Adhesion of oral streptococci to all-ceramics dental restorative materials invitro

In recent years, patients have benefited from the development of better and more esthetic materials, including all-ceramics dental restorative materials. Dental plaque formation on teeth and restorative materials plays an important role in the pathogenesis of oral diseases. This study investigates initial adhesion of stationary phase streptococcal species to different all-ceramics dental restorative materials. The saliva-coated materials were incubated with the bacteria for 1h in an invitro flow chamber which mimics environmental conditions in the oral cavity. Number and vitality of adhering bacteria were determined microscopically after staining. Surface roughness and the composition of the materials had no distinctive influence on bacterial adhesion. However, S.mutans and S.sobrinus adhered about tenfold less numerous to all materials than the other streptococcal species. Further, there was a correlation between bacterial vitality and materials' glass content. The results showed that early plaque formation was influenced predominantly by the presence of the salivary pellicle rather than by material dependent parameters whereas the composition of the all-ceramics appeared to have influenced the percentage of viable cells during the adhesion process. This presented invitro technique may provide a useful model to study the influence of different parameters on adherence of oral streptococcal specie

Nephrotoxicity, high frequency ototoxicity, efficacy and serum kinetics of once versus thrice daily dosing of netilmicin in patients with serious infections

The effect of dosing regimen on nephrotoxicity, high frequency ototoxicity, efficacy and serum kinetics was studied in a prospective, randomised clinical study. Therapy was started with total daily doses of 6 mg/kg given once (od) or thrice (tid) daily to 56 and 57 patients, respectively. Subsequent doses were adjusted according to serum levels. No major differences in toxicity or efficacy were noticed between od and tid regimens: clinical failures occurred in two and two patients, four and five patients suffered from a decrease of ≥20 dB at least unilaterally at one frequency between 8 and 18 kHz, six and seven patients had a >25 μmol/L or >25% increase in serum creatinine, respectively. Serum creatinine or creatinine clearance did not change significantly during either therapy. Major differences between the two study groups were limited to pharmacokinetic parameters. Od dosing resulted in higher peak (mean of 21.6 vs 7.2 mg/L) and lower trough levels (0.5 vs 1.4mg/L). Half-lives of netilmicin determined between 1 and 8 h increased significantly during therapy with tid (from a mean of 2.75 to a mean of 3.33 h, P<0.01) but not significantly with od (rise from 2.8 to 3.03 h). Much longer half-lives were determined between 8 and 24 h in the od group (mean of 5.7 h, P<0.01). In conclusion, only minimal differences in toxicity and efficacy were observed. Their clinical relevance appears to be minima

Moderate toxic effects following acute zonisamide overdose

Zonisamide is an antiepileptic drug that acts on voltage-sensitive sodium and calcium channels, with a modulatory effect on GABA-mediated neuronal inhibition and an inhibitory effect on carbonic anhydrase. It is used mainly for the treatment of partial seizures, and is generally well tolerated at therapeutic doses. The most common reported adverse effects are somnolence, anorexia, dizziness, and headache. There are limited data on zonisamide overdose in the literature, and no case of zonisamide mono-intoxication has been published to date. We describe the first case of zonisamide mono-intoxication in a 25-year-old woman who ingested 12.6 g of this substance with suicidal intent. Despite a plasma zonisamide concentration of 182 mg/L on admission, the patient exhibited a benign clinical course with vomiting and central nervous system depression, requiring brief intubation. Somnolence persisted for 50 hours, and normal-anion-gap metabolic acidosis and polyuria for several days. Complete recovery may be expected with supportive care, even after ingestion of large zonisamide overdoses

Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring.

In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia

Crystal structure of SEL1L: Insight into the roles of SLR motifs in ERAD pathway

Terminally misfolded proteins are selectively recognized and cleared by the endoplasmic reticulum-associated degradation (ERAD) pathway. SEL1L, a component of the ERAD machinery, plays an important role in selecting and transporting ERAD substrates for degradation. We have determined the crystal structure of the mouse SEL1L central domain comprising five Sel1-Like Repeats (SLR motifs 5 to 9; hereafter called SEL1Lcent). Strikingly, SEL1Lcent forms a homodimer with two-fold symmetry in a head-to-tail manner. Particularly, the SLR motif 9 plays an important role in dimer formation by adopting a domain-swapped structure and providing an extensive dimeric interface. We identified that the full-length SEL1L forms a self-oligomer through the SEL1Lcent domain in mammalian cells. Furthermore, we discovered that the SLR-C, comprising SLR motifs 10 and 11, of SEL1L directly interacts with the N-terminus luminal loops of HRD1. Therefore, we propose that certain SLR motifs of SEL1L play a unique role in membrane bound ERAD machinery.ope

Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density

AbstractA novel secreted glycoprotein that regulates bone resorption has been identified. The protein, termed Osteoprotegerin (OPG), is a novel member of the TNF receptor superfamily. In vivo, hepatic expression of OPG in transgenic mice results in a profound yet nonlethal osteopetrosis, coincident with a decrease in later stages of osteoclast differentiation. These same effects are observed upon administration of recombinant OPG into normal mice. In vitro, osteoclast differentiation from precursor cells is blocked in a dose-dependent manner by recombinant OPG. Furthermore, OPG blocks ovariectomy-associated bone loss in rats. These data show that OPG can act as a soluble factor in the regulation of bone mass and imply a utility for OPG in the treatment of osteoporosis associated with increased osteoclast activity

Three-dimensional structure of β-cell-specific zinc transporter, ZnT-8, predicted from the type 2 diabetes-associated gene variant SLC30A8 R325W

<p>Abstract</p> <p>Background</p> <p>We examined the effects of the R325W mutation on the three-dimensional (3D) structure of the β-cell-specific Zn²⁺(zinc) transporter ZnT-8.</p> <p>Methods</p> <p>A model of the C-terminal domain of the human ZnT-8 protein was generated by homology modeling based on the known crystal structure of the <it>Escherichia coli </it>(<it>E. coli</it>) zinc transporter YiiP at 3.8 Å resolution.</p> <p>Results</p> <p>The homodimer ZnT-8 protein structure exists as a Y-shaped architecture with Arg325 located at the ultimate bottom of this motif at approximately 13.5 Å from the transmembrane domain juncture. The C-terminal domain sequences of the human ZnT-8 protein and the <it>E. coli </it>zinc transporter YiiP share 12.3% identical and 39.5% homologous residues resulting in an overall homology of 51.8%. Validation statistics of the homology model showed a reasonable quality of the model. The C-terminal domain exhibited an αββαβ fold with Arg325 as the penultimate N-terminal residue of the α2-helix. The side chains of both Arg325 and Trp325 point away from the interface with the other monomer, whereas the ε-NH₃⁺group of Arg325 is predicted to form an ionic interaction with the β-COO^-group of Asp326 as well as Asp295. An amino acid alignment of the β2-α2 C-terminal loop domain revealed a variety of neutral amino acids at position 325 of different ZnT-8 proteins.</p> <p>Conclusions</p> <p>Our validated homology models predict that both Arg325 and Trp325, amino acids with a helix-forming behavior, and penultimate N-terminal residues in the α2-helix of the C-terminal domain, are shielded by the planar surface of the three cytoplasmic β-strands and hence unable to affect the sensing capacity of the C-terminal domain. Moreover, the amino acid residue at position 325 is too far removed from the docking and transporter parts of ZnT-8 to affect their local protein conformations. These data indicate that the inherited R325W abnormality in SLC30A8 may be tolerated and results in adequate zinc transfer to the correct sites in the pancreatic islet cells and are consistent with the observation that the <it>SLC30A8 </it>gene variant R325W has a low predicted value for future type 2 diabetes at population-based level.</p