Progestogens in postmenopausal hormone therapy and the risk of breast cancer

Hormone therapy is the treatment of choice for the alleviation of menopausal symptoms and the treatment of urogenital atrophy. In women with an intact uterus a progestogen must be added to estrogen therapy to prevent endometrial hyperplasia and cancer. There is a wide variety of marketed progestogens which differ in their pharmacological properties according to their structure. Convincing evidence from both clinical trials and epidemiological studies indicates that combined estrogen–progestogen therapy confers a higher risk of breast cancer compared to estrogen monotherapy. Concerning the different types of progestogens, data from large observational studies suggest that natural progesterone and dydrogesterone are associated with a lower risk of breast cancer compared with the other progestins. Observational studies, furthermore, indicate that sequential estrogen–progestogen regimens may lead to a lower risk elevation compared to continuous regimens. The effect of tibolone on breast cancer is unclear. Concluding, both the type of the progestogen and the mode of HT administration may have an impact on breast cancer risk.     

An in vivo experimental study on osteopenia in diabetic rats

Osteopenia is a significant problem associated with Diabetes mellitus. Osteopenia may result in an increased delay in healing of bone fractures and subsequently affect the quality of life. We evaluated the immunohistochemical localization of TRAIL and its receptor DR5 in the femoral bone of 10-week-old Sprague-Dawley male rats treated with sesame oil (control, group 1), streptozotocin (STZ), a diabetes inducer (group 2), l-NAME, a general inhibitor of NOS activity (group 3), l-arginine (group 4), (arginine acts as a NO substrate) and iNOS immunostaining in group 1 and group 4. Histological and histochemical findings showed decreased growth of metaphyseal cartilage (which was thinner), decreased osteoid surface, and reduced mineral apposition rate in STZ- and l-NAME-treated rats. These findings confirm that bone formation is impaired in diabetic osteopenia. l-arginine supplementation seems to prevent diabetes-induced bone alterations and preserve the calcification process, allowing synthesis of new bone matrix. The immunohistochemical study revealed increased immunostaining of TRAIL and DR5 in osteoblastic cells of the diaphysis (pre-metaphysis) and epiphysis treated with STZ and l-NAME, related to activation of osteoblastic apoptotic death, while the group receiving l-arginine was comparable to the control group and the higher indications of iNOS activity that may reflect its induction by l-arginine administration. The action of l-arginine suggests that increased NO synthesis and availability is potentially useful for effective prevention and treatment of diabetic osteopenia.     

Effects of vitamin K2 on the development of osteopenia in rats as the models of osteoporosis

Vitamin K2 is widely used for the treatment of osteoporosis in Japan. To understand the effects of vitamin K2 on bone mass and bone metabolism, we reviewed its effects on the development of osteopenia in rats, which characterizes models of osteoporosis. Vitamin K2 was found to attenuate the increase in bone resorption and/or maintain bone formation, reduce bone loss, protect against the loss of trabecular bone mass and its connectivity, and prevent the decrease in strength of the long bone in ovariectomized rats. However, combined treatment of bisphosphonates and vitamin K2 had an additive effect in preventing the deterioration of the trabecular bone architecture in ovariectomized rats, while the combined treatment of raloxifene and vitamin K2 improved the bone strength of the femoral neck. The use of vitamin K2 alone suppressed the increase in trabecular bone turnover and endocortical bone resorption, which attenuated the development of cancellous and cortical osteopenia in orchidectomized rats. In addition, vitamin K2 inhibited the decrease in bone formation in prednisolone-treated rats, thereby preventing cancellous and cortical osteopenia. In sciatic neurectomized rats, vitamin K2 suppressed endocortical bone resorption and stimulated bone formation, delaying the reduction of the trabecular thickness and retarding the development of cortical osteopenia. Vitamin K2 also prevented the acceleration of bone resorption and the reduction in bone formation in tail-suspended rats, which counteracted cancellous bone loss. Concomitant use of vitamin K2 with a bisphosphonate ameliorated the suppression of bone formation and more effectively prevented cancellous bone loss in tail-suspended rats. Vitamin K2 stimulated renal calcium reabsorption, retarded the increase in serum parathyroid hormone levels, and attenuated cortical bone loss primarily by suppressing bone resorption in calcium-deficient rats while maintaining the strength of the long bone in rats with magnesium deficiency. These findings suggest that vitamin K2 may not only stimulate bone formation, but may also suppress bone resorption. Thus, vitamin K2 could regulate bone metabolism in rats, which represented the various models of osteoporosis. However, the effects of vitamin K2 on bone mass and bone metabolism seem to be modest.     

Low amplitude, high frequency strains imposed by electrically stimulated skeletal muscle retards the development of osteopenia in the tibiae of hindlimb suspended rats

The purpose of this study was to determine the extent to which high frequency, low amplitude skeletal muscle contractions, induced using electrical stimulation, could prevent or retard disuse osteopenia. Ten minutes of 30 Hz electrical stimulation was delivered, 5 days a week, during a 4 week rat-hindlimb suspension protocol. Each pulse generated a peak compressive dynamic strain on the tibia of approximately 200 microepsilon. We hypothesized that the electrical stimulation protocol would significantly reduce the loss of tibial bone mineral density compared to the contralateral control tibia that did not receive electrical stimulation. Compared to the contralateral control limb, the tibia of the stimulated limb had significantly higher bone mineral density and enhanced newly formed bone in the tibial diaphysis. The diaphysis, specifically the posterior bone cortex, of the tibia of the limb receiving the stimulation also demonstrated substantially larger mineral-binding fluorochrome biomarker within the osteocyte lacunae and canalicular volumes. Although the protocol did not prevent disuse osteopenia the evidence suggests that it was effective at reducing the extent of the osteopenia. One possibility for this outcome may be the insensitivity of bone to static, compared to dynamic compressive loads. In the present study there was a considerable static component to the compressive loads that accounted for a large component of the peak load generated by the stimulated skeletal muscle. Nevertheless, the results provide impetus for further development of the methods by which muscle contraction-induced loading of bone can be clinically exploited.     

Voltage-gated sodium channel organization in neurons: Protein interactions and trafficking pathways

In neurons, voltage-gated sodium (Nav) channels underlie the generation and propagation of the action potential. The proper targeting and concentration of Nav channels at the axon initial segment (AIS) and at the nodes of Ranvier are therefore vital for neuronal function. In AIS and nodes, Nav channels are part of specific supra-molecular complexes that include accessory proteins, adhesion proteins and cytoskeletal adaptors. Multiple approaches, from biochemical characterization of protein–protein interactions to functional studies using mutant mice, have addressed the mechanisms of Nav channel targeting to AIS and nodes. This review summarizes our current knowledge of both the intrinsic determinants and the role of partner proteins in Nav targeting. A few fundamental trafficking mechanisms, such as selective endocytosis and diffusion/retention, have been characterized. However, a lot of exciting questions are still open, such as the mechanism of differentiated Nav subtype localization and targeting, and the possible interplay between electrogenesis properties and Nav concentration at the AIS and the nodes.     

青少年特发性脊柱侧凸矫形手术肩平衡评价指标的研究进展

青少年特发性脊柱侧凸（AIS）是一种常见的青少年脊柱畸形,其发病原因不明,外科矫形手术是治疗AIS的常规手段。随着AIS矫形技术的不断发展,术后肩平衡问题也越来越受到外科医师及患者的关注。一直以来,AIS矫形手术肩平衡的评价指标缺乏统一标准,给术前制定手术方案及术后评价肩平衡矫形效果带来困难。目前相关研究多集中于对AIS术前及术后影像学指标、外观指标及患者主观感知度进行评价,以期获得各项指标与肩平衡的相关性,最终指导临床实践。本文回顾了近年来发表的相关文献,通过综述相关指标（影像学指标、外观指标及患者主观感知度）与AIS矫形手术肩平衡相关性的研究进展,为今后临床及基础研究提供参考。     

Analysis of Single Nucleotide Polymorphism in Adolescent Idiopathic Scoliosis in Korea: For Personalized Treatment

Purpose

The incidence of adolescent idiopathic scoliosis (AIS) has rapidly increased, and with it, physician consultations and expenditures (about one and a half times) in the last 5 years. Recent etiological studies reveal that AIS is a complex genetic disorder that results from the interaction of multiple gene loci and the environment. For personalized treatment of AIS, a tool that can accurately measure the progression of Cobb''s angle would be of great use. Gene analysis utilizing single nucleotide polymorphism (SNP) has been developed as a diagnostic tool for use in Caucasians but not Koreans. Therefore, we attempted to reveal AIS-related genes and their relevance in Koreans, exploring the potential use of gene analysis as a diagnostic tool for personalized treatment of AIS therein.

Materials and Methods

A total of 68 Korean AIS and 35 age- and sex-matched, healthy adolescents were enrolled in this study and were examined for 10 candidate scoliosis gene SNPs.

Results

This study revealed that the SNPs of rs2449539 in lysosomal-associated transmembrane protein 4 beta (LAPTM4B) and rs5742612 in upstream and insulin-like growth factor 1 (IGF1) were associated with both susceptibility to and curve severity in AIS. The results suggested that both LAPTM4B and IGF1 genes were important in AIS predisposition and progression.

Conclusion

Thus, on the basis of this study, if more SNPs or candidate genes are studied in a larger population in Korea, personalized treatment of Korean AIS patients might become a possibility.     

Impact of metabolic complications on antiretroviral treatment adherence: Clinical and public health implications

Antiretroviral therapy (ART) is an effective strategy for preventing disease progression of HIV infection, particularly when patients adhere closely to the treatment regimen. However, ART medications can cause side effects, including metabolic complications that can impact patients’ adherence levels. Selected chronic complications associated with ART include lipodystrophy, hyperlipidemia, insulin resistance and diabetes, peripheral neuropathy, and bone disorders such as osteopenia/osteoporosis. In this article, we review the effects of these metabolic complications on ART adherence and approaches to prevent or reverse them     

Indirubin-3′-monoxime inhibits β-amyloid-induced neurotoxicity in neuroblastoma SH-SY5Y cells

Increasing evidence suggests that the inappropriate activation of cyclin-dependent kinases (CDKs) could induce neuronal apoptosis in Alzheimer's disease (AD), which means that the pharmacological inhibitors of cell-cycle progression may effectively impede the development or progression of AD. Indirubin-3′-monoxime (IMX), a known effective inhibitor of CDKs, has been shown to have therapeutic effects on learning and memory deficits induced by beta-amyloid (Aβ) intracerebroventricular infusion in rats. In the present study, we investigated the neuroprotective effects of IMX on Aβ_25–35-induced neuronal apoptosis and its potential mechanisms in human neuroblastoma SH-SY5Y cells. Aβ_25–35-induced apoptosis, characterized by decreased cell viability, neuronal DNA condensation, and fragmentation, was associated with an increase in tau protein hyperphosphorylation. IMX, however, attenuated Aβ_25–35-induced cell death in a dose-dependent manner. Furthermore, expression of hyperphosphorylation tau protein was significantly decreased with IMX treatment. Our study suggests that IMX may usefully prevent or delay the neuronal loss of AD.     

There may be a same mechanism of the left-right handedness and left-right convex curve pattern of adolescent idiopathic scoliosis

The mechanism of the left-right handedness and pathogenesis of adolescent idiopathic scoliosis (AIS) is still unclear. We speculated that the pathogenesis of AIS may different from the mechanism of the laterality of convex curve pattern in AIS patients. This laterality may have correlation with the right dominance of handedness. The location and gravity of heart and aorta may determine the trend of lateral flexion and axial rotation of normal spine, which may be the reason of both left-right handedness and left-right convex curve pattern of AIS.     

Could genetic determinants of inner ear anomalies be a factor for the development of idiopathic scoliosis?

Adolescent idiopathic scoliosis (AIS) is a condition characterized by a three-dimensional structural deformity of the spine. It is the most common type of spine deformity occurring in children aged 10 to maturity. Although the etiology of AIS still remains unknown, the role of genetic factors in the development of idiopathic scoliosis is widely accepted. However, to date no causative genes of AIS have been identified. Recently, the semicircular canals, which are part of the inner ear, were found to be morphologically abnormal in idiopathic scoliosis patients. Here we hypothesized that genetic predisposition to inner ear anomalies in AIS patients may be a strong factor in the generation of idiopathic scoliosis. The proposed idea is that gene defects could impair the development of the semicircular canals. A malformation of semicircular canals might affect the transmission of sensory signal about rotational movement of the body to the central nervous system; leading to an alteration in the neuronal circuit of balance. This will in turn affect body posture and results in the initiation of the curvature of the spine. This hypothesis may provide new insights in the understanding of the pathophysiologic mechanisms of idiopathic scoliosis. It can also offer hopes for potential early prediction of scoliosis.     

Nitric oxide synthase inhibition attenuates l-DOPA-induced dyskinesias in a rodent model of Parkinson's disease

Chronic l-DOPA pharmacotherapy in Parkinson's disease is often accompanied by the development of abnormal and excessive movements known as l-DOPA-induced dyskinesia. Rats with 6-hydroxydopamine lesion of dopaminergic neurons chronically treated with l-DOPA develop a rodent analog of this dyskinesia characterized by severe axial, limb, locomotor and orofacial abnormal involuntary movements. While the mechanisms by which these effects occur are not clear, they may involve the nitric oxide system. In the present study we investigate if nitric oxide synthase inhibitors can prevent dyskinesias induced by repeated administration of l-DOPA in rats with unilateral 6-hydroxydopamine lesion. Chronic l-DOPA (high fixed dose, 100 mg/kg; low escalating dose, 10–30 mg/kg) treatment induced progressive dyskinesia changes. Two nitric oxide synthase inhibitors, 7-nitroindazole (1–30 mg/kg) and NG-nitro-l-arginine (50 mg/kg), given 30 min before l-DOPA, attenuate dyskinesia. 7-Nitroindazolee also improved motor performance of these animals in the rota-rod test. These results suggest the possibility that nitric oxide synthase inhibitors may be useful to treat l-DOPA-induced dyskinesia.     

青少年特发性脊柱侧凸的术后并发症的研究进展

青少年特发性脊柱侧凸(AIS)是一种复杂的脊柱三维畸形,其病因目前尚不清楚.矫形手术是AIS的常规治疗手段.随着矫形手术的广泛应用,术后并发症也逐渐被临床医师关注.一直以来,关于术后并发症的病因无统一共识.尤其是手术相关的病因对于矫形手术的成败至关重要.目前的研究多集中于对某一种并发症进行阐述评价,以明确其手术相关的病...     

Mesogastrium: A fifth route of metastasis in gastric cancer?

Radical gastrectomy for gastric cancer with D2 lymph node dissection has been widely applied in advanced gastric cancer. It is believed that such surgery should extremely sweep away local–regional tumor tissues and cancer cells and thoroughly prevent tumor recurrence in situ. However, for most patients with advanced gastric cancer, tumor local–regional recurrence has been proven unavoidable. This study has found that isolated cancer cells, separate from the primary lesion and lymph nodes, existed in the mesogastrium of resected gastric cancer specimens, leading to the hypothesis that these cancer cells may have infiltrated the mesogastrium through a fifth metastasis route (here named Metastasis V) which is distinct from the other four classic metastasis routes, and cannot be resected by conventional radical gastrectomy with D2 lymph node dissection. Local–regional recurrence might be closely associated with these cancer cells in the mesogastrium, and therefore, complete mesogastrium excision (CME) should be imperative and become the third radical principle for radical gastrectomy.     

Embryonic vaccines against cancer: An early history

Almost 100 years have passed since the seminal observations of Schöne showing that vaccination of animals with fetal tissue would prevent the growth of transplantable tumors. Many subsequent reports have affirmed the general idea that immunologic rejection of transplantable tumors, as well as prevention of carcinogenesis, may be affected by vaccination with embryonic/fetal material. Following a decade of intense research on this phenomenon during ∼ 1964–1974, interest appears to have waned. This earlier experimental work may be particularly pertinent in view of the rising interest in so-called cancer stem cells. We believe that further work – perhaps involving the use of embryonic stem cells as immunogens – is warranted and that the results reviewed herein support the concept that vaccination against the appearance of cancers of all kinds is a real possibility.     

Anatomical study of the pelvis in patients with adolescent idiopathic scoliosis

Standing posterior-anterior (PA) radiographs from our clinical practice show that the concave and convex ilia are not always symmetrical in patients with adolescent idiopathic scoliosis (AIS). Transverse pelvic rotation may explain this observation, or pelvic asymmetry may be responsible. The present study investigated pelvic symmetry by examining the volume and linear measurements of the two hipbones in patients with AIS. Forty-two female patients with AIS were recruited for the study. Standing PA radiographs (covering the thoracic and lumbar spinal regions and the entire pelvis), CT scans and 3D reconstructions of the pelvis were obtained for all subjects. The concave/convex ratio of the inferior ilium at the sacroiliac joint medially (SI) and the anterior superior iliac spine laterally (ASIS) were measured on PA radiographs. Hipbone volumes and several distortion and abduction parameters were measured by post-processing software. The concave/convex ratio of SI-ASIS on PA radiographs was 0.97, which was significantly < 1 (P < 0.001). The concave and convex hipbone volumes were comparable in patients with AIS. The hipbone volumes were 257.3 ± 43.5 cm(3) and 256.9 ± 42.6 cm(3) at the concave and convex sides, respectively (P > 0.05). Furthermore, all distortion and abduction parameters were comparable between the convex and concave sides. Therefore, the present study showed that there was no pelvic asymmetry in patients with AIS, although the concave/convex ratio of SI-ASIS on PA radiographs was significantly < 1. The clinical phenomenon of asymmetrical concave and convex ilia in patients with AIS in preoperative standing PA radiographs may be caused by transverse pelvic rotation, but it is not due to developmental asymmetry or distortion of the pelvis.     

Scalp acupuncture enhances local brain regions functional activities and functional connections between cerebral hemispheres in acute ischemic stroke patients

This study aimed to explore the changes in functional connections between cerebral hemispheres and local brain regions functional activities in patients with acute ischemic stroke (AIS) treated with International Standard Scalp Acupuncture (ISSA). Thirty patients with middle cerebral artery AIS in the dominant hemisphere were selected and randomly divided into two groups such as the control group and the scalp acupuncture group, with 15 patients in each group. Patients in the control group were treated with conventional Western medicine, while patients in the scalp acupuncture group received ISSA (acupuncture at the parietal midline [MS5], acupuncture at the left anterior parietotemporal oblique line [MS6] and acupuncture at the left posterior parietotemporal oblique line [MS7]) for one course of treatment. All patients were evaluated for treatment efficacy and received whole brain resting state functional magnetic resonance imaging (Rs-fMRI) scan before and after treatment. The observational indicators included: (a) the National Institutes of Health Stroke Scale (NIHSS) scores and the simplified Fugl-Meyer Assessment (SFMA) scores; (b) analyses of the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo) and voxel-mirrored homotopic connectivity (VMHC). The results showed a significant difference in the NIHSS scores before and after treatment in the scalp acupuncture group compared with the control group (p < .05), indicating that patients improved better after scalp acupuncture treatment. Compared with the control group, the VMHC, ALFF and ReHo values in the scalp acupuncture group increased after treatment. The VMHC values increased in the brain regions dominated by bilateral BA6 and BA8; the ALFF values increased in the left BA39 and the adjacent superior temporal gyrus and middle temporal gyrus; and the ReHo values increased in the brain regions extending from left middle temporal gyrus (including BA21) to BA37, and the brain regions extending from the left BA40 and angular gyrus to BA7. The present study indicated that scalp acupuncture can specifically strengthen the functional activities of the brain regions related to sensory integration, language processing and motor coordination in the middle aged and elderly patients with AIS of the dominant cerebral hemisphere, and can strengthen bilateral frontal lobe motor control. This study may provide a scientific basis for the clinical application of ISSA treatment in patients with AIS, and may also provide a preliminary research basis for further animal experiments.     

The clinical and molecular spectrum of androgen insensitivity syndromes

Androgen insensitivity syndromes (AIS) are due to end-organ resistance to androgenic steroids in males leading to defective virilization of the external genitalia. The phenotype encompasses a wide array of genital ambiguity and may range from completely female to undervirilized but unequivocally male with infertility. This disorder is caused by mutations of the androgen receptor and is an X-linked recessive trait. We have studied 47 patients with AIS and have characterized the underlying molecular abnormality in the androgen receptor gene. Twenty patients had complete AIS and twenty-seven had partial AIS. Of the latter, 11 were of predominantly female phenotypic appearance and gender was assigned accordingly, while 16 were raised as males. Within the group of complete AIS, two patients had gross deletions within the gene, one had a small deletion, and one had an insertion. In the other patients with complete AIS, as well as all individuals with partial AIS, single nucleotide substitutions within the coding region were detected, each leading to an amino acid alteration. Seven codons were involved in more than one mutation in different cases. In addition, in one patient with spinal and bulbar muscular atrophy, an elongation of a glutamine-repeat was characterized. We conclude that mutations in the androgen receptor gene may be present throughout the whole coding region. However, our study provides evidence that several mutational hot spots exist. © 1996 Wiley-Liss, Inc.     

The impact of early environmental interventions on structural plasticity of the axon initial segment in neocortex

Plasticity of the axon initial segment (AIS) is a newly discovered type of structural plasticity that regulates cell excitability. AIS plasticity has been reported to happen during normal development of neocortex and also in a few pathological conditions involving disruption of the inhibition/excitation balance. Here we report on the impact of early environmental interventions on structural plasticity of AIS in the mouse neocortex. C57BL/6 mice were raised in standard or enriched environment (EE) from birth up to the time of experiments and were injected with saline or MK‐801 [N‐Methyl‐D‐Aspartate (NMDA) receptor antagonist, 1 mg/kg] on postnatal days (P) 6–10. We used Ankyrin G immunoreactivity to mark the AIS of cortical neurons in two sub‐regions of frontal cortex (frontal association area, FrA and secondary motor cortex, M2) and in the secondary visual cortex (V2). In 1‐month‐old mice, the mean AIS length differed between three areas, with the shortest AISs being observed in V2. Postnatal MK‐801 or EE led to shortening of AIS only in the frontal areas. However, exposure to EE restored AIS shortening induced by MK‐801. Chronic postnatal MK‐801 results in structural plasticity of AIS exclusive to the frontal cortex. EE may modify underlying neuronal mechanisms resulting in restoration of AIS length.

     

A comparison of four techniques to measure anterior and posterior vertebral body heights and sagittal plane wedge angles in adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis (AIS) is a three-dimensional (3D) spinal deformity of unknown aetiology. Increased growth of the anterior part of the vertebrae known as anterior overgrowth has been proposed as a potential driver for AIS initiation and progression. To date, there has been no objective evaluation of the 3D measurement techniques used to identify this phenomenon and the majority of previous studies use 2D planar assessments which contain inherent projection errors due to the vertebral rotation which is part of the AIS deformity. In this study, vertebral body (VB) heights and wedge angles were measured in a test group of AIS patients and healthy controls using four different image analysis and measurement techniques. Significant differences were seen between the techniques in terms of VB heights and VB wedge angles. The low variability, and the fact that the rotation and tilt of the deformed VBs are taken into account, suggests that the proposed technique using the full 3D orientation of the vertebrae is the most reliable method to measure anterior and posterior VB heights and sagittal plane wedge angles in 3D image data sets. These results have relevance for future investigations that aim to quantify anterior overgrowth in AIS patients for comparison with healthy controls.