Motoneuronal reflex firing during vibration of the muscle and gamma loop activation

Summary The reflex response firing pattern of spinal alpha motoneuronal units due to low amplitude and high frequency vibration of the muscle, and concomitant stimulation of the peripheral stump of the cut ventral root, were investigated in decerebrated cats.The threshold for firing of motoneuronal units across the gamma loop was lowered when vibration of the muscle was applied together with fusimotor stimulation. Vibration of the muscle, when applied together with long-term stimulation of the peripheral stump of the cut ventral root, revealed the presence of gamma system influence through the loop, even when a considerable number of gamma motor fibres had not yet been excited. Thus, the extent of gamma influence through the loop during extrafusal contraction was higher when the spindles were excited by vibration of the muscle than was the case when ventral root stimulation was applied separately.These results may serve as an estimate of the ability of the gamma loop to act against changes in muscle length.     

Work-Induced potassium changes in muscle venous effluent blood measured by ion-specific electrodes

Summary Modified Walker's liquid ion-exchanger microelectrodes were employed for measuring changes of K⁺ concentration in venous effluent blood from the cat gastrocnemius muscle during and after isometric tetani of various duration induced by indirect stimulation. The time course of these changes was obtained and the overall loss of K⁺ from a working muscle could thus be estimated. By comparing present results in the venous blood and previous findings of K⁺ concentration changes in the muscle extracellular space, a concentration gradient was found between the muscle and venous effluent blood.The authors wish to acknowledge the assistance of Dr. J. L. Walker in developing the ion-specific microelectrodes and for supplying them with silicone oil and Corning ion-exchanger.     

Stocco dos Santos X-linked mental retardation syndrome: clinical elucidation and localization to Xp11.3-Xq21.3

Mental retardation (MR) affects an estimated 2-3% of the population. A considerable fraction of mental retardation is due to X-linked genes. Of these genes, about 136 are responsible for syndromic X-linked MR (XLMR). One such XLMR syndrome, Stocco dos Santos, was first described in 1991. This family was re-visited, which allowed further delineation of the clinical phenotype. Additionally, linkage analysis was conducted, which resulted in the localization of this XLMR syndrome to the pericentric region, Xp11.3 to Xq21.1, with a maximum LOD score of 3.14 at loci AR and DXS983.     

Synthesis and immunogenicity of hepatitis B virus envelope antigen expressed by recombinant vaccinia virus

Summary Five different recombinant vaccinia viruses expressing the envelope antigen of hepatitis B virus (HBsAg) under the control of the P_7·5 promoter were constructed. Cell cultures infected with some of the recombinant viruses synthesized both middle (M) and major surface (S) protein of HBsAg. It was shown that the length of the nontranslated sequence preceding preS2-ATG influenced the extracellular or intracellular HBV antigen distribution and the preS2:S antigen ratio. Some recombinants synthesized an M protein that was enlarged by additional 35 amino acids of preS1 domain and was entirely retained within the infected cells. Antibody responses to the S and preS2 antigens in mice revealed significant differences in the immunogenicity of individual recombinants.     

Transdermal Permeation and Skin Retention of Diclofenac and Etofenamate/Flufenamic Acid From Over-the-Counter Pain Relief Products

Topical pain relief products differ in the type of drug, concentration, and formulation. All these factors influence the drug transit through the skin barrier, and its eventual retention in the skin as a reservoir for subsequent release. In addition, the drug potency can be different, which is important for the product efficacy. We studied here ex vivo human skin permeation and retention of five over-the-counter NSAID gels containing 2.32% diclofenac (DIC) and 5–10% etofenamate (ETF). The potency of the permeated/retained drug amounts were compared using a composite parameter, the Index of Relative Topical Anti-inflammatory Activity (IRTAA), which is calculated as the product of the skin permeation/retention and the drug relative potency. The IRTAAs of the DIC gel were 94–667-fold higher and 72–208-fold higher for transdermal delivery and skin retention, respectively, than IRTAAs of the ETF gels. These superior IRTAAs indicate that DIC delivered by this topical formulation would achieve a higher bioactivity and would form a potent drug reservoir relevant for its subsequent long-lasting release.     

e-Derma – a Novel Wireless Dermatoscopy System

Cutaneous Melanoma (CM) is a malignant tumour, and is one of the most rapidly growing cancers. Discovering a melanoma in the early stages of the disease is extremely difficult and, as such, only an invasive disease stage can be identified easily with the naked eye. Dermatoscopy is a diagnostic method intended to maximise early detection of CM performed by the dermatoscopy system. To address the limitations of existing systems a novel, wireless digital dermatoscopy system is presented for providing high-resolution images. It integrates a wire-free camera operation and offers a safe transfer of captured images to the computer. The working process of available dermatoscopy systems was studied, which are the most commonly used in everyday dermatology practice. Some findings, like operability, image quality, scalability, user-friendliness, and safeness, were used for the development of an e-Derma dermatoscopy system. An assessment method was performed by a group of dermatoscopy trained dermatologists to evaluate the quality of the testing images. Finally, a laboratory evaluation of images in regard to different parameters like sharpness, colour representation and illumination was performed with the side-by-side comparison of images of available dermatoscopy systems. e-Derma is a novel dermatoscopy system, which eliminates some limitations of existing systems and provides high-quality images. A novel low-budget highly capable dermatoscopy system is presented. The integrated wireless image transfer technology eliminates the movement limitations of a therapist. The image resolution is not limited by the integrated camera; it is easily upgradable with a wide range of on market alternative or improved camera models.     

Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency

DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile.     

Effects of cell penetrating Notch inhibitory peptide conjugated to elastin-like polypeptide on glioblastoma cells

Notch pathway was found to be activated in most glioblastomas (GBMs), underlining the importance of Notch in formation and recurrence of GBM. In this study, a Notch inhibitory peptide, dominant negative MAML (dnMAML), was conjugated to elastin-like polypeptide (ELP) for tumor targeted delivery. ELP is a thermally responsive polypeptide that can be actively and passively targeted to the tumor site by localized application of hyperthermia. This complex was further modified with the addition of a cell penetrating peptide, SynB1, for improved cellular uptake and blood–brain barrier penetration. The SynB1–ELP1–dnMAML was examined for its cellular uptake, cytotoxicity, apoptosis, cell cycle inhibition and the inhibition of target genes’ expression. SynB1–ELP1–dnMAML inhibited the growth of D54 and U251 cells by inducing apoptosis and cell cycle arrest, especially in the presence of hyperthermia. Hyperthermia increased overall uptake of the polypeptide by the cells and enhanced the resulting pharmacological effects of dnMAML, showing the inhibition of targets of Notch pathway such as Hes-1 and Hey-L. These results confirm that dnMAML is an effective Notch inhibitor and combination with ELP may allow thermal targeting of the SynB1–ELP1–dnMAML complex in cancer cells while avoiding the dangers of systemic Notch inhibition.     

Evaluation of brivaracetam: a new drug to treat epilepsy

Introduction: High prevalence of therapy-resistant epilepsy demands development of anticonvulsants with new mechanisms of action. Brivaracetam is an analogue of levetiracetam which binds to the synaptic vesicle protein 2A (SV2A) and decreases release of excitatory neurotransmitters.

Areas covered: Relevant published studies were searched for by predefined strategy in MEDLINE, EBSCO and SCINDEKS electronic databases. Brivaracetam is effective as adjunctive therapy for uncontrolled partial-onset seizures with or without secondary generalization in patients 16 years and older with epilepsy. It reduces baseline-adjusted focal seizure frequency per week from 7.3 to 12.8% over placebo. Adverse events rate in patients with brivaracetam is not higher than in patients with placebo.

Expert opinion: Brivaracetam is an important step forward in the treatment of therapy-resistant partial-onset seizures with or without secondary generalization. Its development was systematic and targeted. Due to its efficacy and excellent safety profile, it is likely that brivaracetam will be often prescribed. In future, efficacy and safety of brivaracetam should be tested in monotherapy settings and also in the first-line therapy of partial-onset seizures.