Migratory properties of ex vivo expanded regulatory T cells: Influence of all-trans retinoic acid and rapamycin.

Adoptively transferred regulatory T-cells represent a promising therapeutic approach for tolerance induction in autoimmunity and transplantation medicine. However, a major hurdle for clinical application is the manufacturing of sufficient Treg cell numbers with respect to the low frequency of naturally occurring Tregs in the peripheral blood. Therefore, ex vivo large-scale expansion is mandatory for most of the clinical conditions. Besides the Treg cell number other parameters of the cell product are of high relevance for safe and efficient clinical Treg cell application like Treg cell purity, suppressive capacity and genetic stability of the Treg cell phenotype. Moreover, migratory properties of ex vivo expanded Tregs should be defined very clearly in order to predict their migration to secondary lymphoid organs as sites of antigen-specific activation, in vivo proliferation and subsequent trafficking to affected target organs. Therefore, we studied different cell culture conditions for Treg large-cell expansion using all-trans retinoic acid (ATRA) and/or rapamycin (Rapa) with focus on their migratory properties. The tested culture conditions revealed comparable chemokine receptor expression profiles (CXCR3, CCR4, CCR6, CCR7) and functional migration capabilities (IP10 and CCL19) with respect to Th1 and Th2 inflammatory conditions. However, the most striking difference was detected for the expansion capacity, suppressive potency and genetic stability likely predisposing large-scale expansion with ATRA and/or Rapa for therapeutic intervention in acute GvHD and without supplementation for chronic GvHD.

Lack of influence of COMT and NET genes variants on executive functions in schizophrenic and bipolar patients, their first-degree relatives and controls.

Abnormal dopaminergic function in the prefrontal cortex (PFC) may be a key factor in the etiopathogeny of schizophrenia and bipolar disorder. Both schizophrenic and bipolar subjects have executive functions (EF) deficits, thought to reflect abnormal PFC function. The main inactivation pathways for dopamine in the PFC are enzymatic cleavage by the Carboxy-O-Methyl-Transferase (COMT) and reuptake by the nor-epinephrine transporter (NET). Our aim in this study was to replicate previous studies that investigated influence of the COMT genotype on EF in schizophrenic subjects, their relatives and controls and extend their scope by including bipolar patients, and their relatives and by exploring NET gene polymorphisms influence on executive performances. We investigated one functional polymorphism of the COMT gene and two polymorphisms of the NET gene. EF were assessed by means of the Trail Making Test (TMT) and the Wisconsin Card Sorting Test (WCST). We assessed the effect of each of the three genotypes on EF for the whole sample (N = 318) and separately in schizophrenic (N = 66), bipolar (N = 94) and healthy subjects (i.e., relatives and controls N = 158). Separate analyses were performed because of the presence, in patients samples, of potentially confounding factors, especially medication. Genotype had no significant effect on the cognitive measures in any of the analyses (for the two EF measures, the three polymorphisms, and the four groups). In our sample we found no evidence in favor of a major effect of COMT or NET polymorphisms on the two tests of EF.

Growth hormone use in pediatric growth hormone deficiency and other pediatric growth disorders.

The diagnosis and management of growth disorders in children, particularly disorders that respond to therapy with growth hormone (GH), raise challenging clinical and economic issues. Several such issues are presented in the following article in which Dr. Ron Rosenfeld examines the evaluation and diagnosis of the child with short stature; Dr. David B. Allen discusses the anabolic and metabolic indications for GH treatment in children; Dr. Margaret H. MacGillivray reviews GH dosing, height outcomes, and follow up; and Dr. Craig Alter presents the payer's perspective on the diagnosis and treatment of pediatric GH deficiency. In addressing the use of GH in other pediatric populations, Dr. Paul Saenger focuses on Turner syndrome, Dr. Henry Anhalt on chronic renal insufficiency of childhood, and Dr. Ray Hintz on idiopathic short stature. Dr. Harvey P. Katz presents one managed care organization's policy and implementation plan that is used to guide decisions regarding coverage for GH treatment.

Self-reported factors that affect glycemic control in college students with type 1 diabetes.

PURPOSE: This study examined the self-reported impact of different factors on the overall diabetes care of college students with type 1 diabetes. METHODS: An 18-item questionnaire was mailed to 164 students with type 1 diabetes attending college away from home; results from 42 students fulfilled study criteria and were analyzed. Metabolic control was assessed by relative changes in glycosylated hemoglobin (HbA1c) levels from medical records. RESULTS: HbA1c levels did not change significantly between high school and college, yet most college students reported that diabetes was more difficult to manage in college. Commonly reported barriers to diabetes control included diet, irregular schedules, lack of parental involvement, peer pressure, drugs and alcohol, fear of hypoglycemia, and finances. Factors identified as improving diabetes control were an increased sense of responsibility, increased frequency of blood glucose testing, exercise, contact with healthcare providers, fear of hyperglycemia, and knowledge of the results of the Diabetes Control and Complications Trial. Many students reported testing their blood more frequently and taking more injections than in high school; most were on intensive insulin regimens. CONCLUSIONS: Despite the perception that diabetes management was more difficult in college, metabolic control was maintained during college, possibly due to a more intensive treatment approach.

The carved-out system's view.

Rarely do issues of mental health care in medical settings and the medical care of severely and persistently mentally ill patients treated in public mental health get addressed. The best approach to ensure that care is integrated is to reduce obstacles to reimbursement. In particular, carved-out systems should ask questions that highlight areas for change.

[Possibilities of follow-up imaging after implantation of a carbon fiber-reinforced hip prosthesis]. / Möglichkeiten der bildgebenden Darstellung eines Hüftendoprothesenschaftes aus Kohlenstoffaserverbundwerkstoff (CFK).

INTRODUCTION: There are many problems in the radiological diagnosis of aseptic loosening in total hip arthroplasty. Computed tomography (CT) and magnetic resonance tomography (MRT) are not usable for metallic implants (stainless steel, cobalt alloy, titanium alloy). MATERIAL AND METHODS: From April 1993 to December 1993 15 CFRP non-cemented hip prostheses have been implanted. In a prospective clinical study plane radiographs, CT and MRT have been analysed. RESULTS: Three stems were revised (1 femoral fracture, 1 severe thigh pain, 1 aseptic loosening). CFRP are not visible in plane radiographs. There was a complete (two-third of the cases) or nearly complete (one-third of the cases) small sclerotic interface between the prosthesis and the bone, these were apparent in CT and MRT in stable implant cases and did not have any clinical correlations. DISCUSSION: The small sclerotic interface is quite different in comparison to so called "Reactive Lines". In one case of aseptic loosening there was an interposition of soft tissue between prosthesis and bone in MRT and CT. CFRP inaugurates new diagnostic possibilities in aseptic loosening of hip prosthesis and in tumour surgery too.

The effects of bereavement on adult sibling bone marrow donors' psychological well-being and reactions to donation.

As living organ, tissue, and bone marrow donation become increasingly prevalent treatments for a variety of diseases, better understanding of living donors' experiences, especially when the recipient does not survive after the transplant, also becomes more critical. Although some psychological outcome data exist concerning living donation, there have been no systematic prospective investigations, to date, of the psychological impact of bereavement among sibling bone marrow donors. Studies of bereavement effects in other donation settings such as unrelated bone marrow donation and related kidney donation, suggest that bereavement may have a significant impact on donors' reactions. The present investigation studied a panel of sibling bone marrow donors at three key points in the donation process in order to (1) examine donor psychological well-being across time, and (2) investigate the effect of the sibling recipient's death on donor well-being. We surveyed sibling donors by mail 1-2 weeks prior to donation, 1-2 weeks following donation, and again 1 year after their donation. In general, all donors reported high levels of predonation self-esteem, mastery, happiness and life satisfaction. As might be expected, bereaved donors felt less as if their donation had really helped their sibling as time passed. However, despite such donation-specific perceptions, bereaved donors experienced global psychological gains following bereavement including enhanced self-esteem, happiness, and life satisfaction compared to donors whose siblings were still living. These findings suggest that physicians and mental health practitioners should monitor donors' psychological well-being for extended periods post-donation, and should consider clinical interventions for bereaved and nonbereaved sibling donors.

Biomechanical and densitometric bone properties after callus distraction in sheep.

Assessment of biomechanical stability of diaphyseal bone lengthened by callus distraction is an unsolved problem. A middiaphyseal corticotomy was performed in the left tibia of 24 sheep. After 7 days, callus distraction was begun at a rate of 0.5 mm every 12 hours for 30 days using a standard unilateral fixator system. Animals were euthanized 4, 8, or 12 weeks after the end of distraction. The lengthened tibia and the contralateral control tibia from each animal were evaluated by radiographic, densitometric (dual energy xray absorptiometry, quantitative computed tomography), and biomechanical (axial compression testing, torsion testing to failure) methods. The bone mineral density and maximum torque for the lengthened tibia were significantly greater in the 8-week group than in the 4-week group. However, the values in the 12-week group were significantly smaller than in the 8-week group. In the lengthened tibias, there was a correlation between the maximum torque and the bone mineral density, and between the maximum torque and the bone density. Bone density measurements are useful prognosticators for the safe removal of external fixators after leg lengthening procedures. By using these methods, clinical fractures after leg lengthening could be avoided in the future.

Funding for consultation-liaison services in public sector-managed care plans. The experience of the Consultation-Liaison Association of Philadelphia.

Recently, the Commonwealth of Pennsylvania initiated plans to implement a mandated behavioral health carve-out program for Medicaid-eligible persons. The Consultation-Liaison Association of Philadelphia (CLAP) discovered that there was no provision for the coverage of psychiatric services for patients with concomitant medical illness. As a result, the authors responded by initiating a series of actions aimed at ensuring inclusion of such services as part of mental health services to be delivered. CLAP developed a brief position paper that includes a description of the need for such services, the types of services typically delivered, the impact of psychiatric input in the medical setting on costs and other outcomes, and a specific set of recommendations. These efforts have lead to the inclusion of consultation-liaison services in the new plan. A description of recent changes in Medicaid, including expansion of managed care plans, the status of mental health carve outs, and the possibility for inclusion of psychiatric consultations for the medically ill within these plans, is detailed.

[Diagnosis of intraorbital meningioma]. / Diagnostik intraorbitaler Meningeome.

Demonstration of radiological appearance and the differential diagnosis of intraorbital meningeomas in two cases. CT-assisted core needle biopsy offers a reliable and easy-to-perform possibility of minimal invasive diagnosis in tumours which are difficult to classify.

Supportive telephone intervention for patients receiving chemotherapy. A pilot study.

Psychosocial interventions have been shown to improve quality of life (QOL) for many cancer patients. A pilot study was conducted to assess the feasibility of a psychoeducational intervention for cancer patients receiving chemotherapy. Eight patients receiving chemotherapy for colorectal carcinoma participated. The intervention is based on a modification of Interpersonal Therapy. It consisted of four sessions, administered biweekly, using a manual format, by a psychiatric nurse clinician over the telephone. The participants also completed a set of QOL measures by telephone to assess tolerance of the planned assessment. The patients received assistance with treatment-related side effects, reported improved ability to communicate with their physician, and gained an understanding of the stresses they discussed. The patients felt satisfied with the emotional support and medical information provided. A randomized trial is planned to test the intervention for patients participating in a cooperative trial sponsored by the National Cancer Institute.

Palliative and supportive care of patients with pancreatic cancer.

Pancreatic cancer tends to be diagnosed at a relatively late stage of disease and often secondary to significant complaints of pain. In addition there is evidence of higher rates of depressive symptoms at diagnosis in pancreatic cancer than in other forms of cancer. These factors, along with the specific tumor anatomy and pathophysiology of pancreatic cancer make palliative considerations central to the care of patients with the disease. The palliative and supportive approach must first include an aggressive evaluation of pain, mood, and emotional symptoms. Attention should be paid to the specific nature of pain complaints and attempts made to make accurate clinicopathological correlates for the pain. Assessment should be complete and ongoing. Pain treatments include pharmacotherapy, invasive anesthetic and surgical procedures, and supportive attention to side effects and other symptoms of disease and treatment. Depression often appears at higher rates than documented in other cancer patients and can be independent of pain complaints and other symptoms present in the preterminal phases of illness. Depression should be treated with pharmacotherapy and supportive psychotherapy as indicated. Hospice should be considered early on in the treatment relationship and can provide pain and symptom management services as well as play an important role in providing emotional support to the patient and family. Attention to pain, mood, psychological distress, and other quality of life issues can often allow for successful treatment of symptoms and improvement in functioning even in the setting of late stage pancreatic cancer.

Identification of PTSD in cancer survivors.

The authors measured the rate and determinants of posttraumatic stress disorder (PTSD) in a group of cancer survivors. Patients who had a history of cancer diagnosis with at least 3 years since diagnosis, receiving no active treatment, such as chemotherapy or radiation, were interviewed (N = 27). Patients, who were part of the DSM-IV PTSD field trial, were compared with a community-based control group matched for age and socioeconomic status. One member of the survivor group (4%) and no members of the control group met criteria for current PTSD (NS). Six of the survivors (22%) and no control subjects met lifetime criteria (P < 0.02). Cancer patients have a higher rate of PTSD than found in the community. Symptoms closely resemble those of individuals who have experienced other traumatic events.

Growth in children after bone marrow transplantation for acute myelogenous leukemia as compared to acute lymphocytic leukemia.

Previous studies of growth in children following bone marrow transplantation for leukemia have demonstrated poor growth with little ability to "catch-up" two to four years after transplantation. Because of small patient numbers, these studies did not distinguish patients with differing types of leukemia. 12 children with acute myelogenous leukemia who survived over 3 years after transplantation were compared with 12 who survived transplantation for acute lymphoblastic leukemia. The initial height standard deviation scores were similar in both groups prior to transplantation. The height standard deviation scores in the acute lymphoblastic leukemia group decreased for each of the 5 years after transplantation while the height score for the acute myelogenous leukemia group after 5 years was not statistically different from pre-transplantation. The growth of the children with myelogenous leukemia was better possibly because these children were older, had received less cranial irradiation at the time of transplantation, and had a lower incidence of severe chronic graft-versus-host disease.

A psychoeducational bereavement-support group for families provided in an outpatient cancer center.

BACKGROUND: Grief is a normal and highly personal reaction to loss. Bereavement care (individual and/or group) can assist family members and friends in coping with their feelings of grief, thereby reducing the possibility of complicated grief reactions. The families and significant others of patients who have died in settings other than a hospice do not automatically have the opportunity for bereavement follow-up. METHODS: An eight-session psychoeducational group that provided psychosocial support and information aimed at assisting in the bereavement process was initiated at an outpatient cancer center. It was led by a family therapist who was a member of a psychosocial services team. Family members and friends of recently deceased patients were invited to participate by letter and phone call. RESULTS: Seven people participated in at least one group session. Participants were asked to complete a face-valid follow-up questionnaire three months after completion of the group. CONCLUSIONS: Group members found the group experience beneficial, especially regarding the opportunity to talk with others who had experienced similar losses, learning about the reactions one would expect in the grieving process, and developing new strategies to deal with the grief associated with the loss.

Identification of phosphatidylinositol 3,4,5-trisphosphate in pancreatic islets and insulin-secreting beta-cells.

The signal transduction mechanisms involved in insulin secretion by the beta-cell are poorly understood. Glucose, the main physiological secretagogue, needs to be metabolized, but the identity of the intracellular messengers which couple glucose metabolism and insulin exocytosis is controversial. We now report the identification of phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3), the end-product of phosphatidylinositol 3-kinase phosphorylation of polyphosphoinositides, in islets and in an insulin-secreting clonal beta-cell line, RINm5F, using a combination of thin layer chromatography and high performance liquid chromatography analyses and by demonstrating that sequential deacylation and deglyceration of PtdIns(3,4,5)P3 yields inositol 1,3,4,5-tetrakisphosphate. Unlike other cell types, significant levels of PtdIns(3,4,5)P3 were detected in beta-cells under non-stimulatory conditions. Insulin secretagogues (28 mM glucose + 0.5 mM carbachol) caused a rapid and transient increase in PtdIns(3,4,5)P3 levels which peaked at 2-5 min, corresponding to peak early phase insulin release.

The new highly sensitive adrenocorticotropin assay improves detection of patients with partial adrenocorticotropin deficiency in a short-term metyrapone test.

This study was designed to evaluate a short term metyrapone test using a highly sensitive (HS) IRMA ACTH assay and to evaluate the usefulness of a morning ACTH level as a screening test for partial ACTH deficiency. ACTH, 11-deoxycortisol and cortisol levels were evaluated over four hours in the morning after a single 40 mg/kg oral dose of metyrapone was administered at 0800 hours. 26 control children and 32 possibly pituitary deficient patients were evaluated. Based on 11-deoxycortisol levels alone, 17 of the patients passed the test, 11 patients failed the test and the result was inconclusive in four patients (12.5%). Evaluation of the increase in ACTH levels (delta ACTH) following metyrapone identified three of the above four with partial ACTH deficiency. The delta ACTH was consistent with the 11-deoxycortisol results in the remainder of patients. There was no difference in morning ACTH levels between controls and patients with partial ACTH deficiency. The measurement of ACTH using the HS IRMA assay, increases the sensitivity of the metyrapone test in detecting patients with partial ACTH deficiency. This test may be used safely in pediatric patients on a repetitive basis, especially in those children who may have progressive ACTH failure following hypothalamic-pituitary irradiation.

Glycogen storage disease in adults.

OBJECTIVE: To identify complications amenable to prevention in adults with glycogen storage disease (GSD) types Ia, Ib, and III and to determine the effect of the disease on social factors. DESIGN: Case series and clinical review. SETTING: Referral medical centers in the United States and Canada. PATIENTS: All patients with GSD-Ia (37 patients), GSD-Ib (5 patients), and GSD-III (9 patients) who were 18 years of age or older. MEASUREMENTS: Ultrasound or radiographic studies identified liver adenomas, nephrocalcinosis, or kidney stones. Radiographic studies identified osteopenia. Reports of the clinical examination, serum chemistry results, and social data were obtained. RESULTS: For patients with GSD-Ia, problems included short stature (90%), hepatomegaly (100%), hepatic adenomas (75%), anemia (81%), proteinuria or microalbuminuria (67%), kidney calcifications (65%), osteopenia or fractures or both (27%), increased alkaline phosphatase (61%) and gamma-glutamyltransferase (93%) activities, and increased serum cholesterol (76%) and triglyceride (100%) levels. Hyperuricemia was frequent (89%). Patients with GSD-Ib had severe recurrent bacterial infections and gingivitis. In patients with GSD-III, 67% (6 of 9) had increased creatinine kinase activity. Four of these patients had myopathy and cardiomyopathy. CONCLUSIONS: For GSD-Ia, hyperuricemia and pyelonephritis should be treated to prevent nephrocalcinosis and additional renal damage. For GSD-Ib, granulocyte-colony-stimulating factor may prevent bacterial infections. For GSD-III, more data are required to determine whether the myopathy and cardiomyopathy can be prevented. Most of the patients with GSD-I and GSD-III had 12 or more years of education and were either currently in school or employed.