Transplantation of frozen-thawed ovarian tissue: an update on worldwide activity published in peer-reviewed papers and on the Danish cohort.

PURPOSE: The purpose of the study is to review all peer-reviewed published reports of women receiving ovarian tissue transplantation (OTT) with frozen/thawed tissue (OTC) with respect to age, diagnosis, transplantation site, fertility outcome, and potential side effects, including data from all women in the Danish program. METHODS: A systematic review of the literature was performed in PubMed combined with results from all patients who had received OTT in Denmark up to December 2017. RESULTS: OTT has been reported from 21 different countries comprising a total of 360 OTT procedures in 318 women. In nine women, malignancy was diagnosed after OTT; none were considered to be directly caused by the OTT. Despite a potential under reporting of cancer recurrence, there is currently no evidence to suggest that OTT causes reseeding of the original cancer. Renewed ovarian endocrine function was reported in 95% of the women. Half of all children born following OTT resulted from natural conception, and newborns were reported to be healthy except for one neonate with a chromosome anomaly with a family disposition. Women who conceived after OTT were significantly younger than those who failed. CONCLUSION: This study found no indications of sufficient numbers of malignant cells present in the ovarian tissue to cause recurrence of cancer after OTT. Further, it is unlikely that OTC affects the well-being of children born. OTC is now an established method of fertility preservation in Denmark with public reimbursement. The current data encourage that women who require gonadotoxic treatment should be offered an individual evaluation considering fertility preservation.

The Region of Difference Four is a Robust Genetic Marker for Subtyping Mycobacterium caprae Isolates and is Linked to Spatial Distribution of Three Subtypes.

Alpine Mycobacterium caprae isolates found in cattle and red deer display at least three genetic variations in the region of difference four (RD4) that can be used for further differentiation of the isolates into the subtypes 'Allgäu', 'Karwendel' and 'Lechtal'. Each genomic subtype is thereby characterized by a specific nucleotide deletion pattern in the 12.7-kb RD4 region. Even though M. caprae infections are frequently documented in cattle and red deer, little is known about the transmission routes. Hence, robust markers for M. caprae subtyping are needed to gain insight into the molecular epidemiology. For this reason, a rapid and robust multiplex PCR was developed for the simultaneous detection of three M. caprae RD4 subtypes and was used to subtype a total number of 241 M. caprae isolates from animals (145 cattle, 95 red deer and one fox) from Bavaria and Austria. All three subtypes occur spatially distributed and are found in cattle and in red deer suggesting transmission between the two species. As subtypes are genetically stable in both species it is hypothesized that the described genetic variations developed within the host due to 'within-host replication'. The results of this study recommend the genomic RD4 region as a reliable diagnostic marker for M. caprae subtype differentiation.

HLA genes associated with autoimmunity and progression to disease in type 1 diabetes.

Insulin dependent diabetes mellitus (type I DM) is caused by an autoimmune process which culminates in destruction of pancreatic beta cells with resultant loss of insulin production. Preceding the clinical diagnosis of type I DM is a preclinical stage characterized by autoantibodies to insulin, glutamic acid decarboxylase (GAD) and a tyrosine phosphatase-like molecule (IA-2). We have studied both HLA class I and class 2 allele distributions in diabetic probands and autoantibody positive individuals in members of 452 families recruited for the Australian type I diabetes DNA repository. The results demonstrate that progression to autoimmunity as measured by the appearance of autoantibodies is strongly associated with the class 2 alleles DRB1*03 and DRB*04 and with DRB1*03/04 heterozygosity. In contrast, the progression to clinical disease appears associated with class I alleles A24, A30 and B18 while A1, A28, B14 and B56 appear negatively associated. The class 2 alleles appear to have a minimal role in the progression from autoantibody positivity to clinical disease. These results are consistent with the view that CD4+ T cells responding to peptides in the context of class 2 molecules are responsible for initiating autoantibody production, while the destruction of islet cells leading to clinical expression of the disease is the function of CD8+ T cells recognizing relevant peptides in the context of class I molecules.

Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes.

Pancreatic islet autoimmunity leading to type 1 diabetes could be triggered by viruses in genetically susceptible individuals. Rotavirus (RV), the most common cause of childhood gastroenteritis, contains peptide sequences highly similar to T-cell epitopes in the islet autoantigens GAD and tyrosine phosphatase IA-2 (IA-2), suggesting T-cells to RV could trigger islet autoimmunity by molecular mimicry. We therefore sought an association between RV infection and islet autoantibody markers in children at risk for diabetes who were followed from birth. There was a specific and highly significant association between RV seroconversion and increases in any of these antibodies: 86% of antibodies to IA-2, 62% to insulin, and 50% to GAD first appeared or increased with increases in RV IgG or IgA. RV infection may therefore trigger or exacerbate islet autoimmunity in genetically susceptible children.

Role of islet autoimmunity in the aetiology of different clinical subtypes of diabetes mellitus in young north Indians.

AIMS: To determine the role of islet autoimmunity in the aetiology of different clinical subtypes of diabetes mellitus in young north Indian patients by measuring islet autoantibodies. METHODS: In a cross-sectional study, 145 young patients with diabetes (onset < 30 years) were subdivided into the following categories: Type 1 diabetes (n = 83), malnutrition-modulated diabetes mellitus (MMDM, n = 31) and fibro-calculous pancreatic diabetes (FCPD, n = 31). MMDM subjects presented with emaciation and severe insulin-requiring but ketosis-resistant diabetes, while FCPD was associated with idiopathic chronic calcific pancreatitis. Antibodies to glutamic acid decarboxylase (GADA) and IA-2 (IA-2 A) were detected by immunoprecipitation of 35S-labelled recombinant antigens and cytoplasmic islet cell antibody (ICA) by indirect immunofluorescence. RESULTS: GADA were present in a significant proportion (23%) of patients with MMDM. In contrast, IA-2 A was increased only among patients with Type 1 diabetes (22%), but not MMDM (3%, P < 0.05). Among patients with a duration of diabetes < 2 years, GADA and/or IA-2 A were found in 61% of Type 1 diabetic and 37% of MMDM patients (P < 0.01). MMDM patients who were positive for GADA had a shorter duration of diabetes, but did not differ in their age at onset of diabetes, body mass index, fasting plasma C-peptide, or frequency of thyroid microsomal and parietal cell antibodies. FCPD subjects had the lowest prevalence of autoantibodies: IA-2 and ICA were absent, while GADA were present in 7% (P < 0.05 vs. Type 1 diabetes). CONCLUSIONS: GADA, though not IA-2 A, were present in a substantial proportion of patients with the MMDM variant of diabetes, suggesting that islet autoimmunity may play a role in its pathogenesis. In contrast, none of the islet antibodies was increased in subjects with FCPD, making it likely that it is a secondary type of diabetes.

Islet autoimmunity in infants with a Type I diabetic relative is common but is frequently restricted to one autoantibody.

AIMS/HYPOTHESIS: To determine the sequence of development of islet autoantibodies and their relation to HLA genes in infants at risk for Type I diabetes followed from birth. METHODS: We followed 357 (189 male, 168 female) infants, with a first degree relative with Type I diabetes for a mean of 3 years from birth. Human leukocyte antigen typing and assays for insulin autoantibodies (IAA), glutamic acid decarboxylase antibodies (GADAb) and tyrosine phosphatase IA2 (IA2Ab) antibodies were done on cord blood, and venous blood was sampled every 6 months for IAA, GADAb and IA2Ab. RESULTS: We did not find any antibodies in 263 (73%) infants; 50 (14%) were positive for a single antibody once, 19 (5%) for a single antibody more than once and 25 (7%) for two or more antibodies. Of the latter, 10 (2.8% overall) were persistently positive; they had higher frequencies of HLA DR4 (p < 0.01) and HLA DR3, 4 (p < 0.05). Of the group persistently positive for two or more antibodies four infants developed diabetes. Insulin autoantibodies were the first ones to develop in 64% of infants with two or more antibodies. CONCLUSION/INTERPRETATION: Infants with high risk HLA-DR alleles and multiple antibodies at high risk for diabetes were identified. A much larger group of infants had transient low level increases usually of a single antibody. Whereas transient low level positivity could be attributed to difficulties with assay technique and cut off levels for normality, the results overall support the phenomenon of transient 'self limited' islet autoimmunity in at risk infants.

Lack of association between duration of breast-feeding or introduction of cow's milk and development of islet autoimmunity.

The hypothesis that early exposure to cow's milk or lack of breast-feeding predisposes to type 1 diabetes remains controversial. We aimed to determine prospectively the relationship of, first, duration of exclusive breast-feeding and total duration of breast-feeding, and second, introduction of cow's milk protein as infant formula, cow's milk, or dairy products, to the development of islet antibodies in early life. Some 317 children with a first-degree relative with type 1 diabetes were followed prospectively from birth for 29 months (4-73). Mothers kept a home diary and answered infant feeding questionnaires at 6-month intervals. No systematic feeding advice was given. Insulin autoantibodies (normal range <5.5%), anti-GAD antibodies (<5.0 U), and anti-IA2 antibodies (<3.0 U) were measured at 6-month intervals. Cox proportional hazards model of survival analysis detected no significant difference between children who did not develop islet antibodies (225 of 317 [71%]), children with one islet antibody raised once (52 of 317 [16.4%]), children with one antibody raised repeatedly (18 of 317 [5.7%]), or children with two or more antibodies raised (22 of 317 [6.9%]), in terms of duration of exclusive breast-feeding, total duration of breast-feeding, or introduction of cow's milk-based infant formulas, cow's milk, or dairy products (relative risk: 0.91-1.09). Four of the children with two or more islet antibodies developed type 1 diabetes. We conclude that there is no prospective association between duration of breast-feeding or introduction of cow's milk and the development of islet autoimmunity in high-risk children.

Malaria prevalence and outcome in the in-patients of the Paediatric Department of the State Specialists Hospital (SSH), Maiduguri, Nigeria.

Of 4651 admissions between February 1995 and February 1996, 1043 had a presumed diagnosis of malaria. Six hundred and twenty-seven cases were confirmed by thick blood film examinations. The highest prevalence was in October (124/480 admissions) and the lowest in March (12/303). Sixty-five children died while 562 survived, 12 with defects. The first treatment in 422 children was chloroquine, in 143 quinine, in 59 halofantrin, and in three pyrimethamine with sulfadoxine (Fansidar). 23/422 patients started on chloroquine were switched to halofantrine, two to quinine. A higher mortality was associated with coma, convulsions, hepatosplenomegaly, pulmonary congestion, jaundice, haemoglobinuria, bladder paralysis, anuria. Anaemia and fever were more severe and hypoglycaemia more frequent in children who died than in children who survived (packed cell volume 18.5 +/- 7.1 per cent vs. 25.6 +/- 7.6 per cent, p < 0.001; temperature 39 +/- 1.1 degrees C vs. 38.7 +/- 0.9 degrees C, p < 0.05; random blood sugar < 40 mg/100 ml; 76 vs. 22 per cent, p < 0.01). There was no difference in the median age, pretreatment duration, and prevalence of diarrhoea and sickle cell disease. The male to female ratio was 1.5:1 in the surviving children vs. 1:1.03 in the dead.

Donor age and graft function.

We evaluated survival and renal function of cadaveric donor grafts according to donor age. The median age of the pediatric donors was 7.0 (0.7-16) years in 46 patients [median age 11.8 years (range) 3-16.8 years]. The median age of the adult donors was 34.4 (19-54) years in 59 patients [median age 12.1 years (range) 7-17.3 years]. Thirty patients were treated with azathioprine and prednisolone and 75 with cyclosporine A and prednisolone. The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) were determined by the clearances of 51chromium-EDTA and 125iodine-hippurate 1-48 months after kidney transplantation. There was no difference in graft survival between pediatric and adult grafts. There were also no differences in GFR in patients receiving grafts from pediatric or adult donors; 2-3 months after transplantation the GFR in recipients of pediatric grafts was 62 +/- 20 ml/min per 1.73 m2 compared with 61 +/- 21 in those receiving adult grafts. The ERPF in recipients of adult grafts was significantly higher in the 1st month after transplantation: 486 +/- 239 versus 362 +/- 158 ml/min per 1.73 m2. From the 4th to the 6th month after transplantation this difference disappeared: the ERPF of grafts from pediatric donors was 279 +/- 131 ml/min per 1.73 m2 compared with 273 +/- 123 ml/min per 1.73 m2 in grafts from adult donors. Using the single-kidney GFR and ERPF on an age-matched group of probands with minor diseases as references, 2-3 months after transplant the mean GFR of grafts from pediatric donors increased to 118% +/- 51%, whereas the GFR of adult donor grafts fell to 60% +/- 22% over the same period. After 4-6 months the ERPF in pediatric grafts was 96% +/- 55% compared with 50% +/- 22% in adult grafts. We conclude that graft survival and function in children with either a pediatric or an adult graft may not differ because graft function adapts to the requirement of the recipient.

Effects of PUVA therapy on kidney allografts: results of a randomized prospective double-blind study.

After successful experimental organ transplant studies on the efficacy of PUVA therapy combining donor pretreatment with the photosensitizer 8-methoxypsoralen (P) and the ex vivo irradiation of organs with long-wave ultraviolet light (UVA) prior to transplantation, we started in 1989 the first randomized, prospective, double-blind study to clarify the efficacy of PUVA therapy in human kidney transplantation. This study included 50 kidney donors, 25 of whom were PUVA-treated. A total of 75 kidneys were transplanted in Berlin, Halle and Rostock. The complete data of these 75 recipients were available for the final evaluation. The PUVA group (n = 36) and the non-PUVA group (n = 39) were not statistically significantly different as to donor and recipient data. Regarding the results, no differences were seen in initial hospitalization time, early graft function, rejection rate, number and time of rejection episodes. After a follow-up of 24 months, both graft survival (PUVA vs. non-PUVA: 75% vs. 71.8%) and patient survival (97.2% vs. 97.4%, respectively) were comparably high. PUVA therapy did not influence the development of vascular rejection. Interestingly, the rate of late graft loss after the 6th posttransplant month was lower, but not statistically significantly so, in the PUVA than in the non-PUVA-group (2 vs. 6 graft losses). Thus, PUVA-pretreated kidneys may be associated with a reduced development of chronic rejection.

Prevalence and management of asthma in a London inner city general practice.

A study was set up to examine the prevalence and management of asthma symptoms in a London inner city general practice. All case records were examined and evidence of past or currently active asthma or wheezing illness was identified in 1032 out of 11,148 records (9.3%). This gave a cumulative prevalence of asthma or wheezing illness of 7.2% among adults and 19.5% among children aged 15 years or under. These figures are consistent with previous estimates of prevalence in the UK published since the mid 1960s. In 92.5% of cases in which information was available, the initial diagnosis of asthma or decision to prescribe a bronchodilator was made in primary care. Only nine cases (0.9%) had evidence of recurrent wheezing without the benefit of bronchodilator therapy at any time. There was significant delay in diagnosis in children under five years compared with older children or adults. There was a significant association between a formal diagnosis of 'asthma' in the case notes and the inclination of general practitioners to monitor peak expiratory flow or offer inhaled bronchodilator or corticosteroid therapy. Of 111 asthmatics (83 adults and 28 children aged five to 15 years) with previously 'severe' disease who sought medical advice for their asthma over a 12 month period, 91.6% of adults and 92.9% of children received bronchodilator therapy; nevertheless, only 47.0% of adults and 14.3% of children received inhaled corticosteroids and only 12.0% of adults and 28.0% of children received inhaled cromoglycate. Only 59.0% of adults and 46.4% of children had at least one measurement of peak expiratory flow during the 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)

[Therapy success in the treatment of severe renal osteopathy as the result of effective interdisciplinary team work. Case report]. / Therapieerfolg in der Behandlung einer schweren renalen Osteopathie im Ergebnis einer effektiven interdisziplinären Zusammenarbeit. Ein Fallbericht.

Report about therapy of a severe renal osteopathy, a case of tertiary hyperparathyroidism. It will be shown the good team work between paediatrics, surgery and orthopaedics. Only on this way the patient get the ability for a later dialysis or kidney transplantation.

[The behavior of serum "liver enzyme" activity in children with chronic renal failure, hemodialysis and kidney transplantation]. / Zum Aktivitätsverhalten von "Leberenzymen" im Serum bei chronisch niereninsuffizienten, hämodialysierten und nierentransplantierten Kindern.

Liver enzymes were measured in 24 children with different degrees of renal insufficiency, in 6 children treated by chronic hemodialysis and in 13 children after kidney transplantation. The hemodialyzed and transplanted patients have the highest ALAT activity, independently of the presence of a liver infection. The AP activity in these patient groups were not different from the reference value. The activity of ALAT, GGT and CHE, respectively were most pathologic in the hemodialysis group. The enzyme activities have not been influenced by a single dialysis and a 6-month dialysis course. In uremic and chronic hemodialyzed patients the enzyme combination of ALAT, GGT and CHE has been recommended in the diagnosis and follow-up control of a liver cell damage. In the evaluation of enzyme activities in comparison with reference values of healthy volunteers an enzyme inhibition by the uremic serum should considered.

[Metabolic changes in bones and modification of growth in children with chronic renal failure, dialyzed and with kidney transplant]. / Stoffwechselstörungen der Knochen und Wachstumsbeeinflussung chronisch niereninsuffizienter, dialysierter und transplantierter Kinder.

Forty to fifty percent of the children with chronic renal insufficiency show a growth retardation. The cause of this disorder is supposed on the cellular level of the target organ bone. Objective prospective studies on the growth characteristics of children with chronic renal insufficiency after dialysis and transplantation, respectively, are necessary in consideration of the internal milieu and external influences.

[Arteriovenous interposed prostheses in children for dialysis of allogenic, aldehyde preserved, form-fixed veins with silicone-coated inner surfaces]. / Arterio-venöse Interponate bei Kindern für die Dialyse aus allogenen, aldehydkonservierten, formfixierten und innenflächensilikonierten Venen.

Arterio-venous shunts of new allogenic, aldehyde-preserved, form-fixed saphena with silicone-coated inner surfaces were applied to the upper arms of seven children aged between four months and ten years. Two children died of open shunt, and two transplants underwent thrombosis, within a follow-up period of 27 months. The causes of death and thrombosis were in no way related to the transplant material. Infection, aneurysm, and stenosis did not occur.

[Initial results of tm-PAH studies in children with kidney transplants]. / Erste Ergebnisse der Tm-PAH-Untersuchungen bei nierentransplantierten Kindern.

In 15 children 2 months to 5 years after a transplantation of a cadaver kidney the renal function was determined by means of a clearance- and Tm-PAH-examination. Only in 4 children the Tm-PAH reached the normal value of a kidney. The calculation of the glomerulo-tubular balance results in increased values. The result for the relative tubular blood supply is normal. Compared with the values of children with an overcome haemolytic-uraemic syndrome or with a chronic glomerulonephritis or pyelonephritis shows that the renal function in children who underwent a transplantation similarly behaves as in a chronic pyelonephritis.

[Growth of transplanted kidneys]. / Das Wachstum transplantierter Nieren.

Two or more years after a kidney transplantation were determined the GFR as 51Cr-EDTA-clearance and the effective renal plasma flow as 125J-hippuran clearance. In 14 children the results of the clearance with the HLA-identity (HLA-I), the quantity of the transfusion units (TU) received before the transplantation and the duration of the cold ischaemia time (CIT) were correlated. While with HLA-I and TU no connections could be proved, the results of the clearance seemed to be reversedly proportional to the CIT (r = -0.53 and -0.64 for GFR and ERPF) for a longer time after transplantation. Different age between donor and recipient shows worse results of clearance in the group of the adults who received a kidney of a child, in contrast to the other three possible combinations of the kidney transplantation.