[Panniculitis of the thigh and lung emphysema in a 54-year-old patient]. / Pannikulitis des Oberschenkels und Lungenemphysem bei einem 54-jährigen Patienten.

This article reports a case of febrile, symmetrical and painful soft tissue swelling on both thighs in a 54-year-old otherwise healthy male patient. Histologically, necrotizing panniculitis of subcutaneous adipose tissue was described as a marker manifestation of a previously unknown alpha-1-antitrypsin (A1AT) deficiency with pulmonary emphysema and low plasma A1AT levels. The PiZZ homozygous form of A1AT could be diagnosed by gene sequencing. Complete remission of panniculitis could be achieved by A1AT replacement therapy.

Motives for maternal filicide: results from a study with female forensic patients.

The objective of this study was to examine different motivational factors, leading mothers to commit neonaticidal, infanticidal or filicidal acts. This study was based on data gathered through a retrospective chart review of all filicidal women admitted to the Mid-Hudson Forensic Psychiatric Hospital in New York State (MHFPC) between 1976 and 2000 (n=57). Because our sample was drawn from MHFPC records it excludes filicidal mothers who went directly to prison. Our women were either found not competent to stand trial, or found not guilty by reason of insanity, or were convicted offenders who were seriously mentally ill and were not sent to prison. Fourteen percent committed neonaticide, meaning that they killed their child within the first day of its life; 21% killed the child after the first day but before it reached its first birthday (infanticide); and 65% committed filicide by murdering a child older than one. Two groups of women could be identified as having different motivational profiles: The neonaticidal mothers were mostly troubled by psychosis and social problems while the filicidal women were defined as severely depressed, with a history of self-directed violence and a high rate of suicide attempts following the filicidal offense.

[Minor foot amputations in diabetic foot syndrome]. / Minor-Amputationen beim diabetischen Fußsyndrom.

OBJECTIVE: The treatment strategy for diabetic foot syndrome must take into account protective sensibility of the foot, open wounds, infection status, and the rules of septic bone surgery. Interventions are classified as elective, prophylactic, curative, or emergency. Amputations in the forefoot and midfoot region are performed as ray amputations (including metatarsal), which can often be carried out as "inner" amputations. Gentle tissue treatment mandatory because of greater risk of revision with re-amputation compared to classical amputation. INDICATIONS: Good demarcation of infection, acute osteomyelitis, osteolytic lesions, neurotropic ulcer, arterial and venous blood flow to the other toes, gangrene of other toes with metatarsal affection. CONTRAINDICATIONS: Arterial occlusive disease, infection of neighboring areas, avoidable amputations, poorly healing ulcers on the lower leg. SURGICAL TECHNIQUE: Primary dorsal approach; minimal incisional distance (5 cm) to minimize skin necrosis risk. Atraumatic preparation, minimize hemostasis to not compromise the borderline perfusion situation. In amputations, plantar skin preparation and longer seams placed as dorsal as possible, either disarticulated and maintain cartilage, or round the cortical metatarsal bone after resection. POSTOPERATIVE TREATMENT: Diabetes control. Braun splint, mobilization in a shoe with forefoot decompression and hindfoot support, physiotherapy. Antibiotics based on resistance testing. If no complications, dressing change on postoperative day 1. Optimal wound drainage by lowering foot several times a day; drainage removal after 12-24 h. Insoles and footwear optimization. RESULTS: Amputations require continued attention and if necessary treatment to avoid sequelae. Insufficient treatment associated with recurrent ulceration and altered anatomy.

Progressive islet graft failure occurs significantly earlier in autoantibody-positive than in autoantibody-negative IDDM recipients of intrahepatic islet allografts.

Alloimmunity has been uncovered to be a cause of graft loss representing a major barrier for clinical islet transplantation, and several studies are designed to evaluate new strategies for immunosuppression to prevent alloimmunity. In contrast, the significance for autoimmune destruction of transplanted beta-cells has remained somewhat controversial. Recently, two case reports based on histological findings have suggested recurrent autoimmune insulitis despite immunosuppressive therapy both in clinical pancreas and in islet transplantation. In the present study, in 23 islet-grafted patients with IDDM receiving standard immunosuppressive therapy, we demonstrate that progressive impairment of islet graft function occurs significantly earlier in those individuals positive for autoantibodies as a typical stigma of diabetes-associated autoimmunity that is well established in the prediabetic periods of IDDM. Intraportal infusion of allogeneic islets was performed in 23 C-peptide-negative IDDM patients, according to the clinical transplantation categories defined as islet after kidney (IAK) or simultaneous islet and kidney (SIK). Complete islet graft failure was defined as the 1st day of permanent C-peptide negativity in the serum (<0.2 ng/ml) and C-peptide negativity in the urine (<2 microg/dl). The median observation period following islet transplantation was 12 months (range 1-50) with a cumulative follow-up of 336 months. Islet cell antibodies (ICAs) and GAD65 antibodies were monitored before and regularly after islet transplantation. Kaplan-Meier survival analysis and log-rank statistics revealed a significant (P < 0.05) difference in cumulative islet graft survival depending on the presence of islet cell and/or GAD65 antibodies. These results strongly suggest that recurrent autoimmunity directed to transplanted beta-cells contributes to islet graft failure despite sustained immunosuppression. For successful clinical islet transplantation in the future, new immunosuppressive therapies are needed to prevent both alloimmunity and autoimmunity.

Metabolic effects of restoring partial beta-cell function after islet allotransplantation in type 1 diabetic patients.

Successful intraportal islet transplantation normalizes glucose metabolism in diabetic humans. To date, full function is not routinely achieved after islet transplantation in humans, with most grafts being characterized by only partial function. Moreover, the duration of full function is variable and cannot be sufficiently predicted with available methods. In contrast, most grafts retain partial function for a long time. We hypothesized that partial function can restore normal protein and lipid metabolism in diabetic individuals. We studied 45 diabetic patients after islet transplantation. Labeled glucose and leucine were infused to assess whole-body glucose and protein turnover in 1) 6 type 1 diabetic patients with full function after intraportal islet transplantation (FF group; C-peptide > 0.6 nmol/l; daily insulin dosage 0.03 +/- 0.02 U x kg(-1) body wt x day(-1); fasting plasma glucose < 7.7 mmol/l; HbA1c < or = 6.5%), 2) 17 patients with partial function (PF group; C-peptide > 0.16 nmol/l; insulin dosage < 0.4 U x kg(-1) body wt x day(-1)), 3) 9 patients with no function (NF group; C-peptide < 0.16 nmol/l; insulin dosage > 0.4 U x kg(-1) body wt x day(-1)), and 4) 6 patients with chronic uveitis as control subjects (CU group). Hepatic albumin synthesis was assessed in an additional five PF and five healthy volunteers by means of a primed-continuous infusion of [3,3,3-2H3]leucine. The insulin requirement was 97% lower than pretransplant levels for the FF group and 57% lower than pretransplant levels for the PF group. In the basal state, the PF group had a plasma glucose concentration slightly higher than that of the FF (P = 0.249) and CU groups (P = 0.08), but was improved with respect to the NF group (P < 0.01). Plasma leucine (101.1 +/- 5.9 micromol/l) and branched-chain amino acids (337.6 +/- 16.6 micromol/l) were similar in the PF, FF, and CU groups, and significantly lower than in the NF group (P < 0.01). During insulin infusion, the metabolic clearance rate of glucose was defective in the NF group versus in the other groups (P < 0.01). Both the basal and insulin-stimulated proteolytic and proteosynthetic rates were comparable in the PF, FF, and CU groups, but significantly higher in the NF group (P = 0.05). In addition, the PF group had a normal hepatic albumin synthesis. Plasma free fatty acid concentrations in the PF and FF groups were similar to those of the CU group, but the NF group showed a reduced insulin-dependent suppression during the clamp. We concluded that the restoration of approximately 60% of endogenous insulin secretion is capable of normalizing the alterations of protein and lipid metabolism in type 1 diabetic kidney recipients, notwithstanding chronic immunosuppressive therapy. The results of the present study indicate that "success" of islet transplantation may be best defined by a number of metabolic criteria, not just glucose concentration/metabolism alone.

Influence of neutral protease activity on human islet isolation outcome.

UNLABELLED: Observations in rat pancreata have revealed that enzymatic islet release is mediated by both collagenase and neutral protease (NP), a critical effector of islet integrity. Since no information is available about the effect of NP activity on islet release from the human pancreas, the present study evaluated the effect of various NP concentrations on the outcome of human islet isolation. METHODS: Following intraductal collagenase distension, pancreata obtained from adult multiorgan donors were digested using 2000 PZ-U of purified Serva collagenase NB 1 supplemented with 2.6 (n = 10) or 4.5% (DMC-U/PZ-U) (n = 10) of NP. RESULTS: Increasing NP from 2.6% to 4.5% reduced the amount of undigested tissue from 22 +/- 2 to 17 +/- 2 g (P < .05) while simultaneously increasing the volume of digested tissue (26 +/- 2 vs 40 +/- 3 mL, P < .01). Increased NP concentrations increased the islet yield prepurification (459,800 +/- 22,900 vs 587,600 +/- 69,000 IEQ, P < .05), but simultaneously affected islet purification, resulting in equal islet yields (345,700 +/- 31,200 vs 391,500 +/- 35,400 IEQ, NS) and less purity (70 +/- 6 vs 49% +/- 5%, P < .01). A NP concentration of 4.5% reduced the stimulation index (4.7 +/- 1.2 vs 2.0 +/- 0.5, P < .01) and viability (100 +/- 1 vs 95% +/- 3%, P < .05). CONCLUSIONS: Although increased NP activity seems to improve islet release from adult human pancreata, it significantly affects islet viability and function. The reduction in purity reflected damage to acinar tissue by increased NP activity presumably affecting islet integrity.

[Less severe sexual child abuse and its sequelae: are there different psychic and psychosomatic symptoms in relation to various forms of sexual interaction?]. / Minderschwere sexuelle Kindesmisshandlung und ihre Folgen. Finden sich unterschiedliche psychische und psychosomatische Symptome in Verbindung mit verschiedenen Formen sexueller Interaktion?

A typology of less severe sexual encounters was used to analyze short and long term sequelae of sexual abuse via intimate skin contact. Well known theoretical approaches on the harmful effects of sexual abuse were tested. Do we find different peri- and posttraumatic reactions dependent upon varied forms of sexual interactions with children? A cluster analysis was calculated with symptom variables that were described in 141 child statements taken out of written expert opinions. Afterwards variance analyses of these symptom clusters were conducted in reference to six different abuse constellations. Different symptom profiles were found for these six abuse constellations. Panic symptoms, shame related feelings, avoidant behavior and physical reactions showed significant results. The sequelae to different forms of less severe sexual child abuse differ and depend more upon the situational dynamic than upon the kind of relationship between adult and child.

Islet autoantibodies as potential markers for disease recurrence in clinical islet transplantation.

At present, indications for clinical islet transplantation exist almost exclusively in type-1 diabetic patients with end-stage renal disease receiving the islets either simultaneously with or after an already established kidney graft. This implies, that islet transplantation is performed in type-1 diabetic patients with long disease duration. The fate of the islet allograft is determined by a combination of immunological effector mechanisms. Beside early non-specific inflammation and alloreactivity, chronic autoimmunity may contribute to islet graft failure. The immunologic characterization of the prediabetic state has considerably progressed, whereas, the nature of autoimmunity years and decades after the onset of diabetes is largely unknown. Islet autoantibodies as surrogate markers for islet autoimmunity are well established in prediabetic periods of type-1 diabetes. In contrast, only few data exists in the setting of long-term type-1 diabetic patients undergoing islet transplantation. This article reviews the original data from the Giessen islet transplantation project and the pertinent literature with respect to islet autoimmunity and disease recurrence. It is demonstrated, that autoimmunity may persist in an individual with type-1 diabetes for decades after diabetes onset and that autoimmune responses to transplanted islets are resistant to the immunosuppressive drugs currently used. It is suggested from pilot trials, that type-1 diabetic patients with persistent autoantibodies and individuals, in whom autoantibodies become detectable after the transplantation are at higher risk for early islet graft failure potentially due to recurrent autoreactivity directed to the islet graft.

Diagnostic algorithm and management of immune-mediated complications associated with subcutaneous insulin therapy.

Immune mediated complications associated with subcutaneous insulin therapy such as insulin neutralizing antibodies and/or skin reactions are rare conditions since human insulin is in general use. Nevertheless, if it occurs, a stepwise diagnostic approach is essential for differential diagnosis and consecutive treatment of these complications. Here we suggest a diagnostic algorithm to deal with e.g. insulin antibody formation of the IgG and/or IgE type and/or severe skin reactions resulting in poor metabolic control and often "brittle diabetes" in affected patients. This diagnostic algorithm includes step 1: Intradermal skin testing with positive and negative controls, additives and different insulin preparations; step 2: Quantification of insulin specific IgG and IgE in the serum, and step 3: Analysis of the time dependent binding/dissociation curves of the insulin neutralizing antibodies in an ex vivo/in vitro assay to assess the clinical significance of these antibodies. Based on 158 insulin treated control subjects and four patients with typical symptoms and signs representing the spectrum of immune-mediated complications subsequent to subcutaneous insulin therapy we demonstrate that the proposed stepwise approach leads to a definite diagnosis as a prerequisite for individual and successful therapy.

Islet transplantation: present clinical situation and future aspects.

Beta-cell replacement either by pancreatic organ or islet cell transplantation is the only treatment to achieve an insulin-independent, normoglycemic state and to avoid hypoglycemic episodes in patients with type 1 diabetes mellitus. This article will review the state-of-the-art in clinical islet cell transplantation at the dawn of the new millennium and will provide an outlook on the basis of extended personal experience.

Pancreatic islet and stem cell transplantation: new strategies in cell therapy of diabetes mellitus.

Long-term studies strongly suggest that tight control of blood glucose can prevent the development and retard the progression of chronic complications of type 1 diabetes mellitus. In contrast to conventional insulin treatment, replacement of a patient's islets of Langerhans either by pancreas organ transplantation of by isolated islet transplantation is the only treatment to achieve a constant normoglycemic state and avoiding hypoglycemic episodes, a typical adverse event of multiple daily insulin injections. However, the expense of this benefit is still the need for immunosuppressive treatment of the recipient with all its potential risks. Islet cell transplantation offers the advantage of being performed as a minimally invasive procedure, in which islets can be perfused percutaneously into the liver via the portal vein. As of June 2003, 705 pancreatic islet transplants worldwide have been reported to the International Islet Transplant Registry (ITR) at our Third Medical Department, University of Giessen/Germany. Data analysis shows at 1 year after adult islet transplantation a patient survival rate of 97%, a functioning islet graft in 54% of the cases, whereas insulin independence was meanwhile achieved in 20% of the cases. However, using a novel protocol established by the Edmonton Center/Canada, the insulin independence rates have improved significantly reaching meanwhile a 50-80% level. Finally, the concept of islet cell or stem cell transplantation is most attractive since it offers many perspectives: islet cell availability could become unlimited and islet or stem cells my be transplanted without life-long immunosuppressive treatment of the recipient, just to mention 2 of them.

Can the density of native pancreatic tissue slices predict human islet isolation and purification outcome?

INTRODUCTION: With currently available technology, the outcomes of human islet isolation and purification are still inconsistent, in part due to a lack of control of the pancreas donor and the procurement conditions. Using a single donor pancreas, the critical islet mass for establishing insulin independence of approximately 5000 engrafted islet equivalents (IEQ)/kg of recipient weight can only be retrieved from about one third of isolations. The purpose of this study was to analyze whether successful islet isolation and purification outcomes might be predicted from the density of native pancreatic tissue. METHODS: Tissue slices (TS) were obtained from the neck of 9 nondistended human donor pancreata. The density of the TS was determined using gravity sedimentation in continuous density gradients under either iso-osmolar or hyperosmolar conditions. Correlation coefficients were calculated with regard to the density of isolated exocrine and endocrine tissue, donor age, body mass index (BMI), cold ischemia time (CIT), IEQ prepurification and postpurification, IEQ recovery, and purity. RESULTS: (1) There was no change in density over time for TS in 300 mOsm/kg (mean, 1.079 +/- 0.0019 g/cm(3)) (2) In 500 mOsm/kg, there was a significant increase in density from 1.086 +/- 0.0021 g/cm(3) to 1.092 +/- 0.0021 g/cm(3) over time. (3) Density of isolated exocrine and endocrine became more distinct with lower density of TS (r = -0.776; P < .05). (4) Donor age, BMI, recovery of IEQ from gradients, and number of IEQ after purification did not correlate significantly with TS density. (5) In contrast, a significant inverse correlation existed betwen TS and CIT (r = -0.829; P < .05), and between TS versus IEQ number prior to purification (r = -0.867; P < .05). CONCLUSION: No homogeneous distribution of pancreas tissue density was seen among 9 consecutive human organs. Taken together, the density of native pancreas TS is not a suitable sole predictor for successful islet isolation and purification.

Optimization in osmolality and range of density of a continuous ficoll-sodium-diatrizoate gradient for isopycnic purification of isolated human islets.

INTRODUCTION: According to previous estimates from large animals and man, a minimum of approximately 5000 to 6000 engrafted islet equivalents (IEQ)/kg recipient weight is critical to establish insulin independence. Utilizing a single donor, this threshold yield of purified islets can be retrieved from approximately one third of all isolations. The aim of this study was to improve human islet purification by optimization of the osmolality and the density range of the continuous Ficoll-sodium-diatrizoate (FSD) gradient to facilitate consistent purities >80% of human islet preparations without considerable loss of islet yield. METHODS: Aliquots of human pancreatic digests were placed on continuous density gradients. After centrifugation, sequential aliquots were extracted for amylase and insulin to determine the relative and cumulative density distribution of endocrine and exocrine tissue. We addressed the impact of two factors: (1) osmolalities (300 to 600 mosm/kg) in the gradient of FSD covering a density range of 1.070 to 1.100 g/cm(3); and (2) density (FSD 500/1.070 to 1.100) versus density-osmolarity gradient (DO-FSD 400-530/1.080 to 1.113). RESULTS: The density of exocrine and endocrine tissue increased with rising osmolality. Differences in density of both tissues were highest at 450 and lowest at 300 and 600 mOsmol/kg. Purity and recovery were highest at 450 versus 400 or 500 mOsm/kg (NS). Exocrine but not endocrine tissue was more dense in DO-FSD than in FSD gradient (P < .05). The differences in density were 0.004 versus 0.013 g/cm(3) (P < .01), resulting in an increased islet purity and recovery. CONCLUSION: The best osmolality for the FSD 1.070 to 1.100 g/cm(3) is at 450 mOsm/kg. Using the DO-FSD may improve human islet purification allowing successful clinical islet transplantation.

The role of current product release criteria for identification of human islet preparations suitable for clinical transplantation.

BACKGROUND: Alloimmunity, autoimmunity, and nonspecific inflammation are known to be potential determinants for long-term islet survival and insulin independence. Sufficient islet mass is a key determinant. But islet engraftment and posttransplant survival may also depend on functional characteristics of the graft. This study investigated the significance of current product release criteria for the transplantation outcome. METHODS: Fourty five consecutive transplanted human islet preparations and their functional outcomes were analyzed. Islet mass was determined according to standard criteria: purity by light microscopy, viability by dye exclusion and Insulin secretory response to static glucose incubation. Islet graft function was monitored for > or = 1 year. Islet function was defined as full (FF), partial (PF), or nonfunction (NF) based on serum C-peptide levels and insulin independence. RESULTS: All islet grafts displayed primary function. Islet mass [IEQ/kg BW]: 7331.3 +/- 679.7 (FF), 5821.3 +/- 546.7 (PF), 6468.6 +/- 658.5 (NF), (FF vs PF p = .032) Purity [%] 86.9 +/- 3.1 (FF), 76.0 +/- 2.87 (PF), 88.2 +/- 2.3 (NF) (FF vs PF P =.045, PF vs NF, P = 0.01). (4) Viability [%]:89.2 +/- 2 (FF), 86.2 +/- 1.7 (PF), 87.3 +/- 1.8 (NF) (ns). Stimulation index (SI): 20 +/- 6.3 (FF), 80.2 +/- 28.2 (PF), 21.6 +/- 3.5 (NF) (ns) No correlation was observed between SI and any other parameter nor between SI and C-peptide levels. Islet mass significantly correlated with C-peptide levels at 6 and 12 months after transplantation for functioning grafts. CONCLUSIONS: Stringent product release criteria allow identification of islet preparations suitable for clinical transplantation. However, currently used parameters are not predictive of long-term graft function, indicating that further refined quality assessments including apoptosis and resistance to early inflammation, are required to assess the primary engrafted islet mass.

Disseminated periportal fatty degeneration after allogeneic intraportal islet transplantation in a patient with type 1 diabetes mellitus: a case report.

Insulin independence after islet transplantation has been significantly improved by using new steroid-free immunosuppressive protocols and increased islet mass. Only little is known about the influence on the morphology of the liver of intraportally transplanted islets. We describe a case of disseminated periportal fatty degeneration after allogeneic intraportal islet transplantation (ITx). A 35-year-old patient with type-1 diabetes mellitus who was suffering from repeated severe hypoglycemic episodes received two sequential intraportal islet grafts. Liver structure was normal before the first ITx, based upon ultrasound and magnetic resonance imaging (MRI). One week after the first ITx, ultrasound demonstrated normal liver morphology. Four months later, at the second ITx, we detected small, disseminated, and hypodense hepatic lesions (1 to 3 mm) by ultrasound, which were confirmed by MRI and interpreted to be fatty degenerations. Histologically we found focal drop-shaped fatty degenerations with signs of mild periportal chronic inflammation. These liver alterations without clinical symptoms or pathological liver function tests matched the predicted distribution of infused islets. Glucose metabolism markedly improved after the first ITx, namely 58.6% reduction of daily insulin requirements, 1.4% decrease in HbA1c, basal C-peptide of 0.8 to 1.3 ng/dl with no severe hypoglycemia. We interpreted these benign changes in liver morphology as reactions to a local hyperinsulinemia in the neighborhood of the transplanted islets. We hypothesized that a steroid-free immunosuppression with rapamycin and tacrolimus may have contributed to changes in the portal microenvironment.