reactivity and abnormal T and B-cell functions in SLE.     

Abnormalities of intrinsic brain activity in essential tremor: A meta‐analysis of resting‐state functional imaging

Neuroimaging studies using a variety of techniques have demonstrated abnormal patterns of spontaneous brain activity in patients with essential tremor (ET). However, the findings are variable and inconsistent, hindering understanding of underlying neuropathology. We conducted a meta‐analysis of whole‐brain resting‐state functional neuroimaging studies in ET compared to healthy controls (HC), using anisotropic effect‐size seed‐based d mapping, to identify the most consistent brain activity alterations and their relation to clinical features. After systematic literature search, we included 13 studies reporting 14 comparisons, describing 286 ET patients and 254 HC. Subgroup analyses were conducted considering medication status, head tremor status, and methodological factors. Brain activity in ET is altered not only in the cerebellum and cerebral motor cortex, but also in nonmotor cortical regions including prefrontal cortex and insula. Most of the results remained unchanged in subgroup analyses of patients with head tremor, medication‐naive patients, studies with statistical threshold correction, and the large subgroup of studies using functional magnetic resonance imaging. These findings not only show consistent and robust abnormalities in specific brain regions but also provide new information on the biology of patient heterogeneity, and thus help to elucidate the pathophysiology of ET.     

Correction to: Irreversible Electroporation For Hepatocellular Carcinoma: Longer-Term Outcomes At A Single Centre

CardioVascular and Interventional Radiology - An author was inadvertently omitted from the author list. Helen Kavnoudias should be listed as third author. The added author’s name and...     

Persistent inhibition of Candida albicans biofilm and hyphae growth on titanium by graphene nanocoating

ObjectivesCandida albicanscolonizes biomaterial surfaces and are highly resistant to therapeutics. Graphene nanocoating on titanium compromises initial biofilm formation. However, its sustained antibiofilm potential is unknown. The objective of this study was to investigate the potential of graphene nanocoating to decrease long-term fungal biofilm development and hyphae growth on titanium.MethodsGraphene nanocoating was deposited twice (TiGD) or five times (TiGV) on grade 4 titanium with vacuum assisted technique and characterized with Raman spectroscopy and atomic force microscope. The biofilm formation and hyphae growth of C. albicans was monitored for seven days by CFU, XTT, confocal, mean cell density and scanning electronic microscopy (SEM). Uncoated titanium was the Control. All tests had three independent biological samples and were performed in independent triplicates. Data was analyzed with one- or two-way ANOVA and Tukey's HSD (α = 0.05).ResultsBoth TiGD and TiGV presented less biofilms at all times points compared with Control. The confocal and SEM images revealed few adhered cells on graphene coated samples, absence of hyphae and no features of a mature biofilm architecture. The increase in number of layers of graphene nanocoating did not improve its antibiofilm potential.SignificanceThe graphene nanocoating exerted a long-term persistent inhibitory effect on the biofilm formation on titanium. The fewer cells that were able to attach on graphene coated titanium were scattered and unable to form a mature biofilm with hyphae elements. The findings open opportunities to prevent microbial attachment and proliferation on implantable materials without the use of antibiotics.     

Retrograde Inversion Stripping as a Complication of the Clarivein? Mechanochemical Venous Ablation Procedure

The endovenous revolution has accelerated the development of new techniques and devices for the treatment of varicose veins. The ClariVein^® mechanochemical ablation device offers tumescentless treatment with a rotating ablation tip that can theoretically become stuck in tissue. We present the first report of retrograde stripping of the small saphenous vein without anaesthesia following attempted use of the ClariVein^® device, without adverse sequelae.     

Platelet—Rich—Plasma Injections in Treating Lateral Epicondylosis: a Review of the Recent Evidence

Lateral epicondylosis is common, with various treatment modalities. Platelet—rich—plasma injections from autologous blood have recently been used in centres worldwide for the treatment of tennis elbow. We review and present the recent published evidence on the effectiveness of PRP injections for lateral epicondylosis. Nine studies met our inclusion criteria including 6 RCT’s for the purpose of analysis. PRP injections have an important and effective role in the treatment of this debilitating pathology, in cases where physiotherapy has been unsuccessful.     

Acute and chronic effects of continuous positive airway pressure therapy on left ventricular systolic and diastolic function in patients with obstructive sleep apnea and congestive heart failure

BACKGROUND:

Obstructive sleep apnea (OSA) may contribute to the pathogenesis of congestive heart failure (CHF). Nocturnal continuous positive airway pressure (CPAP) therapy can alleviate OSA and may have a role in the treatment of CHF patients.

OBJECTIVES:

To investigate the acute and chronic effects of CPAP therapy on left ventricular systolic function, diastolic function and filling pressures in CHF patients with OSA.

METHODS:

Twelve patients with stable CHF (New York Heart Association II or III, radionuclide ejection fraction lower than 40%) underwent overnight polysomnography to detect OSA. In patients with OSA (n=7), echocardiography was performed at baseline (awake, before and during acute CPAP administration) and after 6.9±3.3 weeks of nocturnal CPAP therapy. Patients without OSA (n=5) did not receive CPAP therapy, but underwent a baseline and follow-up echocardiogram.

RESULTS:

In CHF patients with OSA, acute CPAP administration resulted in a decrease in stroke volume (44±15 mL versus 50±14 mL, P=0.002) and left ventricular ejection fraction ([LVEF] 34.8±5.0% versus 38.4±3.3%, P=0.006) compared with baseline, but no change in diastolic function or filling pressures (peak early diastolic mitral annular velocity [Ea]: 6.0±1.6 cm/s versus 6.3±1.6 cm/s, P not significant; peak early filling velocity to peak late filling velocity [E/A] ratio: 1.05±0.74 versus 1.00±0.67, P not significant; E/Ea ratio: 10.9±4.1 versus 11.3±4.1, P not significant). In contrast, chronic CPAP therapy resulted in a trend to an increase in stroke volume (59±19 mL versus 50±14 mL, P=0.07) and a significant increase in LVEF (43.4±4.8% versus 38.4±3.3%, P=0.01) compared with baseline, but no change in diastolic function or filling pressures (Ea: 6.2±1.2 cm/s versus 6.3±1.6 cm/s, P not significant; E/A ratio: 1.13±0.61 versus 1.00±0.67, P not significant; E/Ea ratio: 12.1±2.7 versus 11.3±4.1, P not significant). There was no change in left ventricular systolic function, diastolic function or filling pressures at follow-up in CHF patients without OSA.

CONCLUSIONS:

Acute CPAP administration decreased stroke volume and LVEF in stable CHF patients with OSA. In contrast, chronic CPAP therapy for seven weeks improved left ventricular systolic function, but did not affect diastolic function or filling pressures. The potential clinical implications of the discrepant effects of CPAP therapy on left ventricular systolic and diastolic function in CHF patients with OSA warrant further study.     

Synthetic hexapeptide substrates and inhibitors of 3'':5''-cyclic AMP-dependent protein kinase.

The substrate specificity of the catalytic subunit of rabbit skeletal muscle 3': 5'-cyclic AMP-dependent protein kinase (EC 2.7.1.37; ATP: protein phosphotransferase) has been studied using the synthetic peptide Arg-Gly-Tyr-Ser-Leu-Gly corresponding to the sequence around serine 24, a phosphorylation site in reduced, carboxymethylated, maleylated (RCMM) chicken egg white lysozyme. This peptide served as a substrate for the enzyme and exhibited a 6-fold higher Vmax and a 100-fold higher Km than RCMM-lysozyme. Replacement of the arginine with glycine, histidine, or lysine resulted in a dramatic reduction in the Vmax. These results support the concept that arginine is an important residue in determining the substrate specificity of the protein kinase, predominantly influencing the Vmax of the phosphorylation reaction. Two synthetic peptides in which serine was replaced by an alanine acted as competitive inhibitors of phosphorylation of the synthetic peptide substrate and RCMM-lysozyme.