Optimizing human in vivo dosing and delivery of β-alanine supplements for muscle carnosine synthesis

Interest into the effects of carnosine on cellular metabolism is rapidly expanding. The first study to demonstrate in humans that chronic β-alanine (BA) supplementation (~3-6 g BA/day for ~4 weeks) can result in significantly augmented muscle carnosine concentrations (>50%) was only recently published. BA supplementation is potentially poised for application beyond the niche exercise and performance-enhancement field and into other more clinical populations. When examining all BA supplementation studies that directly measure muscle carnosine (n=8), there is a significant linear correlation between total grams of BA consumed (of daily intake ranges of 1.6-6.4 g BA/day) versus both the relative and absolute increases in muscle carnosine. Supporting this, a recent dose-response study demonstrated a large linear dependency (R2=0.921) based on the total grams of BA consumed over 8 weeks. The pre-supplementation baseline carnosine or individual subjects' body weight (from 65 to 90 kg) does not appear to impact on subsequent carnosine synthesis from BA consumption. Once muscle carnosine is augmented, the washout is very slow (~2%/week). Recently, a slow-release BA tablet supplement has been developed showing a smaller peak plasma BA concentration and delayed time to peak, with no difference in the area under the curve compared to pure BA in solution. Further, this slow-release profile resulted in a reduced urinary BA loss and improved retention, while at the same time, eliciting minimal paraesthesia symptoms. However, our complete understanding of optimizing in vivo delivery and dosing of BA is still in its infancy. Thus, this review will clarify our current knowledge of BA supplementation to augment muscle carnosine as well as highlight future research questions on the regulatory points of control for muscle carnosine synthesis.

Steerable intravitreal inserts for drug delivery: in vitro and ex vivo mobility experiments

The progress of wet age-related macular degeneration can now be controlled by intravitreal drug injection. This approach requires repeated injections, which could be avoided by delivering the drug to the retina. Intraocular implants are a promising solution for drug delivery near the retina. Currently, their accurate placement is challenging, and they can only be removed after a vitrectomy. In this paper, we introduce an approach for minimally invasive retinal drug delivery using magnetic intraocular inserts. We briefly discuss the electromagnetic-control system for magnetic implants and then focus on evaluating their ability to move in the vitreous humor. The mobility of magnetic intraocular implants is estimated in vitro with synthesized vitreous humors, and ex vivo with experiments on cadaver porcine eyes. Preliminary results show that with such magnetic implants a vitrectomy can be avoided.

Anti-infective therapy of peri-implantitis with adjunctive local drug delivery or photodynamic therapy: six-month outcomes of a prospective randomized clinical trial

To compare the adjunctive clinical effects in the non-surgical treatment of peri-implantitis with either local drug delivery (LDD) or photodynamic therapy (PDT).

Osseointegration: the slow delivery of BMP-2 enhances osteoinductivity

Although the placement of dental and orthopedic implants is now generally a safe, reliable and successful undertaking, the functional outcome is less assured in patients whose bone-healing capacity is compromised. To enhance peri-implant osteogenesis in these individuals, BMP-2 could be locally administered. However, neither a free suspension nor an implant-adsorbed depot of the agent is capable of triggering sustained bone formation. We hypothesize that this end could be achieved by incorporating BMP-2 into the three-dimensional crystalline latticework of a bone-mineral like, calcium-phosphate implant coating, where from it would be liberated gradually - as the inorganic layer undergoes osteoclast-mediated degradation - not rapidly, as from an implant-adsorbed (two-dimensional) depot. To test this postulate, we compared the osteoinductive efficacies of implant coatings bearing either an incorporated, an adorbed, or an incorporated and an adsorbed depot of BMP-2 at a maxillary site in miniature pigs. The implants were retrieved 1, 2 and 3 weeks after surgery for the histomorphometric analysis of bone formation within a defined 'osteoinductive' space. At each juncture, the volume of newly-formed bone within the osteoinductive space was greatest around implants that bore a coating-incorporated depot of BMP-2, peak osteogenic activity being attained during the first week and sustained thereafter. In the other groups, the temporal course of bone formation was variable, and the peak levels were not sustained. The findings of this study confirm our hypothesis: they demonstrate that we now have at our disposal a means of efficaciously augmenting and expediting peri-implant bone formation. Clinically, this possibility would render the process of implant placement a safer and a more reliable undertaking in patients whose bone-healing capacity is compromised, and would also permit a curtailment of the postoperative recovery period by a forestallment of the mechanical-loading phase.

Photodynamic drug delivery enhancement in tumours does not depend on leukocyte-endothelial interaction in a human mesothelioma xenograft model

The pre-treatment of tumour neovessels by low-level photodynamic therapy (PDT) improves the distribution of concomitantly administered systemic chemotherapy. The mechanism by which PDT permeabilizes the tumour vessel wall is only partially known. We have recently shown that leukocyte-endothelial cell interaction is essential for photodynamic drug delivery to normal tissue. The present study investigates whether PDT enhances drug delivery in malignant mesothelioma and whether it involves comparable mechanisms of actions.

Novel ADAMTS13 mutations in an obstetric patient with upshaw-schulman syndrome

Upshaw-Schulman syndrome (USS) is a rarely reported congenital form of thrombotic thrombocytopenic purpura (TTP) that results from mutations in the ADAMTS13 gene. Many USS patients are diagnosed during the second or third trimester of their first pregnancy. We present a patient diagnosed with USS following retinal detachments and intrauterine fetal demise at 34 weeks of gestation. The patient's plasma was tested for ADAMTS13 activity, inhibitor, and antibody. Subsequently, she and her first-degree relatives had ADAMTS13 gene sequencing. Initially, the patient was found to have an ADAMTS13 activity of <5% in the absence of an ADAMTS13 inhibitor (FRETS assay) or antibody (immunoassay). Repeat studies in the months following hospital discharge showed persistent, undetectable ADAMTS13 activity and she was given a clinical diagnosis of USS. Molecular sequencing demonstrated two novel missense mutations in the ADAMTS13 gene: one in the maternal exon 17 (p.Ala690Thr due to nucleotide substitution c.2068 G>A) and another in the paternal exon 22 (p.Arg915Cys due to nucleotide substitution c.2746 C>T). In addition to being compound heterozygous for two ADAMTS13 mutations, the patient also had two maternally inherited single nucleotide polymorphisms: p.P618A (exon 16) and p.A732V (exon 18). Her parents and only sister had normal or near-normal ADAMTS13 activity. Each was heterozygous for one of the novel missense mutations. This case highlights the importance of molecular analysis of the ADAMTS13 gene in patients and family members when the severe ADAMTS13 deficiency does not appear to be autoimmune in nature. J. Clin. Apheresis, 2012. © 2012 Wiley Periodicals, Inc.

Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies

In a retrospective cohort study undertaken in 12 European countries, 249 female narcoleptic patients with cataplexy (n = 216) and without cataplexy (n = 33) completed a self-administrated questionnaire regarding pregnancy and childbirth. The cohort was divided further into patients whose symptoms of narcolepsy started before or during pregnancy (308 pregnancies) and those in whom the first symptoms of narcolepsy appeared after delivery (106 pregnancies). Patients with narcolepsy during pregnancy were older during their first pregnancy (P < 0.001) and had a higher body mass index (BMI) prior to pregnancy (P < 0.01). Weight gain during pregnancy was higher in narcoleptic patients with cataplexy (P < 0.01). More patients with narcolepsy-cataplexy during pregnancy had impaired glucose metabolism and anaemia. Three patients experienced cataplexy during delivery. The rate of caesarean sections was higher in the narcolepsy-cataplexy group compared to the narcolepsy group (P < 0.05). The mean birth weight and gestational age of neonates were within the normal range and did not differ across groups. Neonatal care was affected adversely by symptoms of narcolepsy in 60.1% of those with narcolepsy during pregnancy. This study reports more obstetric complications in patients with narcolepsy-cataplexy during pregnancy; however, these were not severe. This group also had a higher BMI and higher incidence of impaired glucose metabolism during pregnancy. Caesarian section was conducted more frequently in narcolepsy-cataplexy patients, despite cataplexy being a rare event during delivery. Furthermore, symptoms of narcolepsy may render care of the infant more difficult.

Stress and pain response of neonates after spontaneous birth and vacuum-assisted and cesarean delivery

The objective of the study was to compare the stress response and pain expression of newborns (NBs) in the early postpartum period.

Rectal paracetamol in newborn infants after assisted vaginal delivery may increase pain response

To assess the efficacy of paracetamol (acetaminophen) for neonatal pain relief.