ינינה גלבויז (1), שרה שפירו (2), ניצה להט (2), אריאל מילר (1,3)

(1) היחידה לנירואימונולוגיה, המח' לנירולוגיה, (2) היחידה לחקר אימונולוגיה, המרכז הרפואי כרמל, הטכניון – הפקולטה לרפואה, (3) מכון רפפורט למחקר במדעי הרפואה, חיפה

אנזימי המטריקס-מטלופרוטאינאזות (matrix metal-loproteinases - MMP's) (אממ"פ)* הם משפחת אנזימים פרוטאוליטיים אשר, יחד עם מעכביהם הריקמתיים – TIMs, מעורבים בעיצוב המירקם החוץ-תאי (ECM) (מח"ת – מירקם חוץ-תאי) במיגוון מצבים פיזיולוגיים, כגון התפתחות עוברית וריפוי פצע. לאחרונה, מצטברות עדויות למעורבות אממ"פ גם במיגוון רחב של מחלות, כגון התפשטות גרורות, טרשת העורקים, מצבי דלקת ומחלות אוטואימוניות.

בתהליכים דלקתיים של מערכת העצבים המרכזית, האממ"פ הם הגורם העיקרי בהרס מחסום הדם-מוח, בהתהוות בצקת מוחית, בהסננת תאי דלקת, בתהליכי הרס מיאלין ובהתהוות צלקת הגליה במוח. פעילות מוגברת של MMPs אובחנה בבעלי-חיים חולים בדגם ניסיוני של מחלות דה-מיאליניות וטרשת נפוצה. רמות גבוהות של אממ"פ, בעיקר MMP-2 ו-MMP-9, התגלו שינויים בפרופיל האממ"פ דווחו גם בהקשר של דלקות עוצבה חיידקיות ונגיפיות. כמו כן, למרות סתירות מסוימות במימצאים, נראה כי אממ"פ מעורבים גם בתהליכי הצטברות חלבון הביתא-amyloid במחלת אלצהיימר. מעורבות אממ"פ במחלות מערכת העצבים המרכזית מעוררת עניין מיוחד בזכות יכולתם לשמש בסימנים לפעילות המחלה ובזכות הפוטנציאל הטיפולי הטמון בשימוש במעכבי אממ"פ.

אביטל פורטר, אלכסנדר בטלר, דוד חסדאי

המערך לקרדיולוגיה, מרכז רפואי רבין, קמפוס בילינסון, פתח תקוה

מחלת לב כלילית מהווה את הגורם העיקרי לתמותה בעולם המערבי בכלל ובאוכלוסיית הקשישים בפרט. באופן כללי, הטיפול הניתן לחולה הקשיש הלוקה בתיסמונת כלילית חדה, הן בשלב החד והן כטיפול ממושך, נרחב פחות ופולשני פחות מזה הניתן לחולה הצעיר ואינו תואם את ההנחיות המקובלות.

חריגויות אלה מבטאות כנראה את תחושת הרופאים, שסיכויי הצלחת הטיפול נמוכים בחולה הקשיש, נוכח מחלות רקע רבות, שכיחות גבוהה של מחלה כלילית רב-כלית, וזמן ממושך יותר, יחסית לצעירים, עד קבלת סיוע רפואי.

המטרות בסקירה זו הן: 1) לבחון את הידוע כיום בספרות אודות טיפול תרופתי ופולשני בחולה הקשיש הלוקה בתיסמונת כלילית חדה; 2) לנסות לענות על השאלה, האם גיל צריך להוות שיקול בגיבוש העמדה הטיפול בתיסמונות כליליות חדות.

אבי בן-הרוש(1), טלי זילברשטיין(2), מרדכי חלק(2), בוריס קפלן(1)

המח' לנשים ויולדות, מרכז רפואי רבין, קמפוס בילינסון, פתח תקווה(1), החטיבה למיילדות וגינקולוגיה, מרכז רפואי סורוקה, באר שבע(2)

בסוף שנות ה-60, הציגו Driscoll’O וחב', מדבלין, "חבילת" טיפול וניהול פעיל ללידה ראשונה. לבד מתמיכה פסיכולוגית ומעקב צמוד לאורך הלידה, הוכנסו מספר חידושים מהפכניים; פקיעה מלאכותית של קרומי השפיר (amniotomy) ומתן אוקסיטוצין במינונים גבוהים מוקדם בתהליך הלידה, שהוגבלה ל-12 שעות בלבד. מסקנתם היתה אז, ששיטה זאת יעילה למניעת לידה ממושכת. בניגוד לסברה שרווחה שהגבלת זמן הלידה תוביל לשיעור גבוה יותר של חיתוכי דופן (cesarean section), במהלך שנות ה-70 נמצא, שבעוד שברחבי העולם שיעור חיתוכי הדופן עולה והולך, הרי ששיעור זה נותר נמוך יחסית בדבלין. מאוחר יותר, דיווחה אותה הקבוצה מדבלין, כי למעשה ניהול פעיל הוא זה המוריד את שיעור חיתוכי הדופן. מאז, חלוקות הדעות בדבר יעילות שיטת ניהול לידה זאת והישגיה, לעומת ניהול לידה שמרני וברירני יותר. בסקירה זאת, נעמוד על הקשר שבין ניהול לידה פעיל לשיעור חיתוכי הדופן.

ג'מאל עווד¹, בלה שינדל², יאיר שינדל¹

¹המח' לרפואה פנימית ו', ביה"ח לגליל המערבי, נהריה, ²מירפאת סוכרת, מרכז רפואי רבין, פתח-תקוה

האירגון האמריקאי לסוכרת (The American Diabetes Association - ADA) – ממליץ, שאם לא הושג איזון של הסוכרת בחולים NIDDM תוך שלושה חודשים על ידי תזונה דלת-סוכר והתעמלות, יש להתחיל בטיפול תרופתי. בדרך כלל מומלץ להתחיל בתרופה פומית אחת המורידה את רמת הסוכר, כמו, לדוגמה, (s‘SLP) sulfonylureas, (MTF) metformin, (ACS) acarbose או אינסולין.

בבחירת התרופה, יש לדעת את הפתוגנזה העיקרית שהביאה להיפרגליקצמיה, מנגנון הפעולה של התרופה, מחירה, השפעות-הלוואי, אופן מתן התרופה ומידת הדחיפות להורדת רמת הסוכר, דהיינו, ההסתמנות הקלינית של החולה.

התרופות מקבוצת ה- sulfonylureas הן השימושיות ביותר היום כטיפול התחלתי. Metformin מקבוצת ה- biguanides הוא תרופה מהקו הראשון לטיפול בחולי NIDDM הלוקים בהשמנת-יתר ועמידות לאינסולין. התרופה יעילה במיוחד במישלב עם תרופה מקבוצת ה- sulfonylureas, במיוחד במצבים בהם ה- s‘SLP בלבד לא הביאו לאיזון החולה.

התרופה החדשה יחסית acarbose מקבוצת האלפא glucosidase מפחיתה בצורה ברירנית את עליית הגלוקוזה לאחר הארוחה, ואין לה כמעט השפעה על רמת הסוכר בצום. שתי הקבוצות שהוכנסו לשימוש רק לאחרונה הן:

קבוצת ה- thiazolidinedione (troglitazon, rosigltazon) מגבירה את רגישות הרקמות ההיקפיות לאינסולין, כלומר, "מעוררת" תגובה חזקה יותר לאינסולין בשריר, בריקמת השומן ובכבד.

קבוצת ה- meglitinides (repagilinide) מגבירה את הפרשת האינסולין מהלבלב בדומה לקב' ה- s‘SLP, אלא שהשפעתה מהירה יותר וקצרה יותר, ומתאימה להפחתת רמות הגלוקוזה בנסיוב לאחר ארוחה.
 

Screening for Early Detection of Prostatic Cancer

A. Neheman, Y. Shotland, Y. Metz, A. Stein

Dept. of Urology, Carmel Hospital, Lady Davis Medical Center, Haifa

Prostatic cancer (PC) is second only to lung cancer as a cause of cancer mortality in men word-wide. In Israel it is the most common cause of cancer mortality in men, after lung cancer and colo-rectal cancer.

We screened, for the first time in Israel, for prostatic cancer using serum levels of PSA and a digital rectal examination (DRE). The purpose was not only to diagnose PC but also to increase public awareness of the condition.

300 men in the Haifa area who met statistical criteria for early diagnosis of PC participated. They filled a questionnaire regarding risk factors for PC (age, family history (FH) of prostatic and breast cancer, cigarette smoking, alcohol consumption, previous PSA sampling) and were examined. Those who had out-of-ragne, age-related PSA values, or a pathologic DRE underwent trans-rectal ultrasound (TRUS) examination and guided biopsy of the prostate. Those with a positive biopsy for PC underwent radical prostatectomy or radiation therapy.

41 (14.3%) had out-of-range, age-related PSA levels and 10 (3.5%) had a pathologic DRE. 39 (13.3%) underwent TRUS and biopsy and 6 (2.04%) had clinically significant PC, all early stages (Gleason 4-6).

Correlation between age and PSA has been proven statistically significant (p<0.05). Symptoms of urinary tract obstruction and nocturia were related to a high PSA (p=0.035 and 0.002, respectively). Those with PC had at least 1 symptom of urinary tract obstruction; 6 (15.3%) who underwent TRUS and biopsy and a FH of prostate cancer. However, no subject with a FH of PC had biopsy-proven cancer. Those with PC had PSA values from 4.9 to 31.8 ng/ml (9.6 median). Age-related PSA had a positive predictive value of 17.1%.

Results of our annual screening for early detection of PC using age-related PSA, and DRE are encouraging: cases detected were clinically significant and treatable. It would appear that screening for PC will result in decreasing the incidence of metastatic cancer and therefore mortality. 
 

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.
 

Regulation of Natural Medicines in Israel and Abroad

T. Lavy, B. Haran, J. Shemer, S. Shani

Israel Ministry of Health, Pharmaceutical Policy and Economics Unit; Israel Center for Technology Assessment in Health Care; Gertner Institute for Epidemiology and Health Policy Research; Sackler Faculty of Medicine, Tel Aviv University

Hand-in-hand with the public's growing interest in health care, there has been an increasing demand for natural health products considered both safe and medically effective. But many such products have not been shown to meet efficacy and safety criteria and therefore can not be registered as pharmaceuticals. On the other hand, it is quite clear that some products do have pharmacological activity and are being used for therapeutic or preventive effects.

In Israel, the marketing rules for food or dietary supplements prevent their manufacturers from claiming medicinal/healing properties that the product might have, and allow only limited health statements. But great demand for these products has created massive publication attributing medicinal indications for products whose quality, efficacy and safety have neither been examined nor proven according to accepted medical criteria.

We review the regulation and supervision of natural health products in Israel and other developed countries and find a broad range of opinions about natural health products. They range from acceptance as conventional drugs reimbursable by the health insurance, as in Switzerland and Germany, to their status as dietary supplements requiring no significant authorization or supervision, as in the USA.

Analysis of the current situation in Israel and the western world would indicate that some natural health products do possess pharmacological activity and therefore manufacturers should be allowed to make limited claims for specified therapeutic properties. A stricter set of registration regulations are needed for proof of safety, efficacy and quality of these products, but more lenient than those for registering a pharmaceutical product.

Problems in Fetal Monitoring: Characteristics of Risks for Malpractice Suits

Moshe D. Fejgin, Yael Gershtanski, Talia Halamish-Shani

Dept. of Obstetrics and Gynecology, Meir Hospital, Kfar Saba; and Medical Risk Management Co., Tel Aviv

Medical malpractice suits in obstetrics comprise about 10% of all claims against medical institutions in Israel. A significant proportion are due to failures relating to fetal monitoring. We studied the characteristics of 102 of 4125 obstetrical cases reported to the Medical Risk Management Co. as being at risk for a malpractice suit.

The cases were divided into those with medical management failures (misinterpretation of fetal monitor tracing, failure to respond promptly to fetal monitoring indicating distress, etc.) and technical failures (loss of monitor tracings, interruption in the tracing at a critical time, unreadable tracings, etc.).

The monetary quantum in fetal monitoring failures exceeded $30,000,000. The majority of these failures could have been avoided by using central electronic fetal monitoring systems with alerting and archival capabilities.

Diphtheria in a Highly Immunized Population 

Rivka Sheffer, Esther Marva, Rachel Mimon, Paul Slater, Avital Cohen, Tamat Shohat

Tel Aviv District Health Office, Central Laboratory and Epidemiology Dept., Public Health Services, Jerusalem

Although diphtheria vaccination is routine world-wide, outbreaks of the disease continue to occur in supposedly vaccinated populations. The incidence of diphtheria in Israel is very low, with only 3 cases reported in the past 24 years (all in unvaccinated children). In 2 of the 3 an asymptomatic carrier was identified among the patients' close contacts, presumable the source of the infection.

We describe a recent case of diphtheria. It is important for physicians to be aware of the possibility of diphtheria occurrimg despite the high rate of vaccination in our population.

Specialty Clinics - Gain or Loss?

Natalya Bilenko, Luna Avnon, Fanya Shimonovich, Dov Heimer

Epidemiology Dept.; and Pulmonary Unit of Soroka Medical Center; Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba

We evaluated the significance of first visits to our pulmonary clinic with regard to diagnosis and treatment by reviewing records of 287 new referrals by medical care providers (Sept. 1998 - Feb. 1999). At the first visit the diagnosis was changed in 30%, and treatment in 40%. These are minimal figures because evaluation had not been completed nor the diagnosis determined in all cases, while further investigation and follow-up continued.

In light of these findings, we believe that recent pressure on primary care physicians to avoid referrals to specialty clinics would result in short-term savings, but in the long term, would increase expenses and diminish quality of care. It is important to consider ways to maximize the interaction between the primary care physician and the specialist to maintain quality of care and decreases costs.

What Primary Care Physicians Think of Israel's Health Policy Reform

Revital Gross, Hava Tabenkin, Shuli Brammli-Greenberg

JDC Brookdale Institute, Jerusalem, HaEmek Hospital, Afula; and Ben-Gurion University of the Negev, Beer Sheba

Opinions of the National Health Insurance (NHI) Law held by primary care physicians were surveyed. A questionnaire was submitted (April-July 1997) to 930 primary care physicians employed by sick funds, including general practitioners, family physicians, pediatricians and internists. Response rate was 86%.

They supported the main components of the NHI law. It was considered desirable "to a great" or "very great extent" to allocate funds to sick funds based on age and number of members (76%), to require them to accept all applicants (72%), to designate a uniform basket of services (65%), to allow members to transfer freely between funds (63%), and to allow sick funds to sell supplemental insurance (59%). However, only 41% were satisfied with the implementation of the law.

Multivariate analysis showed that employment by Maccabi, Meuhedet, or Leumit sick funds had an independent effect on low satisfaction with the law as implemented, and on negative opinions about the uniform basket of services, the accepting of all applicants, and allocation of funding based on age and number of members. Those employed by the Maccabi and Meuhedet funds were in favor of allowing sick funds to sell supplemental insurance.

The findings of the study have implications for policy-makers interested in increasing support for national health reform by physicians. It is important to examine possibilities of developing direct channels of communication between national policy-makers and physicians, as well as institutionalizing mechanisms that involve physicians directly in formulation of national policy.

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.

Tacrolimus does not Accentuate Hepatic Damage due to Hypoperfusion 

Ron Ben Abraham, Ivgeni Isartal, Richard Nakache, Vallery Rudick, Daniel Ogorek, Gideon Paret, Avi Weinbroum

Dept. of Anesthesiology and Critical Care Medicine, Organ Transplantation and Postoperative Care Units, Tel Aviv-Sourasky Medical Center; and Pediatric Intensive Care Units, Sheba Medical Center, Tel Hashomer; and Sackler Faculty of Medicine, Tel Aviv University

Deterioration of hepatic function following liver transplantation is a known complication, sometimes attributed to the use of cyclosporin A. Reaction to tacrolimus (Prograf), a relatively new and effective immunosuppressant drug, is thought to result in a much lower grade of organ dysfunction, especially in the transplanted liver.

Using the ex-vivo rat model of isolated perfused liver, we evaluated hepatocellular damage and oxygen extraction when tacrolimus was administered following liver hypoperfusion. Tacrolimus did not worsen hepatic dysfunction caused by the hypoperfusion. Therefore using tacrolimus in the perioperative period might be safer than cyclosporin A, which tends to worsen hepatic damage in the presence of hypoperfusion.

The Gift of Breastfeeding 

Dorit Nitzan Kaluski, Alex Leventhal

Dept. of Nutrition, Public Health Services, Israel Ministry of Health, Jerusalem

Breast milk is the optimal food for infant growth and development, the prevention of infectious diseases and mother- child bonding. From the economic perspective, breastfeeding is cost-effective both for the family and society as a whole. The Israeli Ministry of Health encourages breastfeeding as the exclusive source of nutrition for infants in the first 4-6 months of life, with gradual addition of complementary foods thereafter. The promotion of breastfeeding in Israel requires comprehensive national activity with involvement of all the stakeholders. This includes implementation of the International Code of Marketing of Breast Milk Substitutes and joining the international "Baby Friendly Hospitals" project. Knowledge of breastfeeding should be spread, health professionals should be encouraged to become agents of change, support by breast counselors should be encouraged, post-delivery vacations from work should be prolonged and empowerment of women implemented.

Family Physicians' Attitudes to Clinical Guidelines for Treatment of Diabetes 

Sasson Nakar, Shlomo Vinker, Tal Baro-Aloni, Eliezer Kitai

Dept. of Family Medicine, Rabin Medical Center and Sackler Faculty of Medicine, Tel Aviv University

Clinical guidelines are systematically developed statements designed to help practitioners and patients make decisions about appropriate health care for specific clinical states. Attitudes of family physicians to clinical guidelines for treating diabetes and guidelines in general were evaluated from anonymous questionnaires answered by physicians participating in continuous medical education throughout the country (May-June 1998). The questionnaire dealt with attitudes to the recently published specific guidelines for treating the diabetic patient and overall perception of the efficacy of clinical guidelines.

293 family physicians, aged 40.2‏7.0 responded (83%). 93.5% appreciated the guidelines and thought them applicable. Most (83.7%) reported the guidelines to be of help in their daily work; 31.4% said they were oversimplified; a quarter said they aimed main at containing costs. Most respondents preferred written guidelines of up to 5 pages.

In view of our results, attention can now be turned to developing ways to implement the guidelines. To improve adherence, they need to be short and the rate of publication of new clinical guidelines should be slowed.