Divergence in CD19-mediated signaling unfolds intraclonal diversity in chronic lymphocytic leukemia, which correlates with disease progression.

Emerging data on intraclonal diversity imply that this phenomenon may play a role in the clinical outcome of patients with chronic lymphocytic leukemia (CLL), where subsets of the CLL clone responding more robustly to external stimuli may gain a growth and survival advantage. In this study, we report intraclonal diversity resolved by responses to CD19 engagement in CLL cells, which can be classified into CD19-responsive (CD19-R) and -nonresponive subpopulations. Engagement of CD19 by anti-CD19 Ab rapidly induced cellular aggregation in the CD19-R CLL cells. The CD19-R CLL cells expressed higher surface levels of CD19 and c-myc mRNA, exhibited distinct morphological features, and were preferentially abolished in rituximab-treated patients. Both subpopulations reacted to sIgM stimulation in a similar manner and exhibited similar levels of Akt and Erk phosphorylation, pointing to functional signaling divergence within the BCR. CD19 unresponsiveness was partially reversible, where nonresponding CD19 cells spontaneously recover their signaling capacity following incubation in vitro, pointing to possible in vivo CD19-signaling attenuating mechanisms. This concept was supported by the lower CD19-R occurrence in bone marrow-derived samples compared with cells derived from the peripheral blood of the same patients. CLL patients with >15.25% of the CD19-R cell fraction had a shorter median time to treatment compared with patients with <15.25% of CD19-R cell fraction. In conclusion, divergence in CD19-mediated signaling unfolds both interpatient and intraclonal diversity in CLL. This signaling diversity is associated with physiological implications, including the location of the cells, their responses to anti-CLL therapeutics, and disease progression.

No change in antibiotic susceptibility patterns in the neonatal ICU over two decades.

OBJECTIVES: To identify trends in early-onset sepsis and late-onset sepsis neonatal rates and to evaluate the appropriateness of the empirical antibiotic protocols. DESIGN: A 17-yr (1993-2009) analysis of positive blood and cerebrospinal fluid cultures. SETTING: The two neonatal ICUs at the Hadassah- Hebrew University Medical Center. RESULTS: During this period, 991 infants had at least one episode of either bacteremia or meningitis. The overall incidence of early-onset sepsis was 0.64 per 1,000 live births with a nonsignificant trend over the study period (p = 0.37). The overall incidence of late-onset sepsis was 7.5 per 100 admissions with a significant positive trend in the incidence rates (p = 0.021). The incidence of late-onset sepsis was 7.5 per 100 admissions with a significant positive trend in the prevalence rates (p = 0.021). The prevalence of early-onset group B Streptococcus bacteremia decreased significantly throughout the study period. Among late-onset sepsis, Gram-positive and fungi infection rates were stable over time, while Gram-negative infection rates showed a significant positive trend (p = 0.007). No significant change in the susceptibility rate of the isolated Gram-negative bacteria in late-onset sepsis for the common antibacterial drugs was found. About 85% and 90% of the isolated organisms were susceptible to our early-onset sepsis (ampicillin and gentamicin) and late-onset sepsis (vancomycin and cefotaxime) protocols, respectively, and these rates were stable over the study period (p = .1 and .55, respectively). Sepsis-related mortality was higher among Gram- negative sepsis cases resistant to our empiric antibiotic protocol. CONCLUSIONS: Our empiric antibiotic protocols are appropriate despite their continuous use over the last 17 yrs. This may have been achieved by the use of a controlled antibiotic program and infection control efforts.

Efficacy of urine alkalinization by oral administration of sodium bicarbonate: a prospective open-label trial.

BACKGROUND: Urine alkalinization is indicated for various medical conditions. Alkalinization is usually achieved by intravenous administration of alkali substances titrated by repeated urinalyses. Some situations such as mass casualty events might require urine alkalinization by the oral route. We evaluated the efficacy of oral sodium bicarbonate administration for urine alkalinization. METHODS: In a prospective open-label trial, 4 g of sodium bicarbonate was administered orally 3 times daily to 9 healthy volunteers for 24 hours. Serial blood and urine samples were collected, and urine pH was evaluated. Plasma electrolytes and pH were also measured for safety purposes. RESULTS: All participants had a urine pH of at least 7 after 10 hours. At 20 hours, all participants had a urine pH of at least 8. No adverse effects or abnormal blood results were documented during the 24-hour follow-up. CONCLUSIONS: Oral administration of a standard dose of sodium bicarbonate tablets resulted in effective urine alkalinization. Further research is needed to investigate the natural course of urine pH after cessation of our protocol and the efficacy of longer periods of treatment.

Treatment with recombinant human growth hormone during childhood is associated with increased intraocular pressure.

OBJECTIVE: To evaluate the association between recombinant human growth hormone (rhGH) treatment and intraocular pressure (IOP) in children. STUDY DESIGN: This is an observational cohort study including comparison between children treated with rhGH for at least 12 months (treatment group), matched children prior to treatment (control group), and population age-adjusted normograms of IOP. All children underwent an ocular slit lamp assessment and Goldmann applanation tonometry. Charts were reviewed for cause of therapy, peak stimulated growth hormone level prior to therapy, treatment duration, insulin-like growth factor 1, and rhGH dosage. RESULTS: The treatment group included 55 children and the control group included 24 children. Mean age at examination was comparable at 11.4 ± 3.3 years and 10.3 ± 2.6 years, respectively (P = .13). Mean treatment duration was 37.5 ± 22.8 months and mean rhGH dose was 0.04 ± 0.01 mg/kg/d. Mean IOP was significantly increased in the treatment group compared with the control group and compared with age-matched normograms (16.09 ± 2.2 mm Hg, 13.26 ± 1.83 mm Hg and 14.6 ± 1.97 mm Hg, respectively, P < .001). IOP was positively correlated with treatment duration (r = 0.559, P < .001) and rhGH dosage (r = 0.274, P = .043). CONCLUSION: IOP in children treated with rhGH is increased compared with a similar population without treatment and compared with healthy population normograms. IOP is associated with longer treatment duration and higher dosages.

Tailoring neoadjuvant chemotherapy for locally advanced breast cancer: a historical prospective study.

BACKGROUND: Despite the growing number of clinical trials assessing preoperative systemic chemotherapy (PST) for locally advanced breast cancer, the optimal regimen has still to be defined. PURPOSE: This was to evaluate the toxicity, operability rate, pathological response rate and disease-free and overall survival associated with a PST regimen consisting of the sequential administration of single agents according to the individual tumor response. METHODS: Medical files were reviewed of 102 consecutive patients with breast cancer treated in 2000-2007 with a neoadjuvant sequential regimen of doxorubicin followed by taxane. The number of cycles and the addition of taxane were based on tumor response. RESULTS: Seventy percent of the patients had inoperable disease at diagnosis and 29% were given preoperative therapy for breast conservation. All patients underwent surgery, 65% achieved breast conservation. An overall pathological complete response (breast and nodes) was achieved in 14% of the patients, and a complete nodal pathologic response in 34%. At a median follow-up of 54 months, the overall survival rate was 82% and the disease-free survival rate was 70%. There was no treatment-related mortality. Febrile neutropenia occurred in 19% of the patients. CONCLUSIONS: A neoadjuvant regimen of doxorubicin with or without a sequential taxane, in which the number of cycles and the sequential administration of taxane are determined according to clinical response, appears to be safe and effective for patients with locally advanced breast cancer and yields a high rate of breast conservation. Tailored PST can spare patients receiving unnecessary chemotherapy.

To resuscitate or not to resuscitate: a logistic regression analysis of physician-related variables influencing the decision.

OBJECTIVE: To determine whether variables in physicians' backgrounds influenced their decision to forego resuscitating a patient they did not previously know. METHODS: Questionnaire survey of a convenience sample of 204 physicians working in the departments of internal medicine, anaesthesiology and cardiology in 11 hospitals in Israel. RESULTS: Twenty per cent of the participants had elected to forego resuscitating a patient they did not previously know without additional consultation. Physicians who had more frequently elected to forego resuscitation had practised medicine for more than 5 years (p=0.013), estimated the number of resuscitations they had performed as being higher (p=0.009), and perceived their experience in resuscitation as sufficient (p=0.001). The variable that predicted the outcome of always performing resuscitation in the logistic regression model was less than 5 years of experience in medicine (OR 0.227, 95% CI 0.065 to 0.793; p=0.02). CONCLUSION: Physicians' level of experience may affect the probability of a patient's receiving resuscitation, whereas the physicians' personal beliefs and values did not seem to affect this outcome.

[Influenza vaccination of pediatric staff as a predictor for recommendations to children].

BACKGROUND: As of February 2010, the 2009 H1N1 influenza has caused more than 15,000 deaths worldwide. Seasonal influenza vaccination rates among health care workers (HCW) have been universally low; the 2009 H1N1 influenza vaccination of HCW has also been disappointing. In several studies, a correlation between HCW seasonal influenza vaccination status and vaccine recommendation to adult patients was found. OBJECTIVE: To examine the correlation between the declared influenza vaccination status of pediatric staff and vaccine recommendations to their patients. INSTRUMENT: Anonymous questionnaire concerning attitudes and practices regarding seasonal and 2009 H1N1 influenza vaccination. RESPONDENTS: 141 pediatric staff attending a conference. RESULTS: Seventy two percent of the respondents had been or intended to be vaccinated against seasonal influenza, 62% against the 2009 H1N1 influenza, and 56% against both diseases. Ambulatory setting employment was positively associated with the recommendation of seasonal influenza vaccination to all children. By multivariate Logistic regression analysis, the "vaccinated or intending to be vaccinated against seasonal influenza" was the only significant independent variable associated with recommending universal pediatric seasonal influenza vaccine (OR=15, 95% CI 6.1-41.4, p < 0.001). Similarly, "being or intending to be vaccinated against the 2009 H1N1 influenza" was the only significant independent variable associated with recommending universal pediatric vaccination against this disease (OR = 5.2, 95% CI 1.85-14.6, P = 0.002). CONCLUSION: A strong correlation between the influenza vaccination status of pediatric staff and the recommendation of the vaccines to children emphasizes that intense education of providers is a crucial step in assuring a positive recommendation to families.

Exposure of extremely low birth weight infants to diagnostic X-Rays: a longitudinal study.

AIM: To quantify the number of chest and abdominal radiograms performed in surviving singleton extremely low birth weight (ELBW) infants in order to examine whether changes in imaging application occurred during the last 21 years (1987-2007). METHODS: Clinical and radiological data of 225 out of 229 surviving infants were obtained and associations with time and clinical variables were evaluated. RESULTS: The number of chest X-Rays performed per infant was 10.3 +/- 11.1 (mean +/- SD), median = 7; range = 0-77 and the number of abdominal radiograms was 5.6 +/- 7.1, median = 3; range = 0-61. The number of chest and abdominal X-Rays performed per patient during 1987-1996 was very similar to that of 1997-2007, and no appreciable change of trend was observed along the years. There were negative and statistically significant correlations between the gestational age and the number of radiograms performed per patient (chest X-Rays: r =-0.402; p < 0.001, abdominal X-Rays: r =-0.182; p = 0.006). Controlling for gestational age, reduced numbers of radiograms per patient (abdominal: b =-1.20, p = 0.235; chest: b =-3.08, p = 0.035) were demonstrated in the second period. Patients with complicated clinical course were exposed to significantly more radiograms. CONCLUSION: Controlling for gestational age, a reduced number of exposures to chest radiograms was demonstrated during 1997-2007 compared with 1987-1996. Measures to reduce radiation, especially in complicated cases, are advocated.

Effect of a 24+ hour fast on breast milk composition.

In this preliminary prospective study, breast milk is sampled surrounding 4 religious fast days to determine the effect of a more than 24-hour fast on breast milk composition. The participants are 48 healthy women nursing healthy babies between 1 and 6 months of age. Samples are collected within 2 days before the fast (baseline), immediately after the fast, and 24 hours after fast completion. Samples are tested for sodium, calcium, phosphorus, triglycerides, total protein, and lactose. From baseline to immediately after fast, mean sodium, calcium, and protein levels increase (P = .013, P < .0001, and P < .0001, respectively) and mean phosphorus and lactose levels decrease (P < .0001 and P = .003, respectively). Mean triglycerides are unchanged. Twenty-four hours after fast, parameters are no longer significantly different from baseline except for elevated mean protein levels (P = .022) and lactose that is still reduced (P = .017). A fast of this nature is statistically associated with certain biochemical changes in breast milk.

The influence of mucositis on oral thermometry: when fever may not reflect infection.

BACKGROUND: The mouth is the most common site for measuring temperature. Oral mucositis may affect up to 40% of patients who receive chemotherapy. Thus far, mucositis has not been studied with regard to accurate thermometry. METHODS: One hundred consecutive patients (25 per group) were self-referred on the basis of perception of mucositis, temperature measurement at home, or malaise or were referred by a nurse on the basis of an assessment of a potential infectious process and/or mucositis. Oral and tympanic temperature were assessed simultaneously in patients with no fever and no mucositis (group A), those with mucositis (group B), those with fever and no mucositis (group C), and those with neutropenia but not fever or mucositis (group D). RESULTS: The 4 groups of patients had higher oral temperatures than tympanic temperatures (group A, 36.9 degrees C vs. 36.8 degrees C [delta = 0.12 degrees C; P = .062]; group B, 38.0 degrees C vs. 37.1 degrees C [delta = 0.89 degrees C; P < .001]; group C, 38.7 degrees C vs. 38.4 degrees C [delta = 0.27 degrees C; P < .001]; and group D, 37.0 degrees C vs. 36.7 degrees C [delta = 0.27 degrees C; P < .001]). Scheffe a-posteriori test revealed that only the delta temperature in group B differed significantly (95% confidence limits, -2.471, -1.584; P < .001). A linear regression model that examined the effect of other variables on the delta temperature found that only mucositis was a significant factor (95% confidence limits, 0.582, 0.820; P < .001). CONCLUSIONS: Mucositis causes an increase in oral temperature but does not elevate systemic body temperature, thereby casting doubt on the diagnosis of infection. Conceivably, mucositis may provide an "inflammation bias" that could lead to the overuse of antibiotics and growth factors in 20%-40% of patients with cancer. When one considers issues of antimicrobial resistance and cost, this concern should be tested and clarified in a prospective study based on accurate temperature measurement.

A systematic review of interventions to increase awareness, knowledge, and folic acid consumption before and during pregnancy.

OBJECTIVE: We conducted a systematic review of studies designed to increase awareness of knowledge about, and consumption of folic acid before and during pregnancy. DATA SOURCES: Studies were identified from Cochrane Library, Medline, and the references of primary studies and reviews. STUDY INCLUSION AND EXCLUSION CRITERIA: Studies included randomized controlled trials, quasi-experimental interrupted time series studies, follow-up studies, case-control studies, and before-and-after studies, all of which were conducted between 1992 and 2005 on women ages 15 to 49 years and/or health professionals, evaluating awareness and/or knowledge and/or consumption of folic acid both before and after intervention. Studies were excluded if data were not presented both before and after intervention or were other outcomes than those mentioned here. DATA EXTRACTION: Data were extracted in relation to characteristics of studies, participants, interventions, and outcomes. DATA SYNTHESIS: Because of heterogeneity, we performed a narrative synthesis describing the direction and the size of effects. RESULTS: On average, women's awareness increased from 60% to 72%, knowledge from 21% to 45%, and consumption from 14% to 23%. CONCLUSIONS: Interventions had a positive effect on folic acid intakes before and during pregnancy, although the average usage reached less than 25%.

Neonatal outcome of inborn and outborn extremely low birth weight infants: relevance of perinatal factors.

BACKGROUND: A substantial number of premature deliveries occur in hospitals lacking neonatal intensive care facilities. We previously demonstrated a comparable outcome of very low birth weight infants delivered in a level II nursery to that of inborn infants delivered in our tertiary care center, but a similar comparison of extremely low birth weight infants has not been done. OBJECTIVES: To compare the neonatal outcome (mortality, severe intraventricular hemorrhage/periventricular leukomalacia, bronchopulmonary dysplasia and intact survival) of inborn and outborn ELBW infants, accounting for sociodemographic, obstetric and perinatal variables. METHODS: We compared 97 ELBW infants (birth weight < or = 1000 g) delivered between the years 2000 and 2004 in a hospital providing neonatal intensive care to 53 ELBW babies delivered in a referring hospital. A univariate model was first applied to examine the associations of the individual independent variables with the outcome variable, followed by a logistic stepwise regression analysis for each of the outcome variables. The odds ratios for each predictor were reported as well as their P values and 95% confidence intervals. RESULTS: In the stepwise logistic regression analysis, accounting for a possible confounding effect of the independent variables, 'hospital of birth' remained a statistically significant predictor in the final step only for mortality, with odds ratio (inborns relative to outborns) of 3.32 (95% CI 1.19-9.28, P = 0.022). No statistically significant associations with the other outcome variables were found (severe IVH/PVL odds ratio = 1.99, 95% CI = 0.77-5.14, P = 0.155; BPD odds ratio = 0.60, 95% CI = 0.19-1.91, P= 0.384; intact survival OR = 0.56, 95% CI = 0.23-1.35, P = 0.195). CONCLUSIONS: ELBW outborn infants may share an outcome comparable with that of inborn babies, if adequate perinatal care is provided.

Acute myocardial infarction with spontaneous reperfusion: clinical characteristics and optimal timing for revascularization.

BACKGROUND: Spontaneous coronary reperfusion occurs in 7-27% of patients with ST elevation myocardial infarction, and is an independent predictor of myocardial salvage, percutaneous coronary intervention success, and improved outcome. OBJECTIVES: To determine the optimal PCI time for patients admitted to the hospital due to STEMI with SCR. METHODS: We performed a retrospective analysis of all patients admitted to the coronary care unit between July 2002 and November 2004 with a diagnosis of STEMI with SCR. RESULTS: The study group comprised 86 patients. There was not a single reinfarction episode during an observation period of 6579 patient hours. Cardiac catheterization was executed early (< 24 hours from pain onset) in 26 patients and late (> 24 hours) in 55. Pre-PCI angiographic TIMI flow 2-3 was seen in > 95% in both groups. PCI was performed more frequently in the "early" group (P = 0.024), while multi-vessel coronary artery disease (P = 0.094) requiring coronary bypass surgery (P = 0.056) was observed more frequently in the "late catheterization" group. Myocardial infarction and angina pectoris at 30 days occurred more frequently in the early catheterization group (P = 0.039), however no difference in any major adverse cardiac events was detected during long-term follow-up (491 +/- 245 days). CONCLUSIONS: Reinfarction after STEMI with SCR is a rare event. Early PCI in patients with STEMI and SCR, even when executed with aggressive antiplatelet therapy, seems to result in an excess of early MACE without any long-term advantage. Prospective randomized trials should determine the optimal PCI timing for these patients.

No-touch aorta off-pump coronary surgery: the effect on stroke.

OBJECTIVE: Studies examining the neuroprotective effects of off-pump coronary artery bypass grafting have shown inconsistent results. Most studies, however, have not differentiated between clampless and clamp off-pump techniques. The aim of this study was to evaluate the effect of avoiding aortic manipulation on major neurologic outcomes after off-pump coronary artery bypass grafting. METHODS: A total of 700 consecutive patients undergoing multiple-vessel off-pump coronary artery bypass grafting between 2000 and 2003 were included. The 429 patients undergoing aortic no-touch technique were compared with 271 patients in whom partial aortic clamps were applied. The aorta was screened by manual palpation, and epiaortic ultrasonography was used selectively. RESULTS: The frequency of detected atherosclerotic aortic disease was higher in the no-touch group (17.4% vs 5.1%, P < .0001). No-touch revascularization was achieved with arterial conduits, arranged in T-graft or in situ configurations (50%). The respective graft/patient ratios were 2.5 +/- 0.6 and 2.6 +/- 0.6 in the side-clamp and no-touch groups ( P = .009); however, revascularization of the posterolateral myocardial territory was comparable (87% vs 90%, difference not significant). The incidence of stroke (0.2% vs 2.2%, P = .01) was significantly lower in the no-touch group (1/429). Logistic regression identified partial aortic clamping as the only independent predictor of stroke (odds ratio 28.5, confidence interval 0.22-333, P = .009), increasing this risk 28-fold. Peripheral vascular disease ( P = .068), diabetes ( P = .072), and history of stroke ( P = .074) trended toward stroke. CONCLUSIONS: Avoiding partial aortic clamping during off-pump coronary artery bypass grafting provides superior neurologic outcome. The results are reproducible and irrespective of the severity of aortic disease or the method of aortic screening. This technique is recommended whenever technically feasible.

Off-pump coronary revascularization of the circumflex system: comparison between sequential and nonsequential arterial grafts.

BACKGROUND: Sequential grafting increases the availability of arterial grafts. This study aims to determine the safety and efficacy of sequential grafting of the circumflex coronary distribution performed off-pump. METHODS: Between 2000 and 2003, 136 patients undergoing off-pump sequential arterial grafting of the circumflex territory were compared to 278 patients who received nonsequential grafts to the same area. RESULTS: The grafts/patient ratio was higher in the sequential than the nonsequential group (3.2 +/- .4 and 2.3 +/- .2, respectively, P < .0001). Radial artery conduits and T-grafts were used more often in the sequential group; conversely, bilateral internal thoracic artery configurations were more frequent in the nonsequential groups (P < .0001). There were 1.2 sequential anastomoses per patient. Early mortality (2.2% versus 2.5%), myocardial infarction (2.2% versus 1.1%) and stroke (.7% versus none) rates were comparable. Use of sequentials or other operative confounders had no independent effect on the occurrence of early adverse events (stepwise logistic regression). At 3.5 years, survival was 95.9% and 84.2% in the sequential and nonsequential groups, respectively (P = .231, log-rank). Despite comparable incidence of major adverse cardiac events (MACE) (6.6% versus 8.6%, P = .470) and similar 3.5-year freedom from MACE (88.7% for both groups, P = .682), Cox regression analysis identified sequential grafting as an independent predictor of MACE (P < .0001, HR 19.9), increasing this risk by 20-fold. CONCLUSIONS: Off-pump sequential grafting of the circumflex system may be safely performed. The use of sequentials, however, had an independent effect on increased midterm MACE. The distribution of events suggests culpability of surgical factors and may reflect a learning curve.

Bilateral versus single internal thoracic artery grafting in oral-treated diabetic subsets: comparative seven-year outcome analysis.

BACKGROUND: Recent interest has focused on the use of arterial conduits in diabetic subsets. To date, the long-term benefits of bilateral internal thoracic artery (BITA) grafting in this subgroup remain in question. METHODS: Two hundred eighty-five consecutive oral-treated diabetics operated on nonemergent basis (1996 to 1998) were compared according to the surgical technique, left-sided skeletonized BITA (n = 228) or single internal thoracic artery- saphenous veins (SITA) (n = 57). Patients with chronic lung disease, usually preselected to SITA grafting, were not included. RESULTS: The respective grafts to patient ratio was 3.1 +/- 1 and 3.2 +/- 0.8 for the SITA and BITA groups (p = NS). Complementary conduits used in the BITA group were gastroepiploic arteries (25%) and saphenous veins (13%). Early outcome was comparable, including the incidence of deep sternal infections (1.8% in both groups). During follow-up (range, 4 to 7.5 years; median, 5), there were less repeat revascularizations (4.4% vs 12.3%, p = 0.025) and major adverse cardiac events (MACE) (11.2% vs 36.8%, p < 0.0001) in the BITA group. At 7 years, survival (Kaplan-Meier) (75% vs 59%, p = 0.006, log-rank), freedom from cardiac mortality (92% vs 68%, p < 0.0001), and freedom from MACE (70% vs 59%, p = 0.004) were superior in the BITA group. Multivariate analysis identified the use of BITA as a protective factor against the occurrence of late cardiac mortality (odds ratio [OR] 0.2) and MACE (OR 0.3); conversely, SITA-saphenous vein arrangements increased the risk by fivefold (OR 5, confidence interval limits [CL] 1.6 to 16.6, p = 0.005) and threefold (OR 3.3, CL 1.5 to 9, p = 0.005), respectively. CONCLUSIONS: Left-sided BITA grafting confers improved long-term survival and event-free survival in oral-treated diabetics. We, therefore, recommended this approach in this diabetic subset.

Integration of automated morphological features resolves a distinct group of atypical chronic lymphocytic leukemias with chromosomal aberrations.

Automated morphological assessment of peripheral blood slides has become an important modality facilitating characterization and quantification of cells in a uniform, fast and robust manner. In this study, we evaluated the morphological diversity in peripheral blood films of 94 chronic lymphocytic leukemia (CLL) patients using the DM1200 CellaVision automated microscopy system. Aberrant lymphocytes and smudge cells were enumerated and correlated with CLL immunophenotype, chromosomal aberrations and prognostic parameters. Herein, we show that the percentages of aberrant and smudge cells was highly variable between patients and did not correlate with each other. Increased aberrant lymphocytes and fewer smudge cells were associated with an atypical immunophenotype including low expression of CD23, higher levels of FMC7 and bright surface levels of CD20. High fraction of aberrant lymphocytes also was associated with trisomy 12. These cells were predominantly of small/medium size, sometimes with cleft nuclei. No correlation was noted between aberrant or smudge cells and clinical stage, CD38, ZA70 or time to first treatment. Taken together, automated morphological analysis of peripheral blood leukocytes emerged as a powerful and robust tool for the quantitative morphological stratification of CLL. Integration of the automated morphological features discriminates between different CLL phenotypes and distinct chromosomal aberrations.

Telomere shortening in liver transplant recipients is not influenced by underlying disease or metabolic derangements.

BACKGROUND: Telomeres are non-coding regions of DNA that cap the ends of chromosomes. Their length is considered a marker of human replicative senescence and premature aging. Given the high association of liver transplantation with the metabolic syndrome, we hypothesized that liver transplant recipients may exhibit premature and accelerated aging. MATERIAL AND METHODS: Telomere length in peripheral blood lymphocytes was measured by polymerase chain reaction in 62 consecutive liver-transplant recipients and 59 healthy control subjects aged 20-76 years. Clinical and laboratory parameters were collected from the medical files. RESULTS: The liver transplant recipients were significantly older than the control subjects (p=0.012), with significantly higher rates of obesity (BMI >30 kg/m(2)), dyslipidemia, hypertension, diabetes, and fatty liver. Mean telomere length was significantly shorter in the transplant group (0.59±0.6 vs. 1.91±1.78 in the controls, p<0.0001). Within the transplant group, there was no significant association between mean telomere length and underlying liver disease or presence of the metabolic syndrome or its constituents. On multivariate analysis, telomere length was negatively associated with patient age (p=0.0001), male sex (p=0.04), acute rejection (p=0.005), and fatty liver (p=0.009), and was positively associated with time from transplantation (p=0.006). CONCLUSIONS: Liver transplantation is associated with shortened telomere length in peripheral blood lymphocytes, suggesting accelerated senescence.

Absolute monocyte count trichotomizes chronic lymphocytic leukemia into high risk patients with immune dysregulation, disease progression and poor survival.

Peripheral absolute monocyte count (AMC) has been reported to correlate with clinical outcome in different types of cancers. This association may relate to alteration in circulating monocytic subpopulations and tumor infiltrating macrophages. In this study we evaluated the clinical significance of peripheral AMC in 80 treatment naive patients with CLL. Measurement of AMC was based on direct morphological enumeration, due to our findings that complete blood count data may yield incorrect monocytes enumeration values in CLL. The median AMC in patients with CLL was within normal limits, however the AMC range exceeded the values of healthy individuals. The AMC trichotomized patients into 3 distinct sub-groups with different characteristics and outcomes. High AMC patients were younger and had higher absolute lymphocytes count, while patients with low AMC had prominent immune dysregulation (lower serum IgA levels, susceptibility to infections and a tendency for positive direct anti-globulin test). The low and high AMC patients had a shorter time to treatment compared to the intermediates AMC subgroups, whereas low AMC was associated with increased mortality caused by infectious complications. In conclusion, AMC quantification during the disease course classifies CLL patients into subgroups with unique clinical features and outcomes.

Lamotrigine serum concentration in children with epilepsy.

The correlation between lamotrigine serum concentration, efficacy, and toxicity in children is controversial. The database of the Clinical Pharmacology Laboratory at Assaf Harofeh Medical Center was retrospectively searched to identify lamotrigine serum concentrations in children aged 2-19 years with refractory epilepsy who received lamotrigine as monotherapy or polytherapy from 2007-2010. Data collected included age at epilepsy onset, additional antiepileptic drugs, lamotrigine dose, monthly seizure frequency before and after lamotrigine treatment, and side effects. Sixty blood samples were collected from 42 children aged 10.1 ± 4.9 years (range, 2-20 years). Seizure types included complex partial (n = 28), simple partial (n = 7), absence (n = 2), and generalized tonic-clonic (n = 23). Decreased seizure frequency was observed in 38 (63.3%) patients. No correlation with lamotrigine serum concentration was evident, but seizure frequency was significantly influenced by age and lamotrigine dose. Side effects were reported in 21 (35%) patients. Only diplopia was significantly correlated with lamotrigine serum concentration. Lamotrigine was more effective at lower doses and in older children. Lamotrigine serum concentration correlated significantly with diplopia, but not with other side effects or with clinical efficacy. Overall, lamotrigine is effective and safe in children with refractory epilepsy.