Academic abilities and glycaemic control in children and young people with Type 1 diabetes mellitus.

AIMS: To determine if children and young people aged < 23 years with Type 1 diabetes differ in academic ability from age-matched control subjects without Type 1 diabetes and whether academic scores are related to glycaemic control. METHODS: Using a cross-sectional study design, we administered cognitive and academic tests (Woodcock-Johnson III Spatial Relations, General Information, Letter-Word Recognition, Calculation and Spelling tests) to young people with Type 1 diabetes (n=61) and control subjects (n=26) aged 9-22 years. The groups did not differ in age or gender. Participants with Type 1 diabetes had a disease duration of 5-17.7 years. History of glycaemic control (HbA1c , diabetic ketoacidosis and severe hypoglycaemic episodes) was obtained via medical records and interviews. RESULTS: The participants with Type 1 diabetes had a lower mean estimated verbal intelligence (IQ) level compared with those in the control group (P=0.04). Greater exposure to hyperglycaemia over time was associated with lower spelling abilities within the group with Type 1 diabetes (P=0.048), even after controlling for age, gender, socio-economic status, blood glucose level at time of testing and verbal IQ (P=0.01). History of severe hypoglycaemia or ketoacidosis was not associated with differences in academic abilities. CONCLUSIONS: In children and young people, Type 1 diabetes was associated with a lower verbal IQ. Moreover, increased exposure to hyperglycaemia was associated with lower spelling performance. These results imply that hyperglycaemia can affect cognitive function and/or learning processes that may affect academic achievement.

Remote sensing in hybridized arrays of nanostrings.

We study high-Q nanostrings that are joined end-to-end to form coupled linear arrays. Whereas isolated individual resonators exhibit sinusoidal vibrational modes with an almost perfectly harmonic spectrum, the modes of the interacting strings are substantially hybridized. Even far-separated strings can show significantly correlated displacement. This remote coupling property is exploited to quantify the deposition of femtogram-scale masses with string-by-string positional discrimination based on measurements of one string only.

Nuclear proteins in mouse brain cells bind specifically to the myelin basic protein regulatory region.

Expression of myelin basic protein (MBP) in mice is regulated in a cell- and stage-specific manner during brain development. The MBP control region contains multiple cis-acting elements, shown by in vivo and in vitro assays, which are responsible for its unique pattern of transcription. Using synthetic DNA fragments spanning the MBP control region, we have analyzed nuclear proteins obtained from newborn (2-3 d), young adult (18-30 d), and adult (60 d) animals; these nuclear proteins form DNA-protein complexes with the MBP regulatory region. Brain extracts from young adult and adult mice showed enhanced binding activities with the sequences supporting transcriptional activation in glial cells. Deletion analysis of the proximal activating sequence located at position -14 to -50 with respect to the RNA initiation site resulted in identification of a small region, located between nucleotides -14 to -37, which is required for formation of the complexes. Southwestern assay revealed a major 39-kD protein from young adult brain extract that recognizes the sequences between nucleotides -14 to -37. An additional minor 37-kD protein, derived from young adult brain extract, was also found to be associated with this proximal activating region. Of particular interest is the observation that the minor 37-kD protein became more abundant in the extract derived from adult brain, whereas the major 39-kD protein became less abundant. The possible role of these proteins in cell/stage-specific transcription of MBP is discussed.

Valence bond solid phases in a cubic antiferromagnet.

We report on a valence bond projector Monte Carlo simulation of the cubic lattice quantum Heisenberg model with additional higher-order exchange interactions in each unit cell. The model supports two different valence bond solid (VBS) ground states. In one of these states, the dimer pattern is a three-dimensional analogue of the columnar pattern familiar from two dimensions. In the other, the dimers are regularly arranged along the four main diagonals in 1/8 of the unit cells. The phases are separated from one another and from a Néel phase by strongly first-order boundaries. Our results strengthen the case for exotic transitions in two dimensions, where no discontinuities have been detected at the Heisenberg Néel-VBS transition driven by four-spin plaquette interactions.

Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin.

PURPOSE: Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the efficacy and safety of recombinant human interleukin-11 (rhIL-11; Neumega, Genetics Institute, Inc, Cambridge, MA), a novel thrombopoietic growth factor, in reducing the need for platelet transfusions in patients who undergo dose-intensive chemotherapy. PATIENTS AND METHODS: Women with advanced breast cancer received cyclophosphamide (3,200 mg/m2) and doxorubicin (75 mg/m2) plus granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/d). Patients were randomized to blinded treatment with placebo or 50 microg/kg/d rhIL-11 subcutaneously for 10 or 17 days after the first two chemotherapy cycles. RESULTS: Seventy-seven patients were randomized and constitute the intent-to-treat (ITT) population. Sixty-seven patients (the assessable subgroup) either completed both cycles without a major protocol violation (n = 62) or received a platelet transfusion before treatment was discontinued after the first cycle. In the ITT population, rhIL-11 significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) patients who received rhIL-11 did not require transfusions, compared with 15 of 37 (41%) in the placebo group (P = .04). Treatment with rhIL-11 significantly reduced the total number of platelet transfusions required in the assessable subgroup (P = .03) and the time to platelet recovery to more than 50,000/microL in the second cycle (P = .01). Most adverse events associated with rhIL-11 were reversible, mild to moderate in severity, and likely related to fluid retention. CONCLUSION: rhIL-11 is safe and effective in reducing treatment-associated thrombocytopenia and the need for platelet transfusions in patients who undergo dose-intensive chemotherapy, and thus may permit chemotherapy to be administered as planned at intended doses and thereby maximize the potential for a successful outcome.

Arteriosclerosis obliterans and associated risk factors in insulin-dependent and non-insulin-dependent diabetes.

The prevalence of arteriosclerosis obliterans (ASO) of the legs was determined by a battery of noninvasive tests in 141 insulin-dependent and 289 non-insulin-dependent diabetic subjects and in 64 other subjects. The prevalence of detectable ASO ranges from 18% in the younger IDDM group to 41% in the diet-treated NIDDM group. The prevalence of ASO increases 7.5% per decade, appears to increase 6.5% in the age-adjusted IDDM group, 9% in males, 19% in those with hypertension, and 12% in smokers. No consistently significant correlations with fasting glucose, glycosylated hemoglobin, or obesity were found. After accounting for the effect of smoking, the increased risk for ASO in males becomes nonsignificant.

Transesophageal echocardiography and carotid ultrasound in patients with cerebral ischemia: prevalence of findings and recurrent stroke risk.

OBJECTIVES: This study was conducted to determine the yield of transesophageal echocardiographic findings in a consecutive series of patients with stroke and transient ischemic attack, with and without carotid stenosis, and to estimate the recurrent stroke risk associated with specific echocardiographic findings. BACKGROUND: Transesophageal echocardiography has a high yield for identification of potential sources of cardiac embolism in patients with cerebral ischemia; however, the clinical significance of the most commonly detected abnormalities is uncertain. METHODS: We evaluated 145 consecutively admitted patients with stroke or transient ischemic attack with both transesophageal echocardiography and carotid ultrasound. Patients were followed up prospectively for a mean duration of 18 months to document the rate of recurrent cerebral ischemia. RESULTS: Transesophageal echocardiography detected at least one potential cardiac source of embolism in 45% of the patients. Atrial septal aneurysm and interatrial shunt were detected more frequently in patients who did not have a significant carotid stenosis that could account for their ischemic event. During follow-up, a higher rate of recurrent stroke or transient ischemic attack occurred in patients with positive transesophageal echocardiographic findings, particularly atrial septal aneurysm, interatrial shunt and left atrial thrombus. CONCLUSIONS: These data support recent studies that suggest that atrial septal aneurysm and interatrial shunts may be a significant source of cardioembolic stroke. Further studies are needed to clarify the optimal management of patients with these abnormalities.

Carotid and lower extremity arterial disease in patients with renal artery atherosclerosis.

BACKGROUND: Atherosclerotic lesions of the carotid and lower extremity arteries may be associated with renal artery stenosis and influence the management of patients with renal artery disease. OBJECTIVE: To document the prevalence and clinical features of carotid and lower extremity arterial disease in patients with renal artery atherosclerosis. METHODS: An analysis of baseline data on 149 patients enrolled in a prospective natural history study of atherosclerotic renal artery stenosis. Patients with at least 1 abnormal renal artery by duplex scanning were eligible. Carotid artery disease was evaluated by duplex scanning, and ankle/brachial indices were used to assess the lower extremity arteries. Disease at each of the 3 arterial sites was classified as mild, moderate, or severe based on the extent of involvement on both sides. Serum urea nitrogen, creatinine, and lipid levels were also measured. RESULTS: Severe renal, carotid, or lower extremity arterial disease was present in 44%, 19%, and 21% of the patients, respectively. There was a trend for patients with increasing degrees of renal artery disease to have increasing degrees of carotid and lower extremity arterial disease. The prevalence of severe carotid artery disease increased from 7% in the mild renal artery group to 28% in the severe renal artery group. Clinical factors that were most predictive of severe disease were elevated apolipoprotein B levels for the renal arteries, high serum urea nitrogen or creatinine levels for the carotid arteries, and smoking for the lower extremity arteries. CONCLUSIONS: There was a strong association between severe renal artery atherosclerosis and severe carotid artery disease. Patients with renal artery disease also had a high prevalence of lower extremity arterial disease. In this patient population, screening for lower extremity arterial disease can be reserved for those with signs or symptoms of peripheral ischemia. Noninvasive carotid screening is justified in patients with renal artery disease to detect asymptomatic lesions that require either immediate surgical treatment or serial follow-up for disease progression.

Carotid artery disease in NIDDM diabetes.

A prospective study of 135 controls, 286 non-insulin-dependent diabetic patients, and 31 subjects with an elevated fasting plasma glucose was performed to assess the prevalence of high-grade carotid artery stenosis. The carotid artery evaluation was performed using an ultrasonic duplex scanner. When those patients with an elevated fasting plasma glucose and non-insulin-dependent diabetes were considered together, the prevalence was 8.2% as compared with 0.7% for the controls (P = 0.0007). Those risk factors found to be significantly related to the higher prevalence of carotid disease in the combined groups of patients included age, ratio of systolic blood pressure to diastolic blood pressure, plasma cholesterol, and cigarette smoking. These findings may be an explanation for the greater incidence of stroke in patients with diabetes mellitus.

Progression of lower-extremity arterial occlusive disease in type II diabetes mellitus.

The prevalence of lower-extremity arterial occlusive disease (LEAOD), the progression of LEAOD, and the incidence of new LEAOD were determined by noninvasive method in 410 volunteers between the ages of 50 and 70 yr; 252 individuals had type II (non-insulin-dependent) diabetes, 158 were control subjects. LEAOD was monitored with the ankle/arm systolic blood pressure index in combination with Doppler arterial velocity waveform analysis. LEAOD was much more prevalent in the type II patients (22%, 55 of 252) than in the control subjects (3%, 4 of 158) (P less than .00001). The prevalence of risk factors for LEAOD was much higher in the type II patients, including elevated triglyceride, depressed high-density lipoprotein (HDL) cholesterol, hypertension, smoking, and elevated systolic blood pressure. In type II diabetic patients the incidence of new LEAOD over a 2-yr period (14%, 28 of 197) was lower than the incidence of LEAOD progression (87%, 45 of 52). Type II patients with LEAOD also had a high incidence of mortality (22%, 12 of 55) compared with those without LEAOD (4%, 8 of 197) (P less than .0005). A risk score including smoking history, duration of diabetes, depressed HDL cholesterol, total cholesterol, elevated systolic blood pressure, and low obesity index is related to LEAOD. After accounting for the effect of all of the risk factors, we suggest that type II diabetes contributes additional risk for LEAOD.

The incidence of pulmonary embolism in unexplained sudden cardiac arrest with pulseless electrical activity.

PURPOSE: The cause of many cases of sudden cardiac arrest from pulseless electrical activity is unknown. We hypothesized that pulmonary embolism was responsible for a substantial proportion of these cases and used transesophageal echocardiography to identify pulmonary embolism among patients with sudden cardiac arrest. SUBJECTS AND METHODS: We performed a prospective study at a tertiary care, university-operated county hospital, with a level 1 trauma center. Consecutive patients (n = 36) who were admitted with (n = 20) or unexpectedly developed (n = 16) sudden cardiac arrest of unknown cause were studied with transesophageal echocardiography during cardiopulmonary resuscitation. We determined the presence of central pulmonary embolism, right ventricular enlargement, and other causes of sudden cardiac arrest (such as myocardial infarction and aortic dissection) using prospectively defined criteria. RESULTS: Of the 25 patients with pulseless electrical activity as the initial event, 9 (36%) had pulmonary emboli (8 seen with transesophageal echocardiography and 1 diagnosed at autopsy) compared with none of the 11 patients with other rhythms, such as asystole or ventricular tachycardia or fibrillation (P = 0.02). Of the 8 patients who had pulmonary embolism diagnosed by transesophageal echocardiography, 2 survived to hospital discharge. CONCLUSIONS: Mortality from massive pulmonary embolism is high, particularly if patients present with sudden cardiac arrest. Earlier diagnosis of pulmonary embolus may permit wider use of thrombolytic agents or other interventions and may potentially increase survival.

A toxicity study of trimetrexate used in combination with cyclosporine as acute graft-versus-host disease prophylaxis in HLA-mismatched, related donor bone marrow transplants.

This study evaluated the acute toxicity of trimetrexate (TMTX) used in combination with cyclosporine (CsA) for prevention of acute graft-versus-host disease (GVHD) in patients undergoing allogeneic marrow transplantation from HLA-mismatched, related donors. TMTX has a mechanism of action similar to that of methotrexate (MTX); however, unlike MTX, TMTX is not primarily dependent on renal excretion. Patients were conditioned for transplant with cyclophosphamide, anti-thymocyte globulin, and total body irradiation. TMTX, 10 mg/m2 i.v., was administered on days 1, 3, 6, 11, 18, 25, 32, and 39 after transplant. CsA, 1.5 mg/kg i.v., was administered every 12 hr beginning on day-1. Eleven patients with hematologic malignancies or aplastic anemia (median age = 34 yr) received TMTX. Toxicity assessed included nausea, vomiting, fever, rash, time to myeloid and platelet engraftment, mucositis, and hepatic and renal dysfunction. Toxicity of TMTX was not different from that observed with MTX in a similar patient population. One patient died on day 16 before engraftment. The other 10 patients all engrafted and all developed acute GVHD at a median time of 11 days after transplant. The major manifestation of acute GVHD was in the skin, and all but one patient responded to primary therapy with corticosteroids. Seven patients have survived a median of 447 days after transplant. No significant toxicity from TMTX was observed. Further trials are warranted to define the role of TMTX in marrow transplantation.

New ultrasound approaches to dialysis access monitoring.

The failure of dialysis access is a frequent source of morbidity and hospitalization. Traditional methods of graft surveillance include: (1) clinical examination, (2) venous line pressure measurements during dialysis, (3) urea or tracer recirculation measurement, (4) continuous wave (CW) Doppler methods, (5) duplex ultrasonography, and (6) radiograph angiography. All these methods require special training and/or laboratory tests. The purpose of this study was to test a simple continuous-wave Doppler method that could be applied to measure the flow rate in dialysis access every time the patient undergoes dialysis. Twenty dialysis patients, 15 with polytetrafluoroethylene grafts and 5 with arteriovenous fistulae, were studied. Two hundred fifty-three examinations were performed over an 8-month period. Doppler waveforms of the access flow were obtained with the pump on, with the pump off, and with the pump on again. Systolic and diastolic Doppler frequency measurements were made, and the pump-on and pump-off measurements were compared. In an access functioning normally, the Doppler frequencies are higher with the pump off than with the pump on. In 22% of the cases, there were abnormal findings in which the Doppler frequencies were lower with the pump off than with the pump on. This occurs if the needles are incorrectly placed, suggesting that recirculation is occurring. Recirculation also occurs if there is stenosis of the access. Examining the hemodialysis access during each dialysis session with an inexpensive directional Doppler may identify a significant stenosis and improve the efficiency of dialysis by detecting those patients in whom the arterial and venous needles are reversed.

Isolation of CD34+ cells from blood stem cell components using the Baxter Isolex system.

The CD34 antigen is expressed by human hematopoietic progenitor and stem cells. These cells are capable of reconstituting marrow function after marrow-ablative chemo-radiotherapy. Several different technologies have been developed for the separation of CD34+ cells from bone marrow or peripheral blood stem cell (PBSC) components. We used an immunomagnetic separation technique to enrich CD34+ cells from PBSC components in anticipation of autologous transplantation for patients with B lymphoid malignancies. Twenty-nine patients enrolled on this study and received mobilization chemotherapy followed by G-CSF. Of these, 21 achieved a peripheral blood CD34+ cell level of at least 2.0 x 10(4)/l required by protocol for separation of the stem cell components. A median of three components per patient was collected for processing. The average CD34+ cell concentration in the components after apheresis was 1.0 +/- 1.2%. After the CD34+ cell selection, the enriched components contained 0.6 +/- 0.6% of the starting nucleated cells. The recovery of CD34+ cells, however, averaged 58.4 +/- 19.2% of the starting cell number, with a purity of 90.8 +/- 6.5%. Overall depletion of CD34- cells was 99.96 +/- 0.06%. Nineteen patients were treated with marrow-ablative conditioning regimens and received an average of 6.2 +/- 2.0 x 10(6) CD34+ cells/kg body weight. These patients recovered to an ANC >0.5 x 10(9)/l at a median of 11 days (range 8-14), and platelet transfusion independence at a median of 9 days (range 5-13). Four patients died of transplant-related complications or relapse before 100 days after transplantation. No patient required infusion of unseparated cells because of failure of sustained bone marrow function. These data demonstrate that peripheral blood-derived CD34+ cells enriched by use of an immunomagnetic separation technique are capable of rapid engraftment after autologous transplantation.

Status of the valves in the superficial and deep venous system in chronic venous disease.

The relationship between the functional status of the venous valves in the superficial and deep veins and ulceration was evaluated in 42 patients. Twenty-five patients had ulcers, 12 of these patients had a history of previous deep venous thrombosis and 13 of these patients denied such an event. Seventeen patients had normal ankle skin, 10 of these patients had a documented history of deep vein thrombosis and seven of these patients had varicose veins only. An ultrasonic duplex scanner was used to document the presence of reflux in all segments of the superficial and deep system. In the entire group of 25 limbs with ulceration, valvular incompetence was noted in 22 limbs at levels involving segments that communicated with the ulcer-bearing area. Of the 17 limbs with normal ankle skin, in only two instances was a single segment of posterior tibial vein in midcalf found to be incompetent. For those patients with normal ankle skin and a history of varicose veins, the deep veins below the common femoral vein level were always competent.

The mechanism of venous valve closure. Its relationship to the velocity of reverse flow.

Venous valves will close when the reversal of the normal pressure gradient generates a sufficient reverse flow velocity. By testing 20 healthy subjects with ultrasonic duplex scanning and controlled limb compression. It was found that the velocity of reflux is related to the external compression pressure. Valve closure is an abrupt cessation of reverse flow. In this study, with subjects in a supine position, valve closure was achieved only after reverse velocities exceeded 30 cm/s. This velocity was not generated by manual compression of the limb. With a Valsalva maneuver, this velocity is achieved only in the common femoral vein in 90% of the tested individuals. The reflux velocities in response to a Valsalva maneuver are progressively lower in more distal veins--the profunda femoris, the superficial femoral vein, and the popliteal vein. With reverse velocities lower than 30 cm/s, the valves will not close and reflux can persist. Valsalva's maneuver only allows a diagnosis of valvular competence at the most proximal level in the venous tree.

An objective assessment of the physiologic changes in the postthrombotic syndrome.

To determine what physiologic changes might contribute to the development of the postthrombotic syndrome, venous outflow, venous refilling time, and valvular competence were assessed in 32 patients (39 limbs) with documented deep venous thrombosis. The follow-up ranged from nine to 144 months (mean, 41 months) after the acute deep venous thrombosis. Pain was noted by 49% of the patients, but more objective end points occurred less frequently (edema, 21%; pigmentation, 26%; ulceration, 3%). Venous outflow was lower in the affected limbs but was not a good indicator of those patients with or without symptoms. Venous refilling time after calf compression was markedly reduced in limbs with incompetent valves (mean +/- SD, 8.4 +/- 3.8 s v 25.3 +/- 12.1 s), as well as in those with edema, pigmentation, and ulceration. It appears that most of the sequelae of the postthrombotic syndrome can be attributed to the loss of valvular function.

Platelet serotonin transporter in children and adolescents with obsessive-compulsive disorder or Tourette's syndrome.

UNLABELLED: Previous studies of serotonin transporter protein (5HTPR) indexed in platelets by 3H-imipramine demonstrate reduction in children with comorbid obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). OBJECTIVE: To use the 5HTPR selective ligand 3H-paroxetine and homogeneous diagnostic groups to reevaluate these findings. METHOD: Platelet Kinetic binding parameters were evaluated using standard techniques from medication-free child and adolescent patients with OCD (n = 18), with TS (n = 10), and normal controls (n = 19). RESULTS: Baseline binding capacity (Bmax) was significantly reduced in patients with OCD (1,342 +/- 952 fmol/mg; protein p < .01) compared with normal controls (2,486 +/- 1309 fmol/mg) and TS patients (2,420 +/- 1,069 fmol/mg; p < .05). Among OCD patients who were subsequently treated on an open-label basis with selective serotonin reuptake inhibitor (SSRI), Bmax values at baseline differentiated between responders (1,718 +/- 1,041 fmol/mg) and nonresponders (802 +/- 713 fmol/mg protein; p < .05). Response to SSRI was greatest in patients with a positive family history of OCD. Among responders (n = 10), baseline Yale-Brown Obsessive Compulsive Scale and Bmax were positively correlated (r = .76, p = .01), as was Clinical Global Impression (r = .67, p = .03). CONCLUSIONS: Platelet 5HTPR capacity (Bmax) is reduced in children and adolescents with OCD, but not in those with TS. 5HTPR may be an indirect measure of basal serotonergic tone.

Platelet serotonin transporter in depressed children and adolescents: 3H-paroxetine platelet binding before and after sertraline.

OBJECTIVE: To evaluate serotonin transporter protein (5HTPR) binding in platelets from children and adolescents with major depression (MDD) compared to normal controls using the selective ligand 3H-paroxetine. METHOD: Children and adolescents with MDD (n = 24) defined by DSM-III-R criteria and normal controls (n = 22) were compared by platelet 5HTPR kinetic analysis with the hypothesis that 5HTPR is reduced in MDD. A subset of MDD subjects (n = 18) continued to participate in a fixed-dose, open-label sertraline trial for 6 weeks followed by drug-free washout and repeated 5HTPR analysis. RESULTS: Sex, prepubertal status, and age had no effect on 5HTPR. Medication-free MDD subjects differed from controls in reduced binding capacity (Bmax) (p < .001). Sertraline therapy decreased binding affinity from baseline non-selectively (p < .05), and Bmax elevation from baseline was associated with nonresponse and suicide attempt history. CONCLUSION: Earlier literature in this population is replicated with regard to reduced platelet 5HTPR Bmax in MDD. Findings support a continuum of 5HTPR involvement in MDD across the developmental spectrum.

Pseudocolor displays in B-mode imaging applied to echocardiography and vascular imaging: an update.

Cardiac and vascular ultrasound systems incorporting colorized gray-scale display options to supplement the standard B-mode gray-scale image have recently reappeared on the market from several manufacturers. As yet, the clinical benefit of this "new" technology is unknown, and recommendations and protocols for its best application are not available. This article reviews the limitations of the gray-scale displays currently used, the rationale of the color-supplemented B-mode image, and some of the potential applications to cardiac and vascular ultrasound.