עבד אלנאסר עזב, יורי ירוסלבסקי,

המח' לפארמאקולוגיה קלינית, אוניברסיטת בן-גוריון בנגב, המרכז לבריאות הנפש, באר-שבע

כיום, מצויה ספרות רחבת יריעה המתבססת על עבודות קליניות המצביעה על כך, שליתיום (litium) לא יוכל לתת מענה לכל החולים הלוקים במחלה אפקטיבית דו-קוטבית (מא"ד), ומכך נבע הצורך בחיפוש אחר אפשרויות טיפוליות נוספות. התרופות הראשונות שיעילותן הוכחה במחקרים קליניים מבוקרים (כפולי-סמיות) הן התרופות נוגדות הכיפיון (תנ"כ), קארבאמזפין חדישות, כגון לאמוטריגין (lamorigine), שגם לגביו קיימת עדות קלינית מצטברת והולכת שהוא עוזר לטיפול במחלה אפקטיבית דו-קוטבית.

את מנגנון הפעולה של התנ"כ (המשמשות כיום לטיפול במא"ד) ניתן לסווג באופן כללי לשלושה סוגים: 1) הגבלת הירי החשמלי המתמשך (היח"מ, sustained repetitive firing) של הנירונים, המושגת דרך הארכת תקופת האיבטול של תעלות נתרן. 2) הגברת השפעת (GABA) הגורמת להשפעה מעכבת באותן סינאפסות. 3) חסימה של תעלות סידן, בעיקר של תעלות בעלות סף נמוך (T-type). עם זאת, המנגנון שעומד מאחורי היות התנ"כ הנ"ל תרופות שעוזרות לטיפול במא"ד, עדיין אינו ברור.

חשוב לציין, שהמשותף לכל התנ"כ הללו הוא יכולתן לחסות את תעלות הנתרן (voltage-activeted sodium channel blockade), אך למרות זאת, התרופה פניטואין, החוסמת ביעילות אותן תעלות נתרן, עדיין לא ניתנה כטיפול במא"ד, על אף העובדה שהיא משמשת כתרופה נוגדת כיפיון כבר קרוב לשישה עשורים. לכן, היה עניין רב לבדוק את ההפעה הנטימאנית של פניטואין ובסקירה זו, יובאו התוצאות של עבודה ראשונית שנעשתה לבדיקת השפעות אלו של התרופה בקרב חולים עם מא"ד ובחולים סכיזואפקטיביים, שבהם נמצאה השפעה חיובית של התרופה.
 

Assisted Reproductive Technologies Reported in Israel National Registry, 1995 and 1996

V. Insler, O. Gonnen, D. Levran, Y. Lotan, B. Fish, G. Potashnik, A. Kogosovsky, R. Ron-El

Committee of the Israel National Registry Assisted Reproductive Technologies*

National registration of the results of assisted reproductive technology (ART) is maintained by many countries. The Israel Committee for Registry of ART asked 19 in-vitro fertilization (IVF) units in 1995 and 20 in 1996 to report on their activities and results.

Data were collected by questionnaires and analyzed by computer. The most common ovarian stimulation was the combination of GnRH agonist and gonadotropins. There were 10,89 treatment cycles in 1995, of which 45% were with intracytoplasmic sperm injection (ICSI). In 1996, of 12,72 cycles, 54% were with the ICSI procedure. Embryos were transferred into the uterine cavity in 90% of the conventional IVF cycles and in 95% of the ICSI cycles. The overall pregnancy rate was 22% per embryo transfer in the conventional IVF and ICSI cycles. The delivery rate was 13.7% and 15.4% per embryo transfer in the conventional IVF and ICSI cycles, respectively. The rates for abortion and tubal pregnancy were 24% and 1.3%, respectively.

These results are better than in previous years and are comparable with results in some western European countries. Efforts are being made to convert the registry into a real-time computerized system.

Committee of the Israel National Registry of ART.

Advantages of Standardized Protocol for Oral Rehydration in Acute Pediatric Gastroenteritis

Avi Weizman, Ahmed Alsheikh, Laura Herzog, Asher Tal, Rafael Gorodischer

Pediatric Depts. A and B, Soroka Medical Center; and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba

Oral rehydration (OR) for acute gastroenteritis in infants and children has been shown to be as effective as IV therapy, with less discomfort and lower costs. In this retrospective study we compared 2 pediatric wards, in 1 of which only a standardized, simplified, bedside protocol, based on American Academy of Pediatrics guidelines, was used.

There were no significant clinical characteristics in the 208 patients. In the ward which used the above protocol, OR utilization was significantly more frequent than in the other ward (48% versus 15%), thus saving equipment costs of nearly $1,000/3 months. There were no significant differences in outcome between the wards.

We conclude that introducing a standardized management protocol may increase OR utilization in hospitalized children with acute diarrhea.
 

Treatment of Phenyl-Ketonuria due to Dihydropteridinereductase Deficiency 

B. Sela, J. Blonder, I. Peled, G. Schwartz

Institute for Pathological Chemistry and Child Development, Sheba Medical Center, Tel Hashomer; Clinical Biochemistry Dept., Sackler Faculty of Medicine, Tel Aviv University

Most cases of hyper-phenylalaninemia are due to deficiency of phenyl-alanine hydroxylase that converts phenyl-alanine to tyrosine. This enzymic reaction is facilitated by the co-factor tetrahydrobiopterin (BH₄). A defect in the latter substrate leads to increased phenyl-alanine in 1-2 cases per million live births. Such cases are characterized by a degenerative brain process, and pronounced neurologic symptoms that cannot be prevented by a low phenyl-alanine diet alone.

In 3 male newborns a deficiency of dihydropteridine reductase (DHPR) activity was diagnosed, the last in a sequence of 3 enzymes involved in the formation of BH₄. Successful outcome of treatment as well as the results of failure to diagnose and treat affected newborns are described, with emphasis on the logistic problems involved in mass screening.

Acute Lymphoblastic Leukemia in Adults Treated with German Multicenter Study Group Protocols

G. Goldstein, O. Shpilberg, P. Raanani, A. Chetrit, I. Ben-Bassat

Institutes of Hematology and of Clinical Epidemiology, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University

Acute lymphoblastic leukemia (ALL) is a malignant disease whose incidence is relatively low among adults, unlike in children. Adults with ALL have a lower rate of long-term disease-free survival. During the last 20 years, a German multicenter group has shown that their protocol have achieved good results in adult ALL.

We reviewed the medical records of 35 ALL patients, aged 19-63 years, whome we treated with these protocol (1988-1997). The remission rate was 94%. At a median follow-up of 46 months the 2-year overall survival was 54% and the disease-free survival was 94%. Although 2 patients died of bone marrow transplant complications, no death was directly associated with drug toxicity. The main grade 3 or 4 side effects (WHO classification) were neutropenia (91%), thrombocytopenia (71%) and anemia (71%).

With there protocols we achieved high overall and disease-free survival rates, especially in comparison with other reports. Despite the high rate of severe treatment toxicity, there were no fatalities directly related to treatment. These results emphasize the need to concentrate treatment of adult ALL patients in large medical centers with expertise in the use of the complicated treatment protocols required.

Preservation of the Larynx in Advanced Cancer

Edward Rosenblatt, Nava Siegelmann-Danieli, Jemal Zidan, Nisim Haim, Abraham Kuten

Oncology Dept., Rambam Medical Center and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa

The effectiveness of sequential chemo-radiotherapy in preserving the larynx in advanced laryngeal carcinoma was assessed. 4 Unselected patients (19 men and 2 women, mean age 60 years) with advanced squamous cell carcinoma of the larynx (T3-4/N0-3) received induction chemotherapy consisting of 2-3 cycles of cisplatin (100 mg/m²) and 5-flourouracil (1000 mg/m²/day) as a continuous infusion on days 1-5 followed by definitive radiotherapy: 50 Gy to the whole neck, 70 Gy to the larynx and clinically involved nodes, using a combination of 6 MV photons and 9-12 MeV electrons.

19 of The 21 patients responded to combined therapy but there was no response to induction therapy in 2 (10%) and 2 did not complete therapy due to severe toxicity. At a mean follow-up of 40 months, 7 had undergone total laryngectomy (33%), for an overall 5-year laryngeal preservation rate of 66%. Reasons for total laryngectomy in 2 patients were no response and in 5 tumor recurrence.

Mean survival was 39 months (range 11-46 months); at last follow-up 17 of 21 were alive and disease-free, 11 of whom had a functional larynx (65% of survivors). 2 died due to disease progression and 1 due to a cardiovascular event. Sequential chemo-radiation allows laryngeal preservation in about 2/3 of surviving patients without compromising survival.

Combined Approach in Management of Penetrating Injury of Vertebral Artery

Y. Kluger, B. Sagie, D. Soffer, N. Hai, D. Oron

Rabin Trauma Center and Division of Invasive Radiology, Tel Aviv Medical Center

Penetrating injuries of the vertebral artery are not common. Although surgical control of this type of injury is well- documented, the combined approach (surgery and packing for temporary control of bleeding, followed by angiography and embolization for permanent control) is now recognized and practiced.

We describe a 40-year-old man who was stabbed in the neck. He was rushed to the operating theater in hemorrhagic shock. A vertebral artery injury was identified and packed. Angiography and embolization permanently controlled the bleeding.

The combined approach is safe and we recommend it in those in whom bleeding from the vertebral artery is initially well controlled with packing.

High-Dose Chemotherapy and Autologous Stem Cell Trans-Plantation for Refractory and Relapsing Hodgkin's Disease

A. Avigdor, I. Hardan, O. Shpilberg, P. Raanani, I. Grotto, I. Ben-Bassat

Hematology Institute and Hemato-oncology Unit, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University

High dose chemotherapy and autologous stem cell transplantation are widely used in relapsed and primary refractory Hodgkin's disease. We transplanted 42 patients with Hodgkin's disease between 1990-1998. Median follow-up was 31 months (range 1-102). 29 (69%) were transplanted after relapse and 13 (31%) were refractory to first line therapy. Median age at transplantation was 29 years (range 19-58) and 23 (55%) were males.

All were treated with the BEAM protocol (carmustine, etoposide, cytarabine and melphelan). 18 who were in remission received radiotherapy following transplantation. The source of the stem cells was bone marrow in 17% and peripheral blood in 83%. At initial diagnosis: 57% had stage III-IV disease and B symptoms were present in 52%. 75% were treated with MOPP, ABVD or with related versions. Radiotherapy followed in 52%. Prior to transplantation, 45% of the relapsed group were in the advanced stage. 33% and 12% of all patients had lung and bone involvement, respectively.

The complete remission rate was 86% for the 2 groups. 2 (5%) died from transplant-related complications and MDS/AML developed in 2 (5%) after transplantation. The 3-year overall survival (OS) and disease-free survival (DFS) were 68% and 60%, respectively. The 3-year OS for the relapsed group was 64% compared with 76% for the refractory group, and the 3-year DFS for the relapsed group was 60% vs. 42% for the refractory group (neither difference significant). Radiotherapy following transplantation did not have a beneficial effect on DFS. No prognostic factors for outcome of transplantation were found, most probably due to the limited number of patients and the high variability of disease characteristics.

We conclude that high dose chemotherapy and autologous stem cell transplantation are effective and relatively safe for relapsed or primary refractory Hodgkin's disease. The DFS at 3 years was longer for those transplanted after relapse than those with primary refractory disease, but not significantly. Patients with primary refractory disease can be salvaged with high dose chemotherapy.

Penile Prosthesis for Erectile Dysfunction: Long-Term Follow-Up 

Ofer N. Gofrit, Ofer Z. Shenfeld, Ran Katz, Amos Shapiro, Ezekiel H. Landau, Dov Pode

Urology Dept., Hadassah University Hospital, Jerusalem

Our armamentarium for the treatment of erectile dysfunction has recently been expanded by addition of Viagra and the MUSE. However, their long-term results are still unknown. The insertion of a penile prosthesis is invasive, expensive, and irreversible, but under optimal condition provides an acceptable, definitive solution for erectile dysfunction. We evaluated our long-term results with penile prosthesis insertion (PPI).

From 1987-1998, 57 patients underwent PPI in our department. Mean age was 55 years and the common causes of erectile dysfunction were atherosclerotic disease (23), radical pelvic surgery (15), and diabetes mellitus (14). Semirigid prostheses were inserted in 12 and inflatable prostheses in 45, including 42 single-component and 3 multi-component prostheses.

Recently we interviewed these patients by telephone, using a standard questionnaire. Those not satisfied with the surgical results (83% of the living patients) were examined in our clinic. Mean follow-up was 53 months. In 37 (84%) the prosthesis was mechanically functional (rates after 1, 5 and 10 years were 87.8%, 80%, and 75%, respectively). In only 2 (2.5%) had serious complications led to prosthesis removal.

All mechanical failures had occurred in those with inflatable prostheses after a mean of 48.5 months (range 4-113). At the time of the survey 68% were sexually active and 64% were satisfied with the surgical result. We conclude that PPI is safe treatment for erectile dysfunction. Although the rate of mechanically functioning prostheses decreases with time, modern multi-component prostheses may lead to better mechanical results.

Anticoagulant Treatment in Pericardial Effusion - A Therapeutic Dilemma 

Marina Katsman, Elie Shiloah, Micha Rappoport

Dept. of Medicine C, Assaf Harofeh Medical Center, Zerifin

Anticoagulant treatment for acute myocardial infarction (AMI) and pericardial effusion is controversial, since the treatment might cause hemopericardium and tamponade. On the other hand, anticoagulants are strongly indicated in many situations in AMI, including: left ventricular thrombus, unstable angina, severe heart failure, deep vein thrombophlebitis, pulmonary embolism, atrial fibrillation, as part of thrombolytic treatment, and during cardiac catheterization.

We describe a 70-year-old man who presented with both pericardial effusion and a left ventricular thrombus 3 weeks after an extensive, anterior wall AMI. Anticoagulants and corticosteroids were administered simultaneously under hem-odynamic and echocardiographic monitoring, without complications.

It is our impression that anticoagulant treatment is safe in patients with pericardial effusion.

Multiresistant Escherichia Coli from Elderly Patients

Ilana Slucky-Shraga, Moshe Wolk, Sofia Volis, Israel Vulikh, David Sompolinsky

Dept. of Medicine and Microbiology Laboratory, Mayanei Hayeshua Hospital, Bnei Brak; Central Laboratories, Ministry of Health, Jerusalem; and Faculty of Life Sciences, Bar Ilan University, Ramat Gan

We examined all ceftriaxone-resistant Escherichia coli isolates obtained from clinical samples during 16 months (1 Dec. '97 - 31 Mar. '99). A total of 97 resistant isolates from 36 patients were obtained, mostly from urine specimens. Of these patients, 35/36 were over 75 years old, most lived in nursing homes, were dependent on nursing in their daily lives, and were incontinent and/or had indwelling catheters.

All 97 isolates had similar susceptibility profiles: resistant to ciprofloxacin, gentamicin, ampicillin, amoxycillin/clavulanate, tricarcillin/clavulanate, aztreonam, and cefuroxime; decreased susceptibility to ceftazidime and cefepime; and susceptible to imipenem and meropenem. Double-disc tests indicated that all strains produced extended spectrum beta-lactamase(s). All the isolates belonged to 1 of 3 E. coli serotypes: 79 were 0153:H31, 13 were 0142:H10, and 5 were 0102:H6.

Videothorascopic Sympathectomy for Palmar Hyperhidriosis

Nahum Nesher, Ronen Galili, Ram Sharony, Gidon Uretzky, Milton Saute

Dept. of Cardiothoracic Surgery, Lady Davis - Carmel Medical Center and Rappaport Faculty of Medicine, Israel Institute of Technology, Haifa

Palmar hyperhidriosis is not a life-threatening disease but leads to loss in the quality of life. Conservative treatment is ineffective and major surgery involves perioperative complications and esthetic impairment.

From 1992 to 1998 we treated 156 patients with palmar hyperhidriosis using a single port, drainless videothoracoscopic procedure with almost no complications.

Sublingual Immunotherapy for Allergic Diseases

David Nelken

Medical Building, Sprinzak St., Tel Aviv

4 patients suffering from severe pollinosis and/or allergic rhinitis, with or without asthma, were treated as follows: 30 minutes before breakfast the vaccine was dropped sublingually and retained for 2-3 minutes before being swallowed. It was a commercial preparation of allergen, diluted 50% w/v in glycerin.

This stock solution was then diluted in physiological saline containing 0.05% human albumin and kept refrigerated in a dark glass bottle for up to 4 weeks. Of the first dilution which contained 10 Au/ml, 1 drop was given on day 1 and 1 drop more each day until days 5 to 17, when 5 drops were given daily. Then 1000 and then 2500 Au/ml were given sequentially in the same manner, and finally 5000 was given for up to 2 years. A maintenance dose of 3 drops of 5000 Au/ml twice weekly was then prescribed.

41 patients showed striking clinical improvement after about 6 months of treatment. A definite reduction in the use of other medications was achieved in all. Sublingual immunotherapy is practically free of unwanted side effects and easy to self-administer at home.

To establish the specificity of sublingual immunotherapy, patients who had severe allergic symptoms to one pollen allergen causing symptoms in the spring and to a second in the autumn, were first immunized sublingually against a single allergen. A year later, after symptoms due to this allergen had subsided, and if symptoms caused by the second allergen had not improved, immunization against the second allergen was started.

Sublingual immunotherapy acts by increasing mucosal antibodies at the site of entry of the allergen into the respiratory tract. It is a safe and practical procedure with results comparable to subcutaneous allergy injections.

Thrombolytic Therapy or Primary Coronary Angioplasty in Acute Myocardial Infarction?

David Pereg, Shlomo Behar, Alexander Battler, Valentina Boyko, Shmuel Gottlieb, Jonathan Leor: Israel Thrombolytic Survey Group

Cardiology Division, Soroka Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba; Neufeld Cardiac Research Institute, Tel Hashomer and Tel Aviv University; and Cardiology Dept., Rabin Medical Center, Petah Tikva

There has been continuous debate over the superiority of primary percutaneous, transluminal, coronary angioplasty (PTCA) over thrombolysis for acute myocardial infarction (AMI). It was questioned whether this advantage of primary PTCA reported in selected populations by experienced centers can be replicated in our clinical practice.

We compared demographic and clinical variables, therapies and outcome in AMI treated with primary PTCA vs thrombolytic therapy. Clinical and demographic variables of 1,678 unselected AMI patients (admitted January/February and May/July 1996) were analyzed in 16 cardiac care units with on-site catheterization facilities and ability to perform PTCA. Of these 803 (48%) were treated by thrombolysis and 99 (6%) by primary PTCA.

The prevalence of adverse prognostic variables, such as anterior wall MI, heart failure on admission or during hospital stay, pulmonary edema, and ventricular tachycardia or fibrillation, was higher in the PTCA group. The 7-day, 30-day and 1-year mortality rates were similar in the 2 groups: 4%, 7.2% and 12.8%, respectively, in the PTCA group and 5%, 7.2% and 11.1% in the thrombolysis group. There was a trend toward lower mortality in subgroups of high-risk patients: those with heart failure on admission (Killip class >1), the elderly (>65 years), and those with previous MI treated with PTCA. After adjusting for confounders, treatment with primary PTCA was not found to be associated with lower mortality.

Only a small proportion of AMI patients in Israel were treated with primary PTCA in 1996. The frequency of adverse prognostic factors among them was higher but their short and long term outcomes were similar to those of high risk patients treated with thrombolysis.

Psychological Treatment for Paruresis (Bashful Bladder)

Baruch Elitzur

Psychiatric Clinic, Ichilov Hospital, Tel Aviv Medical Center

Paruresis, or bashful bladder, is a functional disorder that involves inability to urinate in the presence of others. The symptom meets the DSM-IV diagnostic criteria for simple phobia or social phobia. Although the prevalence of paruresis is relatively high (7% in 1 study and 32% in another), there are few reports of its treatment. The treatment of choice presented in the literature is cognitive-behavioral.

We describe a multidimensional model used in treating 3 men who suffered from paruresis. Promotion of relaxation, mental imagery, paradox, gestalt, metaphor, cognitive-behavioral and psychodynamic techniques were used. After 5 treatment meetings, 2 younger men, 18- and 24-years old, respectively, were able to overcome the condition, while a 50-year-old got only partial relief.