Multiple Looser zones of osteomalacia in Byler disease with associated vitamin D deficiency, phosphaturia, and elevated FGF23.

INTRODUCTION: Byler disease (progressive familial intrahepatic cholestasis) is associated metabolic bone disease as a consequence of chronic malabsorption. CASE PRESENTATION: A 33-year-old man with decompensated liver disease secondary to Byler disease was referred to the orthopaedic department with progressive pain over this right proximal tibia. On examination, he had an antalgic gait. Tenderness was localised to the proximal tibia just distal to the tibial tubercle and bilateral foot swelling. Radiographs showed multiple stress fractures characteristic of Looser zones at various stages of healing in both tibia, metatarsals (third, fourth, and fifth on the right side, and second and fourth on the left) and left femur. Bone mineral density was extremely low. Subsequent investigations were consistent with severe osteomalacia due to a combination of vitamin D deficiency and phosphaturia with elevated fibroblast factor 23 (FGF23). A good clinical response was achieved following supplementation with calcium 1000mg and vitamin D 20µg daily. DISCUSSION: Stress fractures are often associated with delay in diagnosis. Our patient presented to the orthopaedic service with multiple Looser zones that had not been previously detected. As expected, there was biochemical evidence of vitamin D deficiency. An unexpected finding was phosphaturia that was associated with marked elevation in FGF23, which has never been reported previously. CONCLUSION: Byler disease may result in Looser zones of osteomalacia due to chronic malabsorption. Renal phosphorus wasting as a consequence of unexplained marked elevation in FGF23 is thought to have contributed to the onset of osteomalacia.

Correction of vitamin D deficiency in a cohort of newborn infants using daily 200 IU vitamin D supplementation.

INTRODUCTION: Although the role of vitamin D in the prevention of rickets has long been well established, controversies still exist on the ideal dose of vitamin D supplementation in infants. OBJECTIVE: We assessed serum 25-hydroxyvitamin D (25OHD) status simultaneously in maternal and cord samples and the response to vitamin D3 supplementation in neonates. METHODS: Serum 25OHD levels were evaluated from maternal, and umbilical cord samples from term normal pregnancies. Repeat 25OHD levels were assessed in neonates with 25OHD below 30 nmol/L following vitamin D3 200 IU daily after 6 weeks. RESULTS: Blood samples were taken including 57 cord samples and 16 follow-up neonatal samples. Maternal and cord serum 25OHD were 43 ± 21 and 29 ± 15 nmol/L, respectively. Infants with 25OHD < 30 nmol/L (19.8 ± 4.7 nmol/L) had a significant increase in serum 25OHD (63.3 ± 14.5 nmol/L) following vitamin D3 200 IU daily after 6 weeks. CONCLUSION: Healthy Irish infants born at term are at high risk of vitamin D deficiency, but vitamin D3 200 IU daily, rapidly corrects poor vitamin D status.

The double-edged sword of vitamin D in Ireland: the need for public health awareness about too much as well as too little.

INTRODUCTION: The Institute of Medicine (IOM) 2011 on dietary references intakes for calcium and vitamin D specified that a 25-hydroxyvitamin D (25OHD) level below 30 nmol/L indicated risk of deficiency and that a level above 125 nmol/L indicated risk of harm. METHODS: We noted a high prevalence of hypovitaminosis D (23.9 %) and a substantive prevalence of hypervitaminosis D (4.8 %) in a retrospective audit of clinical samples (n = 10,181) obtained over 10 months in 2013. CONCLUSION: Hypovitaminosis D should be corrected by low dose supplementation (5 µg or 200 IU daily) with some at-risk groups needing higher doses (10 µg or 400 IU daily) based on 25OHD levels. Whereas, those taking high-dose vitamin D supplements based on mistaken beliefs about recently authorised claims of benefit for muscle function and misleading unauthorised claims need to be alerted to the potential harms of excessive supplementation.

Association between vitamin D status and physical function in the severely obese.

CONTEXT: Mortality is 85% higher in severely obese subjects (body mass index [BMI] > 40 kg/m(2)) than in subjects with a healthy BMI; poor physical function may be contributory. Hypovitaminosis D is common in obese subjects and is associated with physical dysfunction in the elderly. OBJECTIVE: We determined the relationship between vitamin D status and physical function in severely obese subjects. DESIGN, SETTING, AND PATIENTS: We conducted a clinic-based, cross-sectional study of severely obese subjects. Participants were stratified into three groups according to the Institute of Medicine (IOM) vitamin D status categorization. MAIN OUTCOME MEASURES: We compared levels of self-reported activity and times taken to walk 500 m and to ascend and descend a 17-cm step 50 times. RESULTS: We recruited 252 subjects (age, 43.7 ± 11.2 y; BMI, 50.7 ± 9.7 kg/m(2)); 25-hydroxyvitamin D (25OHD) concentrations were less than 30 nmol/L in 109 participants. Participants with a 25OHD > 50 nmol/L, compared to those with a 25OHD < 30 nmol/L, had the highest activity levels (3.1 ± 3.4 h/wk versus 1.5 ± 2.5 h/wk; P = .015) and the shortest 500-m walk times (6.2 ± 1.1 min versus 7.4 ± 1.5 min; P = .003). Serum 25OHD concentrations had a weakly positive association with activity level (r = 0.19; P = .008) and a moderately negative association with 500-m walk time (r = -0.343; P < .001). CONCLUSIONS: Vitamin D status had a significant relationship with physical activity and physical function in this cohort of severely obese subjects. Low activity levels are likely to perpetuate the problem of hypovitaminosis D due to less time spent outdoors. Studies exploring the effects of vitamin D supplementation in this population are warranted.

Limited utility of tartrate-resistant acid phosphatase isoform 5b in assessing response to therapy in osteoporosis.

BACKGROUND: Tartrate-resistant acid phosphatase isoform 5b (TRACP5b) is a serum bone resorption marker. Our aim was to investigate its utility in monitoring metabolic bone disease. METHODS: Serum TRACP5b, C-terminal cross-linking telopeptide of type I collagen, urine N-terminal cross-linking telopeptide of type I collagen and free deoxypyridinoline were measured pre- and post-treatment with a parathyroid hormone analogue [PTH (1-34)] (n = 14) or a bisphosphonate (N-BP) (n = 8). TRACP5b, bone alkaline phosphatase (bone ALP), 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) were measured in 100 osteoporosis patients on prolonged bisphosphonate therapy. RESULTS: Changes in TRACP5b were smaller in magnitude but mimicked those of other bone resorption markers. Absolute changes in TRACP5b and the other resorption markers correlated significantly (p < 0.001). In patients on long-term bisphosphonates, TRACP5b and bone ALP levels were not suppressed. Vitamin D status was consistent with the level of supplementation. CONCLUSION: TRACP5b has limited utility as a single marker of metabolic bone disease treatment.

Vitamin D and neonatal immune function.

Vitamin D deficiency is widespread in the neonatal and paediatric population of northern latitudes, particularly in children of African, Middle Eastern and Asian ethnicity. This is associated with diminished immune function and increases the risk of Th1 autoimmune diseases like type 1 diabetes. Epidermiological studies have also shown a link between vitamin D deficiency in children and a more severe course of illness with lower respiratory tract infection or Respiratory Syncitial Virus (RSV) bronchiolitis. The mechanism by which vitamin D enhances immunity is complex. It acts through the innate immune system by inducing antimicrobial peptides in epithelial cells, neutrophils and macrophages. The role of Vitamin D in neonatal and paediatric immunomodulation requires further study.

Effects of carnosine on contractile apparatus Ca²âº sensitivity and sarcoplasmic reticulum Ca²âº release in human skeletal muscle fibers.

There is considerable interest in potential ergogenic and therapeutic effects of increasing skeletal muscle carnosine content, although its effects on excitation-contraction (EC) coupling in human muscle have not been defined. Consequently, we sought to characterize what effects carnosine, at levels attained by supplementation, has on human muscle fiber function, using a preparation with all key EC coupling proteins in their in situ positions. Fiber segments, obtained from vastus lateralis muscle of human subjects by needle biopsy, were mechanically skinned, and their Ca(2+) release and contractile apparatus properties were characterized. Ca(2+) sensitivity of the contractile apparatus was significantly increased by 8 and 16 mM carnosine (increase in pCa(50) of 0.073 ± 0.007 and 0.116 ± 0.006 pCa units, respectively, in six type I fibers, and 0.063 ± 0.018 and 0.103 ± 0.013 pCa units, respectively, in five type II fibers). Caffeine-induced force responses were potentiated by 8 mM carnosine in both type I and II fibers, with the potentiation in type II fibers being entirely explicable by the increase in Ca(2+) sensitivity of the contractile apparatus caused by carnosine. However, the potentiation of caffeine-induced responses caused by carnosine in type I fibers was beyond that expected from the associated increase in Ca(2+) sensitivity of the contractile apparatus and suggestive of increased Ca(2+)-induced Ca(2+) release. Thus increasing muscle carnosine content likely confers benefits to muscle performance in both fiber types by increasing the Ca(2+) sensitivity of the contractile apparatus and possibly also by aiding Ca(2+) release in type I fibers, helping to lessen or slow the decline in muscle performance during fatiguing stimulation.

Favorable effect of immunomodulator therapy on bone mineral density in multiple sclerosis.

BACKGROUND: Osteoporosis is a complication of multiple sclerosis (MS), especially if corticosteroid therapy is given. Little is known about the effect on bone of immunomodulatory therapy (IMT) for MS. AIM: We sought to evaluate bone mass in patients with MS on IMT. METHODS: We measured bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) in 37 patients with MS who received IMT. Different IMTs were administered: interferon beta-1a in 70%, interferon beta-1b in 27% and Glatiramer in 3%. High-dose pulse corticosteroid therapy (intravenous methylprednisolone 500 mg) was given to 81% ranging from 1 to 17 courses. RESULTS: Both mean BMD Z-score at spine of 0.53 (CI, 0.15-0.92; P = 0.0084) and mean BMD Z-score at femur of 0.72 (CI, 0.42-1.01; P < 0.0001) were significantly greater than zero. CONCLUSIONS: IMT may have a favorable effect on bone in patients with MS even in the presence of pulse steroid therapy.

Creatine supplementation increases muscle total creatine but not maximal intermittent exercise performance.

This study investigated creatine supplementation (CrS) effects on muscle total creatine (TCr), creatine phosphate (CrP), and intermittent sprinting performance by using a design incorporating the time course of the initial increase and subsequent washout period of muscle TCr. Two groups of seven volunteers ingested either creatine [Cr; 6 x (5 g Cr-H(2)O + 5 g dextrose)/day)] or a placebo (6 x 5 g dextrose/day) over 5 days. Five 10-s maximal cycle ergometer sprints with rest intervals of 180, 50, 20, and 20 s and a resting vastus lateralis biopsy were conducted before and 0, 2, and 4 wk after placebo or CrS. Resting muscle TCr, CrP, and Cr were unchanged after the placebo but were increased (P < 0.05) at 0 [by 22.9 +/- 4.2, 8.9 +/- 1.9, and 14.0 +/- 3.3 (SE) mmol/kg dry mass, respectively] and 2 but not 4 wk after CrS. An apparent placebo main effect of increased peak power and cumulative work was found after placebo and CrS, but no treatment (CrS) main effect was found on either variable. Thus, despite the rise and washout of muscle TCr and CrP, maximal intermittent sprinting performance was unchanged by CrS.

Effect of creatine supplementation on sprint exercise performance and muscle metabolism.

The aim of the present study was to examine the effect of creatine supplementation (CrS) on sprint exercise performance and skeletal muscle anaerobic metabolism during and after sprint exercise. Eight active, untrained men performed a 20-s maximal sprint on an air-braked cycle ergometer after 5 days of CrS [30 g creatine (Cr) + 30 g dextrose per day] or placebo (30 g dextrose per day). The trials were separated by 4 wk, and a double-blind crossover design was used. Muscle and blood samples were obtained at rest, immediately after exercise, and after 2 min of passive recovery. CrS increased the muscle total Cr content (9.5 +/- 2.0%, P < 0.05, mean +/- SE); however, 20-s sprint performance was not improved by CrS. Similarly, the magnitude of the degradation or accumulation of muscle (e.g., adenine nucleotides, phosphocreatine, inosine 5'-monophosphate, lactate, and glycogen) and plasma metabolites (e.g. , lactate, hypoxanthine, and ammonia/ammonium) were also unaffected by CrS during exercise or recovery. These data demonstrated that CrS increased muscle total Cr content, but the increase did not induce an improved sprint exercise performance or alterations in anaerobic muscle metabolism.

Subchronic intravenous toxicity of the antineoplastic drug, amsacrine, in male Wistar rats.

Amsacrine, a DNA intercalator and topoisomerase II inhibitor, is efficacious as an antileukemogenic agent. This study was conducted to assess the subchronic toxicity of amsacrine in rats following a cyclic clinical dosing regimen and as a range-finding experiment for a subsequent carcinogenicity bioassay. Groups of 30 male Wistar rats were administered drug intravenously at doses of 0, 0.25, 1.0, and 3.0 mg/kg daily for 5 days followed by 23 days without treatment. This cycle of dosing and recovery was repeated six times to simulate human clinical usage of the drug. Assessments of hematology, clinical chemistry, and gross and microscopic pathology were conducted 3 and 21 days following completion of dosing in the first, third, and sixth cycles. There were no deaths during the study. Hair loss, diarrhea, tail injuries, chromodacryorrhea, and rhinorrhea were observed primarily in animals administered 3 mg/kg. Hair loss and diarrhea occurred during periods of dosing and generally resolved during the recovery phase of each cycle. Both of these signs became progressively more severe during the latter half of the study. Body weight loss and reduced food consumption also occurred in the 3 mg/kg group during each week of dosing. At study termination, mean body weight and food consumption of the 3 mg/kg group were significantly less than those of controls by approximately 20 and 50%, respectively. Marked, reversible leukopenia associated with reductions in both neutrophil and lymphocyte counts occurred in cycles one and three in animals administered 1 and 3 mg/kg, respectively. Reversible neutropenia was also observed in the 3 mg/kg group in cycle 6. Similar effects on platelet counts were seen in the 3 mg/kg group in all three cycles analyzed. Absolute and relative testes weights of the 3 mg/kg group were significantly less than the vehicle controls at all time points in the third and sixth cycles. Relative testes weights were also decreased in the 1 mg/kg group in cycle 6. Reversible decreases in absolute relative spleen weights occurred in all drug-treated groups in cycle 1 and for the 3 mg/kg group in cycle 3. Lymphoid depletion (spleen, thymus, lymph node), marked hypocellularity of bone marrow, segmental degeneration of seminiferous tubules, and intestinal epithelial cell degeneration were observed at 3 mg/kg. With the exception of testicular changes which remained evident at the end of cycle 6, pathologic lesions were reversible during the 23-day recovery period of each cycle. The results show that the subchronic toxicity of amsacrine is consistent with a cytotoxic mechanism and that target organs are generally tissues with the highest rates of cell turnover. The doses administered in this study induced a range of effects which were minimal at 0.25 mg/kg and dose-limiting at 3 mg/kg and therefore were considered appropriate for use in the subsequent carcinogenicity bioassay.

Safety and efficacy of increasing wintertime vitamin D and calcium intake by milk fortification.

We studied the safety and efficacy of milk fortified with vitamin D3 and calcium. Over the winter, we conducted a double-blind, placebo-controlled trial of fortified milk (12 micrograms vitamin D3 and 1525 mg calcium per litre) compared to unfortified milk (0.3 micrograms vitamin D3 and 1270 mg calcium per litre) in 102 adults (aged 17-54 years). Serum 25-hydroxyvitamin D [25(OH)D], ionized calcium, and creatinine were measured at baseline and after intervention. Fortification reduced the seasonal decline in serum 25(OH)D concentrations by > 50%. In the fortified group, serum 25(OH)D decreased by 15 nmol/l from 77 +/- 35 nmol/l to 62 +/- 26 nmol/l (p < 0.001). In the control group, serum 25(OH)D fell by 31 nmol/l from 85 +/- 38 nmol/l to 54 +/- 25 nmol/l (p < 0.001). We suggest that milk enriched with vitamin D be provided in high-latitude European countries to diminish the wintertime fall in serum 25(OH)D.

Ossiculoplasty with polymaleinate ionomeric prosthesis.

With the continued concern over the possible transmission of viral infections through homologous middle ear implants, there is increasing pressure to develop a truly biocompatible alloplastic middle ear prosthesis. The polymaleinate ionomer, which has been used in dentistry as a filling and luting material for more than 15 years, has recently been used to construct total and partial ossicular replacement prostheses. In an attempt to evaluate these new implants, a multicenter prospective clinical trial was initiated. To date, 92 patients have undergone implantation. The follow-up interval ranged from 3 months to 22 months. Although it is premature to discuss the long-term results, the preliminary surgical experience and audiometric data with these implants are reviewed. From a surgical perspective, the ionomeric prostheses were easily contoured with a diamond burr and were not prone to shattering. Preliminary follow-up audiometric data were available on 80 patients (59 partial ossicular replacement prostheses and 21 total ossicular replacement prostheses). Of the 59 partial ossicular replacement prostheses the air-bone gaps (average of 500 Hz, 1 kHz, 2 kHz and 3 kHz) were as follows: 0 dB to 10 dB, 15 (25%) of 59; 11 dB to 20 dB, 20 (34%) of 59; 21 dB to 30 dB, 11 (19%) of 59; and greater than 30 dB, 13 (22%) of 59. Of the 21 total ossicular replacement prostheses the air-bone gaps were as follows: 0 dB to 10 dB, 6 (29%) of 21; 11 dB to 20 dB, 6 (29%) of 21; 21 dB to 30 dB, 5 (24%) of 21; and greater than 30 dB, 4 (19%) of 21.

Vitamin D supplementation in the elderly: review of safety and effectiveness of different regimes.

Vitamin D deficiency is common in the elderly, especially in countries where effective sunlight or exposure to sunlight is limited. Two regimes for vitamin D supplementation--low-dose daily oral administration and intermittent high-dose administration--were examined with regard to safety and effectiveness. Eleven papers reporting studies in 449 elderly subjects were reviewed. On low-dose continuous supplementation mean concentration of 25 hydroxyvitamin D (25(OH)D) ranged from 57 to 105 nmol/L compared to 55 to 87 nmol/L following high-dose supplementation. These mean values fall within the physiological range for young adults. Hypercalcemia occurred in only 3 subjects and was associated with a predisposing cause in 2 of 3 subjects. We suggest that low dose continuous supplementation (10 to 20 micrograms daily) is the regime of choice but high-dose intermittent supplementation (2.5 mg six monthly) may be suitable where compliance is poor.

Determinants and impact of headache after acoustic neuroma surgery.

Headache after acoustic neuroma surgery is known to occur clinically, but has not been studied systematically until recently. In the present study, 155 patients were surveyed regarding their experience of headache and associated symptoms following resection of an acoustic neuroma: 73 percent (n = 98) of patients undergoing suboccipital resection of an acoustic neuroma and 53 percent (n = 8) of patients undergoing translabyrinthine resection of acoustic neuroma complained of headache following surgery. The average pain intensity was greater for the suboccipital approach. Only 9 percent (n = 14) reported troublesome or frequent headaches preoperatively. Headache was described most often as tension type, with episodic acute exacerbations mimicking migraine. Clinical observations suggest that most patients are treated successfully with various combinations of reassurance, tricyclic antidepressants, nonsteroidal anti-inflammatory medications, trigger-point injections, adjunctive stress management techniques (relaxation), and physical therapy. The impact of recurrent headache on work and recreational function is notable. Several possible pathophysiological and biopsychosocial models are proposed to account for the prevalent headache problem. Although spontaneous resolution usually occurs over time, additional study is needed to determine the natural history of postoperative headache once it occurs.

Differences in vitamin D status between countries in young adults and the elderly.

PURPOSE: To compare vitamin D status between countries in young adults and in the elderly. MATERIALS AND METHODS: Reports on vitamin D status (as assessed by serum 25-hydroxyvitamin D) from 1971 to 1990 were reviewed. Studies were grouped according to geographic regions: North America (including Canada and the United States); Scandinavia (including Denmark, Finland, Norway, and Sweden); and Central and Western Europe (including Belgium, France, Germany, Ireland, The Netherlands, Switzerland, and the United Kingdom). RESULTS: Vitamin D status varies with the season in young adults and in the elderly, and is lower during the winter in Europe than in both North America and Scandinavia. Oral vitamin D intake is lower in Europe than in both North America and Scandinavia. Hypovitaminosis D and related abnormalities in bone chemistry are most common in elderly residents in Europe but are reported in all elderly populations. CONCLUSIONS: The vitamin D status in young adults and the elderly varies widely with the country of residence. Adequate exposure to summer sunlight is the essential means to ample supply, but oral intake augmented by both fortification and supplementation is necessary to maintain baseline stores. All countries should adopt a fortification policy. It seems likely that the elderly would benefit additionally from a daily supplement of 10 micrograms of vitamin D.

Hypovitaminosis D and response to supplementation in older patients with cystic fibrosis.

This study reports serum 25-hydroxy vitamin D (25-(OH)D) levels, bone mineral content and bone maturation in 20 adolescent and adult patients with cystic fibrosis, and their response to the internationally recommended dose of supplementary vitamin D (800 iu/day; 20 micrograms/day). Serum 25-(OH)D values were below normal in 75 per cent of patients and serum alkaline phosphatase values, corrected for age, were increased in 60 per cent. Bone mineral content, measured by photon beam absorptiometry, was below the normal range in 45 per cent of patients and bone age retarded in 45 per cent. Following supplementation with vitamin D 40 per cent of patients failed to achieve normal serum 25-(OH)D levels. We concluded that hypovitaminosis D occurs frequently in older patients with cystic fibrosis and is accompanied by osteopenia and retarded bone maturation.