Israel Medical Association Journal

Background: The highly tissue-specific trafficking of normal and malignant lymphocytes to particular organs is mediated by adhesion molecules, or “homing receptors.” Among our patients with B cell chronic lymphocytic leukemia 15% demonstrate predominantly splenic manifestations and are classified as stage II(S).

Objective: To investigate whether expression of cell surface adhesion molecules can distinguish stage II(S) patients from stage 0 or stage 0 and I CLL[1] patients.

Methods: Expression of adhesion molecules belonging to different families was studied in CD19-positive cells isolated from the blood of 42 patients by dual color flow cytometry. The families included: immunoglobulin superfamily (CD54, CD58), integrin family (β1, β2 and β3 chains, CD11a, CD11c CD49d), selectin family (L-selectin), and lymphocyte homing receptor family (CD44).

Results: The average percentage of leukemic cells expressing CD11c in the 23 patients with stage II(S) was 25.7 compared with 13.2% in the 14 patients with stage 0 disease (P = 0.047). The average percentage of leukemic cells expressing CD44 in patients with stage II(S) was 90.5 compared with 77.2% in patients with stage 0 (P = 0.007) and 80% in patients with stages 0 and I together (n=19, P = 0.008). Other adhesion molecules tested did not show a statistically significance difference in expression between the different disease stages.

Conclusions: The higher expression of CD44 and CD11c in cells of CLL patients with predominantly splenic manifestations may account for the tendency of their lymphocytes to home to the spleen.

Patients with graft-versus-host disease suffer from xerostomia, oral infections and mucosal pathologies. The continuous increase in the number of patients treated worldwide with bone marrow transplants, combined with improved survival statistics result in a concomitant increase in the number of GVHD[1] patients. the pathogenesis of GVHD is based on donor graft T lymphocytes that recognize antigenic disparities between donor and recipient, and on the disregulation of a broad panel of cytokines. Consequently, various tissues and organs, including the mucosa of the oral and gastrointestinal tract, are damaged via cytotoxicity caused by infiltrating T cells. Since the salivary glands are a known major target of GVHD and their secretions significantly contribute to preserving mucosal integrity, this mucosal insult is further enhanced by the reduced quantity and altered quality of saliva. GVHD occurs in 40–70% of patients treated by bone marrow and peripheral blood stem cell transplantation. limited studies suggest that a large percentage of GVHD patients are affected and that the induced salivary dysfunction occurs rapidly following transplantation, affecting both major and minor salivary glands and reflecting the severity of the disease. Moreover, profound sialochemical alterations may be diagnostic of GVHD. an additional reason for the vast amount of research is that GVHD, as an autoimmune-like disease, seems to be an appropriate model for studying a much more prevalent, well-known and studied autoimmune disease involving salivary glands, namely, sjögren’s syndrome. The present review describes the GVHD-related sialometric and sialochemical data available in the literature for both major and minor salivary glands in both human and rodent models, and discusses a possible mechanism.

Background: Intravenous recombinant tissue plasminogen activator therapy within 3 hours of stroke onset is a proven effective treatment for acute ischemic stroke.

Objectives: To assess the feasibility and safety of rt-PA[1] therapy for reperfusion in routine clinical practice in Israel, in a setting of a dedicated stroke unit.

Methods: Consecutive patients presenting within less than 3 hours of stroke onset were evaluated by an emergency physician and the neurology stroke team. After brain computerized tomography eligible patients were treated with intravenous rt-PA (0.9 mg/kg; maximum dose 90 mg) according to an in-hospital protocol corresponding to recommended criteria. Patients were admitted to the acute stroke unit. Safety and clinical outcome were routinely assessed. Re-canalization was assessed by serial transcranial Doppler.

Results: The study group comprised 16 patients, mean age 61 years (range 47–80 years), male to female ratio 10:6, whose median baseline National Institutes of Health stroke scale was 13 (range 6–24). They were treated within a mean door-to-CT time of 39 minutes (range 17–62 min), door-to-drug time 101 minutes (range 72–150), and stroke onset-to-drug time 151 minutes (range 90–180). There was an early improvement within 24 hours (of ≥ 4 points in the NIHSS[2] score) in 7 patients (44%) and no early deteriorations. There were no protocol deviations, no symptomatic intracranial hemorrhages, and no major systemic hemorrhage within 36 hours of rt-PA treatment. Three asymptomatic hemorrhagic transformations of the infarct were noted on routine follow-up brain CT associated with neurologic improvement. Outcome data were comparable to the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study.

Conclusion: Intravenous rt-PA treatment within 3 hours of stroke onset in routine clinical practice in Israel is feasible and appears safe in the setting of a neurology stroke unit and team. Careful implementation of rt-PA therapy for selected patients in Israel is encouraged.

Background: Unexplained pulmonary hypertension is assumed to occur mainly in young adults.

Objectives: To describe the features of the disease in older patients and compare them to those in PHT[1] patients of all ages.

Methods: We conducted a retrospective evaluation of the files of patients over 65 years of age in whom UPHT[2] was diagnosed between 1987 and 1999 at two PHT centers serving a population of 4 million. Patients were followed for survival until March 2003. Clinical variables of the study patients were compared to those in PHT patients of all ages.

Results: The study group included 14 patients, 10 females and four males, with a mean age of 70.5 ± 6.7 years. The calculated mean annual incidence of UPHT for the study population was one new case per year per million persons. Seven patients (50%) had systemic hypertension. The mean interval from onset of symptoms to diagnosis was 8.3 months. At diagnosis, 64% of patients had functional capacity of III-IV according to the New York Heart Association classification, and 43% had right heart failure. Mean systolic pulmonary artery pressure was 80 ± 21 mmHg, peripheral vascular resistance 11.7 ± 7 mmHg/L/min, cardiac index 2.16 ± 0.81, and mean right atrial pressure 10.5 ± 5.9 mmHg. Median survival time was 43 months; survival rates for 1 year, 3 years and 5 years were 92.6%, 50%, 40%, respectively. Compared to data from the U.S. National Institute of Health Registry, UPHT in older patients is more common in females, but the incidence as well as clinical, hemodynamic and survival parameters are similar to those in PHT patients at any age.

Conclusions: UPHT occurs in the elderly more frequently than previously thought, with similar features in PHT patients of all ages. The coexistence of systemic and pulmonary hypertension warrants further investigation.

Background: Pyoderma gangrenosum is an uncommon ulcerative cutaneous condition associated with inflammatory bowel disease. PG[1] occurs rarely in IBD[2] patients and there are insufficient data on the clinical manifestations of this disease with IBD.

Objective: To determine the incidence, clinical manifestations and treatment of PG in patients with IBD and the connection to IBD, its activity and extent.

Methods: All patients hospitalized with IBD at a university hospital during a 20 year period were evaluated for the occurrence of PG.

Results: Of 986 patients hospitalized for IBD 6 suffered from PG (0.6% incidence). Their average age was 37 with equal sex distribution and equal distribution of Crohn’s disease and ulcerative colitis. PG appeared 6.5 years on average after diagnosis of IBD in all patients. The development of PG correlated with significant clinical exacerbation of IBD, the majority having active colitis at the onset of the PG. Extra-intestinal manifestations of IBD occurred in half the patients (sacroiliitis, peripheral arthritis and erythema nodosum). Pathergy was not elicited in any patients. Four patients had multiple skin lesions, frequently on the lower extremities. Diagnosis was made by skin biopsy in four patients. There was little correlation between amelioration of IBD and the skin lesions. Treatment consisted of high dose steroids and immunomodulatory drugs (cyclosporine, azathioprine and dapsone) in conjunction with topical treatment.

Conclusions: PG is a rare extra-intestinal manifestation of IBD that coincides with the exacerbation of the intestinal disease but does not always respond to treatment of the bowel disease.

Background: Genetic hemochromatosis leads to iron overload in many tissues and may lead to liver cirrhosis and hepatocellular carcinoma. Early diagnosis and therapy are crucial. Since 80–100% of hemochromatosis patients of European origin are homozygous for a cysteine to tyrosine exchange in the HFE gene at codon 282, genetic screening might be useful. Representative population studies are needed to evaluate the phenotype of people heterozygous and homozygous for the C282Y mutation.

Objective: To determine the correlation between parameters of iron metabolism and the hemochromatosis genotype in a large population-based study.

Methods: A representative population-based survey, the Diabetomobil study, analyzed 5,083 German probands. Serum transferrin saturation and ferritin levels were determined, and the C282Y mutation of the HFE gene was analyzed by restriction fragment length polymorphism- polymerase chain reaction analysis.

Results: Nine of 373 probands with a transferrin saturation > 55% (2.4%) and none of 264 randomly selected probands with a transferrin saturation £ 55% (0%) were homozygous for the C282Y mutation. Three of the nine homozygous probands had ferritin values less than 250 µg/L. The frequency of the heterozygous genotype was 8.8%, and the percentage of heterozygous probands increased with increasing levels of transferrin saturation.

Conclusion:We propose a population screening strategy with an initial transferrin saturation test, followed by genotyping for the C282Y mutation if the transferrin saturation is above 55%, regardless of the ferritin level. Heterozygous individuals with higher transferrin saturation values may be protected against iron loss but may also be more susceptible for certain liver diseases, depending on the simultaneous prevalence of other diseases.
 

Background: The Dead Sea in Israel has a very high mineral content. Near-drowning in the Dead Sea is expected to result in severe electrolyte abnormalities and respiratory failure. Previous limited studies reported a high mortality rate.

Objective: To evaluate the clinical and biochemical manifestations and disease outcome of near-drowning in the Dead Sea.

Methods: Data were abstracted from the archives of Soroka University Medical Center. The cohort comprised 69 patients who nearly drowned in the Dead Sea.

Results: The median age of the patients was 68 years (range 21–84). There were two major manifestations of near-drowning in the Dead Sea: electrolyte imbalance and acute lung injury. Serum calcium, magnesium and phosphorus (but not sodium, potassium and chloride) were abnormal in most patients. Median serum electrolyte levels (and range) on admission were 10.9 mEq/dl (9–24) for calcium, 4.3 mEq/dl (1–30) for magnesium, and 4.1 mEq/dl (2–9) for phosphorus. These levels quickly normalized with forced diuresis within 24 hours. Acute lung injury – namely, hypoxic bilateral pneumonitis – occurred in 29 patients. Mechanical ventilation was required in 11 patients. Sixty-five patients recovered fully, while the remaining 4 had minor sequelae.

Conclusions: Near-drowning in the Dead Sea is a syndrome of severe electrolyte abnormalities and lung injury. Early treatment, with forced diuresis and supportive care, results in prompt recovery.

Background: The humanized SCID mouse model is an attractive tool for testing gene therapy to combat human immunodeficiency virus infection in vivo.

Objectives: To devise a more specific gene therapy directed against HIV, replacing the formerly used interferon with either soluble CD4 molecule immunoadhesin (sCD4-IgG) and/or anti-gp41 monoclonal antibody (2F5), or negative transdominants (Tat, Rev).

Methods: Human monocytoid cell line (U937) was transfected with IFNa[1], b or g genes. 3T3 murine fibroblastic cell line was transfected with sCD4-IgG or 2F5, or both genes, and a human T4 cell line (CEM) was grafted to SCID mice. Negative transdominant genes (Tat, Rev or both) were also transduced in CEM T cell line. Animals were then challenged with HIV-1[2]. Viral load was followed.

Results: IFNa or b were potent anti-HIV, reducing viral load in vivo and inhibiting reverse transcriptase activity in human-removed cells from animals. sCD4-IgG immunoadhesin and gp41 monoclonal antibody resulted in a dramatic reduction of HIV-1 cellular and plasmatic viral load in humanized SCID mice. The simultaneous introduction of negative Tat and Rev genes resulted in a synergistic inhibition of HIV-1 replication in vivo.

Conclusions: Despite the marked reduction of HIV-1 propagation by IFN genes or by negative Tat and Rev transdominants, the gene therapy using soluble CD4 immunoadhesin or anti-gp41 was a more efficient preventive treatment against HIV infection.

Background: The number of child adoptions from abroad is increasing, but the adverse living conditions of these children prior to the adoption raise questions on their medical and neurodevelopmental status, particularly since there are no guidelines for pre- or post-adoption medical evaluation.

Objectives: To describe the condition of a cohort of young children who were candidates for adoption in East European orphanages and foster homes, and to determine those attributes associated with a family's decision to adopt or refuse a particular child.

Methods: Eighty-two young children, median age 11 months, were evaluated by Israeli pediatricians in Eastern Europe between 3 weeks and 6 months prior to their adoption. The evaluation consisted of comprehensive medical and neurodevelopmental testing on site using a battery of standardized assessment tools, and observation of free play and social interactive behaviors recorded on videotape. Laboratory tests included complete blood count, chemistries, serology screening, and metabolic and genetic testing.

Results: The children were growth-retarded. Medical problems were classified as resolved (pneumonia and diarrhea) in 32.8%; or ongoing, such as hepatitis B and (3, failure to thrive, organomegaly, and visual and hearing disorders, in 14.8%. Neuromotor status was grossly abnormal in 13.4%. Twenty-two percent of the children were rejected for adoption by families in Israel. Factors associated with the adoption decision were performance skills on developmental testing (P = 0.0001), present medical status (P = 0.002), and weight )P = 0.016(.

Conclusions: Pre-placement comprehensive screening of children eligible for foreign adoption, which includes developmental screening, helps to identify a wide variety of strengths and impairments in a child's background before the adoption procedure is finalized. A family's decision to adopt or not was associated with the child's performance on Bayley Scales, weight, and current medical status, but not with language delays, serious past medical history or suspect family background.
 

Background: Dizziness and vertigo can be a complaint in various psychiatric conditions, where it usually constitutes only one of the features of the syndrome. Lately, a somatoform disorder characterized by almost mono-symptomatic dizziness and unsteadiness has been described. Since phobic postural vertigo usually presents without anxiety or other psychological symptomatology, patients with this condition seek help at neurologic and otolaryngologic clinics where they are often misdiagnosed as suffering from organic vertigo.

Objectives: To present the clinical features of 55 consecutive patients diagnosed with phobic postural vertigo at our clinic during 1998–2002.

Methods: We conducted a retrospective review of patients’ medical records and report two typical cases as illustration.

Results: The patients presented with complaints of unsteadiness with or without dizziness, and attacks of sudden veering that caused them to grasp for support. Accompanying anxiety was admitted by only 5% and vegetative symptoms were reported in 18%. In 16% the symptoms resulted in avoidance behavior. A stressful life event or an unrelated somatic disease triggered the onset of PPV[1] in 35% of patients, whereas a vestibular insult preceded the symptoms in 13%. The mean duration of symptoms was 26.7 ± 39.1 months (range 0.5–20 years). In 72% of patients the symptoms resolved after the psychological mechanism of their symptoms were explained to them; 24% improved with antidepressant treatment (selective serotonin reuptake inhibitors or tricyclic antidepressants), and only in 4% did the symptoms persist.

Conclusions: Since PPV is a frequently encountered diagnosis at some specialized dizziness clinics, familiarity with this entity resulting in early diagnosis can avoid unnecessary examinations and lead to effective treatment.