Kyle J. Norton (Scholar)
Health article writer and researcher; Over 10.000 articles and research papers have been written and published on line, including world wide health, ezine articles, article base, healthblogs, selfgrowth, best before it's news, the karate GB daily, etc.,.
Named TOP 50 MEDICAL ESSAYS FOR ARTISTS & AUTHORS TO READ by Disilgold.com Named 50 of the best health Tweeters Canada - Huffington Post
Nominated for shorty award over last 4 years
Some articles have been used as references in medical research, such as international journal Pharma and Bio science, ISSN 0975-6299.
Musculoskeletal disorders (MSDs) are medical condition mostly caused by work related occupations and working environment, affecting patients’ muscles, joints, tendons, ligaments and nerves and developing over time. According to a community sample of 73 females and 32 males aged 85 and over underwent a standardised examination at home, musculoskeletal pain was reported by 57% of those interviewed(1).
Types of Musculo-Skeletal disorders in elder(2)
1. Osteoarthritis
2. Gout
3. Rheumatoid Arthritis
4. Polymalagia Arthritis
5. Cervical myleopathy and spinal canal stenosis
6. Osteoporosis
7. Low back pain
8. Fibromyalgia
Osteoporosis
Osteoporosis is defined as a condition of thinning of bone and bone tissues as a result of the loss of bone density over a long period of time. It is a widespread degenerative disease of skeletal joints and often associated with senescence in vertebrates due to excessive or abnormal mechanical loading of weight-bearing joints, arising from heavy long-term use or specific injuries(6).
The Causes
A. Primary causes
Bone loss is a natural aging process occurs during the normal aging process. Primary osteoporosis is a type of osteoporosis due to involutional losses(65) causes by hormone imbalance associated with aging(59), In men, it is the result of low testosterone(59) and, in women, additional losses related to natural menopause(60)(61). The abnormal secretion(deficiency) of GH due to the effects of age, sex, diet, exercise, stress, and other hormones may also induce the loss of bone density(4)(5) as a result of reduced interaction with GH receptors on osteoblasts(6)(7). Sleep deprivation generally suppresses GH release, also can contribute to the onset of bone loss(8).
2. Secondary causes
According to the study by Department of Medicine, College of Physicians and Surgeons, Columbia University, other disorders or medication exposures causes of osteoporosis are referred as "secondary" osteoporosis(62) also include
1. Other hormone imbalance
Thyroid dysfunction such as hyperthyroidism and hypothyroidism can interfere with the secretion of thyroid hormone of which can have a direct impart on the bone mineral density(11)(10). Bone mineral density deficiency has been found to associate to patient with parathyroid hormone excess(12)(13), especially at the lumbar spine, total hip, and femoral neck in postmenopausal women with osteoporosis(13).
Massachusetts General Hospital, insisted that patient with a higher-than-normal levels of the hormone prolactin in the blood are at higher risk for the development of osteoporosis(14).
Hypogonadism is a condition in which the body doesn't produce enough testosterone due to decrease on alkaline phosphatase (AP), can have a direct influence to the deficiency of bone mineral density, according to Weill Cornell Medical College(16).
"Pituitary disorders, can also influence bone metabolism and cause secondary osteoporosis, induced a significant increase of fracture risk", the Wroclaw Medical University said(17).
2. Calcium deficiency
Calcium, one the mineral has a significant effect on bone turn over in patient with osteoporosis(19), Patient with parathyroid hormone (PTH), the disease with removed calcium from the bone(22) has a progressive link to the early onset of osteoporosis(23). Calcium at dosage of at least 1200 mg has been suggested by researchers in reducing the incidence of non-vertebral and hip fracture(18). Deficiency of vitamin D and calcium in patient with osteoporosis has shown to induced risk of post fracture in associated to the rate of mortality in elder, according to the prospective analysis, conducted by University of Helsinki, Helsinki(20). But the University of Auckland in searching of meta-analyses with data for > 50 000 older adults suggested that calcium with or without vitamin D has only weak, inconsistent effects on fracture, and should not be recommended for fracture prevention in adults with no diagnosed osteoporosis(21).
3. Low serum of Vitamin D
Vitamin D found in a number of food such as liver, and fish oil but abundantly under sunlight has a direct effect for the body in absorb calcium and and phosphate(28) for prevention the onset of osteoporosis(24), through its effect on the control of osteoblast(26) function and bone extracellular matrix mineralization(25), according to the Erasmus Medical Center Rotterdam. In deed, according to the VU University Medical Center, Vitamin D used for stimulate the absorption of calcium may have a direct influence on bone mineral density and bone turnover as vitamin D deficiency is associate to patient with osteoporosis and fracture bone(27). Dr. Yoshida T and Dr. Stern PH. said" Vitamin D analogues has provided new therapeutic options for increasing bone mineral density and reducing fractures"(28)
Adding to secondary causes of osteoporosis, according to Clarke 2010, Confavreux 2009, Lieben 2009; Zhou 2011 include
4. Oxidative stress
Oxidative stress is an imbalance between production of free radicals and the ability of the body antioxidants in neutralizing its harmful effects. Oxidative stress has shown to damage the cellular components of osteoblasts, causing osteoporosis(29), according to the Shanghai Jiaotong University School of Medicine. In aging population, with estrogen deficiency and increased in reactive oxygen species (ROS) production(31), risk of osteoporosis is in the increase, Dr. Manolagas SC said" (there is) an emerging evidence provides a paradigm shift from the "estrogen-centric" account of the pathogenesis of involutional osteoporosis"(30)
5. Hyperglycemia
Hyperglycemia is a medical condition of elevated blood sugar, often associated to diabetes(32).
Insulin dependent diabetes mellitus is shown to associate with osteoporosis and increased fracture rate as a result of modulate osteoblast gene expression(66), function and bone formation(33).
In deed, Individuals with type 2 diabetes has found to associate to increased fracture risk(68), despite normal bone mineral density (BMD) and high BMI-factors, the joint study said(67).
Interestingly, "Although type 1 diabetes is associated with lower bone density, those with type 2 diabetes usually have elevated bone density. Yet for both types of diabetes, bone appears to be more fragile for a given density" said Dr. Schwartz AV1,Dr. Sellmeyer DE.(69).
6. Inflammation
Would there be an association between osteoporosis and inflammation? According to the study in
patients with chronic pancreatitis, bone bone turnover and highest systematic inflammation was shown to be associated patients with osteoporosis(70). In post-menopausal women, withdrawal of estrogen exhibited the production of pro-inflammatory cytokines, the primary mediators in accelerated bone loss(71), reduced osteoclastic bone resorption(71) of that induced risk of osteoporosis(71). According to the Medical University Innsbruck, chronic inflammatory diseases such as inflammatory bowel diseases (IBD) not only affect bone metabolism but also are frequently associated with the presence of osteoporosis(72)..
7. Metabolic syndrome(3)
Metabolic syndrome is the collection of symptoms of which can lead to cardiovascular disease and diabetes(73)(74). According to the study by Tongji University School of Medicine, metabolic syndrome has a negative effect on bone mineral density in men but positive effect in women(75).
In support to above claim, the Military Hospital Mohammed V, Morocco showed that menopause women with MS have a protective effect of osteoporosis due to higher BMD at the hip and spine(76).
[In adolescent, low bone mineral density or secondary osteoporosis is more frequent in young people and is generally due to an underlying cause(9)
8. Nutritional deficiencie
Calcium and vitamin D in many research are best known for theirs effectiveness in managed osteoporosis(77). Children and adult with long term deficiency of vitamin D have found to associate with low mineralization in theskeleton, leading to rickets(78). According to study, Poor nutritional conditions in early life are linked to greater prevalence of OA due the gradual deterioration of function(9).
(see calcium and Vitamin D for more information)]
9. Long-term Glucocorticoid therapy
Glucocorticoid is chemical used to relieve pain caused by inflammation as a result of the over active immune system in induced certain diseases, such as allergies, asthma, autoimmune diseases, and sepsis. The chemical is found to associate to the development of osteoporosis due to its adverse effect in induced apoptosis of steoblasts(79). According to the Chiba University study, glucocorticoid-induced osteoporosis (GIOP) in children with autoimmune diseases by inflating the a high level of bone turnover markers, interferring with femoral neck bone mineral density (BMD), serum bone alkaline phosphatase, and urinary deoxypyridinolin(80)
10. Immunosuppressive therapy
Medication used to suppress the immune system to prevent rejection of transplanted organs and tissues may also induced osteoporosis(83). Patient with solid organ transplant (SOT) patient often are found to have low levels of calcium and vitamin D due to the effects of the medication induced malnutrition(81) In fact, reduced exposure of glucocorticoid and appropriate physical activity before and after transplant has shown to aid the future management of osteoporosis in these patient(81)(82).
Dr. Bia M said" Pretransplant period or early post transplant and should include assessment of fracture risk as well as metabolic factors. Bone mineral density measurement is recommended in all patients even if its predictive value for fracture risk in the transplant population..... Management of bone disease should be directed toward decreasing fracture risk as well as improving bone density"(84)
12. Medication
Medication used for treatment of chronic diseases such as cancers and diabetes have found to associate to the development of osteoporosis, according to The University of Texas MD Anderson Cancer Center(85) and joint study(86) respectively. In patient with schizophrenia, the use of antipsychotic drugs have shown to induce hyperprolactinemia through inhibited hypothalamo-pituitary-gonadal axis and reduced bone mineral density(15)
Other medication may induce osteoporosis include, aromatase inhibitors, gonadotropin-releasing hormone agonists, thyroid replacement therapy, antiepileptics, antidepressants, antipsychotics, lithium, gastric acid lowering agents, thiazolidinediones, loop diuretics, heparins and warfarin, vitamin A and cyclosporine, according to the study of Drug-induced Osteoporosis in the Older Adult led posted in Medscape(87).
13. Medical conditions
13. HIV infected patient
Menopausal women with HIV-infected Postmenopausal Women is found to associated to an additional risk of predictor for osteoporosis and fractures. According to the study, the prevalence of osteoporosis in patient with HIV infected is much higher in uninfected postmenopausal women(89),
13.2. Spinal cord injuriesPatient with spinal cord injuries are associate to bone resorption rate is hypercalciuria, low PTH, and 1,25 (OH)2 vitamin D of that exhibit the risk of decreased bone density and increased risk of fracture, such as lower extremity fractures, according to DR. Ott SM(92). The injures can also can lead to abnormal calcium and phosphate metabolism and the parathyroid hormone (PTH)-vitamin D axis of that increse risk of osteoporosis(93).
In deed, according to the Swiss Paraplegic Center, spinal core injures can cause long-term changes in bone metabolism, bone mineral density, quantitative ultrasound parameters, and fracture incidence(94).
13.3. Weight loss surgery
Weight loss surgery such as gastric bypass is found to increased risk of lower bone mineral density, especially in the femoral neck and among patients who had greater baseline BMD and greater reduction in ghrelin concentrations(95). The American University of Beirut-Medical Center study also concerned of the decreased mechanical loading, calcium, metabolic acidosis, and elevated peptide YY(97) and vitamin D malabsorption(97) with secondary hyperparathyroidism(97), deficiency in other nutrients in patient with weight loss surgery(96).
13.4. Premature ovarian failure
Premature ovarian failure is an early onset of menopause in women younger than age of 40 with the medical occurrence of amenorrhea, hypergonadotropinemia and estrogen deficiency(98) of which can lead to bone loss and increased risk psychological stress and mortility(99).
In a retrospective analysis of 223 consecutive new referrals conducted by King's College Hospital NHS Foundation, women with premature ovarian insufficiency are associated to the risk of low bone minerals density(100).
14. Eating disorder
Anorexia nervosa (AN), type of eating disorder can induce loss of bone mineral density(91), impaired bone quality(91) and increased fracture risk(91) as a result of abnormal production of estrogen(91) in influence to weight loss(91) and menstrual disorder(90).
15. Menstrual disorder
Menstrual disorder is a result of the abnormal production of hormones in women menstrual cycle.
15.1. Abnormal production of prolactin is produced by the anterior lobe of the pituitar can lead to menstrual disorder. Hyperprolactinaemia cause higher serum prolactin levels of that increase of the risk of osteopenia or/and osteoporosis, according to Medical University of Poznań(101).
15.2. Amenorrhea
Young women with an age when bone formation should still be occurring may put themselves at risk of osteoporosis if amenorrhea is untreated(102).
Dr. Golden NH said" Female athlete triad is a condition ....... characterized by the triad of amenorrhea, disordered eating and osteoporosis"(103).
Arthritis Is Curable
You Can Eliminate Osteoarthritis
By addressing the Underlying Causes through Clinical Trials and Studies
Ovarian Cysts And PCOS Elimination
Holistic System In Existence That Will Show You How To
Permanently Eliminate All Types of Ovarian Cysts Within 2 Months
Back to General health http://kylejnorton.blogspot.ca/
Back to Kyle J. Norton Home page http://kylejnorton.blogspot.ca p/general-health.html
Super foods Library, Eat Yourself Healthy With The Best of the Best Nature Has to Offer
References
(1) Prevalence of rheumatic symptoms, rheumatoid arthritis, ankylosing spondylitis, and gout in Shanghai, China: a COPCORD study by Dai SM1, Han XH, Zhao DB, Shi YQ, Liu Y, Meng JM.(PubMed)
(2) Musculoskeletal Disorders in the Elderly by Ramon Gheno, Juan M. Cepparo, Cristina E. Rosca,1 and Anne Cotten(PMC)
(3) Osteoporosis(Life extension)
(4) Hormone and bone by Francisco Bandeira1, Marise Lazaretti-Castro2, John P. Bilezikian3
(5) Growth hormone and bone by Ohlsson C1, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC.(PubMed)
(6) GH and bone--experimental and clinical studies by Isaksson OG1, Ohlsson C, Bengtsson BA, Johannsson G.(PubMed)
(7) Regulation of bone mass by growth hormone by Olney RC1.(PubMed)
(8) Role of Sleep and Sleep Loss in Hormonal Release and Metabolism by Rachel Leproult and Eve Van Cauter(PMC)
(9) Low bone mineral density in a growth hormone deficient (GHD) adolescent by Anna Capozzi, Silvia Della Casa, Barbara Altieri, and Alfredo Pontecorvi(PMC)
(10) [Osteoporosis in thyroid diseases].[Article in Polish] by Kosińska A1, Syrenicz A, Kosiński B, Garanty-Bogacka B, Syrenicz M, Gromniak E.(PubMed)
(11) [Bone metabolism and thyroid disease. Normalized bone metabolism prevents osteoporosis].[Article in Swedish] by Tørring O1.(PubMed)
(12) Enhancing Effect of Intermittent Parathyroid Hormone Administration on Bone Formation After Titanium Implant Placement in an Ovariectomized Rat Maxilla by Heo HA1, Park SH, Jeon YS, Pyo SW.(PubMed)
(13) Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density inpostmenopausal women with osteoporosis by Leder BZ1, O'Dea LS, Zanchetta JR, Kumar P, Banks K, McKay K, Lyttle CR, Hattersley G.(PubMed)
(14) Hyperprolactinemia and bone mineral density: the potential impact of antipsychotic agents by Naidoo U1, Goff DC, Klibanski A.(PubMed)
(15) Antipsychotic-induced hyperprolactinemia inhibits the hypothalamo-pituitary-gonadal axis and reduces bone mineral density in male patients with schizophrenia by Kishimoto T1, Watanabe K, Shimada N, Makita K, Yagi G, Kashima H.(PubMed)
(16) The effect of hypogonadism and testosterone-enhancing therapy on alkaline phosphatase and bone mineral density by Dabaja AA1, Bryson CF, Schlegel PN, Paduch DA.(PubMed)
(17) Pituitary disorders and osteoporosis by Bolanowski M1, Halupczok J1, Jawiarczyk-Przybyłowska A1.(PubMed)
(18) Calcium citrate and vitamin D in the treatment of osteoporosis by Quesada Gómez JM1, Blanch Rubió J, Díaz Curiel M, Díez Pérez A.(PubMed)
(19) Alfacalcidol reduces accelerated bone turnover in elderly women with osteoporosis by Shiraki M1, Fukuchi M, Kiriyama T, Okamoto S, Ueno T, Sakamoto H, Nagai T.(PubMed)
(20) Post-fracture prescribed calcium and vitamin D supplements alone or, in females, with concomitant anti-osteoporotic drugs is associated with lower mortality in elderly hip fracture patients: a prospective analysis by Nurmi-Lüthje I1, Lüthje P, Kaukonen JP, Kataja M, Kuurne S, Naboulsi H, Karjalainen K.(PubMed)
(21) Should we prescribe calcium or vitamin D supplements to treat or prevent osteoporosis? by Bolland MJ1, Grey A1, Reid IR1.(PubMed)
(22) The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone diseases. II. PTH and bone cells: bone turnover and plasma calcium regulation by Parfitt AM.(PubMed)
(23) Osteoporosis and Parathyroid Disease (Hyperparathyroidism)
(24) Dietary Reference Intakes for Calcium and Vitamin D by Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors.Washington (DC): National Academies Press (US); 2011.(NCBI)
(25) Vitamin D control of osteoblast function and bone extracellular matrix mineralization by van Leeuwen JP1, van Driel M, van den Bemd GJ, Pols HA.(PubMed)(26) Skeletal characterization of an osteoblast-specific vitamin D receptor transgenic (ObVDR-B6) mouse model by Triliana R1, Lam NN2, Sawyer RK3, Atkins GJ4, Morris HA5, Anderson PH6.(PubMed)
(27) The effect of vitamin D on bone and osteoporosis by Lips P1, van Schoor NM.(PubMed)
(28) How vitamin D works on bone by Yoshida T1, Stern PH.(PubMed)
(29) Oxidative damage to osteoblasts can be alleviated by early autophagy through the endoplasmic reticulum stresspathway--implications for the treatment of osteoporosis by Yang YH1, Li B1, Zheng XF1, Chen JW1, Chen K1, Jiang(PubMed)
(30) From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis by Manolagas SC1.(PubMed)
(31) Practicality of intermittent fasting in humans and its effect on oxidative stress and genes related to aging and metabolism by Wegman MP1, Guo MH, Bennion DM, Shankar MN, Chrzanowski SM, Goldberg LA, Xu J, Williams TA, Lu X, Hsu SI, Anton SD, Leeuwenburgh C, Brantly ML.(PubMed)
(32) Diabetic hyperglycemic hyperosmolar syndrome(Medline Plus)
(66) Extracellular glucose influences osteoblast differentiation and c-Jun expression by Zayzafoon M1, Stell C, Irwin R, McCabe LR.(PubMed)
(67) Type 2 diabetes and the skeleton: new insights into sweet bones by Shanbhogue VV1, Mitchell DM2, Rosen CJ3, Bouxsein ML4.(PubMed)
(68) Type 2 diabetes mellitus and fracture risk by Dede AD1, Tournis S2, Dontas I2, Trovas G2.(PubMed)
(69) Diabetes, fracture, and bone fragility by Schwartz AV1, Sellmeyer DE.(PubMed)
(70) An association between abnormal bone turnover, systemic inflammation, and osteoporosis in patients with chronic pancreatitis: a case-matched study by Duggan SN1, Purcell C1, Kilbane M2, O'Keane M2, McKenna M2, Gaffney P3, Ridgway PF1, Boran G3, Conlon KC4.(PubMed)
(71) Osteoporosis and inflammation by Mundy GR1.(PubMed)
(72) Gut, inflammation and osteoporosis: basic and clinical concepts by Tilg H1, Moschen AR, Kaser A, Pines A, Dotan I.(PubMed)
(73) Epidemiology of paediatric metabolic syndrome and type 2 diabetes mellitus by De Ferranti SD1, Osganian SK.(PubMed)
(74) Association between salivary pH and metabolic syndrome in women: a cross-sectional study by Tremblay M1, Brisson D, Gaudet D.(PubMed)
(75) Association between metabolic syndrome and osteoporosis: a meta-analysis by Zhou J1, Zhang Q, Yuan X, Wang J, Li C, Sheng H, Qu S, Li H.(PubMed)
(76) Osteoporosis, vertebral fractures and metabolic syndrome in postmenopausal women by El Maghraoui A1, Rezqi A, El Mrahi S, Sadni S, Ghozlani I, Mounach A.(PubMed)
(77) The use of calcium and vitamin D in the management of osteoporosis by John A Sunyecz(PubMed)
(78) Bone Health and Osteoporosis: A Report of the Surgeon General.
(79) Curcumin alleviates glucocorticoid-induced osteoporosis by protecting osteoblasts from apoptosis in vivo and in vitro by Chen Z1, Xue J2, Shen T1, Ba G1, Yu D1, Fu Q1.(PubMed)
(80) Efficacy of intravenous alendronate for the treatment of glucocorticoid-induced osteoporosis in children with autoimmune diseases by Inoue Y1, Shimojo N, Suzuki S, Arima T, Tomiita M, Minagawa M, Kohno Y.(PubMed)
(81) Osteoporosis in the adult solid organ transplant population: underlying mechanisms and available treatment options by Early C1, Stuckey L1, Tischer S2.(PubMed)
(82) [Glucocorticoid induced osteoporosis].[Article in Croatian] by Anić B, Mayer M.(PubMed)
(83) Bone disease after transplantation: osteoporosis and fractures risk by Kulak CA1, Borba VZ1, Kulak Júnior J2, Custódio MR3.(PubMed)
(84) Evaluation and management of bone disease and fractures post transplant by Bia M1.(PubMed)
(85) National comprehensive cancer network(NCCN research)
(86) Osteoporosis Risk in Type 2 Diabetes Patients by Mishaela R Rubin; Ann V Schwartz; John A Kanis; William D Leslie(Medscape)
(87) Drug-induced Osteoporosis in the Older Adult by Mary Beth O'Connell; Laura M Borgelt; Susan K Bowles; Sheryl F Vondracek(Medscape)
(88) [Bone and Joint Involvement in Celiac Disease].[Article in Czech] by Hoffmanová I1, Sánchez D, Džupa V.(PubMed)
(89) Bone Density and Fractures in HIV-infected Postmenopausal Women: A Systematic Review by Cortés YI, Yin MT, Reame NK.(PubMed)
(90) State of the art systematic review of bone disease in anorexia nervosa by Misra M1, Golden NH2, Katzman DK3(PubMed)
(91) Bone health in anorexia nervosa by Misra M1, Klibanski A.(PubMed)
(92) Osteoporosis in women with spinal cord injuries by Ott SM1.(PubMed)
(93)Osteoporosis after spinal cord injury by Jiang SD1, Dai LY, Jiang LS.(PubMed)
(94) Long-term changes in bone metabolism, bone mineral density, quantitative ultrasound parameters, and fracture incidence after spinal cord injury: a cross-sectional observational study in 100 paraplegic men by Zehnder Y1, Lüthi M, Michel D, Knecht H, Perrelet R, Neto I, Kraenzlin M, Zäch G, Lippuner K.(PubMed)
(95) Changes in bone mineral density after sleeve gastrectomy or gastric bypass: relationships with variations in vitamin D, ghrelin, and adiponectin levels by Carrasco F1, Basfi-Fer K, Rojas P, Valencia A, Csendes A, Codoceo J, Inostroza J, Ruz M.(PubMed)
(96) Bone and mineral metabolism in patients undergoing Roux-en-Y gastric bypass. by Hage MP1, El-Hajj Fuleihan G.(PubMed)
(97) Gastric bypass in obese rats causes bone loss, vitamin D deficiency, metabolic acidosis, and elevated peptide YY by Canales BK1, Schafer AL2, Shoback DM2, Carpenter TO3.(PubMed)
(98) Premature ovarian failure: a review by Nippita TA1, Baber RJ.(PubMed)
(99) Premature ovarian failure: clinical presentation and treatment by Kovanci E1, Schutt AK2.(PubMed)
(100) Fertility desires, choice of hormone replacement and the effect of length of time since menopause on bone density in women with premature ovarian insufficiency: a review of 223 consecutive new referrals to a tertiary centre by Mittal M1, Kreatsa M2, Narvekar N2, Savvas M2, Hamoda H2.(PubMed)
(101) [Hyperprolactinaemia and bone mineral density].[Article in Polish] by Kostrzak A1, Męczekalski B1.(PubMed)
(102) Secondary amenorrhea leading to osteoporosis: incidence and prevention by McGee C1.(PubMed)
(103) A review of the female athlete triad (amenorrhea, osteoporosis and disordered eating). by Golden NH1.(PubMed)