Acquisition of expertise on a difficult perceptual-motor task by an amnesic patient.

While numerous studies have reported learning of perceptual-motor skills by amnesic patients, few if any have documented the eventual acquisition of expertise on a given task. This paper recounts the learning of the computer game Tetris by a hippocampal amnesic, whose acquisition of the task in a formal evaluation was somewhat slower than that of a comparison group, but who after many hours of self-paced practice achieved expert-level play.

The Richards type II patellofemoral arthroplasty: 26 cases followed for 1-20 years.

We followed 26 Richards type II patellofemoral arthroplasties in 24 patients (19 women) for a mean of 11 (1-20) years. Their mean age was 59 (22-90) years. The preoperative diagnoses were primary patellofemoral arthrosis in 17 cases and secondary arthrosis in 9 (8 malalignment, 1 patellar fracture). Patellectomy was later performed for persistent pain or patellar malalignment in 3 cases and a conversion to a total knee arthroplasty for progressive tibio-femoral degeneration or patella malalignment in 2. The mean Knee Society knee score for 21 knees at follow-up was 90 (65-100) points. The patients rated the results of surgery in 9 knees as excellent, 7 good, 4 improved, and 1 unimproved at follow-up. None of the implants showed signs of loosening or infection. The Richards type II patellofemoral arthroplasty yields acceptable long-term results in patients with isolated end-stage patellofemoral osteoarthrosis. Patient selection and patella alignment are important.

The use of a skill-based activity in therapeutic induction.

This paper describes a hypnotherapeutic intervention for a brain damaged 36-year-old male who has suffered from asthma since infancy and seizure disorder from the age of eight. In early sessions it was discovered that conventional "passive-relaxation" induction techniques seemed to exacerbate certain disturbing somatic experiences, which he refers to as scary feelings. It was found that his performance of a previously learned skilled activity (the playing of the computer game Tetris) permitted the experience of a highly focused but relaxed state that was conducive to therapeutic interaction. This approach to induction bears similarity to "active-alert" procedures but may be more importantly related to Mihaly Csikszentmihalyi's principle of flow, in that it involves engagement in a subjectively meaningful, skill-based activity.

Review: molecular thyroidology.

Novel disorders involving aberrations of the hypothalamic-pituitary-thyroid gland-thyroid hormone axis have been described in the last 5 to 10 years. The following topics are addressed: molecular mutations causing central hypothyroidism (isolated autosomal recessive TRH deficiency; autosomal recessive TRH-receptor inactivating mutations; TSH beta-subunit bio-inactivating mutations; Pit-1 mutations; Prop1 mutations; high molecular weight bio-inactive TSH); defects in response to TSH (mutations in the TSH receptor: TSH receptor gain-of-function mutations; TSH receptor loss-of-function mutations); defects in thyroid gland formation: transcription factor mutations (TTF-2 and Pax8); defects in peripheral thyroid hormone metabolism (defective intrapituitary conversion of T4 to T3; hemangioma consumption of thyroid hormone); and defects in tissue response to thyroid hormone (generalized thyroid hormone resistance, selective pituitary thyroid hormone resistance). While molecular diagnosis of such conditions is rarely indicated for clinical management, knowledge of the molecular mechanisms of these diseases can greatly enhance the clinical laboratory scientist's ability to advise clinicians about appropriate thyroid testing and to interpret the complex and sometimes confusing results of thyroid function tests.

Cervical adenocarcinoma in situ: a systematic review of therapeutic options and predictors of persistent or recurrent disease.

The incidence of cervical adenocarcinoma in situ is increasing in frequency, and our limited knowledge about this lesion presents the physician with a therapeutic dilemma. Treatment for this lesion has included conservative therapy, large loop excision or cold-knife cone biopsy, or definitive therapy consisting of hysterectomy. But, rates of residual adenocarcinoma in situ after cone biopsy with negative margins vary from 0% to 40%, and residual disease rates as high as 80% have been noted when the margins are positive. Despite these recent data on follow-up after conservative therapy such as cone biopsy, it seems that this method is safe and gaining acceptance by many physicians and patients. However, the short follow-up duration and small number of patients limit the conclusions of many studies. The relative infrequency of this diagnosis has precluded extensive clinical experience with the natural history of this lesion.

The assessment of cognitive procedural learning in amnesia: why the tower of Hanoi has fallen down.

The Tower of Hanoi has been widely accepted as an evaluation of cognitive procedural learning in amnesia but inconsistent findings have raised questions about the nature of the learning process involved in this task. This article presents the performance of a hippocampal amnesic, MS, who, showing poor learning across daily sessions of a formal evaluation, subsequently solved the puzzle through spontaneous use of a declarative-level strategy (the odd-even rule), suggesting that his primary approach to the task was the deployment of declarative solution-searching strategies. The presented data suggest normal learning within daily sessions, but subnormal learning across daily sessions due to the forgetting of acquired declarative information. It is suggested that tasks that are potentially solvable by an algorithm or rule, as is the Tower of Hanoi, be regarded as inappropriate for use in cognitive procedural assessments.

Molecular and genetic bases for maturity onset diabetes of youth.

Maturity onset diabetes of youth (MODY) occurs in children, adolescents and young adults as a non-insulin-requiring form of diabetes mellitus that is inherited as an autosomal dominant trait. Maturity onset diabetes of youth in whites presents subtly similar to type 2 diabetes in adults. In contrast, a MODY variant that occurs in young blacks, termed atypical diabetes mellitus, presents as an acute-onset form of diabetes. Months to years after diagnosis, atypical diabetes mellitus reverts to a noninsulin requiring course similar to MODY in whites. Five molecular causes for MODY have been identified: mutations in four transcription factors and mutations in one enzyme (glucokinase). Transcription factors regulate gene expression within cells. Mutations in hepatocyte nuclear factor-4alpha, hepatocyte nuclear factor-1alpha, insulin promoter factor-1 and hepatocyte nuclear factor-1beta, respectively, cause MODY1, MODY3, MODY4, and MODY5. Glucokinase is the glucosensor of the beta cell. MODY2 is caused by glucokinase mutations. Although testing for MODY mutations is only available in research laboratories, a careful history and review of the patient's clinical course can often allow the clinician to diagnose MODY. The diagnosis of MODY has implications for the clinical management of the patient's diabetes.

Molecular and biochemical analysis of the MODY syndromes.

Maturity onset diabetes of the young (MODY) is characterized by youth-onset diabetes that is inherited in an autosomal dominant (monogenic) pattern. Classic MODY accounts for less than 5% of cases of childhood diabetes in Caucasians, presents prior to age 25 years, is nonketotic, and may not require insulin treatment. A variant form of MODY that lacks a clearly defined genetic basis occurs in African Americans [atypical diabetes mellitus (ADM)] clinically presents more acutely and is initially insulin requiring. To date, five molecular causes of classic MODY have been identified: hepatocyte nuclear factor-4 alpha (HNF-4 alpha; MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha; MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear factor-1 beta (HNF-1 beta; MODY5). MODY is studied as a model of beta cell hypofunction and modest insulinopenia. Clinical recognition of ADM is important for patient management to avoid confusion with type 1 diabetes mellitus.

Monogenic diabetes mellitus in youth. The MODY syndromes.

Maturity onset diabetes of the young is characterized by early onset diabetes inherited in an autosomal dominant pattern. Classic MODY occurs predominantly in Caucasians and presents before age 25, is nonketotic, and is generally not insulin-requiring. Less than 5% of cases of childhood diabetes in Caucasians are caused by MODY. ADM is a subtype of MODY that occurs in approximately 10% of African-Americans with youth onset diabetes. In contrast to MODY in Caucasians, ADM presents clinically as acute onset diabetes often associated with weight loss, ketosis, and even diabetic ketoacidosis. Approximately 50% of patients with ADM are obese. Therefore, based strictly on clinical grounds, at onset, ADM cannot be distinguished from type 1 diabetes. Months to years following diagnosis, a non-insulin-dependent clinical course develops in patients with ADM that is clearly different from type 1 diabetes. Mutations in five genes can cause MODY. These genes encode hepatocyte nuclear factor-4 alpha (HNF-4 alpha, MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha, MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear factor-1 beta (HNF-1 beta, MODY5). These monogenic forms of MODY have been used as model systems to investigate the inheritance and pathophysiology of type 2 diabetes. Clinicians, should be able to diagnose MODY. Type 1 diabetes, the most common form of diabetes in Caucasians, is always insulin-requiring for control and survival, whereas patients with MODY do not usually require long-term insulin for survival. Diagnostic confusion can lead to inappropriate management and patient expectations. Primary care physicians must be alert to avoid therapeutic confusion when patients with ADM enter into the non-insulin-dependent stage. An approach to the diagnosis of childhood diabetes is offered in Table 4. The majority of youth onset diabetes remains type 1; however, the frequency of type 2 diabetes is rising in obese children and adolescents and especially in obese minority youth. The diagnosis of MODY can be made through a careful review of the patient's clinical course, severity of hyperglycemia, and family history. The identification of islet autoantibodies is confirmatory evidence of autoimmune (type 1) diabetes. Because testing for MODY mutations is expensive and is performed at a select number of research laboratories only, routine molecular genetic studies to search for the various MODY mutations should be limited to research investigations. In the future, the availability of gene chip technology may allow rapid screening of mitochondrial and MODY mutations.

Tacrolimus-based triple-drug immunosuppression minimizes serum lipid elevations in pediatric cardiac transplant recipients.

BACKGROUND: Immunosuppression with corticosteroids and cyclosporine has been associated with hyperlipidemia, a risk factor for post-transplant coronary artery disease. The recent development of tacrolimus has created an alternative to cyclosporine-based triple drug immunotherapy. One potential benefit that has been reported in patients receiving tacrolimus is a minimization of elevation of both total and LDL cholesterol, compared to those increases observed in patients receiving cyclosporine-based immunosuppression. It is unclear in previous studies whether this beneficial effect is related to tacrolimus directly or to its corticosteroid sparing potential. To study this relationship, we compared lipid profiles from pediatric cardiac transplant recipients treated with corticosteroids, and either cyclosporine or tacrolimus. METHODS: The study group consisted of 23 patients (mean age = 12.3 years) with pre-transplant and serial post-transplant determinations of total cholesterol, LDL, HDL, and triglycerides. Patients were separated into 4 study groups, defined by immunosuppressive regimen (cyclosporine vs. tacrolimus) and prednisone dose (>0.10 mg/kg/day vs. < or =0.10 mg/kg/day). RESULTS: Patients who received cyclosporine and higher doses of prednisone experienced a mean 74 mg/dl increase from baseline in total cholesterol (p = .0001). None of the other 3 treatment groups demonstrated a statistically significant elevation. Similar trends were observed in LDL and triglyceride alterations between the 4 study groups. Interestingly, patients treated with tacrolimus and higher doses of prednisone demonstrated a significant rise in HDL from baseline (p = .0001), although those who received cyclosporine and higher dose prednisone failed to exhibit this rise. CONCLUSION: The minimal degree of lipid alteration seen in patients receiving tacrolimus and higher doses of prednisone indicates that this effect was not solely based upon the steroid-sparing properties of tacrolimus therapy. The data also suggests a possible synergistic effect between cyclosporine and higher doses of prednisone on hyperlipidemia. Therefore, in pediatric patients requiring higher corticosteroid doses late after transplantation, use of tacrolimus rather than cyclosporine may lead to more favorable lipid profiles and help minimize the risk of post-transplant coronary arteriopathy.

Emerging epidemic of type 2 diabetes in youth.

This review considers the epidemiologic evidence of an increasing incidence of type 2 diabetes in youth, the classification and diagnostic issues related to diabetes in young populations, pathophysiologic mechanisms relevant to the increasing incidence, the role of genetics and environment, and the community challenge for prevention and treatment. Type 2 diabetes in youth has been recognized to be frequent in populations of native North Americans and to comprise some 30 percent of new cases of diabetes in the 2nd decade of life, largely accounted for by minority populations and associated with obesity. Among Japanese schoolchildren, type 2 diabetes is seven times more common than type 1, and its incidence has increased more than 30-fold over the past 20 years, concomitant with changing food patterns and increasing obesity rates. The forms of diabetes seen in children and youth include typical type 1, occurring in all races; type 2, seen predominantly in minority youth; atypical diabetes, seen as an autosomal dominantly transmitted disorder in African-American populations; and maturity-onset diabetes of the young (MODY), seen rarely and only in Caucasians. Of the nonautoimmune forms of diabetes seen in youth, only type 2 diabetes is increasing in incidence. Proper classification requires consideration of onset (acute/severe versus insidious), ethnicity, family history, presence of obesity, and if necessary, studies of diabetes related autoimmunity. Insulin resistance predicts the development of diabetes in Pima Indians, in offspring of parents with type 2 diabetes, and in other high-risk populations. African-American children and youth have greater insulin responses during glucose tolerance testing and during hyperglycemic clamp study than do whites. There is also evidence of altered beta-cell function preceding the development of hyperglycemia. Of particular interest is the evidence that abnormal fetal and infantile nutrition is associated with the development of type 2 diabetes in adulthood. The thrifty phenotype hypothesis states that poor nutrition in fetal and infant life is detrimental to the development and function of the beta-cells and insulin sensitive tissues, leading to insulin resistance under the stress of obesity. The thrifty genotype hypothesis proposes that defective insulin action in utero results in decreased fetal growth as a conservation mechanism, but at the cost of obesity-induced diabetes in later childhood or adulthood. The vast majority of type 2 diabetes in adults is polygenic and associated with obesity. Monogenic forms (MODY, maternally transmitted mitochondrial mutations) are rare, but are more likely to appear in childhood. Linkage studies of the common polygenic type 2 diabetes have emphasized the heterogeneity of the disorder. The prevention and treatment of type 2 diabetes in children and youth is a daunting challenge because of the enormous behavioral influence, difficulty in reversing obesity, and typical nonadherence in this age-group. The emerging epidemic of type 2 diabetes in the pediatric population, especially among minorities whose proportion in the U.S. population is increasing, presents a serious public health problem. The full effect of this epidemic will be felt as these children become adults and develop the long-term complications of diabetes.

Non-insulin dependent diabetes mellitus (NIDDM) in minority youth: research priorities and needs.

The prevalence of non-insulin dependent diabetes mellitus (NIDDM) is increasing in Native American and African-American youth, with females more frequently affected than males. This increase is related to increasing rates of obesity and to the greater demand for insulin at adolescence. This review examines the epidemiologic data about NIDDM in minority youth and addresses questions about the type of diabetes minority youth have, the relative contributions of environment and genetics to their diabetes, and whether prevention or control is possible. The heterogeneity of NIDDM in the minority youth population includes: typical NIDDM; atypical diabetes mellitus (ADM), which has been described in a substantial number of African-American youngsters; and a small proportion with a range of defects in the pathway of insulin action. Clinical and experimental evidence that insulin resistance or insulin deficiency is the primary defect in NIDDM are reviewed, as is evidence that fetal undernutrition may be a contributing factor. The numerous reports of linkages, associations, and mutations or polymorphisms in candidate genes account for a very small proportion of non-type 1 diabetes. Environmental and genetic contributors to obesity are also important. Research issues relating to the questions discussed include the need for data comparing various populations and assessing risk factors associated with the epidemic of NIDDM and obesity, costs to the health system and attendant personal and societal costs, clarification of the types of NIDDM in minority populations that will permit appropriate therapy and counseling, and extensive studies of environmental and genetic factors. Genetic studies include a genome wide search and continued analysis for candidate genes for both NIDDM and obesity. Environmental factors for study include the role of fetal and perinatal nutrition and drug exposure. Finally, collaborative multicenter studies are needed of prevention or control of obesity and NIDDM.

Autoimmune diabetes. The role of autoantibody markers in the prediction and prevention of insulin-dependent diabetes mellitus.

In general, reliable and reproducible ICA results are available only from research laboratories that routinely perform ICA testing. Regarding IAA testing, IAA ELISA must be avoided. There are numerous GADA procedures available that definitely have different sensitivities for GADA detection. IA-2A testing is very new and is performed in only a few research laboratories. Islet autoantibody testing should be performed only as part of research protocols. At the present time, we know much more about the prediction of IDDM than its prevention. Once safe and credible methods are available to prevent IDDM, islet autoantibody screening may become as common as childhood immunizations.

Pharmacological approaches to the prevention of autoimmune diabetes.

Insulin-dependent (type I) diabetes mellitus (IDDM) is the consequence of a chronic cell-mediated immune attack upon the insulin-producing beta-cells. Progressive insulinopenia is characteristic of individuals who eventually develop IDDM. Autoimmunity develops because of a failure in self-nonself discrimination. Autoimmunity is usually detected when autoantibodies are present in the patient's serum. However, autoantibodies are not synonymous with disease, as many autoantibody-positive individuals show no evidence of clinical disease. Studies initiated in the early 1980s demonstrated that short term remission from IDDM could be induced or lengthened with immunosuppressive therapy. However, no long term remissions were achieved. Current prevention strategies use a combination of autoantibody marker testing and beta-cell function testing to identify individuals with 'prediabetes'. The most useful autoantibodies for prediabetes screening include islet cell autoantibodies, insulin autoantibodies, glutamic acid decarboxylase autoantibodies and IA-2 autoantibodies. Immunointervention techniques have focused on protecting beta-cells from oxidative damage and developing tolerance to beta-cell autoantigens. Environmental manipulation may also be of benefit but its effectiveness is unproven. The pharmacist of the future may be involved in dispensing autoantigens, cytokines, anti-cytokine antibodies, anti-cytokine receptor antibodies, vaccines or viral vectors for gene therapy in the prevention of IDDM.

Type I insulin-dependent diabetes mellitus: a model for autoimmune polygenic disorders.

Insulin-dependent diabetes mellitus (IDD) affects between one in 250 and one in 500 Americans. The inheritance of IDD is non-Mendelian and polygenic. Genetic susceptibility predominantly results from specific alleles in the HLA complex and insulin gene region. Autoimmune destruction of pancreatic beta cells leads to profound insulinopenia (Atkinson and Maclaren, 1990). Without insulin treatment, fatal diabetic ketoacidosis results. Even with insulin treatment, after 10 to 20 years of IDD, devastating micro- and macrovascular complications lead to significant morbidity and premature mortality (Rosenbloom, 1983). In order to prevent this catastrophic disease and its consequences, we must understand the pathogenesis and immunogenetics of insulitis (the histologic lesion characteristic of IDD), whose ultimate expression is beta cell necrosis (Cudworth, 1978; Cahill and McDevitt, 1981; Eisenbarth, 1986). Current advances include recognition of new IDD-autoantigens (e.g., glutamic acid decarboxylase), susceptibility genes (e.g., HLA-DQB1*0201 and 0302), and the development of trials to prevent IDD through tolerization to IDD-autoantigens (e.g., insulin) (Maclaren, 1993; Winter et al., 1993). Unlocking the genetic mechanisms responsible for IDD can also reveal more general mechanisms involved in other organ-specific autoimmune diseases.