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Biomedical subjects

A Koch

Publications and source records attributed to A Koch.

At least 37 records · Page 2Linked to original sources

Systematic assessment of atypical deletions reveals genotype-phenotype correlation in 22q11.2.

INTRODUCTION: Clinical variability associated with the common 22q11.2 microdeletion is well known, and has led to a broad application of FISH diagnostics with probes for loci TUPLE1 or D22S75 (N25), although, rarely reported atypical deletions associated with the same phenotypic spectrum would not be discovered by these probes. As most types of 22q11.2 deletions occur between low copy repeats within the region (LCR22), we assumed that atypical deletions should be more common than has been reported. To address this question and the possibility of a deletion size related genotype-phenotype correlation, we systematically assessed the frequency of typical and atypical 22q11.2 deletions in a large cohort of patients. METHODS: We used a set of 10 fluorescent in situ hybridisation (FISH) DNA probes, capable of detecting all reported and hypothetical deletions between the LCR22, and analysed 350 patients. Deletion sizes in atypical deletions were established by use of further FISH probes. Frequency of certain atypical deletions was analysed in controls by FISH and quantitative PCR. RESULTS: Patients with conotruncal heart defects (ctCHD) and with typical VCFS phenotype showed the common 3 Mb or nested 1.5 Mb deletions (in 18.5% and 78.6%, respectively), but no atypical deletion, while 5% (3/63) of patients with a mildly suggestive, atypical phenotype showed atypical distal deletions, which were not detected in patients with mental retardation of unknown origin or in healthy controls. DISCUSSION: These statistically significant differences demonstrate that atypical distal 22q11.2 deletions are very uncommon in patients with ctCHDs, while atypical congenital heart defects and mild dysmorphism are recognisable feature of atypical distal deletions. Further phenotype-genotype analysis disclosed association of significant developmental delay with the distal part of the common deletion region, and choanal atresia and atypical CHDs with the adjacent distal deletion region.

Chromosomes, Human, Pair 22↗

Antibody response to collagen after functional implantation of different polyester vascular prostheses in pigs.

Besides inflammation, specific immune responses are seen also after implantation of biomaterials. The aim was to investigate the humoral response to bovine collagen type I following implantation of various polyester (Dacron) prostheses into pigs. In 24 randomized pigs, the infrarenal aorta was replaced with a segment of collagen-impregnated, woven polyester prosthesis of low, medium, or high porosity. IgG antibodies were detected by immunoassay using native and denatured collagen type I as a target for blood samples taken on day 1 (implantation), 10, 17, 24, 62, and 116. As generally observed, antibodies to native and denatured collagen are of low titer and were significantly correlated with enhanced binding to the denatured form (p < 0.001). The highest overall antibody prevalence to native and denatured collagen was obtained on day 116 with 68% and on day 62 with 59%, respectively. Prostheses with high porosity induced an early immune response on day 10; those with low and medium porosity induced the highest antibody levels later after 2 months. Collagen antibodies neither correlated with serum IgG contents nor with antibodies to the prosthesis polyester matrix. Thus, humoral immune response against implant components may provide a further parameter in describing biocompatibility but also a potential marker that may facilitate monitoring of individual perigraft reaction.

Animals↗

Prospective evaluation of 6895 groin hernia repairs in women.

BACKGROUND: Although 8 per cent of groin hernia repairs are performed in women, there is little published literature relating specifically to women. This study compared differences in outcome between women and men after groin hernia repair. METHODS: Data collected prospectively in the Swedish Hernia Register between 1992 and 2003 were analysed, including 6895 groin hernia repairs in women and 83 753 in men. RESULTS: A higher proportion of emergency operations was carried out in women (16.9 per cent) than men (5.0 per cent), leading to bowel resection in 16.6 and 5.6 per cent respectively. During reoperation femoral hernias were found in 41.6 per cent of the women who were diagnosed with a direct or indirect inguinal hernia at the primary operation. The corresponding proportion for men was 4.6 per cent. The hernia repair was not classified as a standard operation (e.g. Shouldice, Lichtenstein, Plug/Mesh, TAPP/TEP) in 38.2 per cent of women and 11.2 per cent of men. Women had a significantly higher risk of reoperation for recurrence than men, and techniques associated with the lowest risk for reoperation in men had the highest risk in women. CONCLUSION: A greater proportion of women than men require emergency groin hernia repair, with consequently higher rates of bowel resection, complications and death. Surgical techniques developed for use in men may put women at unnecessary risk.

Adolescent↗

Biostatistical methods for demonstrating efficacy in the regulatory setting. An epistemological approach to adaptive designs.

Adaptive designs are one of the most promising developments in statistics with applications to clinical trials. Obviously the knowledge at the beginning of a clinical trial will always be limited. In consequence it may be considered necessary that the knowledge from accumulating information should be used to optimize the design of the trial. This paper discusses conditions under which this may be possible in phase III clinical trials where the principle aim is confirmation of hypotheses that have been developed in earlier stages of drug development.

Biometry↗

[Biometrical methods for the proof of efficacy in regulatory submissions. Non-inferiority in clinical studies].

The increasing number of approved efficacious therapies for various indications raises the question of whether the inclusion of a placebo group is still justified. In addition, pharmaceutical companies and regulatory agencies acknowledge that it may be sufficient to prove that a new therapy is comparable to an approved reference therapy regarding efficacy and safety in some situations. This becomes especially striking for the approval to market a generic drug. Another, perhaps even more important example is the increasing resistance of bacteria which calls for new antibiotics based on new therapeutic principles without having the claim for better efficacy. In these situations, a comparable efficacy would constitute progress. In the present paper, we discuss the numerous methodological challenges and approaches to overcome these problems that occur when it is not possible or even not wanted to use the classic approach of a randomized placebo-controlled superiority trial. Here, the field of medical biometry, which has proved in the last 25 years to be an integral part of the development of new drugs, demonstrates its suitability as a flexible and scientifically based means to fulfil the requirements resulting from clinical practice. Starting from the fact that statistical methods are not able to prove "equality" of two treatments, "shifted" hypotheses are considered and their importance for the different study designs is discussed. We show how the classic hypotheses known from placebo-controlled clinical trials can be embedded in this concept. The implications of this approach for the analysis and interpretation of study results is further discussed. The relevant guidelines of the European and US regulatory agencies are taken into account.

Biometry↗

[Cervical origin of the subclavian artery: echocardiographic diagnosis in patients with monosomy 22q11].

OBJECTIVE: To assess the sensitivity and specificity of echocardiography in the detection of anomalies of the subclavian artery (cervical origin, aberrant origin from the descending aorta or isolation) in patients with monosomy 22q11. METHOD: From 1/1998 until 03/2002 we examined 57 patients with conotruncal cardiac malformations. 30 patients had pulmonary atresia and ventricular septal defect (53 %), 13 interrupted aortic arch (23 %), 9 tetralogy of Fallot (16 %) and 5 common truncus arteriosus (9 %). Echocardiographic examination included identification of the laterality of the aortic arch as well as examination of the origin of the brachiocephalic vessels. The results were compared with angiographic and intraoperative findings. Median age at echocardiographic investigation was 74 days (range 1 d - 33.4 yrs.). RESULTS: Laterality of the aortic arch was assessed correctly in all patients. 20/57 patients had a right-sided aortic arch (35 %). Echocardiography detected all anomalies of the subclavian artery (14/57 patients, 25 %, sensitivity 100 %) and excluded these anomalies correctly in 43 patients (specificity 100 %). Exact classification of the anomaly of the subclavian artery was possible in 6/6 patients with a cervical origin of the artery and in 7/8 patients with aberrant origin from the descending aorta. Monosomy 22q11 was diagnosed in 21 patients (37 %). CONCLUSION: Echocardiography achieves a high sensitivity in the detection of anomalies of the subclavian artery. The diagnosis of cervical origin of the artery, in particular, can be easily established. As this anomaly appears to be a specific marker for monosomy 22q11, echocardiography facilitates reliable identification of these patients in clinical practice.

Adolescent↗

[Options for quality improvement in the treatment of rectum carcinoma].

By means of a prospective multi centre study, 13 419 cases of surgically treated patients with rectum carcinomas were registered between 1.1.2000 and 31.12.2003 and assessed in regard to possible problems concerning indications and operative procedures. Beside a high rate of non-local resective procedures in T1-low risk carcinomas, unnecessary extirpations in cases of tumour localisation over 8 cm from the anal verge were found. Tumours of the lower two-thirds of the rectum were treated by incomplete TME in 20 % of the patients. In addition, there seems to be too low a rate of neo-adjuvant therapy procedures. Protective stomata were frequently foregone after low anterior resection. Endoscopic interventional methods were still used reluctantly in inoperable situations.

Germany↗

Pattern of drug prescription for children under the age of four years in a population in Greenland.

AIM: To provide knowledge of drug prescription patterns in general and of antibiotics in particular, and number of consultations and diagnoses leading to prescriptions among children aged 0-4 y in the Arctic. METHODS: A population-based cohort of children aged 0-4 y, living in Sisimiut, the second largest town in Greenland, was followed from August 1996 to December 1998. Information on consultations, diagnoses and drug prescriptions was obtained from medical files at the local health centre. RESULTS: Among 280 participating children, the mean number of consultations per child was 5.64 per year at risk (range 0-17), of prescriptions 4.02 per year at risk (range 0-17.2), and of prescribed systemic antibiotics per child 1.47 per year at risk (range 0-7.25). Systemic antibiotics formed the therapeutic subgroup most often issued for children, constituting 33.5% of all prescriptions. Of the systemic antibiotics, 50% were broad-spectrum penicillins, 34% penicillin V, 14% macrolides and 2% other antibiotics. The most frequent diagnoses leading to drug prescription in general as well as to prescription of systemic antibiotics were respiratory tract infections, accounting for 59% of all prescriptions and 81% of prescriptions of systemic antibiotics. Children aged 1/2-1 y of age had the highest prescription rates of drugs in general and of systemic antibiotics. CONCLUSIONS: Compared to other countries, prescription rates of drugs in general and of systemic antibiotics in particular were high. The use of broad-spectrum penicillins was higher than recommended in Greenlandic national guidelines, and might be reduced.

Age Distribution↗

Detection of dysbaric osteonecrosis in military divers using magnetic resonance imaging.

This was a controlled cross-sectional study to investigate the prevalence of dysbaric osteonecrosis (DON) in military divers. MRI examinations of the large joints and adjacent bones were performed in a cross-sectional group of 32 highly experienced military divers and 28 non-divers matched for age and anthropometric data. Additional plain radiographs and follow-up controls were performed in all persons with signs certain or suspicious of DON. In two subject groups (one of divers and one of non-divers), lesions characteristic of DON were detected. From this controlled study, it may be concluded that MRI is a highly sensitive method to detect signs of osteonecrosis. It could be shown that the prevalence of bone lesions characteristic of osteonecrosis in highly experienced military divers is not higher than in non-diving subjects of comparable age. The outcome of this comparably small study group fits to the results of previous extensive studies performed with radiographs. The detected low incidence of DON in this collective may be due to the fact that military divers follow stricter selection criteria, decompression schemes and medical surveillance than commercial divers.

Adult↗

Magnetic resonance imaging and neuropathology findings in the goat nervous system following hyperbaric exposures.

Divers may be at risk of long-term CNS damage from non-symptomatic hyperbaric exposure. We investigated the effect of severe, controlled hyperbaric exposure on a group of healthy goats with similar histories. Thirty goats were exposed to various dive profiles over a period of 5 years, with 17 experiencing decompression sickness (DCS). Brains were scanned using magnetic resonance (MR) imaging techniques. The animals were then culled and grossly examined, with the brain and spinal cord sent for neuropathological examination. No significant correlation was found between age, years diving, DCS or exposure to pressure with MR-detectable lesions in the brain, or with neuropathological lesions in the brain or spinal cord. However, spinal scarring was noted in 3 animals that had suffered from spinal DCS.

Animals↗

[Hartmann's procedure indication in colorectal carcinoma].

Based on data obtained in a prospective, multicenter trial investigating the surgical treatment of colorectal carcinomas, the aim of this study was to investigate the value and relevance of Hartmann's procedure compared with alternative surgical approaches in elective interventions and emergency situations in carcinoma of the rectum (n=10,355) and the left hemicolon (n=8,825). Only in 3.4% (n=353) of patients with rectal carcinoma was the Hartmann's procedure executed with curative intention, indicating that this approach is recommendable only in (1) rare emergency situations (1.66%, n=172), (2) selected cases with elective intervention such as high-risk patients or subjects with poor prognosis, and (3) individuals with rectal carcinoma of the lower third who require deep resection (2+3, 1.75%, n=181). However, Hartmann's procedure resulted in the lowest mortality (7.5%) of the various procedures aiming for radical resection in the case of luminal obstruction or perforation at the left hemicolon. With palliative intention, 4.3% of patients with rectal carcinoma (n=449) received primary colostomies. At the left hemicolon, palliative segmental colon resection with primary anastomosis maintaining intestinal passage showed the lowest mortality (6.1%) and perioperative morbidity (33.9%) under elective circumstances, whereas Hartmann's procedure was preferred in emergency situations.

Adenocarcinoma↗

Emergency operation in carcinomas of the left colon: value of Hartmann's procedure.

BACKGROUND: Colonic resection according to the procedure by Hartmann is considered a fast and safe surgical intervention, which has been used for years, in particular, in emergency situations. METHODS: Using data of a prospective multicentre study on the operative treatment of colorectal carcinoma over the time period from 1 January 2000 to 31 December 2002, the value of Hartmann's procedure was investigated in carcinoma of the left colon (n=8825) compared with alternative surgical options under emergency circumstances. The significant impact of independent variables on the type of the selected approach was determined by means of logistic regression. RESULTS: While in total 422 primary Hartmann's procedures (4.8%) were executed under curative intention, 213 (50.5%) of those were carried out in emergency situations. Hartmann's procedure was beneficial in cases with tumour-associated obstruction and perforation of the left colon as it resulted in the lowest mortality (7.5%) of the radical operations. Even under palliative intention, Hartmann's procedure was preferred at the left colon but led to a postoperative mortality (32.7%) very similar to that in creation of a colostoma (33.3%) or segmental colonic resection (38.9%). CONCLUSIONS: Hartmann's procedure has been widely accepted as a curative intervention in emergency cases (oncosurgically adequate R0 resection) for the carcinoma of the left colon. Because of the high postoperative morbidity and mortality in emergency situations with only palliative options (R0 resection not possible), alternative endoscopic treatment should be considered more frequently.

Adenocarcinoma↗

Comparison of renal morphology in the Streptozotocin and the SHR/N-cp models of diabetes.

The Streptozotocin (STZ) model of diabetes is commonly used for studies of diabetic nephropathy although the histological lesions of the kidney are mild and do not resemble those seen in diabetic patients. The SHR/N-cp rat model of type II diabetes spontaneously develops pronounced abnormalities in renal histology. In the present study, we compared renal morphology in the STZ rat and the diabetic SHR/N-cp rat. Sprague-Dawley rats received STZ, developed diabetes after 2 days and were treated with insulin. In the SHR/N-cp rat, obesity is inherited as an autosomal recessive trait. The progeny are either lean (used as controls) or obese and diabetic. After 6 months of observation, STZ and SHR/N-cp rats were killed. The renal damage was evaluated by assessing damage indices and by using stereological techniques. In addition, immunohistochemistry and electron microscopy were performed. The glomerular and tubulointerstitial changes were much more pronounced in the diabetic SHR/N-cp compared to the STZ model. In parallel glomerular PCNA+cells were significantly more frequent and expression of TGF-beta and PDGF by immunohistochemistry in glomeruli and in the tubulointerstitial space was more pronounced in SHR/N-cp compared to STZ rats. The glomeruli of SHR/N-cp contained less and larger podocytes as well as smaller mesangial cells embedded in more mesangial matrix compared to STZ. Similarly, less, but larger endothelial cells were found in SHR/N-cp than in STZ rats. The mean glomerular volume was similarly increased in the two models. Albumin excretion was only modestly increased in STZ diabetes, but pronounced in the SHR/N-cp rat. Although the STZ model of diabetes exhibits numerous biochemical sequelae of hyperglycemia, the morphological lesions are unimpressive. In contrast, the diabetic SHR/N-cp exhibits marked structural lesions, particularly podocyte damage and mesangial expansion that promise to make it a more suitable model for investigation of diabetic glomerulosclerosis.

Albuminuria↗

Definition of polymorphisms and haplotypes in the interleukin-12B gene: association with IL-12 production but not with Crohn's disease.

Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. Recently, functional polymorphisms in IL-12p40 (IL12B) were found to be associated with susceptibility to several autoimmune diseases. Similarly, variation in IL12B might be involved in susceptibility to Crohn's disease (CD), a chronic inflammatory bowel disorder associated with high IL-12 expression. We searched for additional polymorphism in IL12B and genotyped a large cohort of CD patients. Differential in vitro secretors of IL-12 were tested for polymorphism. Polymorphisms were analyzed using the intrafamilial transmission disequilibrium test (TDT) and by case-control analysis. A novel polymorphism was strongly associated with differential expression of IL-12. However, no association with susceptibility to CD was seen for this and other polymorphisms. The high level of conservation is consistent with the key regulatory role of IL-12. The lack of association with IL12B makes it unlikely that this gene is directly involved in the susceptibility to CD.

Base Sequence↗

Late pulmonary valve replacement after correction of Fallot's tetralogy.

BACKGROUND: The aim of this study was to investigate necessity and outcome of late pulmonary valve replacement (PVR) after repair of tetralogy of Fallot (TOF). METHODS: Hospital records from patients operated on for TOF at our institution between 1960 and 2002 were reviewed and patients were interviewed by questionnaires. RESULTS: Out of 411 long-term survivors after TOF-repair, 47 (11.4 %) patients required reoperation after 13.2 +/- 7.4 years. Preoperative right ventricular (RV) dilatation was present in 36 (76.6 %) patients including 16 (34 %) with impaired RV function. Isolated PVR was performed in 12 patients (25.5 %). Additional procedures were necessary in 35 patients (74.5 %), including closure of residual defects (VSD, n = 11), tricuspid valve replacement (n = 1) and repair (n = 3). Obstructive right ventricular or pulmonary artery lesions (34 patients, 72.3 %) were all surgically addressed. RV pressure decreased from 61.1 +/- 27.7 to 42.9 +/- 13.3 mm Hg (p < 0.01) after PVR. RV size was reduced and RV function improved compared to preoperative values. Early mortality after reoperation was 2.1 % (n = 1) with one patient dying from biventricular failure. There was no late mortality. CONCLUSIONS: PVR after Fallot repair is frequently required because of progressive RV enlargement with dysfunction. It can be performed with relatively low risk, even in the setting of multiple reoperation. Obstructive lesions (RVOTO, PA stenosis) and residual defects are frequently observed in patients needing late PVR and may play a crucial role in the development of RV failure. Timely valve replacement with repair of all obstructive lesions proximal and distal to the implanted valve is the key to preserving RV function.

Adolescent↗