The role of intramyocellular lipids during hypoglycemia in patients with intensively treated type 1 diabetes

CONTEXT: Endocrine defensive mechanisms provide for energy supply during hypoglycemia. Intramyocellular lipids (IMCL) were recently shown to contribute to energy supply during exercise. OBJECTIVE: The objective of this study was to assess the contribution of IMCL compared with lipolysis and endogenous glucose production (EGP) to insulin-mediated hypoglycemia counterregulation in patients with type 1 diabetes mellitus (T1DM). DESIGN AND SETTING: This was a prospective explorative study performed in a university research facility. PARTICIPANTS: Six well-controlled T1DM (age, 29 +/- 4 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 6.3 +/- 0.1%) and six nondiabetic humans (controls; age, 28 +/- 2 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 5.1 +/- 0.1%) were studied. INTERVENTIONS: We performed 240-min hypoglycemic (approximately 3 mM)-hyperinsulinemic (0.8 mU/kg x min) clamps on separate days to measure: 1) systemic lipolysis ([2H5]glycerol turnover), EGP ([6,6-(2)H2]glucose), and local lipolysis in abdominal s.c. adipose tissue and gastrocnemius muscle (microdialysis); and 2) IMCL (by 1H nuclear magnetic resonance spectroscopy) in soleus and tibialis anterior muscle. MAIN OUTCOME MEASURES: The main outcome measures were changes in IMCL during prolonged hypoglycemia. RESULTS: At baseline, EGP, glycerol turnover, and IMCL were not different between the groups. During hypoglycemia, hormonal counterregulation was blunted in T1DM (peak: glucagon, 68 +/- 4 vs. 170 +/- 37 pg/ml; cortisol, 16 +/- 2 vs. 24 +/- 2 microg/dl; epinephrine, 274 +/- 84 vs. 597 +/- 212 pg/ml; all P < 0.05 vs. control). T1DM had approximately 50% lower EGP (4.6 +/- 0.6 vs. 10.9 +/- 0.5 micromol/kg x min; P < 0.005), but approximately 40% higher glycerol turnover (374 +/- 21 vs. 272 +/- 19 micromol/kg x min; P < 0.01). Glycerol concentrations in muscle (T1DM, 302 +/- 22 control, 346 +/- 17 micromol/liter) and adipose tissue (264 +/- 25 vs. 318 +/- 25 micromol/liter) did not differ between groups. IMCL in soleus and tibialis anterior muscle did not change from baseline during hypoglycemia. CONCLUSIONS: In well-controlled T1DM, impaired hypoglycemia counterregulation is associated with decreased glucose production and augmented whole body lipolysis, which cannot be explained by either hydrolysis of muscle triglycerides or increased abdominal s.c. adipose tissue lipolysis.     

Challenges of alloimmunization in patients with haemoglobinopathies

Red blood cell (RBC) transfusions can be life-sustaining in chronic inherited anaemias, such as thalassaemia, and the indications for blood transfusions in patients with sickle cell disease continue to expand. Complications of transfusions, such as allosensitization, can create significant medical challenges in the management of patients with haemoglobinopathies. This review summarizes key findings from the medical literature related to alloimmunization in haemoglobinopathies and examines potential measures to mitigate these risks. Areas where future studies are needed are also addressed.     

Menarcheal timing in intensively treated girls with type 1 diabetes mellitus

Background and aimPrevious studies on menarcheal age (MA) in type 1 diabetes mellitus (T1DM) have shown conflicting results about the effects of DM, but most lack a control group. The present study design is peculiar in that it covers a study population of 73 intensively treated menarcheal adolescents with premenarcheal onset of T1DM (Group A), whose MA was compared with that recorded in three control populations: the first one consisting of 280 healthy adolescents, the second one consisting of 20 T1DM adolescents with postmenarcheal DM onset (Group B) and the third one represented by the respective mothers.Methods and resultsMA of Group A patients was significantly delayed when compared with the respective mothers, healthy controls and Group B patients. By contrast MA of Group B girls was superimposable to the one of both their respective mothers and healthy controls. In Group A MA was strongly related (p < 0.0005) to HbA1c at the time of menarche and to average HbA1c concentrations during the last years before menarche. In Group A no relationship between patients' and mothers' MAs was found, whilst such a correlation was significant in Group B.Conclusions(a) MA is significantly delayed in girls with premenarcheal presentation of T1DM, even if intensively treated; (b) menarcheal retardation is more severe in the patients with suboptimal metabolic control at the time of menarche; and (c) MA in premenarcheal presenting T1DM is irrespective of maternal MA, age and HbA1c concentrations at DM presentation, body mass index and daily insulin dose at menarche.     

Suppression of natural killer activity in patients treated with cisplatin and methylprednisolone

Summary The achievable concentrations of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl-3-nitrosourea (ACNU), adriamycin, mitomycin C, vindesine, and epipodophyllotoxin suppressed the natural killer (NK) activity of human peripheral blood lymphocytes in vitro, whereas NK activity was not decreased 24h after incubation with the maximum achievable concentration of cisplatin (cDDP). NK activity of patients treated with 80 mg per square meter of cDDP alone was not decreased for 3 weeks after cDDP administration. In contrast, NK activity of patients treated with the same dose of cDDP and methylprednisolone was significantly decreased 1 week after cDDP administration. It was concluded that methylprednisolone, used as an antiemetic agent, had an immunosuppressive effect.     

Does metformin decrease blood pressure in patients with Type 2 diabetes intensively treated with insulin?

AIMS: We investigated in a double-blind study whether metformin reduces blood pressure (BP) in patients with Type 2 diabetes intensively treated with insulin. METHODS: A total of 220 patients with Type 2 diabetes were asked to undergo 24-h ambulatory BP monitoring (24-h ABPM). One hundred and eighty-two gave informed consent. Eighty-nine were randomized to metformin and 93 to placebo. Thirty-five subjects dropped out (13 placebo, 22 metformin users); 147 patients underwent a second 24-h ABPM, 16 weeks after randomization. RESULTS: Systolic BP (SBP), diastolic BP (DBP), pulse BP (PP), mean BP (MP) and heart rate (HR) were measured as office BP measurements and as 24-h ABPM for 24-h, day and night. Office BP measurements did not differ significantly between the placebo- and metformin-treated groups for any BP measure, but showed a non-significant trend for SBP reduction with metformin use (mean baseline-adjusted difference, metformin minus placebo: -4.2 mmHg, 95% CI, -9.9 to +1.5; P = 0.15). The baseline-adjusted differences of the ambulatory measurements were -0.2 mmHg (95% CI, -2.9 to +2.6) for the 24-h SBP, and +1.1 mmHg (95% CI, -0.7 to +2.8) for the 24-h DBP. On the whole, BP differences between metformin- and placebo-treated groups were not statistically significant. The only significant difference was for night-time PP (baseline-adjusted difference: -2.2 mmHg; 95% CI, -4.2 to -0.2). These results were not different after adjustment for age and diabetes duration, or for (changes in) body mass index, glycated haemoglobin, insulin dose or plasma homocysteine. CONCLUSION: Metformin does not significantly affect BP in patients with Type 2 diabetes intensively treated with insulin.     

Value of immunophenotype in intensively treated adult acute lymphoblastic leukemia: cancer and leukemia Group B study 8364.

The prognostic value of immunophenotype in adult acute lymphoblastic leukemia (ALL) has varied based on the methods used, surface markers studied, and therapy administered. From April 1991 to September 1996, samples of leukemic marrow or blood from 259 eligible and evaluable adult ALL patients entering dose-intensive Cancer and Leukemia Group B (CALGB) front-line treatment protocols were prospectively studied for immunophenotypic classification by multiparameter flow cytometry (MFC) in a central laboratory. A B-lineage (B-LIN) phenotype was expressed in 79% of cases, with one third coexpressing myeloid antigens. A T-lineage (T-LIN) phenotype was expressed in 17% of cases, with one quarter coexpressing myeloid antigens. Since the advent of more intensive CALGB therapy which incorporated cyclophosphamide and the early use of L-asparaginase into the backbone of daunorubicin, vincristine and prednisone, together with central nervous system prophylaxis for adult ALL, no significant differences in response rates, remission duration, or survival have been seen in those patients coexpressing myeloid antigens. The T-LIN phenotype was associated with younger age (P =.01), a higher male to female ratio (P =.01), higher white blood cell count (P =.001) and hemoglobin (P <.001) levels, presence of a mediastinal mass (P <. 001), and longer survival (P =.01) and disease-free survival (DFS) (P =.01) when compared to patients with a B-LIN phenotype. The 3-year probability of survival and DFS (95% confidence interval [CI]) of T-LIN adult ALL was 0.62 (0.46 to 0.76) and 0.62 (0.44 to 0. 77), respectively. Comparatively, the 3-year probability of survival and DFS (95% CI) of B-LIN adult ALL was 0.42 (0.35 to 0.50) and 0.39 (0.31 to 0.47), respectively. The number of T markers expressed in T-LIN ALL cases was shown to have prognostic significance. In particular, patients expressing six or more markers compared with patients expressing three or fewer markers had longer DFS (P =.003) and survival (P =.004). The presence of the Philadelphia chromosome was significantly associated with B-LIN ALL cases which coexpressed CD19(+), CD34(+), and CD10(+) (49%; P =.003), whereas the majority of t(4;11) cases were CD19(+), CD34(+) but CD10(-). The knowledge gained from this study of MFC of a large number of patients will permit a reduction in the number of antigens to be evaluated in future studies. Overall, this should lead to cost savings without loss of valuable information. A rational approach for future studies would be to use four-color flow cytometry (instead of the current three-color) to help further streamline the study of immunophenotype of adult ALL by MFC.     

RBC alloimmunization and double alloantibodies in thalassemic patients

Abstract

Purpose

Alloimmunization is a common consequence of chronic blood transfusion. Double alloantibody production may complicate the condition of such patients especially for finding matched blood. In this study, we evaluated the frequency of alloantibodies in thalassemic patients with previous history of transfusion reactions.

Samples and methods

This study was performed on 441 multiply transfused thalassemia patients Antibody screening test was carried out using three cell-panel by gel method. Positive patients were followed up for antibody identification using 11-cell panel. Direct combs’ test was performed to detect auto antibodies.

Results

In a total of 441 cases (362 thalassemia major and 79 intermedia), 234 were males (53.1%) and 207 females (46.9%); mean age 22 years, range 3-61 years. Alloimmunization was detected in 50(11.3%) patients, including 37(74%) patients with one alloantibody, 8(16%) with two antibodies, 4(8%) patients with unknown antibodies and one patient (2%) with autoantibody. The most common alloantibodies were anti-Rh antibodies (-E/e/C/c/Cw) (26%), anti-K (28%), anti-D (16%), and anti-Colton (4%). Double antibodies were detected in eight out of 50 patients, including: Anti-D+anti-C (8%), anti-D+anti-E (2%), anti-Kell+anti-D (2%), and anti-Kell+KPa (2%). A significant association was observed between the transfusion reaction history and the alloantibody detection results (p < 0.05).

Conclusion

Antibody production against RBC antigens makes hard condition in regular blood transfusion. Double antibodies production may more complicate this situation. Thus, it is advisable to phenotype patients and matches the red cells in multiply transfused thalassemia patients.     

Programming pre-exercise snacks to prevent post-exercise hypoglycemia in intensively treated insulin-dependent diabetics

Five intensively treated, insulin-dependent diabetics exercised for 45 minutes after fasting while receiving basal insulin injections. Plasma glucose concentrations remained stable during exercise but then declined, resulting in clinical hypoglycemia 1 to 2 hours later. Efficacies of three pre-exercise snacks in preventing the hypoglycemia were compared in a randomized crossover design. Orange juice, whole milk, and skim milk, each containing 13 g of carbohydrate, all prevented postexercise hypoglycemia. However, the more rapidly absorbed snacks, orange juice and skim milk, caused a greater increase in plasma glucose concentrations and the area under the glucose curve during exercise. From the recognized glucose profiles that occur after consumption of different carbohydrates, snacks as well as exercise and insulin can now be programmed for intensively treated, insulin-dependent diabetics. Because plasma glucose levels remain stable during exercise done after fasting and only fall late after exercise, a "lente" carbohydrate snack, such as whole milk, is an appropriate pre-exercise snack.     

Risk assessment and treatment benefit in intensively treated hypertensive patients of the hypertension Optimal Treatment (HOT) study

BACKGROUND: The Hypertension Optimal Treatment (HOT) Study provided information about cardiovascular events in 18,790 hypertensives, subjected to pronounced blood pressure lowering for a mean of 3.8 years. METHODS AND RESULTS: The HOT Study data have been further analysed after risk stratification of the patients (1999 World Health Organization and International Society of Hypertension guidelines criteria): (i) no patients of the HOT Study were classified as low risk, 50% were classified as medium risk, 20.2% as high risk and 29.8% as very high risk; (ii) incidence of cardiovascular events in these patients with excellent blood pressure control [92% had diastolic blood pressure (DBP) < or = 90 mmHg] remained proportional to pretreatment risk. The relative risk of very high- versus medium-risk strata was between two and three both when HOT Study patients were considered independently of, or within the DBP target group they had been randomized to; and (iii) event rates in all risk strata were calculated to be much lower (possibly 60% lower) than rates expected from baseline risk calculated approximately by the Framingham equation. CONCLUSIONS: The low event rate in HOT Study patients is likely to result from pronounced blood pressure lowering, and is not explained by a lower risk profile than in previous controlled trials of antihypertensive treatment. The persistence of a risk gradient despite intensive blood pressure lowering suggests a combination of blood pressure control with other strategies of risk correction and the need to initiate antihypertensive therapy before complications develop.     

Post-transfusion alloimmunization in patients with sickle cell disease.

The transfusion histories over a 33-month period of 50 patients with sickle cell disease were reviewed to determine the frequency of alloimmunization to red cell antigens following transfusion in these patients. There were 30 females and 20 males, aged 19--49 years. Eighteen (36%) were immunized of which thirteen were females. Five of the patients have formed only one antibody so far, while the other 13 have formed two or more. Thirty-six antibodies were identified: 16 against various Rh antigens, 12 anti-Lewis, 5 anti-Kell and one each of anti-Jka, -Fya and -M. The immunized patients received, on the average, more transfusions although there was a considerable degree of overlap between the immunized and nonimmunized groups. An approach to the hemotherapy of patients with sickle cell disease (SCD) is discussed.     

Suppression of clonal evolution in two chronic myelogenous leukaemia patients treated with leucocyte interferon

Two patients with Philadelphia chromosome-positive (Ph1+) chronic myelogenous leukaemia (CML) were treated with human leucocyte interferon (HuIFN-alpha). Karyotypic changes in addition to the Ph1 chromosome developed in these patients before the start of HuIFN-alpha treatment. In one patient the administration of HuIFN-alpha resulted in clinical haematological remission and stable suppression of the secondary Ph1 clone. The second patient was in myeloid blastic crisis when given HuIFN-alpha. While she was receiving HuIFN-alpha, suppression of the blast cell population in the bone marrow occurred. The subsequent cytogenetic changes included a near-complete suppression of a secondary Ph 1 clone of cells carrying a deletion in the short arm of chromosome 7 and partial population of the bone marrow with primary Ph1 clone. These observations suggest a potential role for interferons in altering the progressive course of CML.     

Impaired stimulation of gluconeogenesis during prolonged hypoglycemia in intensively treated insulin-dependent diabetic subjects.

Defective glucose counterregulation commonly seen in intensively treated insulin-dependent diabetes (IDDM) is mediated in part by a failure of compensatory stimulation of hepatic glucose production. Since the response of the liver to insulin-induced hypoglycemia normally involves activation of gluconeogenesis, we measured [14C]alanine conversion to [14C]glucose (a qualitative index of gluconeogenesis) and glucose production (using [3-3H]glucose) in seven intensively treated type I diabetic subjects (hemoglobin-A1, 7.1 +/- 0.4%) during low dose infusion of insulin (0.3 mU/kg.min for 210 min). IDDM patients received insulin overnight to maintain euglycemia before study. Although insulin levels rose to a similar extent as those in normal control subjects (n = 6), the fall in plasma glucose was markedly greater in IDDM (2.5 +/- 0.2 vs. 3.64 +/- 0.2 mM in controls; P < 0.01). The glucagon response was totally lost in IDDM, and epinephrine release was delayed and slightly reduced compared to that in control subjects. In contrast to that in normal subjects, hepatic glucose production in the IDDM subjects remained persistently suppressed by about 60% throughout the study. The conversion of alanine and lactate to glucose remained virtually unchanged in the IDDM, whereas in controls it increased 2-fold above baseline during the last hour of the study. Our data suggest that the failure of gluconeogenesis to increase during hypoglycemia is an important factor contributing to the defective hepatic response observed in the intensively treated type I diabetic subjects.     

Red cell alloimmunization in multitransfused patients and multiparous women

Purpose  To determine the incidence of alloimmunization against red cell antigens and the thermal amplitude and specificity of antibodies in multitransfused patients and multiparous women. Methods  Antibody screening was performed in 30 nontransfused orthopedic surgery cases (control), 504 multitransfused patients and 325 multiparous women. Antibody screening at 4°C, 22°C and 37°C was carried out in a saline phase, by indirect antiglobulin technique (IAT), using papain cystein, low ionic strength solution (LISS) and polyethylene glycol (PEG). Results  In multitransfused patients IgM antibodies were more frequently detected at 4°C and the IgG antibody incidence was 7.1% by enzyme method, 7.7% IAT, 9.4% LISS, 10.2% using PEG & 10.2% multiparous women. Bad obstetric history cases had significantly higher incidence of alloimmunization. The antibody specificity of antibodies was mainly in Lewis, Rh, Kidd and MN systems. Conclusion  Antibody screening before transfusion, at set time intervals after transfusion and during antenatal period is recommended.     

Red blood cell alloimmunization in transfused patients on AZT

Significant numbers of patients receiving azidothymidine (AZT) develop anaemia requiring an adjustment of AZT dosage. Fear of red blood cell (RBC) alloimmunization may act as a deterrent to exposing a patient to long-term transfusion therapy which is the alternative to AZT dosage reduction or discontinuation. This retrospective study was done to assess the incidence of RBC alloimmunization in transfused patients on AZT. Records of 72 patients receiving long-term AZT were analysed to assess the incidence of alloimmunization. Other study parameters included duration of transfusion therapy, total number of pRBC units transfused/patient, alloantibody specificity, rates of autoantibody detection and their specificity. For comparison, a parallel analysis was carried out on 188 male patients transfused during the same period of time for chronic renal failure (CRF). Only one of 72 AZT patients (1.4%) developed an alloantibody compared with seven of the 118 CRF patients (5.9%) (P = NS). The incidence of autoantibodies and positive direct antiglobulin testing in the AZT and CRF populations was found to be similar (9.7% v. 7.6% respectively; P = NS). The two populations were similar with respect to mean number of pRBC units transfused (AZT: 10.5 v. CRF: 11.5 units; P = NS); however, there was a significant difference in the mean duration of transfusion therapy (AZT: 4.5 months v. CRF 19.4 months; P less than 0.001). We conclude there is an insignificant incidence of alloimmunization in the multiply-transfused AZT population. Furthermore, in this study the incidence of RBC autoantibodies in AZT patients appears to be low and no different from that of patients with chronic renal failure.     

HLA alloimmunization in patients receiving multitransfusions of red blood cells

HLA antibodies were studied in 88 patients with chronic hemolytic anemia who received multitransfusions of red blood cells prepared by conventional (PRC-C), inverted centrifugation (LR-I) and leukocyte filter (LR-F) techniques. Their mean age was 8 years and 4 months with a duration of transfusion of 8 years. The patients were divided into five groups: group 1, receiving PRC-C (n=20); group 2, receiving LR-I (n=33); group 3, receiving LR-F (n=11); group 4, subsequently receiving LR-I and LR-F (n=10); and group 5, receiving PRC-C followed by LR-I and LR-F (n=14). The HLA class I antibodies were found in 30 out of 88 patients (34%). All were against HLA antigens commonly found in the Thai population. The patients receiving PRC-C exhibited HLA antibodies of 65%, which was significantly higher than those of patients receiving LR-I (24%) and LR-F (0%). Consequently, the transfusion reactions of fever, chill, rash and urticaria were also commonly found in patients receiving PRC-C (13.4%), which was significantly higher than patients receiving LR-I (0.4%) and LR-F (0%). The leukocyte filter technique has been shown to be effective in preventing HLA alloimmunization and transfusion reactions but the price is rather high. For the inverted centrifugation technique, only transfusion reactions were effectively prevented and the HLA alloimmunization continued to develop. A more effective and low-cost method for the removal of leukocytes should be investigated for these multitransfusion patients.     

Quality of life in cancer patients treated by chemotherapy

Many studies connected with different aspects of the quality of life (QL) have been increasingly reported. In this study we have been used FACT questionnaire to estimate QL in three groups of cancer patients receiving chemotherapy. Questionnaires were completed by 177 patients. Adverse effects of treatment severely influence the cancer patients QL. The most significant worsening of QL was noticed in the group of lung cancer patients receiving the most emetogenic chemotherapy(i.e. cis-platinum, vepesid). In other two groups (gastric and colorectal cancer patients) side effects of chemotherapy caused relatively less QL deterioration. This finding implicates possibility of intensifying the course of treatment (dosage and duration) assuming there is no hematopoetic insufficiency.     

RBC alloimmunization in blood transfusion-dependent beta-thalassemia patients in southern Iran

beta-thalassemia is considered a severe, progressive anemia, which needs regular transfusions for life expectancy. One of the most important complications of regular blood transfusions may be alloimmunization, which increases the need for transfusion. This study was performed to investigate the production of red cell alloantibodies in beta-thalassemia patients in Shiraz, southern Iran. Blood sampling was performed among 711 beta-thalassemia patients in Dastgheib hospital in 2002-2004. Direct and indirect coombs tests were performed to check the auto and alloantibodies and a panel test was conducted to detect the type of alloantibodies. Auto and alloantibodies were observed among 1.7% and 5.3% of patients, respectively. The most common alloantibodies were Anti-kell (50%) > Anti-Rh (D) (15.8%) > Anti-Rh (E) (10.5%). All the patients who had developed alloantibody were in the age group of 6 years or more. So for decreasing the rate of alloantibody synthesis, we should crossmatched the packed cells for minor blood groups especially for kell and Rh(E) in addition to major blood groups from the start of transfusion.