Jacqueline Marie Laurin, M.D.

• Director of Hepatology, Sibley Memorial Hospital
• Assistant Professor of Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/8643043/jacqueline-laurin

Gene defects have been increasingly identified among patients with septo-optic dysplasia infection going around buy zyvox. Holoprosencephaly is a developmental disorder in which there is incomplete separation of the cerebral hemispheres antibiotics for streptococcus viridans uti discount 600mg zyvox free shipping. Both septo-optic dysplasia and holoprosencephaly may represent the consequences of teratogen exposure infection under tongue purchase cheap zyvox on-line. Craniopharyngiomas are nonmalignant epithelial tumors involving the sellar region antibiotics for acne on back purchase zyvox without prescription. Although benign antibiotics jittery generic 600mg zyvox visa, these tumors can infiltrate into the hypothalamus antibiotics japan over counter cheap 600mg zyvox visa, optic chiasm, and local vascular structures. There are two different subtypes of craniopharyngioma-adamantinomatous and papillary. The adamantinomatous form is the most common nonneuroepithelial intracranial lesion in children. The tumor and its treatment often result in hypopituitarism, obesity, and visual deficits. Various regions in the hypothalamus secrete small peptide hormones that use this pathway to regulate pituitary hormone secretion. The neurohypophysis, consisting of unmyelinated axons and axon terminals, extends from the median eminence to the posterior pituitary gland. Aberrant development of the pituitary may be associated with an ectopic location of the posterior pituitary at the base of the hypothalamus in association with absence of the pituitary stalk. Affected individuals manifest varying anterior pituitary hormone deficiencies in the absence of diabetes insipidus. A, Pale optic discs noted on funduscopic examination indicative of optic nerve hypoplasia, which can be associated with septo-optic dysplasia. Clinical features include impaired visual acuity, strabismus, nystagmus, and diencephalic syndrome. Neurofibromatosis type 1 is associated with these tumors, which paradoxically are associated with precocious puberty. Diabetes insipidus can be the presenting endocrine manifestation for germ cell tumors and Langerhans cell histiocytosis. Anterior Pituitary the anterior pituitary, with its diverse cell types and hormonal secretory patterns, controls many important biologic processes. It contains cells that secrete three types of hormones: (1) corticotrophinrelated peptide hormones, (2) glycoprotein hormones, and (3) somatomammotropins. These compounds have great biologic potency with tight regulation of hormone secretion governed by positive and negative feedback signals. Anterior pituitary hormone deficiencies cause subsequent hypofunction in the output of secondary endocrine glands, with substantial consequences for growth and development. Children with midline defects have a higher incidence of hypopituitarism when compared with normal children. Thus, specific alterations in physical appearance should alert physicians to a possible abnormality in anterior pituitary development potentially associated with secondary hormone deficiencies. Many molecular etiologies for autosomal recessive, autosomal dominant, and X-linked disorders affecting anterior pituitary development and function have been elucidated. Heterogeneous, densely enhancing suprasellar mass extending from the pituitary fossa into the hypothalamus and third ventricle. The major known function of prolactin in humans is the initiation and maintenance of lactation. In contrast to other anterior pituitary hormones, prolactin is regulated by tonic inhibition by dopamine secreted by the hypothalamus. Hyperprolactinemia can be observed with pituitary adenomas or secondary to medications, such as neuroleptics, antipsychotics, estrogens, and antihypertensive medications. When hyperprolactinemia is secondary to medications, the prolactin concentrations are generally less than 75 ng/mL. These hormones are synthesized in the hypothalamus and stored in the posterior pituitary gland. Expression of vasopressin and oxytocin genes occurs in the hypothalamic paraventricular and supraoptic nuclei. On magnetic resonance T1-weighted images, the posterior pituitary has characteristic high signal intensity. The presence of this high signal intensity adjacent to the median eminence with absence of the normal pituitary bright spot within the sella on T1-weighted images is evidence of an ectopic posterior pituitary. It is synthesized and carried via axonal transport to the posterior pituitary, its primary site of storage. It has positive effects on carbohydrate, fat, and protein metabolism and causes a decrease in body fat. They are often described as being "cherubic" because of their short stature, excess subcutaneous fat, retarded body proportion changes, and high-pitched voices. Infants with hypopituitarism may present in the early neonatal period with hypoglycemia or prolonged jaundice. After closure of the epiphyses, soft tissue growth of the hands and feet and coarsening of facial features are typically the first clinical manifestations of acromegaly. Diabetes insipidus can result from pituitary tumors, head trauma, infiltrative disease processes (such as Langerhans cell histiocytosis, sarcoidosis, hemochromatosis, and autoimmune hypophysitis), or from any surgery that damages the pituitary gland and hypothalamus. Familial central diabetes insipidus, which is inherited in both recessive and dominant patterns, is rare and has its onset in infancy. Genetic causes of nephrogenic diabetes insipidus include X-linked forms due to mutations in the V2 receptor gene and autosomal forms due to mutations in the aquaporin-2 gene. Psychogenic water drinking, hypercalcemia, hypokalemia, sickle cell anemia, and polycystic kidney disease can also impair renal concentrating ability. This hormone causes contraction of the smooth muscle of the uterus and also of the myoepithelial cells lining the duct of the mammary gland. The thyroid gland is situated in the neck or, in rare cases, at the base of the tongue or in the mediastinum. The gland originates in the floor of the primitive pharynx, near the base of the tongue, approximately 24 days after fertilization, forming initially the thyroid diverticulum. During the elongation of the embryo, the developing thyroid gland moves down anteriorly to the hyoid bone and laryngeal cartilages along a narrow tube, the thyroglossal duct. When reaching its final position anterior to the trachea, the thyroid divides into right and left portions called the thyroid lobes connected by a thin layer of thyroid tissue, the isthmus, which lies ventrally to the second and third tracheal rings. On occasion, the lower portion of the thyroglossal duct fills up with thyroid tissue forming the pyramidal lobe. On occasion, the atrophy of the thyroglossal duct is not complete, leading to the presence of fluid-filled thyroglossal duct cysts, which appear clinically as tense, painless, and movable swellings at any point along the course of the thyroglossal duct. The thyroid gland synthesizes thyroxine (T4) and triiodothyronine (T3); this process is dependent on the availability of iodine. T4 and T3 are metabolized by inner ring deiodination to reverse T3 and diiodothyronine (T2), respectively. After identification of the cricothyroid cartilage, the second and third fingers are moved laterally along the trachea just medial to the sternocleidomastoid muscles. Two distinct lobes are palpable; the right lobe is usually greater in size than the left lobe. The texture of the gland varies with hyperthyroidism and hypothyroidism, the former usually being soft and fleshy, and the latter usually firm or bosselated. Because the thyroid is directly supported by the trachea, having the patient swallow will elevate and depress a palpable gland along with the trachea during the swallowing motion. Restlessness, inability to sit still, emotional lability, short attention span, excessive sweating, decreased school performance, and fatigue may be found. Hyperthyroidism can be due to autoimmune thyroid disease including Graves disease or the hyperthyroid phase of Hashimoto thyroiditis, commonly called hashitoxicosis. The transient hyperthyroidism seen in Hashimoto thyroiditis is related to the release of preformed thyroid hormone from a thyroid gland being disrupted by lymphocytic infiltration. Although rare, thyroid cancer can occur within an autonomously functioning "hot nodule. The hyperthyroid gland can become quite large, as much as three to four times its normal size, and is warm when palpated. Hypothyroidism Hypothyroidism, often associated with a goiter, can be congenital or acquired. Hypothyroidism can be classified as primary when the defect lies in the thyroid gland itself, central when it is due to pituitary dysfunction (referred to as secondary hypothyroidism), or hypothalamic dysfunction (referred to as tertiary hypothyroidism). Iodine deficiency is one of the most common causes of primary acquired hypothyroidism in the world. Because treatment by 3 to 4 weeks old ameliorates these features, newborn screening programs have been implemented to identify Hyperthyroidism Hyperthyroidism refers to excessive thyroid hormone secretion by the thyroid gland. Note the enlarged thyroid gland in a patient with Hashimoto thyroiditis, easily visualized with neck extension. Mild thyromegaly and proptosis or exophthalmos are characteristic findings in patients with Graves disease. Note the coarse facial features, broad nasal bridge, thick lips, and umbilical hernia. Despite the success of screening, thyroid function tests should still be obtained if signs and/or symptoms of congenital hypothyroidism are detected, even in the face of normal screening results. A goiter in an infant with congenital hypothyroidism suggests an enzymatic defect in thyroid hormone biosynthesis, referred to as dyshormonogenesis. As the head falls backward, the neck is elevated and a goiter, if present, will be evident. Acquired hypothyroidism, most frequently due to Hashimoto/ chronic lymphocytic thyroiditis, may present in childhood. Typical features include dry skin, constipation, hair loss, fatigue, cold intolerance, apathy, depressed or delayed relaxation phase of deep tendon reflexes, and weakness. Anti-thyroid antibodies (directed against thyroperoxidase and thyroglobulin) are often detected. Thyroid hormone resistance is a rare cause of either congenital or acquired hypothyroidism. Clinical manifestations (such as mental retardation and delayed bone maturation) have been seen in individuals with generalized thyroid hormone resistance. Other Disorders Affecting Thyroid Function Tests Abnormalities in the serum proteins that transport thyroid hormone do not alter the metabolic state and do not cause thyroid disease. However, they can produce alterations in thyroid hormone concentration in serum and when unrecognized have led to inappropriate treatment. More commonly, abnormal findings on thyroid function tests are found in the setting of a nonthyroidal illness, without preexisting hypothalamic-pituitary and thyroid gland dysfunction. Patients with acute severe nonthyroidal illness may show increased reverse triiodothyronine (rT3) concentrations; rT3 is an inactive metabolite of T4. After recovery from a nonthyroidal illness, these thyroid function test result abnormalities should be completely reversible. Other abnormalities in thyroid function tests without change in the metabolic state are conditions that cause increase in estradiol levels. A lingual thyroid gland is identified with no functioning thyroid tissue in the anatomic thyroid bed. The inserted photographs illustrate the child before onset of acquired hypothyroidism (A), the change in body habitus associated with acquired hypothyroidism (B), and resolution after thyroid replacement at the indicated times (C). Thyroid Nodules and Thyroid Cancer Thyroid nodules and thyroid cancers are more common in children than has been previously reported and thus represent a significant health issue. Recent studies identified thyroid abnormalities in 18% of children using high resolution ultrasound. Although nodules are uncommon in children, the risk for malignancy is higher in children. Approximately 25% of nodules contain malignancy in nodules in children as compared to 5% to 10% in adults. Other neck masses including branchial cyst, thyroglossal cyst, and intrathyroid thymic tissue are also more common in the pediatric population than in adults. Thus, thorough evaluation of pediatric thyroid nodules at a multidisciplinary thyroid center is warranted. This evaluation may include high-resolution ultrasound imaging and fine-needle aspiration, if indicated. The clinical presentation of thyroid cancer often differs between children and adults. However, children may also have lymph node involvement and even pulmonary metastases at the time of diagnosis. Yet, despite extensive disease at clinical presentation, children are much less likely to die from the disease. There are important clinical, molecular and pathological differences in differentiated thyroid cancer among children when compared to adults. For several decades, the treatment of children with thyroid cancer was based on adult treatment guidelines. Recently, a more appropriate risk-stratified treatment and rational end-point for therapy were developed for children. Children with relatively low risk thyroid cancer are treated with close observation after appropriate surgery and do not undergo routine radiofrequency ablation therapy. In the bloodstream, approximately 45% is free, 45% is protein-bound, and 10% is complexed to citrate, sulfate, bicarbonate, and phosphate.

Diseases

• Adenosine monophosphate deaminase deficiency
• Congenital hemolytic anemia
• Pityriasis rubra pilaris
• Procrastination
• Mixed receptive-expressive language disorder
• Dentophobia
• Sclerosing bone dysplasia mental retardation
• Small non-cleaved cell lymphoma
• Hypertonic gingivitus

This easy and highly effective strategy should be a top priority for health care providers worldwide antibiotic xifaxan side effects buy zyvox in united states online. Second antibiotic blue pill buy zyvox 600 mg low cost, the elderly Western population needs to achieve a more optimal vitamin D and calcium status and therefore vitamin D supplementation and calcium intake (>1 g/day) should be implemented as routine care for all elderly subjects antibiotics for scalp acne buy discount zyvox on-line. This strategy has been proven to be safe even when implemented on a very large scale antibiotic resistance reasons purchase generic zyvox from india. Above and beyond these target groups there are no hard data to make valid general recommendations but it seems logical antibiotics for uti when pregnant purchase zyvox 600mg overnight delivery, while waiting for further evidence prophylactic antibiotics for uti guidelines 600 mg zyvox, to try to obtain this minimal adequate vitamin D status for the whole population. Previous situations, where association studies suggested large-scale health benefits from what appeared at first sight to be safe interventions have more frequently been found not to demonstrate health benefits and even to cause harm. Such levels are unlikely to have marked effects on intestinal calcium absorption but may in some individuals have long-term consequences for bone (bone loss and fragility fractures) and maybe muscle function and falls, especially, in the elderly. This severe deficiency is still highly prevalent around the world (overall estimated to affect more than 5% of the world population except in equatorial areas (Table 57A. This deficiency is a situation comparable with iodine or vitamin A deficiency and is in principle easily preventable. Therefore, national and international organizations should implement strategies to eradicate this deficiency and its complications in the near future. According to most recent guidelines this should be implemented fairly systematically in all elderly subjects and even more so in the oldest-old. Daily supplementation could be the preferred method for most of them as they frequently also need some degree of supplementation with calcium. This can and is usually achieved by safe sun exposure and dietary vitamin D intake in the large majority of cases but for some countries or specific target groups a supplementation strategy is needed. There is, however, no cure-all strategy as this depends on climate, skin color, dietary habits, lifestyle, and cultural or other traditions. The implementation of these strategies should be the primary responsibility of national or regional authorities. We hope that our "competing coauthors" of Chapter 57B in the present deliberations will support our recommendations in line with the consensus of most guidelines. We believe that there is at present no evidence that serum levels higher than 30 (up to 40 or maybe 50) ng/mL convey additional health benefits although such levels are probably safe for the large majority of humans. The benefits claimed by others (and our competing coauthors) are based on extrapolations or association studies. Very high levels as found in East African native populations should not be taken as optimal levels but are more likely the maximal levels nature allows amidst plenty of sunlight as to avoid vitamin D toxicity. We strongly recommend that this level should not be exceeded by dietary supplementation. In the absence of proven safety and efficacy such investments of health care resources should be avoided. In addition, long-term oral intake of such high doses of vitamin D has never been found or tested in natural circumstances. As there are a large number of ongoing trials testing the safety and efficacy of higher dosages our recommendations are of course open to revision pending the results of these studies. Levels higher than 45 ng/mL may generate side effects such as falls and fractures and maybe even small increases in mortality rates. Although we consider this conclusion to be at present still speculative, this should, nevertheless, be a signal not to pursue such levels. The consequences of vitamin D status on maternal outcome and long-term outcome of the offspring are still incompletely understood. Appropriate studies in pregnant or lactating women should be a top priority as they frequently have shown a (very) low vitamin D status. While awaiting the results of such studies, we recommend that the guidelines for vitamin intake and vitamin D status applicable for that age group should be carefully implemented. The use of very high doses of vitamin D to replace the vitamin D supplementation of infants or to prevent possible diseases in the offspring is at present not to be recommended without extensive furthers studies. Factors affecting the morbidity of vitamin D deficiency rickets and primary protection. Incidence and characteristics of vitamin D deficiency rickets in New Zealand children: a New Zealand Paediatric Surveillance Unit study. Prevention and consequences of vitamin D deficiency in pregnant and lactating women and children: a symposium to prioritise vitamin D on the global agenda. Determinants of vitamin D status in patients with hip fracture and in elderly control subjects. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Vitamin D status in the elderly: seasonal substrate deficiency causes 1,25-dihydroxycholecalciferol deficiency. Changes in the vitamin D endocrine system and bone turnover after oral vitamin D3 supplementation in healthy adults: results of a randomised trial. Deletion of the vitamin D receptor specifically in the parathyroid demonstrates a limited role for the receptor in parathyroid physiology. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. Effects of high-dose vitamin D2 versus D3 on total and free 25-hydroxyvitamin D and markers of calcium balance. Duodenal calcium absorption in vitamin D receptorknockout mice: functional and molecular aspects. Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. Gene expression profiles in rat intestine identify pathways for 1,25-dihydroxyvitamin D(3) stimulated calcium absorption and clarify its immunomodulatory properties. Mechanisms involved in vitamin D mediated intestinal calcium absorption and in non-classical actions of vitamin D. Intestinal-specific vitamin D receptor null mice maintain normal calcemia but display severe bone loss. Randomized controlled trial of the effects of calcium with or without vitamin D on bone structure and bone-related chemistry in elderly women with vitamin D insufficiency. Vitamin D does not increase calcium absorption in young women: a randomized clinical trial. Calcium malabsorption in the elderly: the effect of treatment with oral 25-hydroxyvitamin D3. Calcium malabsorption in elderly women with vertebral fractures: evidence for resistance to the action of vitamin D metabolites on the bowel. Relationships among vitamin D levels, parathyroid hormone, and calcium absorption in young adolescents. Vitamin D status and sex hormone binding globulin: determinants of bone turnover and bone mineral density in elderly women. Associations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D with bone mineral density, bone mineral density change, and incident nonvertebral fracture. Summary of evidencebased review on vitamin D efficacy and safety in relation to bone health. Serum 25 hydroxyvitamin D, bone mineral density and fracture risk across the menopause. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U. Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation. Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects. Calcium, vitamin D and the vitamin D receptor: impact on prostate and breast cancer in preclinical models. Genomic vitamin D signaling in breast cancer: insights from animal models and human cells. Strengths and limitations of current epidemiologic studies: vitamin D as a modifier of colon and prostate cancer risk. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Vitamin D in the prevention of acute respiratory infection: systematic review of clinical studies. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish Maternity Cohort. Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease. Effect of vitamin D3 supplementation during pregnancy on risk of persistent wheeze in the offspring: a randomized clinical trial. Effects of Vitamin D analogs on gene expression profiling in human coronary artery smooth muscle cells. Cardiomyocytespecific vitamin D receptor gene knockout causes cardiac hypertrophy. Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy. Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis. No improvement in cardiovascular risk factors in overweight and obese subjects after supplementation with vitamin D3 for 1 year. Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D3 synthesis in leptindeficient mice. Predicted 25-hydroxyvitamin D score and incident type 2 diabetes in the Framingham Offspring Study. Associations of serum concentrations of 25-hydroxyvitamin D and parathyroid hormone with surrogate markers of insulin resistance among U. Association of vitamin D with insulin resistance and beta-cell dysfunction in subjects at risk for type 2 diabetes. Adiposity, cardiometabolic risk, and vitamin D status: the Framingham Heart study. Vitamin D status and cardiometabolic risk factors in the United States adolescent population. Closing in on vitamin D action in skeletal muscle: early activity in muscle stem cells Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged > or =60 y. The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials. Interventions for preventing falls in older people in nursing care facilities and hospitals. Maternal vitamin D status and risk of pre-eclampsia: a systematic review and meta-analysis. Princess Anne hospital study, maternal vitamin D status during pregnancy and child outcomes. Effect of vitamin D replacement on maternal and neonatal outcomes: a randomised controlled trial in pregnant women with hypovitaminosis D. Maternal versus infant vitamin D supplementation during lactation: a randomized controlled trial. A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: the CopD study. Is there a reverse J-shaped association between 25-hydroxyvitamin D and all-cause mortality Genetically low vitamin D concentrations and increased mortality: mendelian randomisation analysis in three large cohorts. Current micronutrient recommendations in Europe: towards understanding their differences and similarities.

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Percoll gradient centrifugation is a method used to isolate high-quality spermatozoa for assisted reproductive techniques antibiotics gave me diarrhea discount 600 mg zyvox visa. One may speculate that the presence of an inhibitor of vitamin D signaling may allow spermatozoa to avoid premature stimulatory signaling before they are in the vicinity of the oocyte and/or help regulate such signaling events antibiotic 4 month old order cheap zyvox on-line. Sperm function is therefore strongly dependent on nongenomic signaling pathways and spermatozoa are thus a unique model in which to study these rapid effects antibiotics journal order generic zyvox on line. One of the main cellular signals in human sperm is calcium and changes in intracellular Ca2+ concentration ([Ca2+]i) bacteria description discount zyvox 600 mg on line. The intracellular calcium concentration can be increased by opening of calcium channels in the membrane for instance the sperm specific calcium channel CatSper or by opening intracellular calcium storages antibiotics for dogs after giving birth order zyvox with visa. The initial finding of vitamin D-induced increase in [Ca2+]i was corroborated by investigating changes in calcium using calcium sensitive fluorescent probe fura-2 tween 80 antimicrobial purchase zyvox canada. The calcium increase was initiated in the neck region and propagated afterward in the head but not in the midpiece or tail region [92,97]. Colors indicate intracellular calcium concentration (low to high: blue, green, yellow, and red). A more critical evaluation of the data would mention that the calcium increase was modest compared to the response elicited from progesterone especially when evaluating the whole sperm and not just the neck region where the increase was fourfold higher than baseline calcium levels. The high calcium increase observed in spermatozoa following progesterone stimulation occurs through the CatSper calcium channel, which is dependent upon the extracellular Ca2+ concentration for its maximum effect [111,114]. This suggests that vitamin D is metabolized locally in all the organs in the male reproductive tract. The highest concentrations of the tritiated vitamin D metabolites were found in the kidney followed by the epididymis, prostate, testis and seminal vesicle, and the concentrations were augmented by intravenous route of dosing [116]. The fact that epididymis is an important site for conversion of vitamin D supports a key role in regulation of male reproductive function. Sperm recovered from the cauda epididymis of these mice exhibit reduced motility and failed to fertilize eggs in vitro [64,117,118]. Moreover, male mice with deficient aromatase do not present with such a severe phenotype. In fact, they were initially fertile but developed progressive infertility and disrupted spermatogenesis after 4. Their phenotype was characterized by spermatogenic arrest and Leydig cell hyperplasia/hypertrophy despite no increase in gonadotropins or androgens [119]. The extracellular environment varies significantly in the different parts of epididymis and exerts an important role for sperm maturation and function. The concentration of calcium in the fluid surrounding the spermatozoa changes dramatically from the seminiferous tubules to distal cauda epididymis. In the distal part (cauda) of epididymis where the spermatozoa are stored before ejaculation the concentration of calcium is 25% that of the serum concentration (12. When the sperms are ejaculated the concentration is threefold higher in the ejaculate than that in serum due to high calcium in the secretion from prostate and seminal vesicle [124,126,127]. Indeed, highlighting that a tight control system exists in the male reproductive organs to regulate calcium homeostasis. The calcium concentration varies largely throughout the different regions from when the sperm cells leave the seminiferous tubules in the testis and are transported through epididymis and finally ejaculated. The calcium concentration then increases in the rete testis and in the caput part of the epididymis and then decreases dramatically to 0. The calcium concentration in the seminal fluid is 3X of the serum level due to high calcium in the secretion from prostate and seminal vesicle. Seminal plasma consists of secretion form seminal vesicles (65% of semen volume), prostate (25%), testes and epididymis (10%), and other accessory glands (1%). The effect of estrogen administration in vivo on the elemental composition of the intraluminal fluids of the seminiferous tubules, rete testis, and epididymis of the rat. Concentrations of seven elements in the intraluminal fluids of the rat seminiferous tubules, rate testis, and epididymis. It has not been shown whether most of these proteins are expressed in the epididymis, rete, and/or testis. The impaired motility is the result of an increase in calcium concentration in the fluid in the distal part of the epididymis due to impaired calcium reabsorption. The findings described previously indicate that vitamin D in concert with estrogen may play a key role in regulating fluid composition in the epididymis and thereby be involved in sperm maturation and generation of motility prior to ejaculation. Inhibin B production is dependent on the close interaction between mature Sertoli cells and germ cells in the adult testis. There is a positive correlation between sperm production and inhibin B serum levels and it is therefore used clinically as a quantitative marker of normal spermatogenesis [131]. Clinically, inhibin B can be used to indicate the presence of germ cells in the testis in men with obstructive or nonobstructive azoospermia. Measurements of serum inhibin B can therefore assist in deciding whether a biopsy should be performed to get viable sperm for intracytoplasmic sperm injection if the semen analysis showed no sperm in the ejaculate and serum inhibin B is detectable in serum. Serum inhibin B levels were not measured in this study and although the transcription of inhibin B was not influenced there could theoretically still be changes in serum inhibin B levels in the different genotypes. Interestingly, these endocrine findings were supported by the fact that vitamin D-deficient men also had lower sperm production. However, the difference in Insl3 expression was not significantly different between Vdr-ablated mice and their wildtype littermates, but serum or secreted levels were not determined. The strong link between vitamin D deficiency and hypocalcaemia is important to keep in mind when evaluating functional animal models or human studies [19,72,134]. Reproductive issues as a consequence of vitamin D deficiency were discovered and investigated in detail several years ago because it was obvious that vitamin D, directly or indirectly, was influencing reproductive function in both sexes. Moreover, fertility, which was determined as successful pregnancies in females with sperm positive vaginal smears, was reduced by 73% in litters from a vitamin D-deficient male compared with litters originating from females mated with vitamin D-replete males [135]. Some years later the same group questioned the direct effect of vitamin D on male reproduction because they found that the impaired fertility could be restored by calcium supplements alone (Table 44. This follow-up study was well conducted, but the study conclusion was compromised by methodological problems, which has to be taking into account to address the relevance of vitamin D on reproductive function. When reanalyzing their data the results can be interpreted differently, which changes the original conclusions made by the authors dramatically (Table 44. In the study, each male was sometimes, but not always, mated with only one female rat, and the mating period varied from 1 to 10 days [136]. These factors will obviously influence the results as exposure to more females and longer mating periods increase the chances of pregnancy. Therefore the data should be corrected for number of female per male (female/male ratio) and the number of days they were allowed to mate. The frequency of mating is also important because the chance of spermatozoa being present in the female reproductive tract at the time of ovulation increases with frequent mating, which the study does not take into account. If the data should be extrapolated to the clinical setting it is important to stress that infertility in humans is not a hard endpoint. Infertility in humans is defined as the inability to conceive during 12 months of regular contraceptive-free intercourse [137]. From the revised data, it is obvious that vitamin D-deficient males are responsible for fewer sperm positive smears per day of allowed mating and exposed to fewer females than males with normal vitamin D levels. Detection of spermatozoa in the vaginal smear is not sufficient to obtain an actual pregnancy. After mating the spermatozoa must swim, bind, and fertilize the oocyte in the fallopian tube before fertilization occurs [139]. The presence of sperm in the vagina indicates successful mating, but the frequency of healthy pregnancies and number of pups serve as the best indicators of sperm function. Noteworthy, the vitamin D-deficient males were unable to achieve a reproductive performance level comparable with the male rats with high vitamin D status regardless of the choice of treatment, best exemplified by the high rate of healthy pregnancies and high litter size in the vitamin D-replete male rats. None of the treatments were able to reverse fertility and active vitamin D was definitely not the best treatment option [136]. This indicates that the treatment period and type of vitamin D supplementation may be important and should be considered when correcting vitamin D deficiency. Vitamin D-replete males had a threefold higher chance of healthy pregnancies compared with combined vitamin D deficiency and hypocalcemia and almost twofold higher chance than normocalcemic mice with vitamin D deficiency. This indicates that vitamin D is important for semen quality and the diminished effect caused by vitamin D deficiency cannot be fully reversed by correcting the hypocalcemia induced by vitamin D deficiency [33]. Litter size was lower when the males were vitamin D deficient independent of normocalcemia or hypocalcemia in the vitamin D-replete rats (not statistically significant). In accordance, other animal studies conducted in jaguars, boars, and mice showed positive (borderline significant) effects following supplementation with vitamin D on semen quality variables such as counts, sperm morphology, and sperm motility although sometimes in combination with other vitamins [37,140,141]. Accordingly, a comprehensive reproductive investigation in the Tokyo Vdr-ablated mouse model revealed a marked decrease in sperm count (40%) and sperm motility (ninefold), which resulted in a phenotype with complete infertility [59]. Again the phenotype could be induced at least partly by the concomitant hypocalcemia. Calcium supplementation improved semen quality and fertility in this model, but fertility and semen quality were not restored back to normal until the mice were supplemented with both calcium and estrogen [59]. The low estrogen in the Tokyo Vdr-ablated mouse and the reversibility of the phenotype following supplementation with estrogen and calcium indicates that male fertility is influenced by systemic changes in calcium and estradiol. However, the severity of the phenotype in the Tokyo Vdr-ablated mouse was not similar in two other Vdr-ablated mouse models generated in Munchen and Leuven (Table 44. However, impaired spermatogenesis was observed in some of the seminiferous tubules, and aberrant estrogen production and signaling were detected in both testis and epididymis [59]. The low Er and increased Er expression in the reproductive organs of the Leuven Vdr-ablated mouse model did to some extend corroborate the diminished estrogen responsiveness observed in the Tokyo model and it is likely that the effect of calcium and estrogen may be involved in mediating the influence on sperm motility (Table 44. It is known that estrogen is important for fluid reabsorption in the male reproductive organs and fluid accumulation may lead to impaired spermatogenesis, low sperm motility, and decreased fertility [123]. This is the main and most consistent phenotype of the Vdr-ablated mice models although the severity varies from near-normal to complete infertility. Similar results have been reported in two mouse models with global ablation of Cyp27b1 [100,101]. The mice developed hypocalcemia, hypophosphatemia, hypergonadotropic hypogonadism, had downregulated expression of gonadal calcium channels, decreased sperm count and sperm motility, and histological abnormalities of the testes. Interestingly, proliferation of germ cells decreased and cyclin E and Cdk2 were downregulated, whereas p53 and p21 expression was upregulated (see "Testicular Germ Cell Tumors" section), which led to increased germ cell apoptosis determined by Bax, Bcl-xl, and Caspase 3 expression. However, the phenotype was almost completely reversed by high calcium and phosphate diet, which indicates that the phenotype to a large extend is mediated by changes in calcium/phosphate homeostasis. Combined, all these studies indicate that vitamin D is involved in regulation of male reproduction, but the vitamin D-induced differences in calcium and estrogen signaling in the male reproductive organs seem to be the main mediators of the observed effect in animals with functional or dietary vitamin D deficiency. A few prospective association studies have been published recently and two minor intervention studies. Likewise, other studies comprising both fertile and infertile Chinese [4] and Danish [78,92] men showed that sperm motility was higher in men with high vitamin D status compared with vitamin D-deficient men. The positive link with sperm motility was also corroborated in a small mixed cohort of normal and infertile men where men with vitamin D deficiency had lower sperm motility [142]. However, not all studies have reported significant positive associations between vitamin D metabolites and sperm motility. Men with high vitamin D levels had lower sperm counts and lower percentage of spermatozoa with normal morphology. After using a multivariate analysis and adjustment of several confounders all the crude associations reported in the study weakened and became nonsignificant [67]. This compromises the conclusion of the study because they compared men with sufficient vitamin D level to men with high vitamin D status and thus not men with vitamin D deficiency. The most common problems in these studies are small cohort size and too few men with vitamin D deficiency or insufficiency, which lead to comparison of small groups of men with adequate vitamin D status with high vitamin D status. Another study suggested that high vitamin D status is detrimental to reproductive function and semen quality. However, they had very few men with high vitamin D status, which limits the strength of the study conclusion. Interestingly, the total number of motile and progressive motile spermatozoa was only significantly lower in men with vitamin D deficiency. Importantly, only the vitamin D-deficient men had lower sperm production and sperm motility than men with adequate vitamin D status. Sperm production in vitamin D insufficient infertile men was not significantly different from the men with adequate vitamin D status but significantly higher than the vitamin D-deficient men. These findings may be of clinical importance because they imply that only infertile men with vitamin D deficiency may benefit from vitamin D supplementation [78]. Vitamin D-deficient men are also at greater risk for developing hypocalcemia, which alone may influence male fertility. Interestingly, serum-ionized calcium levels were also investigated in the Copenhagen Bone-Gonadal Study. Total number of progressive motile spermatozoa increased Sperm motility was increased but not significantly Motility and morphology borderline significant Motility borderline significant Few men with low vitamin D Blomberg Jensen et al. Nine human studies investigating the relationship between serum vitamin D levels and semen quality in humans were evaluated. Normalization of serum calcium restores fertility in vitamin D-deficient male rats. An investigation of the differences in semen quality, reproductive hormones, and pregnancies between 150 days of treatment with high vitamin D supplementation or placebo will reveal whether vitamin D supplementation can improve semen quality and fertility in infertile men. This study will show whether vitamin D can influence semen quality and if it can be used to treat all or a subgroup of infertile men by supplementation of vitamin D alone or in combination with other factors. If the finding in infertile men is correct then the predefined subgroup analysis testing the effect only in vitamin D-deficient men will be of great interest because the effect may only be detectable in these men. This is an important point because semen quality, and in particularly sperm concentration, is prone to tremendous intraindividual variability. Moreover, sperm production is predictive for fertility potential, but a modest increase in sperm production or sperm motility is not necessarily reflected in increased conception rates.

Di-Calcium Phosphate (Calcium). Zyvox.

• Is Calcium effective?
• Use as an antacid as calcium carbonate.
• Reducing bone loss in people taking drugs called corticosteroids.
• Reducing tooth loss in elderly people.
• Preventing fluoride poisoning in children when taken with vitamin C and D.
• Preventing colorectal cancer.
• Reducing phosphate levels in people with kidney disease.
• What is Calcium?
• Are there any interactions with medications?

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