The effect of idursulfase on growth in patients with Hunter syndrome: data from the Hunter Outcome Survey (HOS)

Hunter syndrome (mucopolysaccharidosis type II) is a rare and life-limiting multisystemic disorder with an X-linked recessive pattern of inheritance. Short stature is a prominent feature of this condition. This analysis aimed to investigate the effects of enzyme replacement therapy with idursulfase on growth in patients enrolled in HOS - the Hunter Outcome Survey which is a multinational observational database. As of Jan 2012, height data before treatment were available for 567 of 740 males followed prospectively after HOS entry. Cross-sectional analysis showed that short stature became apparent after approximately 8 years of age; before this, height remained within the normal range. Age-corrected standardized height scores (z-scores) before and after treatment were assessed using piecewise regression model analysis in 133 patients (8-15 years of age at treatment start; data available on ≥ 1 occasion within +/-24 months of treatment start; growth hormone-treated patients excluded). Results showed that the slope after treatment (slope=-0.005) was significantly improved compared with before treatment (slope=-0.043) (difference=0.038, p=0.004). Analysis of covariates (age at treatment start, cognitive involvement, presence of puberty at the start of ERT, mutation type, functional classification), showed a significant influence on growth of mutation type (height deficit in terms of z-scores most pronounced in patients with deletions/large rearrangements/nonsense mutations, p<0.0001) and age (most pronounced in the 12-15-year group, p<0.0001). Cognitive involvement, pubertal status at the start of ERT and functional classification were not related to the growth deficit or response to treatment. In conclusion, the data showed an improvement in growth rate in patients with Hunter syndrome following idursulfase treatment.

In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes.

BACKGROUND: Congenital afibrinogenemia is a rare inherited autosomal recessive disorder in which a mutation in one of three genes coding for the fibrinogen polypeptide chains Aα, Bβ and γ results in the absence of a functional coagulation protein. A patient with congenital afibrinogenemia, resulting from an FGA homozygous gene deletion, underwent an orthotopic liver transplant that resulted in complete restoration of normal hemostasis. The patient's explanted liver provided a unique opportunity to further investigate a potential novel treatment modality. OBJECTIVE: To explore a targeted gene therapy approach for patients with congenital afibrinogenemia. METHODS AND RESULTS: At the time of transplant, the patient's FGA-deficient hepatocytes were isolated and transduced with lentiviral vectors encoding the human fibrinogen Aα-chain. FGA-transduced hepatocytes produced fully functional fibrinogen in vitro. CONCLUSIONS: Orthotopic liver transplantation is a possible rescue treatment for failure of on-demand fibrinogen replacement therapy. In addition, we provide evidence that hepatocytes homozygous for a large FGA deletion can be genetically modified to restore Aα-chain protein expression and secrete a functional fibrinogen hexamer.

Cessation and resuming of alglucosidase alfa in Pompe disease: a retrospective analysis.

Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) in late-onset Pompe disease is moderately effective. Little is known about the clinical course after treatment termination and the resumption of ERT. In Switzerland, rhGAA therapy for Pompe disease was temporarily withdrawn after the federal court judged that the treatment costs were greatly out of proportion compared to the benefits. Re-treatment was initiated after the therapy was finally licensed. We retrospectively analysed seven Pompe patients, who underwent cessation and resumption of ERT (median age 43 years). The delay from first symptoms to final diagnosis ranged from 4 to 20 years. The demographics, clinical characteristics, assessments with the 6-min walking test (6-MWT), the predicted forced vital capacity (FVC) and muscle strength were analysed. Before initiation of ERT, all patients suffered from proximal muscle weakness of the lower limbs; one was wheelchair-bound and two patients received night-time non-invasive ventilation. Initial treatment stabilised respiratory function in most patients and improved their walking performance. After treatment cessation, upright FVC declined in most and the 6-MWT declined in all patients. Two patients needed additional non-invasive ventilatory support. Twelve months after resuming ERT, the respiratory and walking capacity improved again in most patients. However, aside for one patient, none of the patients reached the same level of respiratory function or distance walked in 6 min, as at the time of ERT withdrawal. We conclude that cessation of ERT in Pompe disease causes a decline in clinical function and should be avoided. Resuming treatment only partially recovers respiratory function and walking capacity.

[Klinik und Diagnose von Hypogonadismus und Andropause]

Diagnosis and therapy of male hypogonadism is still a challenge because of the unspecific clinical signs and symptoms. The clinical presentation of a androgen deficiency is age-related. In the adult men, one can often observe fatigue, decrease in physical capacity, loss of libido and erectile dysfunction. At the physical examination, genitalia have always to be assessed in search of a testes/penis atrophy. Two fasting measurements of total testosterone concentrations by a reliable assay are needed to confirm the diagnosis. By assessing gonadotropines the origin of hypogonadism can be determined (central/secondary or peripheral/primary). Exogenous administration of androgens should be considered in young, sportive, healthy and muscular males. Patients with metabolic syndrome should only be screened for hypogonadism in the presence of suggestive symptoms. Prostate disease, hematocrit higher than 50 %, uncontrolled heart failure and severe obstructive sleep apnea are contraindications of a testosterone replacement therapy. Patients with metabolic-syndrome-associated low testosterone levels should firstly benefit from a lifestyle intervention that can normalize clinical and biochemical hypogonadism. So far, there is no clear evidence for a possible benefit of testosterone therapy in patients with the metabolic syndrome. Similarly, in patients with PADAM (partial androgen deficiency of the aging male) testosterone therapy is not established or recommended.

Recent advances and future prospects in choroideremia.

Choroideremia is a complex and rare disease that is frequently misdiagnosed due to its similar appearance to classic retinitis pigmentosa. Recent advances in genetic testing have identified specific genetic mutations in many retinal dystrophies, and the identification of the mutation of the CHM gene on the X chromosome 25 years ago has paved the way for gene replacement therapy with the first human trials now underway. This article reviews the epidemiological and pathological features of choroideremia and new prospects in imaging to monitor disease progression, as well as potential treatment approaches for choroideremia.

Life style habits such as alcohol consumption and physical activity in relation to serum apoB / apoA-I ratio amongst 64-year-old women with varying degrees of glucose tolerance.

OBJECTIVES To investigate how life style factors such as alcohol consumption and physical activity relate to the serum apoB / apoA-I ratio in a cohort of middle-aged women with varying degrees of glucose tolerance. DESIGN Observational, cross-sectional cohort study. SETTING Research laboratory at a University Hospital. SUBJECTS A screened cohort of 64-year-old postmenopausal women with varying degrees of glucose tolerance, ranging from diabetes (n = 232), impaired (n = 212) and normal (n = 191) glucose tolerance. MAIN OUTCOME MEASURE ApoB / apoA-I ratio in relation to alcohol consumption and physical activity as assessed by questionnaires. RESULTS Alcohol consumption and regular physical activity at high levels were inversely associated with the serum apoB / apoA-I ratio independently of confounding factors such as obesity, lipid-lowering treatment, degree of glucose tolerance and hormone replacement therapy. Alcohol seemed related to the apoB / apoA-I ratio mainly through increasing apoA-I, whereas physical activity seemed mainly related to lowering of apoB. Alcohol consumption above a daily intake of 8.9 g, i.e. less than a glass of wine was accompanied by a decrease in apoB / apoA-I ratio. CONCLUSIONS Amongst these 64-year-old women with varying degrees of glucose tolerance, a moderate alcohol intake and regular physical exercise leading to sweating were associated with lower apoB / apoA-I ratio and these effects seem to be additive.

Abdominal aortic calcification and risk of fracture among older women - The SOF study

Data concerning the link between severity of abdominal aortic calcification (AAC) and fracture risk in postmenopausal women are discordant. This association may vary by skeletal site and duration of follow-up. Our aim was to assess the association between the AAC severity and fracture risk in older women over the short- and long term. This is a case-cohort study nested in a large multicenter prospective cohort study. The association between AAC and fracture was assessed using Odds Ratios (OR) and 95% confidence intervals (95%CI) for vertebral fractures and using Hazard Risks (HR) and 95%CI for non-vertebral and hip fractures. AAC severity was evaluated from lateral spine radiographs using Kauppila's semiquantitative score. Severe AAC (AAC score 5+) was associated with higher risk of vertebral fracture during 4 years of follow-up, after adjustment for confounders (age, BMI, walking, smoking, hip bone mineral density, prevalent vertebral fracture, systolic blood pressure, hormone replacement therapy) (OR=2.31, 95%CI: 1.24-4.30, p<0.01). In a similar model, severe AAC was associated with an increase in the hip fracture risk (HR=2.88, 95%CI: 1.00-8.36, p=0.05). AAC was not associated with the risk of any non-vertebral fracture. AAC was not associated with the fracture risk after 15 years of follow-up. In elderly women, severe AAC is associated with higher short-term risk of vertebral and hip fractures, but not with the long-term risk of these fractures. There is no association between AAC and risk of non-vertebral-non-hip fracture in older women. Our findings lend further support to the hypothesis that AAC and skeletal fragility are related.

Renal function in patients with HIV starting therapy with tenofovir and either efavirenz, lopinavir or atazanavir

Tenofovir is associated with reduced renal function, but it is not clear whether there is a greater decline in renal function when tenofovir is co-administered with a boosted protease inhibitor rather than with a nonnucleoside reverse transcriptase inhibitor (NNRTI).

[Hypertension therapy in patients with renal artery stenosis]

Renovascular hypertension is due to reduced renal parenchymal perfusion. The correct diagnosis can be difficult. It is important to note that the demonstration of renal artery stenosis in a patient with hypertension does not necessarily constitute renovascular hypertension. Often, clinically nonsignificant and asymptomatic renal artery stenosis are found in patients with essential hypertension, or renal failure of other origin. Renovascular disease is a complex disorder with various clinical presentations. In patients with significant renovascular hypertension plasma renin is increased. For this reason the therapy aims to block the renin-angiotensin-aldosterone system. Bilateral renal artery stenosis causes renal sodium retention. In this situation a diuretic drug has to be added to the therapy. Endovascular or surgical therapy has to be considered in patients with flash pulmonary edema or fibromuscular dysplasia. The control of cardiovascular risk factors is important.

[Endovascular therapy of an abdominal aortic aneurysm in a renal transplant recipient]

INTRODUCTION: The indications for endovascular aortic aneurysm repair (EVAR) are mainly established in hostile abdomen, in patients with significant comorbidities which affect the general operability of the patient and, given the necessary infrastructure, also in ruptured aneurysm. Along to those, we present another possible indication in the presence of a kidney allograft in patients with aortic aneurysm. METHODS: Based on a case report of aorto-biiliac stent-graft repair of an infrarenal aortic aneurysm in a patient with renal allograft, a systematic review of the literature was performed of all similar cases concerning surgical therapy in this constellation. RESULTS: EVAR was performed using an aorto-biiliac system (Zenith) Trifab, COOK) in a 61-year-old male patient 11 years after heterotopic renal allotransplantation in the right iliac fossa. Preoperative renal function was normal. Because the donor renal artery was anastomosed to the recipient's external iliac artery the stent-graft was implanted from the left common femoral artery to minimize temporary allograft ischemia. The intra- and postoperative course was uneventful with a follow-up of presently 12 months. A primary type-II endoleak (retroleak from a lumbar artery) is being treated conservatively so far with embolization being a future option. At present there are 15 cases of EVAR in renal allograft patients that have been reported, all of them being successful. DISCUSSION: All data existing in the literature reported to date as well as our own experience justify the first choice of EVAR in morphologically suitable cases. One major advantage of EVAR in this constellation is the avoidance of aortic cross clamping which poses the graft at risk of ischemia. Long-term results will be most important for definite assessment of EVAR. However, contrast media application during the operation and for CT surveillance should be considered as a major disadvantage.

Impact of Baseline Renal Function on Tenofovir-containing Antiretroviral Therapy Outcomes in Zambia

Background. Although tenofovir (TDF) use has increased as part of first-line antiretroviral therapy (ART) across sub-Saharan Africa, renal outcomes among patients receiving TDF remain poorly understood. We assessed changes in renal function and mortality in patients starting TDF- or non-TDF-containing ART in Lusaka, Zambia. Methods. We included patients aged ≥16 years who started ART from 2007 onward, with documented baseline weight and serum creatinine. Renal dysfunction was categorized as mild (eGFR 60-89 mL/min), moderate (30-59 mL/min) or severe (<30 mL/min) using the CKD-EPI formula. Differences in eGFR during ART were analyzed using linear mixed-effect models, the odds of developing moderate or severe eGFR decrease with logistic regression and mortality with competing risk regression. Results. We included 62,230 adults, of which 38,716 (62%) initiated a TDF-based regimen. The proportion with moderate or severe renal dysfunction at baseline was lower in the TDF compared to the non-TDF group (1.9% vs. 4.0%). Among patients with no or mild renal dysfunction, those on TDF were more likely to develop moderate (adjusted OR: 3.11; 95%CI: 2.52-3.87) or severe eGFR decrease (adjusted OR: 2.43; 95%CI: 1.80-3.28), although the incidence of such episodes was low. Among patients with moderate or severe renal dysfunction at baseline, renal function improved independently of ART regimen and mortality was similar in both treatment groups. Conclusions. TDF use did not attenuate renal function recovery or increase mortality in patients with renal dysfunction. Further studies are needed to determine the role of routine renal function monitoring before and during ART use in Africa.

Skin cancers in renal transplant recipients: A description of the renal transplant cohort in Bern

BACKGROUND/AIMS: Skin tumours, in particular squamous-cell carcinomas (SCC), are the most common malignant conditions developing in transplant recipients. The aim of this study is to investigate the frequency and type of skin cancer in patients receiving immunosuppressive therapy after organ transplantation. METHODS: Multivariate logistic regression analysis was performed on data of 243 renal transplant patients who attended the dermatology outpatient clinic for the first time after transplantation in the period January 2002-October 2005. RESULTS: We found an increased risk of actinic keratosis (AK) and SCC in renal transplant recipients with a basal cell carcinoma (BCC) / SCC ratio of 1:7. Older patients had AK more frequently (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.06-1.15; p <0.0001) and SCC (OR 1.14, CI 1.07-1.22; p <0.0001) than younger patients. Men had AK (OR 0.19, CI 0.08-0.45; p = 0.0002) and SCC (OR 0.25, CI 0.07-0.89; p = 0.0332) more frequently than women. The duration of immunosuppressive therapy correlated significantly with the numbers of AKs (OR 1.15, CI 1.08-1.24; p <0.0001) and SCCs (OR 1.16, CI 1.05-1.28; p = 0.0025), and patients with fair skin had more AKs (OR 0.31, CI 0.14-1.24; p <0.0001) and SCCs (OR 0.11, CI 0.02-0.52; p = 0.0054) than darker skinned patients. We could not identify any specific immunosuppressive drug as a distinct risk factor for AK or non-melanoma skin cancer (NMSC). CONCLUSION: Skin cancers are increased in the renal transplant population. Main risk factors for skin cancers are fair skin type and long duration of immunosuppressive therapy. A follow-up programme is necessary for early detection of skin cancer and precancerous conditions. Preventive strategies should include specialist dermatological monitoring and self-examination.

Impact of long-term corticosteroid therapy on the distribution pattern of lower limb atherosclerosis

OBJECTIVE: Ectopic calcification and mediacalcinosis can be promoted by corticosteroid use. Aim of the present investigation is to describe macrovascular disease features in patients with long-term corticosteroid therapy and symptomatic lower limb peripheral arterial occlusive disease (PAD). METHODS: A consecutive series of 2783 patients undergoing clinical and angiographic work-up of PAD were screened for long-term (>5 years) corticosteroid use (group A). Comparison was performed to a randomly selected age-, sex- and risk factor-matched PAD control cohort from the same series without corticosteroid use (group B). Patients with diabetes mellitus or severe renal failure were excluded. Arterial calcification was evaluated by qualitative assessment on radiographic images. Severity of atherosclerotic lesions was analysed from angiographic images using a semi-quantitative score (Bollinger score). RESULTS: In general, 12 patients (5 males, mean age 78.5 +/- 9.0 years) with 15 ischaemic limbs qualified to be enrolled in group A and were compared to 23 matching control patients (6 2 males, mean age 79.5 +/- 6 years) with 32 ischaemic limbs. Incompressibility of ankle arteries determined by measurement of the ankle-brachial index was seen in 12 limbs (80%) in group A compared to 3 limbs (9%) in group B (p = 0.0009). No significant difference was found comparing group A and B for segmental calcification, whereas comparison of the atherosclerotic burden using the angiographic severity score showed a significantly higher score at the infragenicular arterial level in group A (p = 0.001). CONCLUSION: Findings suggest that the long-term corticosteroid therapy is associated with a distally accentuated, calcifying peripheral atherosclerosis inducing arterial incompressibility. This occlusion pattern is comparable to patients with renal failure or diabetes. Further research is required to support our observations.

[Partial clinical remission of chronic IgA nephropathy with therapy of tuberculosis]

A 36-year-old patient suffered from repeated exsudative pleural effusions and renal insufficiency (serum creatinine 1.9 mg/dl) combined with glomerular erythrocyturia, proteinuria and renal hypertension.