[Molecular genetic analysis and clinical aspects of patients with hereditary hemochromatosis]. / Molekulargenetische Analyse und klinische Aspekte bei Patienten mit hereditärer Hämochromatose.

BACKGROUND: The purpose of the study was to perform a molecular genetic analysis and to document clinical aspects in patients with hereditary hemochromatosis. PATIENTS AND METHODS: The study included 33 outpatients (23 males average age 50.6 years and 10 females average age 60.6 years) with a disorder of iron metabolism (transferrin saturation > 75 %) as confirmation of hemochromatosis who were subjected to molecular genetic and clinical analyses. RESULTS: A homozygous mutation of the hemochromatosis (HFE) gene (C282YY) was detected in 63.6 %, a compound heterozygous mutation (C282Y/H63D) in 30.3% and no mutation of the HFE gene was detected in 6.1 %. The following organ manifestations could be objectified: arthralgia (78.8 %), liver disease (39.9 %), skin hyperpigmentation (30.3 %), osteoporosis (24.2 %), diabetes mellitus (24.2 %) and cardiomyopathy (12.1 %). Comparison between patients with heterozygous and homozygous hemochromatosis revealed the following differences: compound heterozygote patients presented less frequently with osteoarthritis of the metacarpophalangeal (MCP) joints and hands (85.7 %/71.4 % homozygotes vs. 60 %/60 % heterozygotes). Osteoarthritis of the shoulder joints and osteoporosis as well as hypothyroidism were more frequent in compound heterozygote patients, whereas osteoarthritis of the knee and hip joints as well as liver disease were more common in homozygote patients. No differences between both groups were seen with respect to the clinical manifestations of cardiomyopathy and diabetes mellitus. CONCLUSION: Prevalent causes of death in hereditary hemochromatosis are heart failure, liver disease (cirrhosis and hepatocellular carcinoma) and portal hypertension. Therefore, an early diagnosis, adequate therapy and genetic screening of family members are of great importance. Medicinal treatment will only effectively prevent deleterious organ involvement and subsequent complications if initiated at an early stage. Furthermore, an overview of the current data is given.

3D-printed digital pneumatic logic for the control of soft robotic actuators.

Soft robots are paving their way to catch up with the application range of metal-based machines and to occupy fields that are challenging for traditional machines. Pneumatic actuators play an important role in this development, allowing the construction of bioinspired motion systems. Pneumatic logic gates provide a powerful alternative for controlling pressure-activated soft robots, which are often controlled by metallic valves and electric circuits. Many existing approaches for fully compliant pneumatic control logic suffer from high manual effort and low pressure tolerance. In our work, we invented three-dimensional (3D) printable, pneumatic logic gates that perform Boolean operations and imitate electric circuits. Within 7 hours, a filament printer is able to produce a module that serves as an OR, AND, or NOT gate; the logic function is defined by the assigned input signals. The gate contains two alternately acting pneumatic valves, whose work principle is based on the interaction of pressurized chambers and a 3D-printed 1-millimeter tube inside. The gate design does not require any kind of support material for its hollow parts, which makes the modules ready to use directly after printing. Depending on the chosen material, the modules can operate on a pressure supply between 80 and more than 750 kilopascals. The capabilities of the invented gates were verified by implementing an electronics-free drink dispenser based on a pneumatic ring oscillator and a 1-bit memory. Their high compliance is demonstrated by driving a car over a fully flexible, 3D-printed robotic walker controlled by an integrated circuit.

[Physiotherapy in outpatients with osteoporosis. Insufficient evidence for therapy success]. / Ambulante Physiotherapie bei Osteoporose. Unzureichende Evidenz des Therapieerfolges.

AIM: This prospective study analyzed the quality and number of physiotherapeutic reports, the cooperation between physiotherapists and rheumatologists/osteologists as well as the correctness of the physiotherapy in relation to the respective prescription within the German medical healthcare system. Furthermore, it was evaluated whether reported information is sufficient to evaluate outpatient physiotherapy. METHOD: In 475 physiotherapeutic prescriptions for conservative treatment of patients with osteoporosis, the report quality was evaluated prospectively. The types of prescription and actually performed physiotherapy were compared. The ability of the patients to demonstrate the exercises, as had to be learned during therapy, was analyzed and also the number of mandatory documented questioned follow-up forms. Furthermore, the efficiency of different types of physiotherapy was evaluated. RESULTS: Only 46 reports from 475 prescriptions were received, i.e., the obligation to report was performed only in 9.7% of the cases. Depending on the type of physiotherapy, there was a different range in reporting (classical massage 6.8%, thermotherapy 12.8%, active muscle training with weights and resistant exercises or in water 9.1-20.4% and electrical field treatment 20%). In 141 prescriptions the patients should have learned to do the exercises by themselves as a home program. However, only 38 patients (27%) were able to demonstrate this at the reassessment appointment. In addition in 38 cases of the 46 reports, i.e. in 82.6%, the physiotherapist asked for another prescription. CONCLUSION: The data illustrate that for outpatient treatment of osteoporosis patients there is insufficient cooperation between physiotherapists and rheumatologists and/or osteologists. Owing to this shortcoming, the efficiency of physiotherapy could not be evaluated due to lack of prescription reports. Therefore, new control mechanisms as well as sufficient education in prescription of physiotherapy should be implemented.

[Coagulation management of trauma patients with unstabile circulation : establishment of a hemoglobin-oriented standard operating procedure]. / Gerinnungsmanagement beim kreislaufinstabilen Polytraumapatienten : Erarbeitung einer hämoglobinorientierten "standard operating procedure"

INTRODUCTION: Massive hemorrhage is the leading cause of death in the first few hours following multiple trauma, therefore, early and aggressive treatment of clotting disorders and surgical intervention to stop the bleeding are of utmost importance. However, commonly performed clotting tests have a considerable latency of at least 30-45 min, whereas hemoglobin (Hb) levels can be tested very quickly. If a multiple trauma patient has already received fluid resuscitation, a certain relationship may be observed between the hemoglobin value and the development of clotting disturbances. Hence, hemoglobin may be a useful and rapidly available parameter for guiding the initial treatment of clotting disturbances in multiple trauma patients. METHODS: A Hb-guided algorithm has been developed to initiate initial clotting therapy. The algorithm contains three stages of different aggressive clotting therapy with fibrinogen, prothrombin complex concentrate (PCC), factor VIIa, tranexamic acid and desmopressin, depending on the first Hb value measured. For admission Hb levels > 5.5 mmol/l (≈8.8 g/dl) coagulation therapy is managed on the basis of the laboratory tests and if in doubt 2 g fibrinogen is administered. For admission Hb levels between 5.5 mmol/l (≈8.8 g/dl) and 4 mmol/l (≈6.5 g/dl) 2-4 g fibrinogen and 2,500-3,000 IU PCC are administered and tranexamic acid and desmopressin administration should be considered. For admission Hb levels < 4 mmol/l (≈6.5 g/dl) 4-6 g fibrinogen, 3,000-5,000 IU PCC and 1 mg factor VIIa should be administered and tranexamic acid and desmopression should be considered. All drugs mentioned should be stored in a special "coagulation box" in the hospital pharmacy and this box is brought immediately to the patient on demand. In addition to the use of clotting factors, infusions should be performed with balanced crystalloids and transfusions with an RBC/FFP ratio of 2:1-1:1. To assess the efficiency of the algorithm the routinely measured clotting parameters at trauma bay admission were compared with intensive care unit (ICU) admission and the standardized mortality ratio (SMR) was calculated. RESULTS: During a 6-month investigation period 71 severe multiple trauma patients were admitted to the trauma center and 19 patients were treated using the coagulation box of which 13 required massive transfusions. The routinely used clotting parameters markedly improved between admission to the trauma bay and ICU admission: Quick 61% versus 97% (p < 0.001), partial prothromboplastin time (PTT) 50 s versus 42 s (not significant), fibrinogen 1.7 g/l versus 2.15 g/l (not significant). Of the 19 patients 11 (58%) survived. The revised injury severity classification (RISC) predicted a survival rate of 40%, which corresponds to an SMR of 0.69, thus implying a higher survival rate than predicted. CONCLUSIONS: The Hb-driven algorithm, in combination with the coagulation box and the early use of clotting factors, may be a simple and effective tool for improving coagulopathy in multiple trauma patients.

[Epidemiology and classification of diabetic foot syndrome]. / Epidemiologie und Klassifikation des diabetischen Fusssyndroms.

The diabetic foot syndrome (DFS) is an important complication of diabetes mellitus resulting in severe undesired consequences, such as amputation, disability and reduced quality of life. In Germany there are approximately 300,000 patients with lesions of the foot caused by diabetes of which approximately 50% have to be amputated within 4 years of diagnosis. To achieve a reduction of the amputation rate it is necessary to identify the main causes. The use of the Wagner-Armstrong wound classification is well accepted in Germany. Therapy and diagnosis of the diabetic foot syndrome are almost standardized and all procedures are well established. In addition a professional stage-adjusted wound therapy has to take place in an interdisciplinary collaboration at a centre for wound care.

Fecal elastase 1 and vitamin D3 in patients with osteoporotic bone fractures.

BACKGROUND AND AIMS: The aim of the present study was to clarify if patients with osteoporotic bone fractures have exocrine pancreatic insufficiency, especially reduced fecal elastase 1, connected with lowered serum levels of vitamin D3 that could be relevant for predominant osteoporosis. METHODS: Between October 1999 and September 2001, we investigated on 167 patients with an average age of approx. 69 years suffering from typical osteoporotic bone fractures, as well as 20 healthy controls with an average age of 53 years. A standardized osteodensitometry via dual energy X-ray absorptiometry (DEXA) was performed in all participants. Levels of PTH, 1,25(OH)(2) Vitamin D(3), 25(OH) Vitamin D(3), calcium and phosphate in serum, elastase 1 in feces as well as the body mass index were determined in all patients and controls. RESULTS: In patients 25(OH)D3 was more than 60% and 1,25(OH)(2)D(3) was more than 53% decreased compared to controls. Fecal elastase 1 was lower than the lowest reference of 200 microg/g feces in more than 34% of the patients and it was more than 65% reduced in comparison to healthy controls (fecal elastase 1 patients: 240.7 +/- 96.3 microg/g; controls 694.9 +/- 138.6 microg/g). Separation of the patients in accordance with the elastase 1 contend in feces into four groups (below 100 microg/g, between 100 and 200 microg/g, between 201 and 300 microg/g and above 300 microg/g) resulted in significant variations for 25(OH)D(3), 1,25(OH)(2)D(3), calcium and PTH between these groups (p < 0.01). Furthermore 25(OH)D(3), 1,25(OH)(2)D(3), calcium and PTH correlated significantly with elastase 1 in feces (p < 0.01) the way, that lower fecal elastase 1 was connected with lower levels of the other parameters. BMI shows no relevant differences within the patients or between patients and controls. CONCLUSION: Exocrine pancreatic insufficiency, especially lowered fecal elastase 1, may be much more frequent in patients with osteoporotic bone fractures than suggested so far. Lowered exocrine pancreatic function with lowered fecal elastase 1 seems to be relevant as a reason for reduced levels of circulating vitamin D3 metabolites being an appropriate additional cause for predominant osteoporosis.

Parathormone levels and Vitamin D metabolism in female patients with various grades of fecal elastase 1 deficiency.

BACKGROUND: There are still too few conclusive reports about conspicuous parathormone (PTH) and Vitamin D metabolism in patients with fecal elastase 1 deficiency or any connection of the calcium metabolism to the severity of exocrine pancreas insufficiency. METHODS: Between March 1998 and September 2002, we investigated on 240 female patients with fecal elastase 1 deficiency at an average age of approx. 56.4 years and suffering from meteorism and weight loss as well as on age matched 80 healthy female controls. Serum levels of PTH, total calcium, D subset3-vitamins, calcitriol and calcefediol, as well as the concentration of fecal elastase 1 were determined in patients and controls. RESULTS: In 240 female patients with deficiency of fecal elastase 1 only two patients show milder cases of new diagnosed primary hyperparathyroidism. Calcitriol was markedly decreased (14.3 +/- 6.1 and 20.7 +/- 9.4 pg/ml) compared to controls (41.8 +/- 8.3 pg / ml) ( p < 0.01). Calcefediol was not significantly different within the various elastase-groups (p = 0.07). Nevertheless, vitamin D subset3 and fecal elastase 1 in patients correlated significantly (p < 0.01) and, compared to controls, both were extremely low (means in patients. Both D subset3-vitamins in patients were significantly lower when elastase 1 in feces was under 200 microg/g compared to the others (for calcitriol p < 0.05, for calcefediol p < 0.05). CONCLUSION: In female patients elastase 1 in feces confirm the grade of vitamin D supply, and thus show a vitamin D subset3-deficiency, depending on the loss of stool content. There seems to be a connection here between the loss of exocrine function and may be even the characteristic of sterol-binding of elastase 1 in the pancreas, which seems to be relevant for vitamin D-supply.

Silicon chemistry in zero to three dimensions: from dichlorosilylene to silafullerane.

Silylenes and silanides, prominent Si(ii) species, are not only interesting in their own right, but also constitute important building blocks in oligosilane and organosilane chemistry. The past decade has witnessed tremendous advances in the understanding of the ambiphilic behavior of silylenes and the nucleophilic properties of silanides, as well as the mutual relationships between both species. Especially the readily available SiCl2/[SiCl3]- system is intriguing, because it features highly functionalized silicon centers, amenable to late-stage modifications. Moreover, SiCl2 and [SiCl3]- are interconvertible by mere chloride association/dissociation. This Feature Article first provides a brief introduction to isolable (functionalized) silylenes and silanides and then focusses on the SiCl2/[SiCl3]- couple. Classical high-temperature protocols for the generation of SiCl2 are juxtaposed with convenient recent solution phase methods that provide access to R3N-SiCl2 and [SiCl3]-via deprotonation of HSiCl3 or the amine-/chloride-induced disproportionation of Si2Cl6. We give a comprehensive overview of key mechanistic issues and highlight the utility of R3N-SiCl2 and [SiCl3]- for the synthesis of open-chain and cyclic oligosilanes as well as nanoscale, fullerene-type silicon clusters.

Preoperative assessment of the risk of postoperative death in patients with oral squamous cell carcinoma: a consideration beyond age, sex, and stage of cancer.

Despite improvements in the management of patients in critical care, about 3% patients who have an operation with curative intent for oral squamous cell carcinoma (SCC) do not survive their stay in hospital. Our aim was to assess the risk factors for postoperative death that were independent of the stage of the cancer, or the age and sex of the patients. We screened 4760 consecutive inpatients at a maxillofacial tertiary care centre from 2011 to 2016, and 34 of them had died within the first three months after operation. We matched them with a further 34 patients with the same TNM stage, age, and sex. General personal and clinical data and preoperative laboratory values were screened, and we applied a Charlson Comorbidity Score (for anaesthetic risk) for each group. Patients' mean (SD) age was 66 (12) years old. There was no significant difference in sex (p=1), age (p=0.718), or TNM classification. Those who died after operation had significantly more renal (p=0.027) and gastrointestinal (p=0.006) diseases, but cardiac diseases (p=0.468) and diabetes mellitus (p=1) were not significant risk factors in themselves. Patients who died postoperatively had significantly worse risk scores (p=0.001) overall. The most common causes of death were septic shock (n=10) and acute cardiac (n=9) or respiratory failure (n=7). Our findings suggested that general diseases were not intrinsically a contraindication for operation with curative intent. The Charlson Comorbidity Score helped to detect potentially fatal courses and could be useful in the preoperative assessment of patients whose general health is not good.

Pathologic alterations of the heart and the kidney in patients with ankylosing spondylitis.

BACKGROUND: The occurrence of a variety of pathological lesions of the heart and kidneys have been described in patients with ankylosing spondylitis (AS). The frequency of these alterations and whether they are specific for AS has been discussed controversially. - METHODS: Outpatients with AS were studied to determine the frequency of cardiac and renal alterations and to assess the associated clinical and demographic factors. - RESULTS: A total of 77 patients with AS participated in the study (male 84.4%, mean age 48.3 +/- 1.5 years, mean duration of disease 15.4 +/- 1.2 years). Hypertension was present in 36.4% and diabetes mellitus in 13.0%. Impaired renal function (defined by a decrease in GFR) combined with markers of kidney damage suspective for chronic kidney disease were present in 3 patients (3.9%). Pathologic alterations of the heart were found in 25 patients (37.3%). Echocardiographic abnormalities were present in 20 patients (e.g. aortic and mitral insufficiency). Electrocardiographic abnormalities were present in 12 patients (e.g. atrioventricular, left and right branch block). Patients with cardiac abnormalities were older (54.2 +/- 2.9 vs. 44.9 +/- 1.7 years) and had a longer duration of disease (20.6 +/- 2.1 vs. 13.9 +/- 1.6 years) as compared to non-affected patients. - CONCLUSION: In our study, cardiac abnormalities were frequently seen in patients with AS, while renal disease was more rare and might be due to diseases not related to AS in most of patients. In contrast to cardiac involvement, it therefore appears questionable, that chronic kidney disease is part of the extraskeletal manifestations, or at least that AS has a high impact on renal integrity.

Alterations of vitamin D3 metabolism in young women with various grades of chronic pancreatitis.

BACKGROUND: There are still too few conclusive reports about conspicuous vitamin D-deficiency in young female patients with chronic pancreatitis, or any connection of the deficiency to the severity of the disease. Therefore the aim of this study was to examine marker of vitamin D3 metabolism in female patients with episode of biliary pancreatitis to determine if increased severity of the disease would correlate with impaired vitamin D3 metabolism. METHODS: Between 1996 and 2003, we investigated 53 premenopausal patients with an average age of approximately 33 years suffering from an episode of chronic pancreatitis, as well as 30 female healthy controls with an average age of 32.4 years. The severity of chronic pancreatitis in patients was determined via endoscopic retrograde cholangiopancreaticography (ERCP) and assigned to 1 of 3 grades based on the Cambridge classification. Additional parameter assessed were demographics, smoking, consumption of alcohol and CD-transferrin, fasting metabolic parameters, biochemical markers of vitamin D3 metabolism and fecal elastase 1. None of the patients received hormone replacement therapy, Vitamin D or Calcium-supplementation. RESULTS: The serum levels of 1,25-dihydroxyvitamin D [1,25(OH2)D] were significantly reduced compared to female healthy controls. Fecal elastase 1 correlated with this classification of severity of chronic pancreatitis (p < 0.01). Furthermore, fecal elastase 1 of patients correlated the same way with both D-vitamins (p <0.01). The level of both D3 vitamins in patients were significantly lowered when the content of fecal elastase 1 was under 200 microg/g compared to the others [for 1,25-(OH2)D3 p < 0.01; 25-OH- D3 p < 0.01]. CONCLUSION: Premenopausal patients with chronic pancreatitis are at risk of developing decreased levels of 1,25(OH2)D3. This fact may contribute to a negative calcium balance and alteration of bone metabolism. Therefore, ERCP and fecal elastase 1 verify the severity grade of a chronic pancreatitis, and thus show a vitamin D3 deficiency in young women, depending on the progress of disease.

Phenotypic and genotypic heterogeneity in infant acute leukemia. I. Acute lymphoblastic leukemia.

We have studied the immunophenotypic and genotypic features in 35 infants aged less than 1 year with acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia (AUL). A CD10 (common ALL antigen)-negative, CD19-positive pre-pre-B ALL phenotype was observed in 24 infants. Seventeen of them had blast cells coexpressing myeloid-associated markers such as CD15A (VIM-D5, MZ17) and/or VIM-2, but neither myeloperoxidase nor platelet peroxidase was detected in five of these cases analyzed by electron microscopy. Five patients showed a typical common ALL, five a pre-B ALL phenotype, and one infant was unclassifiable by surface-marker and morphologic analysis. Cytogenetic data, available in 21 of these patients, revealed chromosomal abnormalities involving 11q23 in 10 infants with a CD10-negative pre-pre-B ALL. Immunoglobulin (Ig) and T cell receptor (TCR) gamma, beta and delta gene analysis of 31 infants showed Ig heavy-chain gene rearrangement in all but one patient with evidence for clonal evolution in six and kappa-light-chain rearrangement in three infants. TCR beta-chain and TCR gamma-chain rearrangement occurred in six and five patients respectively, while TCR delta-chain rearrangement was identified in 15 patients. Our data indicate that ALL in infancy may present with heterogeneous immunophenotypic and genotypic features. The high frequency of coexpression of B-lineage and myeloid surface markers as well as of chromosomal rearrangement involving 11q23 suggests that the clonogenic cell of infant ALL may relate to a multipotent progenitor cell in most cases.

Exercises and physiotherapeutic strategies for preventing and treating osteoporosis.

For the treatment of osteoporosis, appropiate physiotherapy needs to use the given or remaining abilities of a patient to modulate and optimize the biological functions and structures (bone, muscle) in an adaptive, stimulating and regenerating sense. In addition physiotherapy can set serial physical stimuli to minimize pain perception by bio-psychosocial effects. Physiotherapy for osteoporosis has to be seen equivalent to pharmacotherapy with respect to prevention, cure and rehabilitation. In general, 2 different aims for effective treatment can be defined: 1. Aims that can be achieved solely with physical therapy, such as structural improvement of the existing and pharmacologically increased bone mass, slowdown of round-back formation and fall prophylaxis. 2. Aims that can be mainly achieved with physiotherapy and pharmacotherapy, such as increase of bone density and differentiated amelioration of pain. This article summarises the current knowledge on exercise and physiotherapy in preventing and treating osteoporosis, and focuses specifically on the diagnostic-orientated stimulating preventative, curative and/or rehabilitative effects, in which the choice of the individual regimen and the dosage need to be optimized for every patient individually.

Metabolic clearance rates of catechol estrogens in rats.

MCRs of the catechol estrogens 4-hydroxyestradiol (4-OHE2) and 2-hydroxyestradiol (2-OHE2) and of the parent estrogen 17 beta-estradiol (E2) were determined in rats. Long term ovariectomized Wistar rats were infused with the steroids at a constant rate for 3 days via a catheter placed in the abdominal aorta. Blood samples were drawn discontinually by retroorbital puncture, and the serum concentrations of E2, 4-OHE2, and 2-OHE2 were measured by RIA. Steady state was reached within 24 h of infusion. Mean serum MCRs were calculated to be 740 +/- 117 ml/h for E2, 2700 +/- 1000 ml/h for 4-OHE2, and 8300 +/- 1700 ml/h for 2-OHE2. Thus, the MCRs of the catechol estrogens were definitely higher than the MCR of E2 resulting in an apparent ratio of 1:4:11 (E2:4-OHE2:2-OHE2).

Cytotoxicity of interleukin 2-induced lymphokine-activated killer (LAK) cells against human leukemia and augmentation of killing by interferons and tumor necrosis factor.

Adoptive immunotherapy with interleukin 2-induced lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TIL) and the induction of anti-tumor responses by IL-2 alone having proven to be promising approaches in cancer therapy. The present study investigated the cytotoxicity of LAK cells towards human leukemia cells. LAK cells were generated by culturing peripheral blood mononuclear cells from normal donors for six days in the presence of recombinant interleukin 2 (IL-2). Cytotoxicity was evaluated using a standard 4-h chromium-release assay. A significant lysis of fresh uncultured leukemia cells by IL-2-activated killer cells could be detected in 77 of 150 leukemias examined. The mean Cr-release was 35.7 +/- 12.9% in the LAK cell-sensitive vs 9.9 +/- 5.9% in the resistant leukemias. With a view to the therapeutic utilization of the LAK-cell system, we attempted to improve the efficiency of its cytotoxic mechanisms. Combined application of IL-2 and interferon-alpha, interferon-gamma, or tumor necrosis factor-alpha in cultures for generation of activated killer cells significantly improved the effectiveness of cytotoxic mechanisms. Our results suggest that the performance of adoptive immunotherapy with ex vivo-activated LAK cells and the in vivo induction of cytotoxic immune responses by IL-2 alone or combined with different lymphokines or cytokines may be of value in treating human leukemia, especially when the tumor burden is low, e.g. during maintenance therapy or after bone marrow transplantation to eliminate minimal residual disease or in early relapse.

Chronic myelocytic leukemia as a second neoplasia in the course of chronic lymphocytic leukemia. Case report and review of the literature.

A patient with chronic lymphocytic leukemia developed Ph1-positive chronic myelocytic leukemia after a 6-yr course of CLL. Chemotherapy for CLL consisted of chlorambucil and steroids, later vincristine and bleomycin; after resistance to these agents, cyclophosphamide, vincristine and prednisolone were applied. When CML was diagnosed, we found two morphologically distinct populations of malignant cells in the bone marrow; the Ph1-chromosome was identified, and immunological surface marker studies also demonstrated two distinct malignant cell populations. Up to now, only five cases of CML have been reported following CLL and one case accompanying it. Three patients were treated with cytostatic drugs, one patient by total body irradiation and two patients received no therapy. At present, it is not clear whether the development of CML during CLL represents a therapy-induced complication or an increased susceptibility to second malignancies due to the leukemic process itself or possibly to immunological deficiencies in CLL. Since two patients received no treatment for CLL, previous therapy does not seem to be a prerequisite for the development of CML.

Abnormalities of B cell activation and immunoregulation in patients with chronic inflammatory liver diseases.

The immunoglobulin production capacities of peripheral blood lymphocytes obtained from patients with various chronic inflammatory liver diseases and from normal individuals were compared. Using a reverse hemolytic plaque assay, immunoglobulin-secreting cells (ISC) were counted immediately after isolation (immediate ISC) and again after 6-day, in vitro cultivation without stimulant (spontaneous ISC) or in the presence of pokeweed mitogen, PWM (PWM-induced ISC). An increased number of immediate ISC were observed in patients with chronic active hepatitis (CAH) of the autoimmune type (n = 7) or with CAH type B (n = 32), probably reflecting a defect of the in vivo suppressor cell system as previously demonstrated. In vitro preincubation of cells with 5 x 10(-8) M prednisolone reduced the increase in the number of immediate ISC in patients with CAH of the autoimmune type. On the other hand, lymphocytes obtained from patients with CAH-type NANB (n = 9) and with primary biliary cirrhosis (PBC) (n = 12) showed an impaired capacity to generate ISC upon stimulation with PWM. Spontaneous ISC from patients' lymphocytes were not significantly different from those of normal individuals. Using allogeneic co-cultures with lymphocytes from normal individuals and from patients with CAH NANB hepatitis or primary biliary cirrhosis, we observed no increase in suppressor cell activity. Therefore, the diminished responses to PWM are probably attributable to an alteration in the peripheral helper T-cell compartment.

Alterations of bone mineral density and bone metabolism in patients with various grades of chronic pancreatitis.

The aim of this study was to examine bone mineral density (BMD) and bone metabolism in patients with chronic pancreatitis to determine if increased severity of the disease would correlate with increased bone loss. Between October 1999 and September 2000, we investigated 42 patients with an average age of approximately 53 years suffering from chronic pancreatitis, as well as 20 healthy male controls with an average age of 49 years. Dual energy x-ray absorptiometry (DEXA) was performed on patients and controls, and serum levels of parathyroid hormone (PTH), osteocalcin (OC), carboxy-terminal propeptide of type I procollagen (CICP), bone-specific alkaline phosphatase (BAP), 1,25(OH)(2) vitamin D(3) and 25(OH) vitamin D(3), as well as fecal elastase 1 were also determined. The severity of chronic pancreatitis in patients was determined via endoscopic retrograde cholangiopancreatography (ERCP) and assigned to 1 of 3 grades based on the Cambridge classification. BMD of patients with chronic pancreatitis was markedly decreased compared to controls (means in patients: DEXA lumbar vertebra anterior/posterior (LV ap) 96.8% +/- 4.2%, DEXA Ward's triangle (WARD) 92.2% +/- 5.2%; controls: DEXA LV ap 98.7% +/- 3.7%, DEXA WARD 97.1% +/- 3.1%; P <.05 and P <.0001) and correlated with the various Cambridge-grades (DEXA LV ap and DEXA WARD, P <.01). Fecal elastase 1 showed sensitivities of 14%, 87%, and 95% for the Cambridge-grades I, II, and III, respectively, and correlated with this classification of severity of chronic pancreatitis (P <.01). Furthermore, fecal elastase 1 of patients correlated the same way with both D(3)-vitamins (P <.01), as well as with parameters of BMD (P <.01). If fecal elastase 1 in patients was below 200 micro g/g, then the BMD and vitamin D(3) values were also significantly decreased compared to those with fecal elastase 1 above 200 micro g/g. In patients with Cambridge grades II and III 1,25(OH)(2)D(3) was markedly decreased (26.7 +/- 7.7 pg/mL and 27.6 +/- 9.0 pg/mL) compared to those with Cambridge grade I (38.0 +/- 10.5 pg/mL; between I and II, P =.027; between I and III, P =.033). 25(OH)D(3) was not significantly different within the various Cambridge groups (P =.07). Compared to controls, both D(3) vitamins, as well as fecal elastase 1, were extremely low (means in patients: fecal elastase 1, 140.7 +/- 75.7 micro g/g; 1,25(OH)(2)D(3), 29.9 +/- 9.5 pg/mL; 25(OH)D(3), 26.7 +/- 9.7 nmol/L; controls: fecal elastase 1, 694.9 +/- 138.6 micro g/g; 1,25(OH)(2)D(3), 67.5 +/- 4.3 pg/mL; 25(OH)D(3), 69.5 +/- 13.5 nmol/L). A significant correlation was observed between increased severity of chronic pancreatitis based on both endoscopic retrograde cholangiopancreatography and levels of fecal elastase 1, with decreased circulating levels of vitmain D(3) and decreased BMD. This supports a connection between the inflammatory destruction of the pancreas (Cambridge classification), exocrine pancreatic insufficiency (fecal elastase 1), altered levels of vitamin D metabolites, and loss of skeletal mass.

Changes in calciotropic hormones and biochemical markers of bone metabolism in patients with human immunodeficiency virus infection.

Data on the bone metabolism of human immunodeficiency virus (HIV)-infected patients are still extremely rare. To investigate the influence of HIV infection on the calciotropic hormones and markers of bone metabolism, we therefore performed a cross-sectional study on 100 patients (65 males and 35 females) with proven HIV infection. The following criteria were used for exclusion from the study: age less than 20/more than 50 years, confinement to bed, wasting symptoms, treatment with agents containing ketoconazole, renal or hepatic insufficiency, clinical or echographic signs of liver cirrhosis, endocrine diseases, or treatment with medications known to influence bone metabolism. Bone mineral content (BMC) was determined by single-photon absorptiometry on the left forearm. Reduced BMC was found among the male and female HIV-infected patients. Additional long-term use of heroin resulted in a severe loss of mineralization in the respective females. The markers of bone metabolism were determined in urine and serum samples. Significantly lower osteocalcin concentrations were found, indicating a reduced bone formation rate whose severity showed a significant correlation with the progressive loss of CD4 helper cells and was independent of low vitamin D3 levels (1,25-dihydroxycholecalciferol) and alterations of protein metabolism. Increased urinary excretion of cross-links as an expression of enhanced bone resorption was likewise significantly correlated with the loss of CD4 helper cells and independent of the vitamin D concentration and protein metabolism. It is therefore concluded that the changes in bone metabolism are mainly due to mechanisms of the impaired immune defense of HIV-infected patients.

GM-CSF-mediated proliferation induction improves the susceptibility of leukemia cells to lymphokine-activated killer cells.

Our studies on the susceptibility of fresh noncultured leukemia cells to interleukin-2 (IL-2)-induced lymphokine-activated killer (LAK) cells have shown that about two thirds of the leukemias are susceptible to the LAK-cell-mediated cytolysis. Analysis of 214 acute leukemias revealed considerable variation in the degree of cytotoxicity achieved. Cytolysis was substantially lower in fresh noncultured acute leukemia samples than in K562 and Daudi cell lines (mean Cr-release 21.0 +/- 16.0% versus 69.2 +/- 6.6% and 70.8 +/- 7.9%). Augmentation of susceptibility to LAK-cell lysis is desirable in connection with therapeutic application of IL-2-induced effector mechanisms. We observed a relationship between the LAK-cell susceptibility of leukemia cells and their spontaneous proliferation rate, which is significantly higher in LAK-cell-sensitive than in LAK-cell-resistant leukemias. It was therefore considered useful to examine the possibility of augmenting LAK-cell sensitivity by proliferation induction. These studies demonstrate that incubation of blast cells from acute myeloid leukemia (AML) and chronic myelogenous leukemia in myeloid blast crisis (CML-BC) with recombinant granulocyte-macrophage colony stimulating factor (GM-CSF) significantly augments LAK-cell susceptibility and that this is associated with an increased cell proliferation.