Effects of streptozotocin-induced diabetes on leg muscle contractile properties and motor neuron morphology in rats

Skeletal muscle fiber subtypes are differentially sensitive to diabetes-related pathology; For example, fast-twitch muscles exhibit severe decreases in contraction force while slow-twitch muscles demonstrate prolonged half-relaxation time. However, such alterations have only been examined after a relatively short period following diabetes onset, with no information available regarding muscle damage caused by longer disease periods (>20 weeks). This study examined alterations in the contractile properties of the medial gastrocnemius (fast-twitch) and soleus (slow-twitch) muscles, as well as morphological changes in their motor neurons 12 and 22 weeks after diabetes onset. Adult male Wistar rats were divided into diabetic (12- or 22-week post-streptozotocin injection) and age-matched control groups. Electrically evoked maximum twitch and tetanic tension were recorded from leg muscles. Additionally, motor neuron number and cell body size were examined. At 12 weeks after diabetes onset, decreases in twitch force were observed predominantly in medial gastrocnemius muscles, while soleus muscles exhibited prolonged half-relaxation time. However, these differences became ambiguous at 22 weeks, with decreased twitch force and prolonged half-relaxation time observed in both muscles. On the other hand, reduction in soleus motor neurons was observed 12 weeks after diabetes onset, while medial gastrocnemius motor neurons were diminished at 22 weeks. These data indicate that experimental diabetes induces differential damage to medial gastrocnemius and soleus muscles as well as motor neurons. These diabetes-induced differences may partly underlie the differential deficits observed in gastrocnemius and soleus.     

Estimated number of off‐target candidate sites for antisense oligonucleotides in human mRNA sequences

Antisense oligonucleotide (ASO) therapeutics are single‐stranded oligonucleotides which bind to RNA through sequence‐specific Watson–Crick base pairings. A unique mechanism of toxicity for ASOs is hybridization‐dependent off‐target effects that can potentially occur due to the binding of ASOs to complementary regions of unintended RNAs. To reduce the off‐target effects of ASOs, it would be useful to know the approximate number of complementary regions of ASOs, or off‐target candidate sites of ASOs, of a given oligonucleotide length and complementarity with their target RNAs. However, the theoretical number of complementary regions with mismatches has not been reported to date. In this study, we estimated the general number of complementary regions of ASOs with mismatches in human mRNA sequences by mathematical calculation and in silico analysis using several thousand hypothetical ASOs. By comparing the theoretical number of complementary regions estimated by mathematical calculation to the actual number obtained by in silico analysis, we found that the number of complementary regions of ASOs could be broadly estimated by the theoretical number calculated mathematically. Our analysis showed that the number of complementary regions increases dramatically as the number of tolerated mismatches increases, highlighting the need for expression analysis of such genes to assess the safety of ASOs.     

Lateralization of Neurobiological Response in Adolescents with Post-Traumatic Stress Disorder Related to Severe Childhood Sexual Abuse: the Tri-Modal Reaction (T-MR) Model of Protection

This study inquires into neurobiological response to stress and its clinical correlates among adolescents with post-traumatic stress disorder (PTSD). Structural magnetic resonance imaging (MRI) measures of cerebral anatomy were carried out on 23 female adolescents with PTSD related to severe childhood sexual abuse and 21 matched healthy controls. Clinician Administered PTSD Scale for Children and Adolescents, Adolescent Dissociative Experiences Scale, Childhood Trauma Questionnaire, Schedule for Affective Disorders and Schizophrenia for School Age Children, Beck Depression Scale, and a set of neuro-cognitive tests were administered to all participants. Compared to controls, PTSD group bilaterally had smaller amygdala, hippocampus, anterior cingulate, and thinner prefrontal cortex but normal thalamus. Further analyses within the PTSD group suggested an association between symptoms of PTSD and sizes of right brain structures including smaller amygdala but larger hippocampus and anterior cingulate. Thinner right prefrontal cortex and larger right thalamus seemed to be related to denial and response prevention, respectively. Being related to both hemispheres, dissociative amnesia was negatively associated with proportion of the right amygdala to right thalamus and to both left and right prefrontal cortex. Suggesting a neuro-protective effect against traumatic stress at least through adolescence, depersonalization–derealization and identity alteration were correlated with thicker left prefrontal cortex. Unlike the lateralization within PTSD group, correlations between regions of interest were rather symmetrical in controls. The graded response to stress seemed to be aimed at mental protection by lateralization of brain functions and possibly diminished connection between two hemispheres. A Tri-Modal Reaction (T-MR) Model of protection is proposed.     

Lumped parameter model for hemodynamic simulation of congenital heart diseases

The recent development of computer technology has made it possible to simulate the hemodynamics of congenital heart diseases on a desktop computer. However, multi-scale modeling of the cardiovascular system based on computed tomographic and magnetic resonance images still requires long simulation times. The lumped parameter model is potentially beneficial for real-time bedside simulation of congenital heart diseases. In this review, we introduce the basics of the lumped parameter model (time-varying elastance chamber model combined with modified Windkessel vasculature model) and illustrate its usage in hemodynamic simulation of congenital heart diseases using examples such as hypoplastic left heart syndrome and Fontan circulation. We also discuss the advantages of the lumped parameter model and the problems for clinical use.     

New mouse model of skeletal muscle atrophy using spiral wire immobilization

Introduction: Disuse‐induced skeletal muscle atrophy is a serious concern; however, there is not an effective mouse model to elucidate the molecular mechanisms. We developed a noninvasive atrophy model in mice. Methods: After the ankle joints of mice were bandaged into a bilateral plantar flexed position, either bilateral or unilateral hindlimbs were immobilized by wrapping in bonsai steel wire. Results: After 3, 5, or 10 days of immobilization of the hip, knee, and ankle, the weight of the soleus and plantaris muscles decreased significantly in both bilateral and unilateral immobilization. MAFbx/atrogin‐1 and MuRF1 mRNA was found to have significantly increased in both muscles, consistent with disuse‐induced atrophy. Notably, the procedure did not result in either edema or necrosis in the fixed hindlimbs. Conclusions: This method allows repeated, direct access to the immobilized muscle, making it a useful procedure for concurrent application and assessment of various therapeutic interventions. Muscle Nerve 54 : 788–791, 2016     

Reform of Japan's NTP and its technical perspectives

The 1951 Tuberculosis Control Law of Japan is now faced with tremendous changes that have occurred during the last 50 years in tuberculosis epidemiology and in the environment in tuberculosis control implementation. The law is also challenged with the shift of the paradigm for the National Tuberculosis (TB) Programme. In order to respond properly to these changes, the Tuberculosis Panel of the Health Science Council of the Ministry of Health, Labor and Welfare submitted its report for the amendment of the law in March 2002. Based on this report, a new Tuberculosis Control Law was passed in Parliament last June, and related decrees of the Cabinet and the Ministry are now being revised in preparation for it's enactment in April 2005. In this special lecture, the main points and framework of the revisions were discussed with the perspective of the development of new technical innovations relevant to each area of the revised TB control legislation. 1. Case detection. There will be a shift from the current "indiscriminate" screening scheme to a selective one regarding periodic mass health examination. Only subjects aged 65 or older will be eligible for the screening, supplemented with selected occupational groups who are considered to be at a higher risk of TB, or may be a danger to others if they develop TB, such as health-care providers and school teachers. In addition, local autonomies are responsible for offering screening to the socio-economic high-risk populations, such as homeless people, slum residents, day laborers, and/or workers in small businesses. This means that the efforts of the autonomies are critical for the new system to be effective. The extra-ordinary examination will be limited to only the patient's contacts, and will be mandatory for those contacts so they cannot refuse to be examined by the Health Center. The public services used in the contact investigations will be greatly facilitated by such new technologies as DNA fingerprinting of TB bacilli and a new diagnostic of TB infection using whole-blood interferon-gamma determination (QuantiFERON). The quality of clinical diagnosis and monitoring of treatment should also be improved by introducing an external quality assurance system of commercial laboratory services. 2. Chemoprophylaxis. Although not explicitly defined in the new legislation, the expansion and improvement of chemoprophylaxis to cover anyone with any risk of clinical development of TB would have a tremendous effect in Japan, especially since 90% of patients who developed TB were infected tens of years ago. These technical innovations in diagnosis of TB infection will be very helpful. Development of new drug regimens for the preventive treatment is also badly needed. 3. Immunization. Prior to the amendment of the Law, the BCG vaccination of students entering primary and junior high schools has been already abandoned. In order to encourage the early primary vaccination for infants, the new Law will adopt the direct vaccination scheme in which babies will be given the BCG vaccine without tuberculin testing. This program will be implemented safely, only if it is given to young babies, e.g., less than one year old, as defined by the decree. It is essential to maintain the high level of vaccination coverage under the new program. The autonomy may encounter difficulty mobilizing client babies shortly after their birth (only one year, as compared with the current four years). To avoid the possible, though very rare, adverse health effects due to the vaccination of infected babies, careful questioning should be conducted regarding the risk of exposure to infection prior to vaccination. A ready course of treatment and examinations for abnormal reactions after vaccination (Koch's phenomenon) is also warranted. 4. Treatment and patient care: The revised Law clearly states the governmental responsibility for treating TB patients in close cooperation with a doctor. This is an important legal basis for the expansion of the DOTS Japan version. While the development of new anti-tuberculosis drugs will be realized in the near future, Japan still has to overcome the issue of improper practice of treatment, as well as the government's slow process for approving new drugs to be used for multi-drug resistant TB and non-tuberculous mycobacterioses. 5. Prefectural TB Control Plan: In order to resolve the problems specific to the respective prefectures in terms of epidemiological parameters or available resources, the new Law requests every prefecture to develop its own TB control plan. In order for the new TB Control Law to be effective, strong government commitment supported by technological innovation is mandatory. It is for that reason that the Japanese Society of Tuberculosis should aggressively join the global movement to stop TB along with the general public of Japan.