Adaptive behaviour deficits in individuals with 3q29 deletion syndrome.

BACKGROUND: 3q29 deletion syndrome (3q29del) is associated with a significantly increased risk for neurodevelopmental and neuropsychiatric phenotypes. Mild to moderate intellectual disability (ID) is common in this population, and previous work by our team identified substantial deficits in adaptive behaviour. However, the full profile of adaptive function in 3q29del has not been described nor has it been compared with other genomic syndromes associated with elevated risk for neurodevelopmental and neuropsychiatric phenotypes. METHODS: Individuals with 3q29del (n = 32, 62.5% male) were evaluated using the Vineland Adaptive Behaviour Scales, Third Edition, Comprehensive Parent/Caregiver Form (Vineland-3). We explored the relationship between adaptive behaviour and cognitive function, executive function, and neurodevelopmental and neuropsychiatric comorbidities in our 3q29del study sample, and we compared subjects with 3q29del with published data on fragile X syndrome, 22q11.2 deletion syndrome and 16p11.2 deletion and duplication syndromes. RESULTS: Individuals with 3q29del had global deficits in adaptive behaviour that were not driven by specific weaknesses in any given domain. Individual neurodevelopmental and neuropsychiatric diagnoses had a small effect on adaptive behaviour, and the cumulative number of comorbid diagnoses was significantly negatively associated with Vineland-3 performance. Both cognitive ability and executive function were significantly associated with adaptive behaviour, and executive function was a better predictor of Vineland-3 performance than cognitive ability. Finally, the severity of adaptive behaviour deficits in 3q29del was distinct from previously published data on comparable genomic disorders. CONCLUSIONS: Individuals with 3q29del have significant deficits in adaptive behaviour, affecting all domains assessed by the Vineland-3. Executive function is a better predictor of adaptive behaviour than cognitive ability in this population and suggests that interventions targeting executive function may be an effective therapeutic strategy.

A phase II, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of VT-1161 oral tablets in the treatment of patients with distal and lateral subungual onychomycosis of the toenail.

BACKGROUND: Onychomycosis is a fungal disease that affects the fingernails and toenails and is predominantly caused by dermatophytes. VT-1161 is a novel inhibitor of fungal CYP51 through the inhibition of lanosterol demethylase, and has demonstrated potent activity against Trichophyton rubrum and Trichophyton mentagrophytes. OBJECTIVES: To evaluate the safety and efficacy of four dosing regimens of orally administered VT-1161 compared with placebo in patients with moderate-to-severe distal and lateral subungual onychomycosis of the toenail. METHODS: This was a phase II, randomized, double-blind, placebo-controlled, multicentre study (ClinicalTrials.gov identifier NCT02267356). Patients aged 18-70 years (n = 259) who had 25-75% mycotic involvement were randomized to five treatment groups. They received 300 mg VT-1161 as a 2-week daily dose, followed by a once-weekly dose for either 10 or 22 weeks, or 600 mg VT-1161 as a 2-week daily dose, followed by a once-weekly dose for either 10 or 22 weeks. All treatments were followed by a nontreatment period of 36 weeks. A matching placebo arm was included. RESULTS: In the intent-to-treat population, at week 48 the complete cure rates were 0% in the placebo group and ranged from 32% to 42% in the VT-1161 treatment groups (P < 0·001 vs. placebo). VT-1161 was well tolerated, with no evidence of an adverse effect on liver function or QT intervals. CONCLUSIONS: VT-1161 treatment led to high nail clearance rates and a favourable safety profile. VT-1161 exhibits characteristics that appear promising for the treatment of this chronic and difficult-to-treat condition and warrants further evaluation in larger studies.

Reduced Sirtuin1 expression at the femoral neck in women who sustained an osteoporotic hip fracture.

UNLABELLED: To investigate the role of Sirtuin1 in osteoporosis, Sirtuin1 was determined at the femoral neck in female patients undergoing hip operation for fractured hip or osteoarthritis. Reduced Sirtuin1 was found in osteoporotic patients. Pharmacologic activation of Sirtuin1 reduced sclerostin, an inhibitor of bone formation. Activation of Sirtuin1 may be a new direction to generate therapies for osteoporosis. INTRODUCTION: The aim of the study are to investigate the role of Sirtuin1 (Sirt1), an anti-aging factor and a player in age-associated diseases, in osteoporotic hip fractures, and test the hypothesis that Sirt1 is a negative regulator of sclerostin, a bone formation inhibitor, in human femoral bone marrow mesenchymal cells (BM-MSCs). METHODS: Sirt1 and sclerostin were determined by western blot in bone samples obtained intra-operatively from the inferior medial cortex of the femoral neck (calcar region) in female patients undergoing partial hip replacement for fractured neck of femur (N = 10) or hip replacement for osteoarthritis (N = 8) (mean ± SD age 81 ± 8.1 vs. 68 ± 9.3 years; BMI 26.2 ± 3.6 vs. 25.9 ± 7.1 kg/m(2) in osteoporotic and osteoarthritis patients). Calcar thickness and femoral bone mineral density (BMD) were determined preoperatively by X-ray using a digital TraumaCad(™) software and DEXA. Femoral BM-MSCs were collected intra-operatively and treated with SRT3025, a Sirt1 activator. Sclerostin and dentin matrix acidic phosphoprotein (DMP1) were determined by western blot and messenger RNA (mRNA) expression of Lef1 and DMP1 was evaluated by quantitative real-time PCR. RESULTS: Osteoporotic (OP) patients had reduced cortical thickness, femoral neck, and total hip BMD compared to osteoarthritis (OA) patients. Calcar Sirt1 expression was significantly reduced, while sclerostin was markedly increased in OP compared to OA patients. Sirt1 and sclersotin expressions were inversely correlated (r = -0.49, P = 0.047). SRT3025 administration down-regulated sclerostin and up-regulated DMP1 protein level and increased LEF1 and DMP1 mRNA expressions in OP patient-derived BM-MSCs. CONCLUSIONS: Reduced femoral neck Sirt1 may play a role in osteoporotic hip fractures in part via influencing local sclerostin expression. The therapeutic potential of Sirt1 activation in osteoporosis warrants further investigation.

A randomized, placebo- and active-controlled, parallel-group, multicentre, investigator-blinded study of four treatment regimens of posaconazole in adults with toenail onychomycosis.

BACKGROUND: Onychomycosis accounts for up to 50% of all onychopathies. OBJECTIVES: To evaluate the efficacy of four posaconazole regimens compared with placebo in the treatment of toenail onychomycosis, to assess the safety and tolerability of posaconazole, and to estimate the relative efficacy of posaconazole against terbinafine. METHODS: A phase 2B, randomized, placebo- and active-controlled, parallel-group, multicentre, investigator-blinded (double blind for placebo) study (ClinicalTrials.gov identifier: NCT00491764). Onychomycosis patients aged 18-75years (n=218) were randomized equally to one of six treatment regimens: posaconazole (oral suspension) 100, 200 or 400mg once daily (24weeks); posaconazole 400 mg once daily (12weeks); terbinafine (tablets) 250mg once daily (12weeks); or placebo (24weeks). The primary efficacy variable was complete cure (negative mycology and 0% nail involvement) at week 48. RESULTS: All posaconazole treatment arms had a significantly (P≤0·012) greater proportion of patients with complete cure at week 48 compared with placebo. The proportions of patients with complete cure were numerically higher for posaconazole 200mg/24weeks (54·1%) and 400mg/24weeks (45·5%), but lower for 400mg/12weeks (20%) compared with terbinafine (37%; differences were not statistically significant). Posaconazole was well tolerated. Seven patients receiving posaconazole withdrew because of asymptomatic liver enzyme increases, as mandated by protocol discontinuation criteria. CONCLUSIONS: The efficacy and favourable safety profile of posaconazole suggest a potential new treatment for onychomycosis. The availability of low-cost generic terbinafine may limit posaconazole use to second-line treatment of infections refractory to, or patients intolerant of, terbinafine, or nondermatophyte mould infections.

Effect of different dress style on vitamin D level in healthy young Orthodox and ultra-Orthodox students in Israel.

UNLABELLED: Ultra-orthodox Jewish lifestyle, which encourages modest dress and indoor scholarly activity, represents a risk factor for vitamin-D deficiency. Our study in healthy young males from higher education religious institutions located in the same geographical area showed frequent and severe vitamin D deficiency, strongly correlated with the degree of sun exposure. However, PTH level was usually normal. INTRODUCTION: Ultra-orthodox Jewish lifestyle encourages modest dress and indoor scholarly activity. As such, it represents a risk factor for vitamin-D deficiency, a worldwide problem previously underestimated in sunny countries. Our aim was to characterize the vitamin-D status of religious Jewish males according to sun exposure and outdoor activity, and study the correlation between serum 25-hydroxyvitamin D (25(OH) D) and PTH level. METHODS: Seventy-four young adult males were recruited from three Jewish higher education institutions (Yeshiva) in Jerusalem. Yeshiva-A ultra-Orthodox students (aged 20.1 ± 0.6) wear traditional clothing, live in dormitories and stay mostly indoor. Yeshiva-B ultra-Orthodox students (aged 33.0 ± 4.2) dress similarly but have regular outdoor activities. Yeshiva-C religious students (aged 19 ± 2.0) participate in a mixed army/Yeshiva program. Weekly outdoor activity time and degree of sun exposure were estimated by questionnaire. RESULTS: 25(OH)D was 8.9 ± 3.6, 10.2 ± 5.7 and 21.7 ± 10.4 ng/ml (mean ± SD) in Yeshiva A, B and C. 25(OH)D was correlated with degree of sun exposure (r = 0.54, p < 0.0001) and inversely correlated with PTH (r = -0.3, p = 0.01). Levels below 20 ng/ml were considered as vitamin D deficiency. PTH was normal in 87% of vitamin D-deficient subjects from Yeshiva-A and Yeshiva-C (mean age 20), compared to 52% of Yeshiva-B students (mean age 33). Bone mineral density studied in a random subset (n = 14) of vitamin D-deficient subjects showed Z-scores of -1.5 ± 1.0, -1.8 ± 0.8, -2.1 ± 0.4 in femoral neck, spine and radius. CONCLUSIONS: Severe vitamin-D deficiency is extremely prevalent in ultra-Orthodox males. Despite rare secondary hyperparathyroidism, they represent an important previously unrecognized high-risk group for metabolic bone disease.

Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers.

OBJECTIVE: To assess the safety/tolerability and perform a preliminary efficacy evaluation of a multiple-dosing regimen of recombinant human vascular endothelial growth factor (VEGF165 or rhVEGF; telbermin) applied topically to chronic diabetic neuropathic foot ulcers. METHOD: Subjects with type 1 or 2 diabetes mellitus were randomised to receive either topical applied telbermin (72 microg/cm2) (n=29) or placebo (n=26) treatment to the foot ulcer surface in conjunction with standard ulcer care. Subjects received treatment every 48 hours (maximum three doses per week) for up to six weeks. Weekly 35mm photography, quantitative planimetry and physical examinations documented the ulcer appearance, surface area and stage. Safety endpoints included incidence of clinically significant hypotension, adverse events and ulcer infection. Exploratory efficacy endpoints included percentage reduction in total ulcer surface area, incidence of complete ulcer healing and time to complete ulcer healing. RESULTS: Incidence of adverse events was comparable in the two treatment groups. None of the adverse events were attributed to study drug, and no hypotension was observed as a result of telbermin treatment. Occurrence of infected study ulcers appeared to be balanced between the treatment groups. Positive trends suggestive of potential signals of biological activity were observed for incidence of complete ulcer healing (41.4% telbermin versus 26.9% placebo at day 43 [P=0.39]) and time to complete ulcer healing (25th percentile of 32.5 days telbermin versus 43.0 days placebo [log-rank P=0.13]). CONCLUSION: The topical application of telbermin 72 microg/cm2 three times a week for up to six weeks appeared to be well tolerated. Further studies are required to characterise the safety/efficacy of telbermin more completely.

Bone mineral density and metabolism in familial dysautonomia.

Familial dysautonomia (FD) patients suffer from multiple fractures and have reduced bone pain, which defers the diagnosis. The pathogenesis of bone fragility in FD is unknown. This study aimed to characterize bone mineral metabolism and density in FD. Seventy-nine FD patients aged 8 months to 48 years (mean age 13.9 +/- 10.4 years, median 12.3) were studied. Clinical data included weight, height, bone age, weekly physical activity and history of fractures. Bone mineral density (BMD) of the lumbar spine (n = 43), femoral neck (n = 26), total hip (n = 22) and whole body (n = 15) were determined by dual-energy X-ray absorptiometry. Serum 25-hydroxyvitamin D3, osteocalcin, bone alkaline phosphatase (B-ALP), parathyroid hormone and urinary N-telopeptide cross-linked type 1 collagen (NTx) were determined in 68 patients and age- and sex-matched controls. Forty-two of 79 patients (53%) sustained 75 fractures. Twenty-four of 43 patients had a spine Z-score < -2.0, and 13 of 26 had a femoral neck Z-score < -2.0. Mean femoral neck BMD Z-score was lower in patients with fractures compared with those without (-2.5 +/- 0.9 vs -1.5 +/- 1.0, p = 0.01). Mean body mass index (BMI) was 16 kg/m2 in prepubertal patients and 18.4 kg/m2 in postpubertal patients. Bone age was significantly lower than chronological age (75.5 vs 99.3 months in prepubertal patients, p < 0.001; 151 vs 174 in postpubertal patients, p < 0.05). NTx and osteocalcin levels were higher in FD patients compared with controls (400 +/- 338 vs 303 +/- 308, BCE/mM creatinine p < 0.02; 90 +/- 59.5 vs 61.8 +/- 36.9 ng/ml, p < 0.001, respectively). B-ALP was lower in FD patients compared with controls (44.66 +/- 21.8 vs 55.36 +/- 36.6 ng/ml, p < 0.04). Mean spine Z-score was significantly lower in physically inactive compared with active patients (-3.00 +/- 1.70 vs -1.77 +/- 1.3, respectively, p = 0.05). We conclude that fractures in FD patients are associated with reduced BMD. FD patients have increased NTx and osteocalcin. Contributing factors include reduced BMI, failure to thrive and reduced physical activity. Preventive therapy and early diagnosis are essential.

Impact of mycophenolate mofetil on recurrent rejection in kidney transplant patients.

PURPOSE: Mycophenolate mofetil (MMF) has emerged as a valuable adjunctive agent in renal transplantation. However, due to intolerable adverse effects associated with MMF use in our transplant population, we have used MMF selectively in patients at high risk for recurrent graft rejection, since these patients are known to be at risk for poor long-term graft outcomes. The purpose of this study was to assess the efficacy of MMF in preventing the recurrence of acute rejection following an initial rejection episode in kidney transplant patients in the first year following transplantation. METHODS: Forty-four kidney transplant recipients were given MMF prospectively following treatment of their initial rejection episode to prevent recurrent rejection. MMF 1-2 g/d was given. Doses were adjusted based on tolerance; MMF therapy was to be continued for at least 6 months. The control group consisted of 124 consecutive kidney transplant recipients who had received standard anti-rejection therapy without the addition of MMF. Maintenance immunosuppression consisted predominantly of cyclosporine, prednisone+/-azathioprine. Anti-rejection therapy for both groups consisted of either corticosteroids (methylprednisolone 500 mg i.v. for 3 d or oral prednisone 2 mg/kg/d with rapid taper over 3 wk), OKT3 5 mg/d for 10 d or ATG 15 mg/kg/d for 10 d. All rejection episodes were confirmed by biopsy. RESULTS: The majority of rejection episodes were characterized histologically as mild or moderate. Most patients (76%) received corticosteroids for treatment of their first rejection episode. There was a 68% reduction in the incidence of recurrent rejection episodes within the first year of transplant in patients receiving MMF; only 14% of recipients receiving MMF developed recurrent rejection compared to 44% of patients in the control group (p<0.05). Approximately 50% of patients developed MMF-associated adverse effects (leukopenia, GI toxicity). Only 52% of patients remained on MMF at 6 months. One-yr graft survival was 86% in the MMF group and 89% in the control group (p>0.05). One-year patient survival was 93 and 100%, respectively (p>0.05). CONCLUSIONS: The addition of MMF to maintenance therapy for patients experiencing acute renal allograft rejection may prevent recurrent rejection episodes in the subsequent follow-up year.

The BsmI vitamin D receptor gene polymorphism in Israeli populations and in perimenopausal and osteoporotic Ashkenazi women.

BACKGROUND: The association between vitamin D receptor (VDR) gene polymorphisms and bone mineral density (BMD) is controversial, and may be effected by ethnic ancestry and age. AIMS: To determine the distribution of the BsmI VDR gene polymorphism in healthy Israeli populations, and to study its association with BMD in perimenopausal and osteoporotic Ashkenazi women. METHODS: Allele and genotype frequencies of the VDR gene defined by BsmI restriction site were determined in 634 healthy Israelis of seven ethnic groups, 90 Ashkenazi perimenopausal women and in 75 Ashkenazi osteoporotic women. Genotype-related differences in spinal and femoral neck BMD were determined in Ashkenazi perimenopausal women. Allele and genotype frequencies in Ashkenazi osteoporotic women were compared with Ashkenazi controls. RESULTS: The frequency of the BB genotype was higher in Yemenites compared with Ashkenazi and Libyan Jews (23, 11 and 8%, respectively, p < 0.05), and lower in Ashkenazi compared with Iraqi and Persian Jews (11, 20 and 21%, respectively, p = 0.05). BMD did not vary by genotype in perimenopausal women, nor were there differences in the frequencies of the B allele or the BB genotype in osteoporotic women compared with controls. CONCLUSIONS: There is ethnic variability in the frequency of the BsmI VDR gene polymorphism. In Ashkenazi perimenopausal and osteoporotic women this polymorphism is not associated with BMD.

Efficacy of terbinafine for toenail onychomycosis. A multicenter trial of various treatment durations.

The efficacy of terbinafine (250 mg/day) in the treatment of toenail onychomycosis was evaluated in a large open-label, multicenter trial of 12, 18, and 24 weeks of therapy. All 1,534 patients had onychomycosis, confirmed by either positive potassium hydroxide (KOH) wet mount, positive fungal culture, or both, and all received at least 12 weeks of treatment. Treatment was continued for an additional 6 or 12 weeks, depending on the extent of the disease at follow-up. Mycologic cure rates (negative culture plus negative KOH) at week 72 were 72.1% in the 12-week treatment group, 72.5% in the 18-week group, and 77.0% in the 24-week group. In all groups, clinical cure rates were higher at week 72 than at week 48: 49.5% of the 12-week group, 49.2% of the 18-week group, and 44.6% of the 24-week group experienced clinical cure by the end of the study. Both mycologic and clinical recurrence rates were low in all treatment groups at the 72-week assessment. The results of this study confirm the efficacy of terbinafine in the treatment of toenail onychomycosis as demonstrated in previous registration and large-scale clinical trials.

Clotrimazole increases tacrolimus blood levels: a drug interaction in kidney transplant patients.

In order to substantiate a previous case report of a drug interaction between tacrolimus and clotrimazole, we randomly assigned tacrolimus-treated renal allograft recipients to therapy with either clotrimazole or nystatin for oral thrush prophylaxis immediately following transplantation. Patients receiving other agents known to interact with cytochrome P450 were excluded from the study. The clotrimazole group consisted of 17 patients and the nystatin group, which served as the control group, consisted of 18 patients. An oral loading dose (approximately 0.3 mg/kg) of tacrolimus was given pre-operatively. Post-transplant, tacrolimus (approximately 0.15 mg/kg) was orally administered twice daily. Clotrimazole therapy consisted of a 10-mg troche administered three times daily. Nystatin therapy consisted of the oral suspension (5 mL) administered as a 'swish and swallow' four times daily. We evaluated tacrolimus trough blood levels and tacrolimus doses on days 1, 3, 5, and 7 following transplantation. On post-transplant day 1, mean tacrolimus trough levels did not differ between clotrimazole- and nystatin-treated patients. Mean tacrolimus blood trough levels were significantly higher in clotrimazole-treated patients on days 3, 5, and 7 post-transplant, 42+/-14, 53+/-7, and 33+/-17 ng/mL, respectively, compared to 15+/-8, 15+/-7, and 14+/-6 ng/mL in nystatin-treated patients (p<0.05). The mean tacrolimus dose was significantly lower in the clotrimazole group by day 7 post-transplant (p<0.05). We conclude that clotrimazole therapy may cause a significant rise in tacrolimus trough blood levels. Recognition of this potential drug interaction is essential to minimize tacrolimus-associated toxicities in the early post-transplant period.

Ethnic differences in clinical response to corticosteroid treatment of acute renal allograft rejection.

BACKGROUND: Limited in vitro data suggest that African-Americans exhibit greater resistance to corticosteroids than do non-African-American transplant recipients. However, ethnic differences in clinical response to corticosteroids for treatment of acute rejection have not been investigated previously. The purpose of this study was to evaluate the clinical response to corticosteroid treatment for acute rejection in both African-American and non-African-American renal allograft recipients. METHODS: We retrospectively reviewed the medical records of 497 consecutive renal allograft recipients to identify patients who had received corticosteroids as initial treatment of acute rejection. One hundred and twenty patients who received corticosteroids for treatment of acute rejection were evaluated in this analysis. The study population was divided into two groups: the African-American group (n=73) and non-African-American group (n=47). All acute rejection episodes were documented by biopsy and were classified as mild-moderate histologically. Corticosteroid therapy consisted of either methylprednisolone, 500 mg intravenously for 3 days, or oral prednisone, 2 mg/kg/day rapidly tapered over 3 weeks. RESULTS: Twenty-six percent (26%) of African-Americans were considered corticosteroid treatment failures compared to an 8.0% failure rate among non-African-Americans (P<0.05). One-year graft survival was 78% in African-American versus 96% in non-African-American (P<0.05). Among African-American and non-African-American recipients, 1-year patient survival rates were 97% and 100, respectively (P=NS). CONCLUSIONS: African-American patients exhibit higher failure rates with corticosteroid treatment of acute rejection. Alternative anti-rejection therapies may need to be considered for this "high-risk" patient population to improve long-term graft survival.

Orthopaedic manifestations of familial dysautonomia. A review of one hundred and thirty-six patients.

BACKGROUND: Familial dysautonomia is a hereditary multisystemic disease primarily affecting people of Ashkenazi Jewish descent. Musculoskeletal problems are related to gait disorders, spinal deformities, foot deformities, fractures, and arthropathies. METHODS: The charts and radiographs of 136 patients who ranged in age from three months to forty-six years (mean, sixteen years) were reviewed. Sixty-four patients were available for follow-up examination. RESULTS: Spinal deformity was the most common orthopaedic problem and was diagnosed in seventy-eight patients starting at the age of four years, with a prevalence of 86 percent (forty-eight of fifty-six) by the age of fifteen years. Forty-one (53 percent) of the seventy-eight patients had scoliosis only, thirty-four (44 percent) had kyphoscoliosis, and three (4 percent) had kyphosis only. Bracing was accompanied by emotional, pulmonary, and skin problems, leading to a high rate of noncompliance and progression of the curve. Twenty-four patients had an operation at a mean age of thirteen years (range, five to eighteen years): twenty patients had posterior spinal arthrodesis, and four had combined anterior and posterior arthrodesis. Fifteen patients had a total of nineteen complications, of which seven were systemic and twelve were related to the spinal fixation. Eight patients had revision surgery. At the time of the surgery, scoliosis was corrected from a mean of 55 degrees to a mean of 35 degrees and kyphosis was corrected from a mean of 69 degrees to a mean of 61 degrees. After a mean duration of follow-up of sixty-five months, scoliosis measured 49 degrees (range, 18 to 62 degrees) and kyphosis measured 67 degrees (range, 30 to 115 degrees). Postoperative progression of the deformity was caused by failure of the instrumentation or progression in unfused segments. Walking was delayed in 72 percent (ninety-four) of the 130 patients who were of walking age. All sixty-four of the patients who were examined had an ataxic gait. Foot deformities were found in sixteen patients, six of whom were treated surgically. Two patients had Charcot joints. Fifty-five patients sustained at least one fracture before skeletal maturity, with a mean of 1.5 fractures per patient. All but one of the fractures was treated nonoperatively, and fracture-healing was often accompanied by profuse callus formation. CONCLUSIONS: Spinal deformity is common in patients with familial dysautonomia. Bracing is of questionable benefit, and surgical intervention should be considered once curve progression is well documented. Arthrodesis should be extended as far proximally as possible to prevent junctional kyphosis. Swelling and warmth in a limb should raise suspicion of an undiagnosed fracture.

Organ donor or graft pretreatment to prolong allograft survival: lessons learned in the murine model.

Permanent donor-specific tolerance to allografts is the goal of transplantation research. Currently, morbid immunosuppressive therapy is used to mitigate rejection initiated in part by Ia-bearing interstitial graft dendritic or antigen-presenting cells (APCs) that are thought to migrate into the host after transplantation. We hypothesized that donor or organ immune modulation directed against graft APCs might influence graft immunogenicity and promote prolonged graft acceptance in histoincompatible hosts in the absence of immunosuppressive therapy. Haplotype-specific monoclonal antibodies (mAb), mAb specific to graft APC, adhesion or costimulatory molecules and anti-LFA-1-Ricin and anti-Iak-Ricin immunoconjugates (IC) were prepared and administered in varying doses and time intervals to donor C3H/HeJ (H-2k) mice. Thereafter, their spleens and hearts were removed at varying time intervals and used either as stimulator cells in one-way mixed lymphocyte reaction or transplanted into naive Balb/c (H-2d) recipients, respectively. Explanted C3H hearts were pretreated with anti-Iak mAb on the Langendorf apparatus. Hearts were also used from major histocompatibility complex (MHC) class I, MHC class II, and MHC class I- and II-deficient "knockout" mice. Splenocytes exposed to at least 500 microg of anti-Iak mAb in vivo for more than 4 hr were able to inhibit the mixed lymphocyte reaction to almost background levels, but only after incubation with rabbit complement in vitro. Similarly pretreated cardiac allografts (both in vivo or explanted and pretreated on the Langendorf apparatus) did not experience prolonged survival in nonimmunosuppressed Balb/C recipients when compared with control solutions, regardless of the concomitant use of complement. Splenocytes from immunoconjugate pretreated donors inhibited the mixed lymphocyte reaction completely without the use of complement; however, hearts from these donors also did not experience prolonged survival nor donor hearts exposed to mAb specific for graft APC, adhesion or costimulatory molecules. Only hearts from MHC class I and class II "knockout" mice survived significantly longer than controls. We conclude that donor or graft pretreatment with haplotype-specific anti-Ia mAb, haplotype-specific immunoconjugates, or mAb directed against graft APC, adhesion or costimulation molecules have little efficacy in promoting acceptance of cardiac allografts in nonimmunosuppressed recipients. The enhanced survival of hearts from MHC class I- and class II-deficient donors suggest that novel methods to effect the immunogenicity of the graft will be required if long-term allograft acceptance is to be achieved in the absence of host immunosuppression.

The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular dementia.

OBJECTIVE: To determine the association between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular dementia in Ashkenazi and non-Ashkenazi Jews. DESIGN: A case-control study. SETTING: Nursing homes in Jerusalem, Israel. PARTICIPANTS: Two hundred fifty nine Jewish people of Ashkenazi and non-Ashkenazi origin, older than age 70, who have vascular dementia (VD) (n = 85), Alzheimer's disease (AD) (n = 92), and who are cognitively intact (n = 82) with no clinical evidence of atherosclerotic vascular disease. MEASUREMENTS: The frequencies of the mutant allele (T allele) and homozygotes for the C677T MTHFR mutation (T/T genotype). The total plasma homocysteine (tHCT) level in 75 subjects. RESULTS: There were no significant differences in the frequencies of the T/T genotype or T allele among VD, AD, and cognitively intact older people of the same ethnic origin (0.15, 0.19, 0.25 T/T genotype and 0.42, 0.46, 0.47 T allele in Ashkenazi; 0.08, 0.06, 0.10 T/T genotype and 0.28, 0.32, 0.33 T allele in non-Ashkenazi with VD and AD, and in cognitively intact older people, respectively). The relative risk of VD associated with the T/T genotype versus the C/C genotype was 0.62 (95% CI, 0.19-1.19) in Ashkenazi and 0.65 (95% CI, 0.11-3.7) in non-Ashkenazi, respectively. The relative risk of AD associated with the T/T genotype was 0.85 (95% CI, 0.29-2.45) in Ashkenazi and 0.62 (95% CI, 0.1-4.3) in non-Ashkenazi, respectively. The frequencies of mutant homozygotes and allele were significantly higher in Ashkenazi than in non-Ashkenazi Jews (19.9% vs 7.5% T/T genotype, chi2 = 6.2, P = .01, 0.45 vs 0.31 T allele, chi2 = 9.77, P = .002 in Ashkenazi vs non-Ashkenazi, respectively). There were no differences in mean tHCT concentration among VD, AD, and cognitively intact older people. CONCLUSIONS: The MTHFR C677T is not associated with an increased risk of vascular dementia or Alzheimer's disease. The frequency of the mutation is significantly higher in Ashkenazi compared with non-Ashkenazi Jews.

Chondrosarcoma of the foot.

Chondrosarcomas have been seen clinically as aggressive tumors, with radiographic and histologic findings consistent with malignancy; however, they may have an insidious clinical course, with relatively benign radiographic and histopathologic findings. Rarely, a chondrosarcoma may present as a primary lesion of the foot. It is important to recognize these lesions as malignancies. The authors provide an overview of these neoplasms and describe a case of a low-grade chondrosarcoma in a 64-year-old woman.

Increased urinary N-telopeptide cross-linked type 1 collagen predicts bone loss in patients with inflammatory bowel disease.

OBJECTIVE: Reduced bone mineral density (BMD) is common in patients with inflammatory bowel disease (IBD), but the factors associated with its longitudinal rate of change have not been established. We prospectively assessed the rate of change in BMD, and its association with biochemical markers of bone turnover. METHODS: Twenty-two patients with Crohn's disease and 14 ulcerative colitis patients age 37.1 +/- 11.6 yr were followed for 2 yr. Lumbar spine (L2-L4) and femoral neck BMD were measured by dual x-ray absorptiometry at baseline and 24 months. Bone-specific alkaline phosphatase, osteocalcin, urinary N-telopeptide crosslinked type 1 collagen (NTx), parathyroid hormone, and 25-hydroxyvitamin-D were determined at baseline. RESULTS: At baseline, 59% of Crohn's patients and 43% of ulcerative colitis patients were osteoporotic, with spine or femoral neck BMD T-score < -2.5. Spine BMD, and spine and femoral neck T-scores were lower and disease duration was longer in nine patients with ileal resection compared with nonoperated patients (0.84 +/- 0.15 g/cm2 vs 0.96 +/- 0.11 g/cm2, -3.0 +/- 1.5 vs -1.7 +/- 1.3, -3.2 +/- 1.5 vs -2.2 +/- 1.0, respectively; all p < 0.05). At 24 months, 13/36 (36%) and 14/36 (39%) patients experienced spinal and femoral neck bone loss, respectively, with mean annual percent BMD changes of -2.0% and -1.5%, respectively. NTx, a bone resorption marker, inversely correlated with spinal BMD rate of change (r = -0.4, p < 0.05). Using quartiles analysis, patients with the highest NTx (Q4) experienced the greatest decrease in spine BMD compared with patients with the lowest NTx (Q1). CONCLUSIONS: Spine and femoral neck bone loss continues over time in more than one-third of IBD patients. Increased NTx level predicts spinal bone loss in IBD patients.

The decrease in serum bone-specific alkaline phosphatase predicts bone mineral density response to hormone replacement therapy in early postmenopausal women.

Hormone replacement therapy (HRT) prevents bone loss in postmenopausal women. Up to 20% of women demonstrate no increase in bone mineral density (BMD) on HRT. We examined whether early changes in serum bone alkaline phosphatase (B-ALP) predict long-term BMD changes in postmenopausal women on HRT. Ninety women within 1 year of menopause were randomly assigned to continuous or sequential estrogen/progestin (beta estradiol/norethisterone acetate) if naturally postmenopausal, or beta estradiol if within 1 month of surgical menopause. Spine, femoral neck BMD (DXA), and B-ALP were determined over 2 years. The mean percent BMD changes were 3.8%, 2.9%, 1.6% in the spine and 2.4%, 4.0%, 1.1% in the femoral neck in sequential, continuous, and estrogen alone treatment groups, respectively, significantly different from zero except for femoral neck BMD change in the estrogen alone group. HRT was associated with spine and femoral neck BMD loss in 17.4% and 25.3% of women, respectively. In estrogen/progestin-treated women, baseline B-ALP correlated with spine BMD change (r = 0.42, P < 0.01). At 3 months, B-ALP dropped significantly in the estrogen/progestin-groups with a maximal decrease at 12 months, but no change from baseline in the estrogen alone group. Using quartile analysis, women with the greatest drop in B-ALP (> or = 50%) at 6 months demonstrated the greatest gain in spine BMD at 2 years. A 40% decrease at 6 months in B-ALP had a 56% sensitivity, 83% specificity, 95% positive predictive value for spine BMD gain at 2 years. The decrease in B-ALP can be used to monitor BMD response to HRT.

Ethnic differences in the frequency of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in healthy Israeli populations.

Hyperhomocysteinemia is an independent risk factor for arteriosclerotic vascular disease. It can result from deficiencies of co-factors required for homocysteine metabolism and/or from genetic disorders of its metabolism. The association between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular disease is controversial, and may be affected by ethnic origin. A unique feature of the Israeli population is its ethnic diversity. The aim of this study was to study the frequency of the C677T MTHFR mutation in healthy Israeli ethnic groups. The frequency of the mutation was determined in 897 young healthy Jewish and Muslim Arab Israelis of eight different ethnic groups. Marked ethnic differences in the frequency of mutant homozygotes were found, ranging from 2% in Yemenite Jews, 4% in Sephardic Jews, 9% in Oriental Jews, 10% in Muslim Arabs, 16% in North African Jews, and 19% in Ashkenazi Jews. The frequency of mutant homozygotes was significantly higher in Ashkenazi Jews compared to Yemenites Oriental Jews, Sephardic Jews, and Muslim Arabs (chi2 = 12.35p < 0.001, chi2 = 8.17p = 0.004, chi2 = 6.04p = 0.01, chi2 = 6.54 p = 0.01, respectively). Our findings demonstrate the need for matching ethnic background in patients and controls when studying the association between the C677T MTHFR mutation and any disease.