Sclerosing injections to treat midportion Achilles tendinosis: a randomised controlled study evaluating two different concentrations of Polidocanol

Two to three ultrasound (US) and colour Doppler (CD)-guided injections of the sclerosing substance Polidocanol (5 mg/ml) have been demonstrated to give good clinical results in patients with chronic midportion Achilles tendinopathy. This study aimed to investigate if a higher concentration of Polidocanol (10 mg/ml) would lead to a less number of treatments, and lower volumes, needed for good clinical results. Fifty-two consecutive Achilles tendons (48 patients, mean age 49.6 years) with chronic painful midportion Achilles tendinopathy, were randomised to treatment with Polidocanol 5 mg/ml (group A) or 10 mg/ml (group B). The patients and treating physician were blinded to the concentration of Polidocanol injected. All patients had structural tendon changes and neovascularisation in the Achilles midportion. Treatment was US + CD-guided injections targeting the region with neovascularisation (outside ventral tendon). A maximum of three treatments (6-8 weeks in between) were given before evaluation. Patients not satisfied after three treatments were given additional treatment with Polidocanol 10 mg/ml, up to five treatments. For evaluation, the patients recorded the severity of Achilles tendon pain during activity on a visual analogue scale (VAS), before and after treatment. Patient satisfaction with treatment was also assessed. At follow-up (mean 14 months) after three treatments, 18/26 patients in group A and 19/26 patients in group B were satisfied with the treatment and had a significantly reduced level of tendon pain (P < 0.05). After completion of the study, additional treatments with Polidocanol 10 mg/ml in the not satisfied patients resulted in 26/26 satisfied patients in both groups A and B. In summary, we found no significant differences in the number of satisfied patients, number of injections or volumes given, between patients treated with 5 or 10 mg/ml Polidocanol.     

Low birth weight,but not postnatal weight gain,aggravates the course of nephrotic syndrome

Clinical and animal studies have shown a higher risk of an aggravated course of renal disease in childhood after birth for babies small for gestational age (SGA). In addition relative “supernutrition” and fast weight gain in early infancy seem to support the development of later disease. In a retrospective analysis of 62 cases of idiopathic nephrotic syndrome treated between 1994 and 2004 at a university centre for paediatric nephrology, we related the course of disease to birth weight and to the weight gain in the first 2 years of life. Six children were born SGA (birth weight <−1.5 standard deviation score), and 56 were born as appropriate for gestational age (AGA). In all SGA children renal biopsy was performed, while only 55% of the AGA children underwent renal biopsy (P = 0.07), showing no difference in renal histology. In the SGA group, four of six patients developed steroid resistance (vs 12/56 AGA, P < 0.05). Of the SGA children, 83% needed antihypertensive treatment in the course of the disease compared to 39% of the AGA children (P = 0.07). The extent of weight gain between birth and 24 months of age did not influence the course of disease. In conclusion, we were able to find evidence for an aggravated course of idiopathic nephrotic syndrome in former SGA children. Independently of birth weight, weight gain in the first 2 years of life did not influence the course of disease.     

Growth impairment shows an age-dependent pattern in boys with chronic kidney disease

The impact of chronological age on longitudinal body growth from early childhood through adolescence using detailed anthropometric methods has not yet been studied in children with chronic kidney disease (CKD). We have evaluated growth failure by measuring four components of linear growth: body height (HT), sitting height (SHT), arm length (AL) and leg length (LL). Data were prospectively collected for up to 7 years on 190 boys (3–21 years old) with congenital or hereditary CKD (all had developed at least stage 2 CKD by the age of 10 years). Patients showed the most severe growth failure in early childhood, followed by an acceleration in growth in pre-puberty, a slowing-down of growth at puberty, as expected, and thereafter a late speeding-up of growth until early adulthood. This pattern was observed irrespective of the degree of CKD and different treatment modalities, such as conservative treatment, recombinant human growth hormone (rhGH) therapy or transplantation. LL showed the most dynamic growth changes of all the parameters evaluated and emerged as the best indicator of statural growth in children with CKD. A specific age-dependent pattern of physical growth was identified in pediatric male CKD patients. This growth pattern should be considered in the evaluation of individual growth and the assessment of treatment efficacy such as rhGH therapy.     

Colony-Stimulating Factor-1: A Potential Biomarker for Lupus Nephritis

A noninvasive means to predict the onset and recurrence of lupus nephritis (LN) before overt renal injury is needed to optimize and individualize treatment. Colony-stimulating factor-1 (CSF-1) is expressed by kidney tubules at the onset of LN, increases with disease progression, and spills into the circulation in lupus-prone mice. We tested the hypothesis that amplified expression of CSF-1 detected in the serum or urine correlates with intrarenal CSF-1 expression and histopathology (increased macrophage accumulation, activity indices) and clinical kidney disease activity and predicts the onset and recurrence of nephritis in patients with systemic lupus erythematosus (SLE). We found increased serum or urine CSF-1 levels in patients with cutaneous, serositis, and musculoskeletal disease; however, the increase in CSF-1 levels was far greater in LN. Moreover, an elevation in serum or urine CSF-1 levels correlated with increasing intrarenal CSF-1 expression and histopathology. By longitudinally tracking patients, we found that elevated serum CSF-1 heralded the initial onset of disease, and a rise in serum or urine CSF-1 predicted recurrences of LN before clinical evidence of glomerular dysfunction and conventional serologic measures, even in patients with other manifestations of SLE. These findings indicate that serial monitoring for a rise in serum or urine CSF-1 levels in patients with SLE reflects kidney histopathology and may predict renal disease activity and the onset and recurrence of LN more accurately than conventional laboratory measures.     

Splenectomy improves survival by increasing arterial blood supply in a rat model of reduced‐size liver

Prevention of acute portal hyperperfusion in small‐for‐size livers by inflow modulation results in beneficial postoperative outcome. The objective of this study was to unravel the underlying mechanism, emphasizing the intimate relationship between portal venous (PV) and hepatic arterial (HA) blood flow (BF). Rats underwent partial hepatectomy (pHx), splenectomy before pHx or splenectomy and ligation of the A. hepatica before pHx. Portal venous blood flow (PVBF), hepatic arterial blood flow (HABF), and tissue pO₂ were assessed during stepwise resection from 30% to 90%. Hepatic regeneration and hypoxia‐responsive gene expression were analyzed in each group after nonlethal 85% pHx. 90% pHx caused a fourfold rise in PVBF, a slight decrease in HABF with a 50% reduction in pO₂, and high mortality. Splenectomy before pHx reduced the PVBF and caused a rise in HABF with doubling in tissue pO₂. An attenuation of hypoxia‐responsive gene expression turned into enhanced hepatocellular regeneration and improved survival. A. hepatica ligation abolished the beneficial effect of splenectomy on tissue oxygenation, proliferation, and outcome. In conclusion, the beneficial effect of splenectomy in small‐for‐size livers can be attributed to a rise in HABF with sufficient oxygen supply rather than to a reduced portal venous hyperperfusion to the remnant liver.     

Importance of Early Screening and Prophylactic Thyroidectomy in Asymptomatic Nonindex RET Germline Carriers

Genetic testing for RET germline mutations affords rapid identification of germline carriers, offering the prospect of cure before C-cell hyperplasia (CCH) has progressed to medullary thyroid carcinoma (MTC). Although nonindex RET mutation carriers have a better prognosis than do the index patients, it remains to be ascertained whether age represents a risk factor for MTC when screening patients. The current institutional study (October 1994 through June 1999) was set up to compare asymptomatic nonindex patients who were grouped by age: < 20 years and ≥ 20 years. Inclusion criteria were confirmed RET mutations in the germline, with no MTC being more advanced than pT1pN1M0. Adult patients (≥ 20 years) had MTC significantly more often (84% vs. 43%), significantly larger tumors (5 mm vs. 3 mm), and significantly higher basal calcitonin levels preoperatively (78.0 vs. 9.7 pg/ml) than their pediatric/adolescent counterparts (< 20 years). There was a close correlation between pT1 MTC and an elevated basal serum calcitonin level (r= 0.67; Spearman's rho). All three patients with lymph node metastases from MTC had elevated basal calcitonin levels. The two groups did not differ in terms of multifocality of MTC (pT1b), lymph node involvement (pN1) or bilateral lymph node metastasis (pN1b), or preoperative stimulated and postoperative basal and stimulated serum calcitonin. Prophylactic thyroidectomy should not be postponed beyond the age of 20, and it should be performed before basal serum calcitonin has turned positive. Pathologic conversion of stimulated serum calcitonin obviously marks the time in carriers of RET germline mutations when surgery should be scheduled at the latest to be prophylactic.     

Combined Risk Allele Score of Eight Type 2 Diabetes Genes Is Associated With Reduced First-Phase Glucose-Stimulated Insulin Secretion During Hyperglycemic Clamps

OBJECTIVE

At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered β-cell function. In this study, we have investigated the combined effects of eight known β-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps.

RESEARCH DESIGN AND METHODS

A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting.

RESULTS

The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 × 10⁻⁶). The effect size was equal in subjects with NGT and IGT. We also noted an inverse correlation with the disposition index (P = 1.6 × 10⁻³). When we stratified the study population according to the number of risk alleles into three groups, those with a medium- or high-risk allele score had 9 and 23% lower first-phase GSIS. Second-phase GSIS, insulin sensitivity index and GLP-1, or arginine-stimulated insulin release were not significantly different.

CONCLUSIONS

A combined risk allele score for eight known β-cell genes is associated with the rapid first-phase GSIS and the disposition index. The slower second-phase GSIS, GLP-1, and arginine-stimulated insulin secretion are not associated, suggesting that especially processes involved in rapid granule recruitment and exocytosis are affected in the majority of risk loci.Type 2 diabetes is a polygenic disease in which the contribution of a number of detrimental gene variants in combination with environmental factors is thought to be necessary for the development of disease. In the past 2 years, results of several genome-wide association studies (GWASs) have been published (1–5), leading to a rapidly increasing number of detrimental type 2 diabetes susceptibility loci. More recently, it has indeed been shown that combining information from these diabetes loci into a risk allele score for all loci enhances diabetes risk (6–9). However, the predictive power of this combined risk allele score is yet insufficient to substitute or largely improve predictive power of known clinical risk factors (8,9). At present, little is known about how these gene variants in combination affect insulin secretion or insulin resistance. Based on recent data, mainly obtained from oral glucose tolerance tests (OGTTs), it was shown that a combined risk allele score from gene variants associated with type 2 diabetes is associated with insulin secretion and not with insulin sensitivity (10–13). However, the OGTT is unable to distinguish between first- and second-phase insulin secretion. Furthermore, other secretagogues, like glucagon-like peptide (GLP)-1 and arginine, were not included in these studies.It is thought that the rapid recruitment and release of insulin granules from the readily releasable pool (RRP) is responsible for the first phase of insulin secretion, whereas the slower prolonged second phase involves recruitment to the membrane of more distant granules and de novo insulin synthesis. Although the exact pathways regulating both phases of glucose-stimulated insulin secretion (GSIS) are not completely resolved, it seems logical that they are at least in part different. This is further corroborated by our recent observation that the heritability for both phases of GSIS in twins is derived from partly nonoverlapping sets of genes (13a).Also, other nonglucose, stimuli-like incretins and amino acids can evoke an insulin response. Detailed phenotypic investigations of the response to these different stimuli may help to elucidate which processes are primarily affected by these loci. Previously, we have already shown that type 2 diabetes genes/loci can have different effects on first- and second-phase GSIS, as measured using hyperglycemic clamps. Also, based on the method of stimulation (i.e., oral versus intravenous), the outcome may differ substantially (14–17), which provides further clues about the mechanism by which they affect insulin secretion.In this study, we genotyped gene variants in TCF7L2, KCNJ11, HHEX/IDE, CDKAL1, IGF2BP2, SLC30A8, CDKN2A/CDKN2B, and MTNR1B in 447 hyperglycemic clamped subjects (256 with normal glucose tolerance [NGT] and 191 with impaired glucose tolerance [IGT]) from four independent studies in the Netherlands and Germany. These eight loci were chosen based on the fact that they were reproducibly associated with β-cell function in various studies (rev. in 18,19). A combined risk allele score of all eight gene variants was calculated for each individual and tested against the various detailed measurements of β-cell function using the hyperglycemic clamp, generally considered to be the gold standard for quantification of first- and second-phase GSIS (20). Furthermore, we also assessed the combined effect of these eight genes on two other stimuli, GLP-1 and arginine-stimulated insulin secretion during hyperglycemia, in a subset of the study sample (n = 224). The latter test provides an estimation of the maximal insulin secretion capacity of a subject and may, according to animal studies, serve as a proxy for β-cell mass (21).     

ABO-incompatible kidney transplantation of an 8-yr-old girl with donor/recipient-constellation A1B/B

BACKGROUND: Antigen-specific immunoadsorption combined with rituximab offers the possibility for ABO-incompatible kidney transplantation without splenectomy. PATIENT AND METHOD: An 8-year-old mentally retarded girl with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis due to mitochondriopathy poorly tolerated hemodialysis. Paternal blood group A1B was incompatible with blood group B of the child. Therefore, we decided to perform the first ABO-incompatible renal transplantation in a child in Germany using antigen-specific immunoadsorption. Rituximab (1 x 375 mg/m2) was administered 2 weeks before the first immunoadsorption (Glycosorb) ABO A-column). Triple-drug immunosuppression (tacrolimus, mycophenolate mofetil and prednisolone) was simultaneously started with immunoadsorption. Initial tacrolimus levels were targeted between 15 and 20 ng/ml. Before transplantation, six immunoadsorptions were applied on days -9, -7, -4, -3, -2 and -1. Intravenous immunoglobulin (0.5 g/kg) was administered preoperatively. After transplantation, three immunoadsorptions were performed on days +4, +6 and +8. RESULTS: Before transplantation, antibody (Ab) titers against paternal erythrocytes (20 degrees C) were reduced from 1 : 64 to 1 : 4 by six antigen-specific immunoadsorptions. After transplantation, we performed three more immunoadsorptions and the Ab titers were stable between 1 : 1 and 1 : 8. One, 2 and 8 months later we observed increases in the Ab titer up to 1 : 32 requiring no change in immunosuppressive therapy. No side effects of immunoadsorption were observed. The girl had excellent initial graft function with a serum creatinine of 55 to 70 micromol/l. Two weeks after transplantation, graft biopsy showed no signs of rejection; there was focal positivity for C4d only. Twelve months after transplantation, renal function was stable, with a serum creatinine of 117 micromol/l. Episodes of rejection or severe infections were absent. CONCLUSION: ABO-incompatible transplantation using antigen-specific immunoadsorption and rituximab may serve as a suitable alternative for children urgently needing renal transplantation and missing a blood group-compatible donor.     

Root resorption diagnosed with cone beam computed tomography after 6 months of orthodontic treatment with fixed appliance and the relation to risk factors

Objectives:To investigate root resorption after 6 months of active orthodontic treatment and its relation to possible risk factors.Materials and Methods:Ninety-seven patients (10–18 years) with a Class I malocclusion and crowding treated with fixed appliance and premolar extractions were examined with cone beam computed tomography before and after 6 months of active treatment. The exposure covered all teeth from first molar to first molar in both jaws. The Malmgren index was used to evaluate the degree of root resorption. Irregular root contour (score 1) was seen in most teeth already before active treatment, and therefore resorptions were registered only as score 2 (<2 mm, minor resorption) or higher.Results:Minor root resorption was noted in 10% of the patients and severe root resorption, >2 mm (score 3) was found in four patients. Root resorption was more frequently seen in the upper jaw, especially the incisors. There was no statistically significant correlation of root resorption with any of the selected risk factors.Conclusions:After 6 months of treatment, clinically significant resorption was diagnosed in 4% of the patients, ie, in 96% of the patients the radiographic examination did not reveal any significant information. The selected risk factors did not have any impact on the amount of resorption after 6 months of active treatment.