Induction of Androgen Formation in the Male by a TAT-VDAC1 Fusion Peptide Blocking 14-3-3ɛ Protein Adaptor and Mitochondrial VDAC1 Interactions

Low testosterone (T), a major cause of male hypogonadism and infertility, is linked to mood changes, fatigue, osteoporosis, reduced bone-mass index, and aging. The treatment of choice, T replacement therapy, has been linked with increased risk for prostate cancer and luteinizing hormone (LH) suppression, and shown to lead to infertility, cardiovascular diseases, and obesity. Alternate methods to induce T with lower side effects are desirable. In search of the mechanisms regulating T synthesis in the testes, we identified the 14-3-3ɛ protein adaptor as a negative regulator of steroidogenesis. Steroidogenesis begins in mitochondria. 14-3-3ɛ interacts with the outer mitochondrial membrane voltage-dependent anion channel (VDAC1) protein, forming a scaffold that limits the availability of cholesterol for steroidogenesis. We report the development of a tool able to induce endogenous T formation. Peptides able to penetrate testes conjugated to 14-3-3ɛ site of interaction with VDAC1 blocked 14-3-3ɛ-VDAC1 interactions while at the same time increased VDAC1-translocator protein (18 kDa) interactions that induced steroid formation in rat testes, leading to increased serum T levels. These peptides rescued intratesticular and serum T formation in adult male rats treated with gonadotropin-releasing hormone antagonist, which dampened LH and T production.     

Enhancement of arm and leg locomotor coupling with augmented cutaneous feedback from the hand

Cutaneous feedback from the hand could assist with coordination between the arms and legs during locomotion. Previously we used a reduced walking model of combined arm and leg (ARM&LEG) cycling to examine the separate effects of rhythmic arm (ARM) and leg (LEG) movement. Here we use this same paradigm to test the modulation H-reflexes with and without interlimb cutaneous conditioning evoked by stimulating a nerve innervating the hand (superficial radial, SR). It was hypothesized that both ARM and LEG would contribute significantly to suppression of H-reflex amplitude during ARM&LEG. We also predicted a conservation of interlimb cutaneous conditioning during movement and an interaction between arm and leg rhythmic movement control. Subjects were seated in a recumbent ARM&LEG cycle ergometer and maintained a low-level soleus contraction for all tasks. H-reflex amplitude was facilitated by cutaneous conditioning evoked by stimulation of the SR nerve. H-reflex amplitudes were taken from recruitment curves and included modulation of 50% H max and H max. The suppressive effect of arm was less than that for LEG and ARM&LEG, while suppression during LEG and ARM&LEG were generally equivalent. For H-reflexes conditioned by cutaneous input, amplitudes during ARM&LEG instead were in between those for ARM and LEG modulation. Multiple regression analysis revealed a significant contribution for arm only in trials when SR stimulation was used to condition H-reflex amplitudes. We suggest that there is a measurable interaction between neural activity regulating arm and leg movement during locomotion that is specifically enhanced when cutaneous input from the hand is present.     

A hematoma detector-a practical application of instrumental motion as signal in near infra-red imaging

In this paper we discuss results based on using instrumental motion as a signal rather than treating it as noise in Near Infra-Red (NIR) imaging. As a practical application to demonstrate this approach we show the design of a novel NIR hematoma detection device. The proposed device is based on a simplified single source configuration with a dual separation detector array and uses motion as a signal for detecting changes in blood volume in the dural regions of the head. The rapid triage of hematomas in the emergency room will lead to improved use of more sophisticated/expensive imaging facilities such as CT/MRI units. We present simulation results demonstrating the viability of such a device and initial phantom results from a proof of principle device. The results demonstrate excellent localization of inclusions as well as good quantitative comparisons.     

Disseminated Bisifusarium infection following toxic epidermal necrolysis in a child with B-cell acute lymphoblastic leukemia

Fusarium is a polyphyletic genus of plant pathogens, members of which can cause opportunistic human infections with varying superficial and systemic presentations, including disseminated infections which typically occur in immunocompromised patients and have a poor prognosis. Treatment is challenging due to intrinsic resistance to many antifungal agents, and antifungal susceptibility testing is therefore essential. Early suspicion, isolation of the organism, and prompt initiation of management are crucial to improving survival. We present a case of disseminated Bisifusarium infection following toxic epidermal necrolysis in a child with B-cell acute lymphoblastic leukemia, successfully treated with liposomal amphotericin B, voriconazole, flucytosine, and terbinafine.     

Chronic Administration of Methylphenidate Induced Degeneration of Spermatogenesis in Adult Male Rats

Pharmaceutical Chemistry Journal - Apossible mechanism of methylphenidate (MPH) action upon reproductive system, in particular on the fertility rate of male mice, is discussed.     

Relationship between airway reactivity induced by methacholine or ultrasonically nebulized distilled cold water and BAL fluid cellular constituents in patients with sulfur mustard gas-induced asthma.

The objective of this article was to evaluate the relationship between the bronchial reactivity to methacholine and distilled cold water and inflammatory bronchial alveolar lavage (BAL) cells in mustard gas-induced asthma. This was a randomized, crossover clinical study set in a university hospital. The patients were 17 veterans with mustard gas-induced asthma and 17 normal veterans as a control group. Inhalation challenges with ultrasonically nebulized distilled water and methacholine and BAL via bronchoscopy and were performed in all patients and subjects. All patients did sustain a 20% fall in FEV(1) after methacholine, whereas two of them did not with distilled cold water. The patients were sensitive to distilled cold water with a median PD20 of 8.44 +/- 6.55 mL and sensitive to methacholine with the median PC20 of 4.88 +/- 4.22 mg/mL. Significant correlation was found between PC20 of methacholine and PD20 of distilled cold water (r = -0.74, p = 0.005). The proportion of BAL macrophages was significantly lower in patients with asthma than in the control group (p = 0.001). The proportions of lymphocytes and neutrophils were similar in the two groups. The percentage of eosinophils was higher in BAL fluid from the asthmatics compared with that in BAL fluid from the control group (p < 0.001). The percentage of the BAL eosinophils significantly correlated with both PC20 of methacholine (r = - 0.58, p = 0.01) and PD20 of distilled cold water (r = -0.81, p = 0.002). No relationship between PC20 of methacholine or PD20 of distilled cold water was found for other inflammatory BAL cells. This study showed that in patients with mustard gas-induced asthma, the degree of airway responsiveness to both methacholine and distilled water was associated with the percentage of BAL eosinophils.     

Transparent nanocrystalline yttria-stabilized-zirconia calvarium prosthesis

Laser-based diagnostics and therapeutics show promise for many neurological disorders. However, the poor transparency of cranial bone (calvaria) limits the spatial resolution and interaction depth that can be achieved, thus constraining opportunity in this regard. Herein, we report preliminary results from efforts seeking to address this limitation through use of novel transparent cranial implants made from nanocrystalline yttria-stabilized zirconia (nc-YSZ). Using optical coherence tomography (OCT) imaging of underlying brain in an acute murine model, we show that signal strength is improved when imaging through nc-YSZ implants relative to native cranium. As such, this provides initial evidence supporting the feasibility of nc-YSZ as a transparent cranial implant material. Furthermore, it represents a crucial first step towards realization of an innovative new concept we are developing, which seeks to eventually provide a clinically-viable means for optically accessing the brain, on-demand, over large areas, and on a chronically-recurring basis, without need for repeated craniectomies.From the Clinical EditorIn this study, transparent nanocrystalline yttria-stabilized-zirconia is used as an experimental “cranium prosthesis” material, enabling the replacement of segments of cranial bone with a material that allows for optical access to the brain on a recurrent basis using optical imaging methods such as OCT.