Israel Medical Association Journal

Background: The cognitive impairment (frontal, parietal) in many patients with multiple sclerosis does not correlate with the degree of neurological disability and disease duration. Frontal/prefrontal cognitive impairment requires neuropsychological diagnostic tools.

Objectives: To evaluate the clinical effect of IFNβ-1b[1] (Betaferon®) treatment on cognitive function and event-related potential as compared to the clinical course (EDSS[2]) in MS patients during 1 year of follow-up.

Methods: This prospective open-label design study included 16 consecutive patients with relapsing forms of MS attending the MS outpatient clinic. Mean EDSS score was calculated prior to starting treatment. Parietal lobe event-related potential P300 was elicited using an auditory physical stimulus to an alert subject. Mean P300 amplitude and latency were calculated for the group before treatment. The Wisconsin Card Sorting Test, which measures frontal lobe functions, was performed before the treatment. After 1 year of treatment a second P300 and Wisconsin Card Sorting Test were performed and the mean change between visit 1 and baseline was calculated for each parameter. Correlation between the change in P300 and the Wisconsin Card Sorting Test score at baseline was measured using the paired t-test.

Results: There was a significant reduction in P300 amplitude and latency after 1 year of treatment with IFNβ-1b: from 20.3 ± 8.3 μv to 13.1 ± 10.6 μv (P = 0.026) for amplitude, and from 312.9 ± 15.6 msec to 302.0 ± 17.0 msec (P = 0.002) for latency. The Perseverative Response (raw score) and the Perseverative Response U.S. Census age-matched standard score showed a significant improvement – from 20.7 ± 30.7 to 13.1 ± 10.6 (P = 0.001) and 96.7 ± 15.7 to 100.1 ± 11.1 (P = 0.0025) respectively – after 1 year of treatment. A mild but not significant improvement was observed on the EDSS after 1 year of treatment: 2.9 ± 0.5 to 2.8 ± 1.1.

Conclusions: A cognitive decline in MS patients may have a negative impact on the quality of life, affecting all active daily living domains. IFNβ-1b, a disease-modifying therapy, has demonstrated a positive therapeutic effect on cognitive dysfunction, unrelated to its effect on the EDSS score and course of the disease.

Background: Heart failure with preserved systolic left ventricular function is a major cause of cardiac disability.

Objectives: To examine the prevalence, characteristics and late clinical outcome of patients hospitalized with HF-PSF[1] on a nationwide basis in Israel.

Methods: The Israel nationwide HF survey examined prospectively 4102 consecutive HF patients admitted to 93 internal medicine and 24 cardiology departments in all 25 public hospitals in the country. Echocardiographic LV function measurements were available in 2845 patients (69%). The present report relates to the 1364 patients who had HF-PSF (LV ejection fraction ≥ 40%).

Results: Mortality of HF-PSF patients was high (in-hospital 3.5%, 6 months 14.2%, 12 months 22.0%), but lower than in patients with reduced systolic function (all P < 0.01). Mortality was higher in patients with HF as the primary hospitalization diagnosis (16.0% vs. 12.5% at 6 months, P = 0.07 and 26.2% vs. 18.0% at 12 months, P = 0.0002). Patients with HF-PSF who died were older (78 ± 10 vs. 71 ± 12 years, P < 0.001), more often female (P = 0.05) and had atrial fibrillation more frequently (44% vs. 33%, P < 0.01). There was also a relationship between mortality and pharmacotherapy: after adjustment for age and co-morbid conditions, mortality was lower in patients treated with angiotensin-converting enzyme inhibitors (P = 0.0003) and angiotensin receptor blockers (P = 0.002) and higher in those receiving digoxin (P = 0.003) and diuretic therapy (P = 0.009).

Conclusions: This nationwide survey highlights the very high late mortality rates in patients hospitalized for HF without a decrease in systolic function. The findings mandate a focus on better evidence-based treatment strategies to improve outcome in HF-PSF patients.

Background: Echocardiographic ventricular function predicts prognosis and guides management in patients with acute coronary syndromes. In elderly patients, interpretation of echocardiographic measurements may be difficult, especially regarding assessment of diastolic left ventricular function.

Objectives: To examine the usefulness of echocardiographic systolic and echocardiographic diastolic LV[1] function measurements as predictors of long-term outcome in elderly patients with ACS[2].

Methods: We studied 142 consecutive elderly patients (≥ 70 years old, mean age 80 ± 6 years) with ACS who had an echocardiogram at index hospitalization and were in sinus rhythm. LV ejection fraction and diastolic mitral inflow pattern were examined as predictors of survival and repeat hospitalization over a period of 18–24 months.

Results: During the 2 year mean follow-up period 35/142 patients died (25%). Survival was lower in patients with EF[3] < 40% (n=42) as compared to EF ≥ 40% (n=100) (2 year survival rate 61% vs. 81%, P = 0.038). Patients with severe diastolic dysfunction (a restrictive LV filling pattern, n=7) had a lower survival rate than those without (43 vs. 76%, P = 0.009). The most powerful independent predictor of mortality was a restrictive filling pattern (hazard ratio 4.6, 95% confidence interval 1.6–13.5), followed by a clinical diagnosis of heart failure on admission and older age. Rate of survival free of repeat hospitalization was low (33% at 18 months) but repeat hospitalization was not predicted either by EF or by a restrictive filling pattern.

Conclusions: As in the young, echocardiographic measurements of systolic and diastolic LV function predicted long-term survival in elderly patients with ACS. A restrictive filling pattern was the strongest independent predictor of mortality.

Background: Endothelial dysfunction is recognized as a major factor in the development of atherosclerosis and it has a prognostic value.

Objectives: To detect the long-term association of peripheral vascular endothelial function and clinical outcome in healthy subjects and patients with cardiovascular disease.

Methods: We prospectively assessed brachial artery flow-mediated dilation in 110 consecutive subjects (46 CVD[1] patients and 64 healthy controls), mean age 57 ± 11 years; 68 were men. After an overnight fast and discontinuation of all medications for ≥ 12 hours, percent improvement in FMD and nitroglycerin-mediated vasodilatation were assessed using high resolution ultrasound.

Results: %FMD[2] but not %NTG[3] was significantly lower in CVD patients (9.5 ± 8.0% vs. 13.5 ± 8.0%, P = 0.012) compared to healthy controls (13.4 ± 8.0% vs. 16.7 ± 11.0%, P = 0.084; respectively). In addition, an inverse correlation between %FMD and the number of traditional CVD risk factors was found among all study participants (r = -0.23, P = 0.015) and healthy controls (r = -0.23, P = 0.036). In a mean follow-up of 15 ± 2 months, the composite CVD endpoints (all-cause mortality, myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting and percutaneous coronary interventions) were significantly more common in subjects with FMD < 6% compared to subjects with FMD > 6% (33.3% vs. 12.1%, P < 0.03, respectively).
Conclusions: Thus, brachial artery %FMD provides important prognostic information in addition to that derived from traditional risk factor assessment

Background: Echocardiographic assessment of left ventricular function includes calculation of ejection fraction and regional wall motion analysis. Recently, speckle imaging was introduced for quantification of left ventricular function.

Objectives: To assess LVEF[1] by speckle imaging and compare it with Simpson’s method, and to assess the regional LV strain obtained by speckle imaging in relation to conventional echocardiographic scores.

Methods: Thirty consecutive patients, 28 with regional LV dysfunction, underwent standard echocardiographic evaluation. LV end-diastolic volume, LV end-systolic volume and EF were calculated independently by speckle imaging and Simpson’s rule. The regional peak systolic strain presented by speckle imaging as a bull's-eye map was compared with the conventional visual estimate of echo score.

Results: Average EDV[2] obtained by speckle imaging and by Simpson’s method were 85.1 vs. 92.7 ml (P = 0.38), average ESV[3] was 49.4 vs. 48.8 ml (P = 0.94), calculated EF was 43.9 vs. 50.5% (P = 0.08). The correlation rate with Simpson’s rule was high: 0.92 for EDV, 0.96 for ESV, and 0.89 for EF. The peak systolic strain in two patients without wall motion abnormality was 17.3 ± 4.7; in normal segments of patients with regional dysfunction, peak systolic strain (13.4 ± 4.9) was significantly higher than in hypokinetic segments  (10.5 ± 4.5) (P < 0.000001). The strain in hypokinetic segments was significantly higher than in akinetic segments (6.2 ± 3.6) (P < 0.000001).

Conclusions: Speckle imaging can be successfully used for the assessment of LV volumes and EF. Bull's-eye strain map, created by speckle imaging, can achieve an accurate real-time segmental wall motion analysis.

Background: The etiology of chest pain with normal epicardial coronary arteries (cardiac syndrome X) seems to be related to endothelial cell dysfunction. Multiple factors are implicated in the pathophysiology, including evelated levels of homocysteine in the blood. Mutations in the MTHFR gene are associated with evelated levels of homocysteine.

Objectives: To test whether abnormal homocysteine metabolism is associated with syndrome X.

Methods: Forty-two women with chest pain, positive stress test and normal coronary arteries (syndrome X) and 100 asymptomatic women (controls) were studied for the C677T mutation. Vitamin B12, folic acid, and plasma levels of homocysteine were also measured. Endothelial cell function was studied in 10 patients with syndrome X and homozygosity for C677T mutation, and in 10 matched healthy controls. Folic acid (5 mg daily) was prescribed to syndrome X patients after initial measurements of ECF[1]. Following 13 weeks of treatment, ECF and blood tests were repeated and compared to baseline measurements.

Results: Homozygosity for C677T mutation was doubled in syndrome X vs. control (33%, 14/42 vs. 16%, 16/100, P < 0.02), and homocysteine levels were increased (9.16 ± 2.4 vs. 8.06 ± 2.6 μmol/L, P = 0.02). In the 10 homozygous patients, homocysteine levels decreased significantly after treatment with 5 mg/day folic acid (10 ± 3.3 vs. 5.4 ± 1.1 µmol/L, P = 0.004). Abnormal baseline ECF improved after treatment with folic acid: flow-mediated dilatation was greater (11.3 ± 7.9% vs. 0.7 ± 4.5%, P < 0.002), as was nitroglycerin-mediated dilatation (15.2 ± 9.0% vs. 5.6 ± 6.4%, P < 0.003). Frequency of chest pain episodes was significantly reduced after 13 weeks of folic acid treatment.

Conclusion: Our findings establish the association between the C677T mutation, endothelial cell dysfunction and cardiac syndrome X, and provide a novel and simple therapy for a subset of patients with syndrome X and homozygosity for the C677T mutation.

Background: Ion Channel Innovations has developed a gene transfer product, ftMaxi-K, and has begun clinical trials to investigate the effect of increased expression of Maxi-K channels in the smooth muscle of the penis or bladder in patients with erectile dysfunction and those with overactive bladder. The primary function of K channels is to modulate Ca⁺⁺ influx through Ca-channels (i.e., L-type, voltage-dependent). The amount of Ca⁺⁺ that enters the cell through these channels is a major determinant of the free intracellular calcium levels inside the smooth muscle cell, which in turn determines the degree of smooth muscle cell contraction. Increased Maxi-K channel activity is associated with smooth muscle cell relaxation, resulting in, for example, penile erection and detrussor muscle relaxation. A phase I clinical trial that used dMaxi-K has been completed and a similar trial to assess safety of the transfer for overactive bladder is about to begin.

Objectives: To assess the safety and tolerability of escalating dMaxi-K doses by clinical evaluations and laboratory tests, and to measure efficacy objectives by means of the International Index of Erectile Function scale.

Methods: In the erectile dysfunction trial 11 patients with moderate to severe erectile dysfunction were given a single-dose corpus cavernosum injection of dMaxi-K, a "naked" DMA plasmid carrying the human cDNA encoding for the gene for the a, or pore-forming, subunit of the human smooth muscle Maxi-K channel, hSIo. Three patients each were given 500,1000, and 5000 pg and two patients were given 7500 pg doses of ftMaxi-K and followed for 24 weeks. Patient responses were validated by partner responses.

Results: There were no serious adverse events and no dose-related adverse events attributed to gene transfer for any patient at any dose or study visit. No clinically significant changes from baseline were seen in physical evaluations (general and genitourinary), hematology, chemistry and hormone analyses, or in cardiac events evaluated by repeated electrocardiograms. Importantly, no plasmid was detected in the semen of patients at any time after the injections. Patients given the two highest doses of dMaxi-K had apparent sustained improvements in erectile function as indicated by improved IIEF-EF domain scores over the length of the study. One patient given 5000 (jg and one given 7500 [jg reported EF category improvements that were highly clinically significant and were also maintained through the 24 weeks of study.
Conclusions: Efficacy conclusions cannot be drawn from results of a phase 1 trial with no control group. However, the promising primary safety outcomes of the study and preliminary indications of effectiveness provide evidence that ftMaxi-K gene transfer is a viable approach to the treatment of erectile dysfunction and other smooth muscle diseases with targeted access

Background: Measurement of function is an essential component of routine rehabilitation work (mainly for quantifying function at different phases in the rehabilitation process), rehabilitation policy (admission and discharge criteria, length of stay in rehabilitation), goal setting, and outcome measurement.

Objective: To explore the scope of the scales used for function assessment by the various disciplines of rehabilitation medicine in rehabilitation facilities.

Method: A structured questionnaire was sent to 36 rehabilitation facilities. Respondents were asked to specify the scales they use for functional assessment for each of 15 selected pathologies. Also examined were satisfaction with the scales, as well as the existence of a computerized database of routine function assessment in the facility and the willingness to create a national agreed “common data set” of the assessments.

Results: The general response rate was 86.1% (31 of 36 questionnaires were returned). For the sake of data presentation, rehabilitation facilities were classified into four categories: general, geriatric, pediatric, and community. Most facilities performed function assessment using a total of 125 scales. Heterogeneity was found between facilities and between pathologies. The highest number of scales was found in the area of neurologic pathologies. For most pathologies, assessment of impairment was used more than assessment of disability. Most facilities in the survey did not have a computerized database of function assessments.

Conclusions: A “common data set” of function assessments in everyday clinical work would ensure standardization without necessarily limiting the use of additional scales and at the same time significantly minimize the current heterogeneity.
 

Objectives: To assess the feasibility and efficacy of high dose preoperative radiotherapy and TATA[1] as a sphincter-preserving method in Jiangsu, an economically well-developed region of China with a population of 70 million people.

Methods: From September 1994 to September 2000, 25 consecutive patients with pathologically confirmed distal rectal adenocarcinoma were treated preoperatively with a total dose of 45–46 Gy at 1.8–2.0 Gy per fraction during 5 weeks. Sphincter-preserving surgery by TATA was performed 4–6 weeks after radiotherapy.　

Results: Acute toxicity of preoperative radiotherapy was tolerable. Eight percent of the patients presented pathologic complete tumor response after preoperative radiotherapy. All patients underwent TATA as scheduled. During a median follow-up of 70 months, the 5 year survival rate was 88%. The 5 year survival rate for those tumors down-staged to pathological T0 or to pT1 was 100%.

Conclusions: High dose preoperative radiotherapy and TATA as a sphincter-preserving method was feasible and efficient in Chinese patients with distal rectal cancer. In this study, the subset of patients with a good response to radiotherapy had a better clinical outcome.

Objectives: To investigate the mechanisms of these effects.

Methods: The study group included 106 long-term care stable geriatric inpatients. Diet and drugs were kept stable. The study lasted 5 weeks; during the first 2 weeks 100 mg aspirin was administered once a day. Clinical and laboratory follow-up were performed at baseline and weekly for the next 3 weeks. The glomerular filtration rate was estimated by creatinine clearance measured in 24 hour urine and serum creatinine, and by the Cockcroft-Gault formula (C-G) equation. Uric acid clearance (Cu acid) was determined from serum concentrations and 24 hour excretion of uric acid. Patients with serum creatinine > 1.5 mg/dl were not included.

Results: After 2 weeks on low dose aspirin, measured creatinine and uric acid clearances decreased significantly compared with the initial values in 70% and 62% of the patients, respectively, with mean decreases of 19% and 17%, respectively (P < 0.001). Blood urea nitrogen increased by 17% while serum creatinine and uric acid concentrations increased by 4% (P < 0.05 for all). The C-G[1] values decreased by 3% (P < 0.05). After withdrawal of aspirin all parameters improved. However, 67% of the patients remained with some impairment in their measured Ccr[2], compared to baseline. Patients who reacted adversely to low dose aspirin had significantly better pre-study renal function (Ccr), lower hemoglobin and lower levels of serum albumin.

Conclusions: Short-term low dose aspirin affected renal tubular creatinine and uric acid transport in the elderly, which may result in a prolonged or permanent deterioration of the renal function. It is suggested that renal functions be monitored even with the use of low dose aspirin in elderly patients.

Background: The degree of left ventricular dysfunction determines the prognostic outcome of patients with acute myocardial infarction.

Objectives: To define the clinical, angiographic and procedural variables related to LV[1][1] dysfunction in patients with  with anterior wall AMI[1][2] referred for primary percutaneous coronary intervention.

Methods: The sample included 168 patients treated by primary PCI[1][3] for first anterior wall AMI. Clinical, demographic and medical data were collected prospectively into a computerized registry, and clinical outcome (death, reinfarction, major cardiovascular event) were evaluated during hospitalization and 30 days after discharge. Patients were divided into three groups by degree of LV dysfunction (mild, moderate, severe) and compared for clinical, angiographic and procedural variables.

Results: LV dysfunction was associated with pre-PCI renal failure (serum creatinine > 1.4 mg/dl), peripheral vascular disease, high peak creatine kinase level, longer door to balloon time, low TIMI flow grade before and after PCI, and use of an intraaortic balloon pump. On multivariate analysis adjusted for baseline differences, peak creatine kinase level (r = 0.3, P = 0.0001) and door to needle time (r = 0.2, P = 0.008) were the most significant independent predictors of moderate or severe LV dysfunction after anterior AMI.

Conclusion: Abnormal LV function after first anterior AMI can be predicted by door to balloon time and the size of the infarction as assessed by creatine kinase levels. Major efforts should be made to decrease the time to myocardial reperfusion.

[1][1] LV = left ventricular

[1][2] AMI = acute myocardial infarction

[1][3] PCI = percutaneous coronary intervention 

Objectives: To determine whether reliable data could be obtained at lower cost.

Methods: The study sample consisted of 50 patients with mild to severe stable COPD]1[. All underwent pulmonary function test and the cardiopulmonary exercise test, 6 minute walk and 15 step exercise oximetry test as part of their regular follow-up visit. Functional capacity was graded according to each test separately and the functional capacities obtained were correlated.

Results: The results showed that most of the patients had severe COPD according to pulmonary function tests (mean forced expiratory volume in the first second 46.3 ± 19.9% of predicted value). There was a good correlation between the cardiopulmonary exercise test and the 6 minute walk functional capacity classes (r = 0.44, P = 0.0013). We did not find such correlation between the 15 step exercise oximetry test and the cardiopulmonary exercise test (r = 0.07, P = 0.64).

Conclusions: The study shows that the 6 minute walk is a reliable and accurate test in the evaluation of functional capacity in COPD patients.