Leukocyte Depletion by Therapeutic Leukocytapheresis in Patients with Leukemia

Hyperleukocytosis is a complication of various leukemias and can result in life-threatening leukostasis. Critical white blood cell (WBC) counts are conventionally defined as higher than 100 × 10⁹/l in acute myeloid leukemia and > 300 × 10⁹/l in acute lymphatic leukemia and other leukemic disorders (e. g. chronic myeloid leukemia). Leukocytapheresis is a therapeutic tool to reduce leukocyte counts in patients with symptomatic or threatening leukostasis until induction chemotherapy works. In patients with temporary contraindications against cytotoxic drugs, e.g. during pregnancy, leukocytapheresis can be used as a bridging therapy until conventional chemotherapy can be started. Therapeutic leukocytapheresis should be performed in specialized centers by experienced, well-trained staff. Thorough monitoring of the patients is extremely relevant. During a single procedure, WBC count can be reduced by 10–70%. Treatment should be repeated daily and can be discontinued when the symptoms of leukostasis have been resolved and/or leukocyte counts have fallen below the critical thresholds. There are no prospective studies evaluating the clinical efficacy of therapeutic leukocytapheresis in patients with hyperleukocytosis. It can be concluded from retrospective studies that leukocytapheresis might have some beneficial effect in early morbidity and mortality of patients with newly diagnosed AML but has no influence on overall long-term survival. Induction chemotherapy is the most important treatment in these patients and must never be postponed.     

Structural connectivity allows for multi-threading during rest: the structure of the cortex leads to efficient alternation between resting state exploratory behavior and default mode processing

Despite the absence of stimulation or task conditions the cortex exhibits highly structured spatio-temporal activity patterns. These patterns are known as resting state networks (RSNs) and emerge as low-frequency fluctuations (<0.1 Hz) observed in the fMRI signal of human subjects during rest. We are interested in the relationship between structural connectivity of the cortex and the fluctuations exhibited during resting conditions. We are especially interested in the effect of degree of connectivity on resting state dynamics as the default mode network (DMN) is highly connected. We find in experimental resting fMRI data that the DMN is the functional network that is most frequently active and for the longest time. In large-scale computational simulations of the cortex based on the corresponding underlying DTI/DSI based neuroanatomical connectivity matrix, we additionally find a strong correlation between the mean degree of functional networks and the proportion of time they are active. By artificially modifying different types of neuroanatomical connectivity matrices in the model, we were able to demonstrate that only models based on structural connectivity containing hubs give rise to this relationship. We conclude that, during rest, the cortex alternates efficiently between explorations of its externally oriented functional repertoire and internally oriented processing as a consequence of the DMN's high degree of connectivity.     

What is the relationship between the Glasgow coma scale and airway protective reflexes in the Chinese population?

Aim

To describe the relationship of gag and cough reflexes to Glasgow coma score (GCS) in Chinese adults requiring critical care.

Method

Prospective observational study of adult patients requiring treatment in the trauma or resuscitation rooms of the Emergency Department, Prince of Wales Hospital, Hong Kong. A long cotton bud to stimulate the posterior pharyngeal wall (gag reflex) and a soft tracheal suction catheter were introduced through the mouth to stimulate the laryngopharynx and elicit the cough reflex. Reflexes were classified as normal, attenuated or absent.

Results

A total of 208 patients were recruited. Reduced gag and cough reflexes were found to be significantly related to reduced GCS (p = 0.014 and 0.002, respectively). Of 33 patients with a GCS ≤ 8, 12 (36.4%) had normal gag reflexes and 8 (24.2%) had normal cough reflexes. 23/62 (37.1%) patients with a GCS of 9-14 had absent gag reflexes, and 27 (43.5%) had absent cough reflexes. In patients with a normal GCS, 22.1% (25/113) had absent gag reflexes and 25.7% (29) had absent cough reflexes.

Conclusions

Our study has shown that in a Chinese population with a wide range of critical illness (but little trauma or intoxication), reduced GCS is significantly related to gag and cough reflexes. However, a considerable proportion of patients with a GCS ≤ 8 have intact airway reflexes and may be capable of maintaining their own airway, whilst many patients with a GCS > 8 have impaired airway reflexes and may be at risk of aspiration. This has important implications for airway management decisions.     

13-year follow-up of the German angioplasty bypass surgery investigation.

AIMS: The German Angioplasty Bypass Surgery Investigation was designed to compare symptomatic efficacy and safety of percutaneous coronary balloon angioplasty (PTCA) with coronary artery bypass surgery (CABG) in patients with symptomatic multi-vessel disease. This follow-up study was performed to determine the long-term outcome of patients following these interventions. METHODS AND RESULTS: From 1986 to 1991, 359 patients with angina CCS class II-IV, age below 75 years, and coronary multi-vessel disease requiring revascularization of at least two major coronary vessels were recruited at eight German centres and randomized to PTCA or CABG. From 337 patients undergoing the planned procedure, 324 patients could be followed-up (96%). Baseline parameters were identical in both groups, 2.2+/-0.6 vessels were treated in CABG patients, whereas 1.9+/-0.5 vessels were treated in PTCA patients. Thirty-seven per cent of surgical patients received internal mammary artery grafts, while no stents were used in patients undergoing PTCA. At the end of the 13-year follow-up period, the degree of angina, the degree of dyspnea, and the utilization of nitrates were comparable in both groups. With a total number of 76 deaths, Kaplan-Meier analysis revealed a comparable distribution in both groups. Although time to first re-intervention was significantly shorter in the PTCA group, P<0.001, frequencies of re-intervention (CABG, n=94; PTCA, n=136) and crossover rates (CABG to PTCA, n=49; PTCA to CABG, n=51) were comparable in both groups. CONCLUSION: The results of our 13-year follow-up suggest that in patients with symptomatic multi-vessel disease, both PTCA and CABG are associated with a comparable long-term survival and symptomatic efficacy. How far these results may be altered by developments such as drug-eluting stents or off-pump surgery remains to be determined.     

A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation

Light stimuli produce graded hyperpolarizations of the photoreceptor plasma membrane and an associated decrease in a voltagegated calcium channel conductance that mediates release of glutamate neurotransmitter. The Ca(v)1.4 channel is thought to be involved in this process. The CACNA1F gene encodes the poreforming subunit of the Ca(v)1.4 channel and various mutations in CACNA1F cause X-linked incomplete congenital stationary night blindness (CSNB2). The molecular mechanism of the pathology underlying the CSNB2 phenotype remains to be established. Recent clinical investigations of a New Zealand family found a severe visual disorder that has some clinical similarities to, but is clearly distinct from, CSNB2. Here, we report investigations into the molecular mechanism of the pathology of this condition. Molecular genetic analyses identified a previously undescribed nucleotide substitution in CACNA1F that is predicted to encode an isoleucine to threonine substitution at CACNA1F residue 745. The I745T CACNA1F allele produced a remarkable approximately -30-mV shift in the voltage dependence of Ca(v)1.4 channel activation and significantly slower inactivation kinetics in an expression system. These findings imply that substitution of this wild-type residue in transmembrane segment IIS6 may have decreased the energy required to open the channel. Collectively, these findings suggest that a gain-of-function mechanism involving increased Ca(v)1.4 channel activity is likely to cause the unusual phenotype.     

Clinical and psychological correlates of quality-of-life in polycystic ovary syndrome

OBJECTIVE: Polycystic ovary syndrome (PCOS) has been shown to cause a reduction in quality of life. This study examines the extent of different PCOS symptoms on quality-of-life, psychosocial well-being and sexual satisfaction. METHODS: Complete metabolic, hormonal, clinical and psychosocial data were obtained from a total of 120 women with PCOS. Patients were compared with 50 healthy women to establish reductions in quality-of-life and emotional well-being. In addition, the correlation between psychosocial variables and the major clinical PCOS features obesity (body mass index (BMI)), excessive body hair (hirsutism score), acne, hyperandrogenism (serum testosterone levels), disturbed insulin regulation (area under the insulin response curve and homeostasis model assessment of insulin resistance), menstrual cycle disturbances and infertility were analyzed. RESULTS: PCOS patients showed significant reductions in quality-of-life, increased psychological disturbances, and decreased sexual satisfaction when compared with healthy controls. BMI and hirsutism scores, but not the presence of acne, were associated with physical aspects of quality-of-life and sexual satisfaction. No clear effect of androgens or insulin resistance on psychosocial variables was detected. Similarly, the type of menstrual cycle disturbances or infertility had no impact on psychological well-being. CONCLUSION: In PCOS, changes in appearance, particularly obesity and hirsutism, reduce physical dimensions of quality-of-life and decrease sexual satisfaction. The role of biochemical, endocrine and metabolic parameters as well as menstrual irregularities and infertility appeared to be less important. Clinicians should pay attention to the psychosocial dimensions of PCOS on an individual basis, regardless of symptom severity or treatment response.     

Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia

Valproic acid (VPA) inhibits histone deacetylase activity and induces differentiation of acute myeloid leukemia (AML) blasts in vitro. We observed clinical responses to VPA in patients with myelodysplastic syndrome (MDS) and AML. Here, we report follow-up data on 75 patients. Of these, 66 were started on VPA monotherapy, with later addition of all-trans retinoic acid (ATRA) in patients who did not respond or relapsed. Nine patients were treated with VPA + ATRA from the start. Median treatment duration was 4 months for VPA and 2 months for ATRA. Hematological improvement, according to international working group criteria for MDS, was observed in 18 patients (24%). Median response duration was 4 months. ATRA exerted no additional effect in patients receiving the combination from the start or benefited primary VPA nonresponders. However, of ten VPA responders who relapsed, four achieved a second response after addition of ATRA. Response rates were strongly dependent on disease type according to WHO classification. We found a response rate of 52% in MDS patients with a normal blast count (refractory sideroblastic anemia, refractory cytopenia with multilineage dysplasia, and refractory sideroblastic cytopenia with multilineage dysplasia). The response rate was 6% in refractory anemia with excess blasts (I + II), 16% in AML, and 0% in chronic myelomonocytic leukemia. Bone marrow blast count was the only variable that predicted responses. We conclude that VPA is clinically useful in low-risk MDS. For patients with high-risk MDS, VPA may be combined with chemotherapy or demethylating drugs. If patients relapse after an initial response to VPA, ATRA has the potential to induce a prolonged second response.     

Connexin 43 in ischemic pre- and postconditioning

Connexin 43 (Cx43) is the predominant protein forming gap junctions and non-junctional hemichannels in ventricular myocardium, but Cx43 is also localized at the inner membrane of cardiomyocyte mitochondria. In cardiomyocytes, Cx43 is involved in the formation of reactive oxygen species, which are central to the signal transduction cascade of ischemic preconditioning’s protection. Accordingly, genetically-induced or age-related loss of Cx43 abolishes infarct size reduction by ischemic preconditioning. Similarly, mitochondrial import inhibition of Cx43 completely blocks infarct size reduction by pharmacological preconditioning with diazoxide. In contrast to its importance for preconditioning-induced cardioprotection, Cx43 is not important for infarct size reduction by ischemic postconditioning. In summary, Cx43––especially Cx43 localized in mitochondria––appears to be one key element of the signal transduction cascade of the protection by preconditioning. The authors’ studies were supported by the German Research Foundation (Schu843/7-1).     

Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA

Hyperhomocysteinemia is associated with an enhanced risk for cardiovascular disease. Patients with peripheral arterial disease (PAD) show an increased prevalence of hyperhomocysteinemia. A decreased biological activity of nitric oxide (NO) may contribute to homocysteine-associated endothelial dysfunction. This study was designed to investigate whether elevated levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) are involved in endothelial dysfunction in patients with chronic hyperhomocysteinemia and PAD. A total of 76 patients (58 males and 18 females; mean age 65.2 +/- 2.0 years) with PAD were included in the analysis and characterized according to demographic variables and cardiovascular risk factors. Flow-dependent vasodilation (FDD) was determined by high-resolution ultrasound in the radial artery. Total plasma homocysteine (plasma tHcy) and ADMA levels were measured by HPLC. Urinary nitrate was quantified using gas chromatography-mass spectrometry. Patients with plasma tHcy in the highest tertile (n = 27; i.e. > 10.6 micromol/l) had a mean plasma level of 14.4 +/- 1.21 mol/l compared with 9.9 +/- 0.1 micromol/l in those patients in the middle tertile (n = 22; p < 0.05) and 9.4 +/- 0.1 micromol/l in those in the lowest tertile (n = 27; i.e. <9.6 micromol/l; p < 0.05). The hyperhomocysteinemic individuals (highest tertile) had a significantly decreased FDD compared with healthy age-matched controls (n = 15) (7.6 +/- 1.0 vs 13.0 +/- 0.4%; p < 0.05), higher plasma ADMA concentrations (4.0 +/- 0.3 vs 2.6 +/- 0.3 micromol/l; p < 0.05), and a lower urinary nitrate excretion rate (89.5 +/- 13.4 vs 131.3 +/- 17.9 micromol/mmol creatinine; p < 0.05) compared with patients with plasma tHcy in the lowest tertile. Multivariate regression analysis including plasma tHcy, ADMA, total cholesterol, diabetes mellitus, smoking, and systolic blood pressure revealed ADMA as the only significant factor determining FDD (p < 0.05). In conclusion, we demonstrated a stronger relationship between impaired endothelial function and elevated ADMA levels in comparison with plasma tHcy concentrations in patients with PAD and chronic hyperhomocysteinemia. This may raise the question of whether different therapeutical options that interact indirectly with plasma tHcy, i.e. treatment with ACE inhibitors and AT1-receptor blockers to reduce ADMA plasma concentrations or L-arginine, could be a beneficial tool for treating patients with hyperhomocysteinemia.     

Two different therapeutic strategies in ICD lead defects: additional combined lead versus replacement of the lead

Objectives: Implantation of an additional HV-P/S lead versus extraction of the defective HV-P/S lead and implantation of a new one is one possible therapeutic approach in cases of a defective high-voltage pace/sense lead (HV-P/S). No information is available on potential differences in clinical outcome in these different approaches.
Methods: Between January 2000 and February 2006, 86 patients with HV-P/S lead defect received either an additional transvenous HV-P/S lead (n = 33, group 1) or the HV-P/S lead was replaced (n = 53, group 2). The duration of the initially implanted leads was significantly different in the two groups (7.4 ± 2.9; group 1 and 4.1 ± 3.4 years; group 2).The outcome of these two groups of patients was retrospectively analyzed.
Results: Seventy-three patients [85%] survived until the end of follow-up of 29 ± 15 (group 1) and 33 ± 21 (group 2) months (P = ns), respectively. Thirteen patients died: six in group 1 and seven in group 2 (P = ns). Fourteen patients experienced perioperative complications (group 1: six; group 2: eight; P = ns). ICD system-related complications occurred in 22 patients (group 1: seven; group two: 15; P = ns). The event-free cumulative survival of patients with additional and replaced HV-P/S lead for postoperative events (including death) after 1, 2, and 3 years was 82%, 70%, 70%, and 86%, 81%, 66%, respectively (P = 0.93).
Conclusions: Implantation of an additional HV-P/S lead or replacement of the HV-P/S lead in case of HV-P/S lead failure is statistically not different concerning mortality and morbidity. There are no predictors for further lead defects. Implantation of an additional HV-P/S lead should not be recommended in young patients or patients with greater likelihood of living many years. Predictors for death were an age over 70 years and renal insufficiency.