Fuel utilization in subjects with carnitine palmitoyltransferase 2 gene mutations

Patients with the myopathic form of carnitine palmitoyltransferase II (CPT II) deficiency typically experience muscle pain, cramps, and myoglobinuria during prolonged exercise. It has been suggested that carriers of CPT2 gene mutations also may have milder clinical symptoms, but fatty acid oxidation (FAO) has never been investigated in vivo in this group. We studied fuel utilization by indirect calorimetry and stable isotope methodology in four patients with CPT II deficiency, three subjects who carried one CPT2 gene mutation, and five healthy control subjects. Cycle exercise at a constant workload of 50% of maximal oxygen uptake capacity was used to facilitate FAO. We found that in vivo oxidation of long-chain fatty acids was normal at rest but severely impaired during prolonged, low-intensity exercise in patients with CPT II deficiency, and that two of the single CPT2 gene mutation carriers, who displayed symptoms of CPT II deficiency, had an FAO comparable with the patients. These results indicate that residual CPT II activity is sufficient to maintain long-chain FAO at rest in CPT II deficiency but not to increase FAO during exercise. The findings also suggest that single CPT2 gene mutations may exert a dominant-negative effect on the tetrameric CPT II protein.     

Venlafaxine and asthma

A 54-year-old man of Asian origin with major depression developed an asthma-like reaction during venlafaxine treatment. Two weeks after therapy was initiated, he experienced gradually worsening dry cough at night and periodically dyspnea during the daytime. After 5 weeks, clinical examination revealed marked signs of pulmonary obstruction and the forced expiratory volume (FEV1) was assessed to only 32% of the expected value. The venlafaxine medication was gradually decreased and eventually discontinued 9 weeks after its initiation, resulting in a successive improvement of the patient's respiratory complaints.     

Do panic symptoms during periods of remission predict relapse of panic disorder?

This study investigated the relationship between panic symptoms during remission and subsequent relapse of panic disorder. Research subjects were 169 individuals, enrolled in the Harvard/Brown Anxiety Research Project, who were in episodes of panic disorder at intake and remitted during the 8-year follow-up period. Panic symptoms during remission were examined as predictors of panic disorder relapse. For the relapses that did occur, we report the level of symptomatology during the previous 4 weeks. Depending on symptom severity and whether or not the relapse included agoraphobia, panic symptoms during remission were associated with an approximate two- to threefold increased risk of relapse. However, on examination of symptoms during the 4 weeks before relapse, we found that the majority of relapses were preceded by no panic symptoms. Thus, although panic symptoms during remission may indicate an increased risk of subsequent relapse, the absence of symptoms during remission does not indicate that relapse is unlikely.     

Exercise tolerance in carnitine palmitoyltransferase II deficiency with IV and oral glucose

BACKGROUND: Patients with carnitine palmitoyltransferase II (CPT II) deficiency often experience muscle pain and myoglobinuria during prolonged exercise because of impaired oxidation of long-chain fatty acids. OBJECTIVE: To investigate whether IV or oral glucose can improve exercise tolerance in CPT II deficiency. METHODS: Five patients with CPT II deficiency and healthy matched volunteers were investigated on a cycle ergometer at a constant workload of 60% of VO(2max). Perceived exertion, heart rate, and venous plasma glucose and insulin levels were monitored. The study was randomized, placebo controlled, single blind, and crossover. Glucose and placebo were administered both orally and IV in patients and IV in healthy subjects. RESULTS: In patients with CPT II, exercise duration was prolonged by 28 +/- 8% (p = 0.02), and perceived exertion (p = 0.05) and heart rate (p = 0.09) were lowered by glucose infusion. In contrast, IV glucose resulted in higher heart rate during exercise in healthy subjects. Oral glucose and placebo resulted in the same exercise duration, perceived exertion, and heart rate in patients. Plasma glucose and insulin were consistently elevated during exercise by oral and IV glucose vs placebo, but plasma glucose was higher and insulin lower in IV vs oral glucose studies in patients (p = 0.02). CONCLUSION: Exercise tolerance is markedly improved by a glucose infusion in patients with CPT II deficiency, but because of lower glucose availability and higher insulin levels that inhibit muscle glycogenolysis, the patients cannot achieve this effect themselves by oral glucose ingestion.     

Functional evaluation of proliferative T cell responses in patients with severe T lymphopenia: characterization of optimal culture conditions and standardized activation signals for a simple whole blood assay

In this methodological study, we describe an assay for analysis of proliferative T cell responses in patients with severe leukopenia. Severe treatment-induced cytopenia is observed in patients with malignant disorders who receive conventional intensive chemotherapy or autologous stem cell transplantation. The quantitative T cell defect can then be characterized by flow cytometric analysis of membrane molecule expression, whereas the functional status of the remaining T cell population is more difficult to evaluate. In the present study, we describe a standardized whole blood assay that requires small sample volumes and can be used for repeated analysis even in severely ill patients. The assay is based on the following strategy: (i) blood samples are diluted with the serum-free medium X-vivo 10, (ii) T cells are activated either with monoclonal immunoglobulin E (IgE) anti-CD3 or anti-CD3 plus anti-CD28; (iii) T cell proliferation is assayed by [(3)H]thymidine incorporation after 4 days of in vitro culture. These proliferative responses are not affected by the plasma levels of interleukin-2 (IL-2), sIL-2-R alpha, IL-7 and IL-15, and the kinetics of the response are not altered by the presence of exogenous cytokines. Detectable proliferation is observed for most patients with treatment-induced cytopenia. We conclude that the assay can be used for functional characterization of remaining T lymphocytes in patients with severe T lymphopenia.     

A case study of shifting a patient with percutaneous endoscopic gastrostomy (PEG) to home care

We studied the primary factor preventing a patient with PEG from being transferred to home care focusing on the dietetic situation. The study has revealed differences in not the age of the patient, the days of hospitalization or hematological and biochemical test data but in the condition of use of home care services or family makeup. In other words, insufficient use of social resources is considered to prevent shifting to home care or continuation of home care of patients with PEG. It is necessary to understand not only dietetic situation but social backgrounds of patients and supply information.     

Pharmacokinetic and Pharmacodynamic Properties of Insulin Aspart and Human Insulin

The preferred approach to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of insulin analogues is the euglycemic glucose clamp. Currently, non-compartmental data analytical approaches are used to analyze data. The purpose of the present study is to propose a novel compartmental-model for analysis of data from glucose clamp studies. Data used in this trial only involved 18 of the 20 originally treated subjects. Data was obtained from a crossover trial where 18 healthy subjects each received a single subcutaneous (sc) dose of 1.2 nmol/kg (body weight) insulin aspart (IAsp) or 1.2 nmol/kg human insulin (HI) during a euglycemic glucose clamp after overnight fast. Serum insulin and glucose concentrations were measured and the glucose infusion rate (GIR) was adjusted after dosing, to maintain blood glucose near basal levels. Individual model parameters were estimated for IAsp, HI, and the corresponding glucose and GIR data. We found statistically significant differences between most of the HI and IAsp pharmacokinetic parameters, including the sigmoidicity of the time course of absorption (1.5 for HI vs. 2.1 for IAsp (unit less), P=0.0005, Wilcoxon Signed-rank test), elimination rate constant (0.010 min^–1 for HI vs. 0.016 min^–1 for IAsp (P=0.002)). The PD model parameters were mostly not different, except for the rate of insulin action (0.012 min^–1 for HI vs. 0.017 min^–1 for IAsp (P=0.03)). The model may provide a framework to account for different PK properties when estimating the PD properties of insulin and insulin analogues in glucose clamp experiments.     

Children,family and cancer survival in Norway

Models for all-cause mortality among 45,000 men and women with cancer in 12 different sites were estimated, using register and census data for complete Norwegian birth cohorts. This observed-survival method appeared to be an adequate approach. The results support the idea that women who were pregnant shortly before a breast cancer diagnosis may have a poorer prognosis than others. In principle, such an effect may also reflect that these women have a young child during the follow-up period and are burdened by that. However, this social explanation can hardly be very important, given the absence of a corresponding significant effect in men and for other cancer sites in women. Breast cancer is different from other malignancies also with respect to the effect of parenthood more generally, regardless of the timing of the pregnancies. On the whole, male and female cancer patients with children experience lower mortality than the childless, though without a special advantage associated with adult children. This suggests a social effect, perhaps operating through a link between parenthood, lifestyle and general health. No parity effect was seen for breast cancer, however, which may signal that the social effect is set off against an adverse physiologic effect of motherhood for this particular cancer. Among men, both marriage and parenthood were associated with a good prognosis. Married male cancer patients with children had mortality one-third lower than that among the childless and never-married. Women who had never married did not have the same disadvantage.