Israel Medical Association Journal

Background: Cell-mediated immunity is impaired in uremia. Cell-matrix interactions of immune cells such as CD4+T lymphocytes with extracellular matrix are an important requirement for an intact immune response. The adherence of CD4+T cells of healthy subjects (normal T cells) to ECM components is inhibited in the presence of uremic serum. Such decreased adhesive capacity is also found in T cells of dialysis patients. Various chemokines and cytokines affect the attachment of CD4+T cells to ECM.

Objective: To evaluate chemokine (MIP-1β and RANTES) and tumor necrosis factor α-induced adhesion of CD4+T cells to ECM in a uremic milieu.

Methods: We examined adhesion of normal CD4+T cells (resting and activated) to intact ECM in response to soluble or bound chemokines (MIP-1β and RANTES) and to TNF-α following incubation in uremic versus normal serum. Thereafter, we evaluated the adhesion of resting CD4+T cells from dialysis patients in a similar fashion and compared it to that obtained from a healthy control group.

Results: Addition of uremic serum diminished soluble and anchored chemokine-induced attachment of normal resting and activated CD4+T cells to ECM compared to a normal milieu (a peak response of 10–11% vs. 24–29% for soluble chemokines, P<0.001; 12–13% vs. 37–39% for bound chemokines on resting cells, P<0.01; and 18–20% vs. 45–47% for bound chemokines on activated cells, P<0.02). The same pattern of response was noted following stimulation with immobilized TNF-α (7 vs. 12% for resting cells, P<0.05; 17 vs. 51% for activated cells, P<0.01).  Adherence of dialysis patients’ cells to ECM following stimulation with both bound chemokines was reduced compared to control T cells (15–17% vs. 25–32%, P<0.0000). In contrast, adherence following stimulation by TNF-α was of equal magnitude.

Conclusions: Abnormal adhesive capacity of T lymphocytes to ECM in uremia may, in part, be related to a diminished response to MIP-1β, RANTES and TNF-α. However, whereas reduced adhesion to chemokines was present in both normal CD4+T cells in a uremic environment and in dialysis patients’ T cells, TNF-α-induced adhesion was found to be inhibited only in normal cells in a uremic milieu.

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ECM = extracellular matrix

TNF-α = tumor necrosis factor-a

Background: Articular cartilage is incapable of undergoing self-repair since chondrocytes lose their mitotic ability as early as the first year of life. Defects in articular cartilage, especially in weight-bearing joints, will predictably deteriorate toward osteoarthritis.  No method has been found to prevent this deterioration. Drilling of the subchondral bone can lead to fibrocartilage formation and temporary repair that slowly degrades. Animal experiments indicate that introducing proliferating chondrocytes such as cultured articular chondrocytes can reliably reconstruct joint defects.

Objectives: To describe our clinical experience in culturing and transplanting autologous chondrocytes. 

Methods: Biopsies were obtained from 10 patients, aged 18–45, undergoing a routine arthroscopy in which a cartilage defect was identified with indications for cartilage transplantation. The biopsies were further processed to establish chondrocyte cultures. ACT was performed in 8 of the 10 patients because of persistent symptoms for at least 2 months post-arthroscopy. All patients (6 men and 2 women) had a grade IV cartilage defect in the medial or lateral femoral condyle, and three had a defect in the trochlear region as well. Biopsies were removed from the lateral rim of the superior aspect of the femur, and cells were cultured in a clean room. Following a 2 order of magnitude expansion, cells were implanted under a periosteal flap.

Results: The eight patients implanted with autologous cells were followed for 6 months to 5 years (average 1 year). Complaints of giving-way, effusion and joint locking resolved in all patients, and pain as assessed by the visual analogue score was reduced by an average of 50%. Follow-up magnetic resonance imaging studies in all patients revealed that the defects were filled with tissue having similar signal characteristics to cartilage.

Conclusions: Chondrocyte implantation is a procedure capable of restoring normal articular cartilage in cases with isolated joint defects. Pain can be predictably reduced, while joint locking and effusion are eliminated. The effect on osteoarthritis progression in humans has not yet been elucidated.

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ACT = autologous chondrocyte transplantation

Background: Spectral analysis of heart rate variability has been shown to be a reliable non-invasive test for quantitative assessment of cardiovascular autonomic regulatory responses, providing a window reflecting the interaction of sympathetic and parasympathetic tone. Alterations in autonomic function are associated with a variety of physiologic and pathophysiologic processes and may contribute substantially to morbidity and mortality. Our previous study shows that patients with post-traumatic stress disorder have significantly lower HRV compared to controls, reflecting a basal autonomic state characterized by increased sympathetic and decreased parasympathetic tone.

Objectives: To apply this tool to PTSD patients treated with selective serotonin re-uptake inhibitors in order to assess the impact of such treatment on the autonomic dysregulation characterizing these patients.

Methods: Standardized heart rate analysis was carried out in nine PTSD patients treated with SSRI agents and compared to that in a matched control group of nine healthy volunteers and in nine untreated PTSD patients, based on a 15 minute resting electrocardiogram.

Results: Our preliminary results show that the HRV parameters indicating autonomic dysregulation, which characterize PTSD patients at rest, are normalized in responding patients by use of SSRIs. Neither the clinical implications of these findings nor their physiological mechanisms are clear at present, although we presume that they reflect a central effect, since the peripheral autonomic effects of SSRIs are relatively negligible.   

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HRV = heart rate variability

PTSD = post-traumatic stress disorder

SSRI = selective serotonin re-uptake inhibitor

Background: Despite current treatment protocols, the long-term complications of insulin-dependent diabetes mellitus have prompted the investigation of strategies for the prevention of IDDM.

Objectives: To investigate the effect of oral vanadate in reducing diabetes type I in non-obese diabetic mice.

Methods: Sodium metavanadate, 3.92 mmol/L, was added to the drinking water of 8-week-old female NOD mice. Blood glucose levels, water consumption and body weight were measured, and the end point of the study was judged by the appearance of hyperglycemia in the mice.

Results: Treatment with vanadate did not significantly reduce the incidence of type I diabetes as compared to the control group. However, oral vanadate therapy significantly reduced the blood glucose levels after the fourth week of treatment compared to the control group (3.83±10.67 vs. 4.44±10.83 mmol/L, P<0.03). There was a consistent and significant increase in body weight of the vanadate-treated pre-diabetic NOD mice compared to the controls. Diabetic mice treated with vanadate had significantly lower levels of serum insulin as compared to control diabetic mice (104±27 vs. 151±36 mol/L, P<0.03). Histologically, no significant differences were found in inflammatory response of the islets of Langerhans between the control and treated groups.

Conclusions: This study suggests that the post-receptor insulin-like effect induced by vanadate is not sufficient to prevent the development of diabetes and insulitis in pre-diabetic NOD mice.

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IDDM= insulin-dependent diabetes mellitus

NOD= non-obese diabetic

Background: Cholestasis is a frequent problem in patients on total parenteral nutrition. Cisapride has a prokinetic effect on the biliary system, but its effect on hepatic excretory function is unknown.

Objectives: To study the effect of cisapride on TPN-induced cholestasis in a rat model.

Methods: Bile flow and bile salt secretion rate were measured in rats given TPN. There were four groups of 8 to 13 animals each. After a one hour baseline period during which all four groups received i.v. saline infusion, two groups received a TPN solution for another 2 hours, while saline was infused in the two control groups.

At the beginning of the second hour, 2 mg/kg cisapride was injected i.v. as a bolus into one experimental and one control group. Bile was collected from the common bile duct.

Results: At the end of the third hour, TPN caused a significant reduction in bile flow (P<0.02) and bile salt secretion rate (P<0.001) (61.24 vs. 50.74 µl/min/kg, and 1.173 vs. 0.799 µmol/min/kg, respectively). Addition of cisapride abolished the cholestatic effect of TPN.

Conclusions: Cisapride has a protective effect against TPN-associated cholestasis. This may have clinical significance, and further studies are warranted.

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TPN= total parenteral nutrition
 

Background: Anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital malformation that presents a diagnostic challenge to the pediatrician and pediatric cardiologist. Although surgical repair is always indicated, the optimal technique has yet to be determined.      

Objectives: To review our experience with the diagnosis of children with ALCAPA and to assess short to midterm surgical results.

Methods: Between 1992 and 1998, 13 infants and children (2 months to 15 years) were treated for ALCAPA at our medical center. Eight were diagnosed during the first year of life; all were symptomatic and had severe dysfunction of the left ventricle. The five patients diagnosed at an older age had normal myocardial function. Diagnosis was established by echocardiography alone in seven patients; six required catheterization (one infant and all older patients). Surgery was performed in 12 patients to establish dual coronary artery system: 7 underwent the Takeuchi procedure and 5 had re-implantation of the anomalous left coronary artery.

Results: One infant died shortly after diagnosis before surgical repair was attempted, and one died postoperatively. Four patients required additional surgery: three for late complications of the Takeuchi procedure and one valve replacement for mitral insufficiency. Recent evaluation revealed good global left ventricle function in all patients except for one, who is still within the recovery phase and shows gradual improvement. However, most patients who presented with severe myocardial dysfunction upon diagnosis still display abnormal features such as echo-dense papillary muscles or evidence of small akinetic segments. In this group, early repair was associated with faster myocardial recovery.

Conclusions: The diagnosis of ALCAPA remains a clinical challenge to the pediatrician and cardiologist. Diagnosis can be established echocardiographically, and early diagnosis and treatment may lead to faster myocardial recovery. The preferred surgical method appears to be re-implantation of the ALCA. The chance for good recovery of global ventricular function is high even in the sickest patients, nonetheless abnormal myocardial features can be identified even years after surgery.

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ALCAPA= anomolous origin of the left coronary artery from pulmonary artery.

Background: The need for aortic valve replacement in children and young adults poses a special problem to cardiologists and surgeons. Replacing the sick aortic valve with the patient’s pulmonary valve as described by Ross has proven to be a good option in this special age group.

Objective: To review our initial experience in order to assess the short-term results.

Methods: From January 1996 to June 1999, 40 patients (age 8 months to 41 years) underwent aortic valve replacement with pulmonary autograft. Indications for surgery were congenital aortic valve disease in 30 patients, bacterial endocarditis in 5, rheumatic fever in 3, and complex left ventricular outflow tract obstruction in 3. Trans-esophageal echocardiography was performed preoperatively and post-bypass in all patients, and transthoracic echocardiography was done prior to discharge and on follow-up.

Results: There was no preoperative or late mortality. All patients remain in functional class I (New York Heart Association) and are free of complications and medication. None showed progression of autograft insufficiency or LVOT obstruction. Homograft insufficiency in the pulmonary position has progressed from mild to moderate in one patient, and three developed mild homograft stenosis.

Conclusions: The Ross procedure can be performed with good results in the young population and is considered an elegant surgical alternative to prosthetic valves and homografts.

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LVOT = left ventricular outflow tract

Background: Small bowel obstruction with perforation is an unusual and rare complication of bezoars.

Objective: To describe our use of emergency laparotomy to treat intestinal obstruction caused by bizarre bezoars.

Conclusions: An aggressive surgical approach to intestinal obstruction in the pediatric disabled or mentally retarded population is recommended.
 

Objective: To describe the clinical and epidemiological features of hepatitis B virus infection in Israeli children, and to evaluate their response and compliance to therapy.

Methods: We retrospectively studied 51 patients (34 males, 17 females), aged 2–18 years, from several medical centers in Israel.

Results: Of the 51 patients, 38 with elevated transaminase, positive hepatitis B e antigen and/or HBV DNA, and histologic evidence of liver inflammation were treated. Interferon was administered by subcutaneous injections three times a week for 3-12 months (dosage range 3–6 MU/m²). Only 16% were native Israelis, while 78% of the children were of USSR origin. A family history of HBV infection was recorded in 25 of the 51 patients (9 mothers, 16 fathers or siblings). Five children had a history of blood transfusion. The histological findings were normal in 3 patients, 24 had chronic persistent hepatitis, 14 had chronic active hepatitis and 2 had chronic lobular hepatitis. Five children also had anti-hepatitis D virus antibodies. Twelve of the 38 treated patients (31.5%) responded to IFN completely, with normalization of the transaminase levels and disappearance of HBeAg and HBV DNA. In no patient was there a loss of hepatitis B surface antigen. The main side effects of IFN were fever in 20 children, weakness in 10, headaches in 9, and anorexia in 6; nausea, abdominal pain, and leukopenia were present in 3 cases each. The response rate was not affected by age, country of origin, alanine/aspartate aminotransferase levels, or histological findings. However, a history of blood transfusion was a predictor of good response, 60% vs 27% (P<0.05).

Conclusions: We found IFN to be a safe and adequate mode of treatment in children with chronic HBV infection, regardless of their liver histology and transaminase levels. Therefore, in view of the transient side effects associated with this drug, we recommend considering its use in all children with chronic hepatitis B. 

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HBV = hepatitis B virus

IFN = interferon

HBeAg = hepatitis B e antigen

Background: Previous studies have documented an increased incidence of cardiac mortality and sudden death during winter months.

Objectives: To evaluate seasonal variation in sudden death in a hot climate such as the desert region of southern Israel.

Methods: We analyzed the files of 243 consecutive patients treated for out-of-hospital sudden death by the Beer Sheva Mobile Intensive Care Unit during 1989-90. Daily, monthly and seasonal incidence of sudden death was correlated with meteorological data, including temperature, heat stress, relative humidity and barometric pressure.

Results: The seasonal distribution of sudden death was 23% in spring, 21% in summer, 25% in autumn and 31% in winter (not significant). In patients with known heart disease there were more episodes of sudden death in cold weather (<15.4°C) than hot (>34.2°C) (16 vs. 3, P<0.05). Resuscitation was less successful in cold compared with hot weather (28 vs. 11, P<0.05). Of patients older than 65 years, 11 sustained sudden death when heat stress was below 12.4°C compared to 2 patients when heat stress was above 27.5°C (P=0.05).

Conclusion: Despite the warm desert climate, there were more cases of sudden death in older patients and in those with known heart disease during the winter season and on particularly cold days.
 

Background: Hallway medicine is an integral part of physicians' medical culture, but little is known about it.

Objective: To characterize the practice of hallway medicine among hospital physicians, both as providers and consumers.

Methods: We conducted a survey of 112 randomly chosen hospital physicians at the Soroka Medical Center in Beer Sheva, Israel between November 1997 and May 1998. A self-administered 39-item questionnaire was used that included sociodemographic data, the extent to which hallway medicine is practiced, and satisfaction from and attitudes to it.

Results: Of the 112 selected physicians, 111 responded (99.1%). Of these, 91 (82%) had been asked by their colleagues to provide hallway medicine. Most of them (91%) agreed because of "willingness to help," because "it's unpleasant to refuse," or "it's the acceptable thing to do." Most of the requests (72%) were unscheduled and time consuming (41% up to 10 minutes and 21% more than 20 minutes). Records were kept in only 36% of the cases and follow-up in 62%. Physicians who provided hallway medicine were also consumers of it (P<0.001), based on personal acquaintance, time saved and easy accessibility. In general, the attitude to hallway medicine was negative (54%) or ambiguous (37%). Most requests for hallway medicine were made to Israeli-trained physicians, surgeons or gynecologists, and senior physicians.

Conclusions: Hallway medicine is practiced frequently among hospital physicians. A formal organization of health care service within medical centers might provide physicians with better medical care and reduce potential ethical, medical, legal, psychosocial and economic problems.

Background: Acute respiratory distress syndrome is a well-recognized condition resulting in high permeability pulmonary edema associated with a high morbidity.

Objectives: To examine a 10 year experience of predisposing factors, describe the clinical course, and assess predictors of mortality in children with this syndrome.

Methods: The medical records of all admissions to the pediatric intensive care unit over a 10 year period were evaluated to identify children with ARDS¹. Patients were considered to have ARDS if they met all of the following criteria: acute onset of diffuse bilateral pulmonary infiltrates of non-cardiac origin and severe hypoxemia defined by <200 partial pressure of oxygen during ³6 cm H2O positive end-expiratory pressure for a minimum of 24 hours. The medical records were reviewed for demographic, clinical, and physiologic information including PaO2² /forced expiratory O2, alveolar–arterial O2 difference, and ventilation index.

Results: We identified 39 children with the adult respiratory distress syndrome. Mean age was 7.4 years (range 50 days to 16 years) and the male:female ratio was 24:15. Predisposing insults included sepsis, pneumonias, malignancy, major trauma, shock, aspiration, near drowning, burns, and envenomation. The mortality rate was 61.5%. Predictors of death included the PaO2/FIO2, ventilation index and A-aDO2³ on the second day after diagnosis. Non-survivors had significantly lower PaO2/FIO2 (116±12 vs. 175±8.3, P<0.001), and higher A-aDO2 (368±28.9 vs. 228.0±15.5, P<0.001) and ventilation index (43.3±2.9 vs. 53.1±18.0, P<0.001) than survivors.

Conclusions: Local mortality outcome for ARDS is comparable to those in tertiary referral institutions in the United States and Western Europe. The PaO2/FIO2, A-aDO2 and ventilation index are valuable for predicting outcome in ARDS by the second day of conventional therapy. The development of a local risk profile may allow early application of innovative therapies in this population. 

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¹ARDS = acute respiratory distress syndrome

² PaO2 = partial pressure of oxygen

³A-aDO2 = alveolar–arterial O2 difference