The Effect of Gastro-Esophageal Reflux Therapy on Respiratory Diseases in Children

Y. Levin¹, A. Mandelberg², A. Gornstein³, F. Srour³, S. Reif⁴

¹The Sackler Faculty of Medicine, Tel-Aviv University, ²The Unit of Pediatric-Pulmonology, Wolfson Hospital, ³The Unit of Pediatric-Surgery, Wolfson Hospital, ⁴The Unit of Pediatric-Gastroenterology, Dana Children's Hospital

In order to examine the effect of reflux therapy on Hyper Reactive Airway Disease (HRAD) and apnea severity, 107 children, 78 with HRAD and 29 with apnea, underwent pH monitoring in the Pediatric Surgery Unit of Wolfson Hospital and the Dana Children's Hospital during the years 1995-1998. Pathological reflux was defined by means of the Boix-Ochoa and RI (Reflux Index) scores. In patients with positive reflux, anti-reflux treatment was initiated. Prior to and following pH monitoring, the respiratory status of all patients (both with and without reflux) was evaluated by a pediatric pulmonologist employing commonly used scores to determine severity.

Results: Subject age ranged between one day and 15 years (mean: 15.44±29 months, median: 6.37 months). In HRAD, following anti-reflex treatment the reflux positive group showed a significant score improvement, from an average of 2.9±1.1 units to 1.54±1.2 units (p<0.0001); a decrease in the number of patients treated with oral corticosteroids (p<0.01); a close to significant decrease (p=0.069) in the average dose of inhaled corticosteroids; and a decrease in the number of patients using bronchodilators (p=0.042). The reflux-negative group, not treated for reflux, displayed no significant improvement, with only a decrease in the severity scores from 2.44±1.0 to 1.78±1.2 units (p=0.14), and no change on any of the other parameters.

In apnea, all patients improved, from an average score of 2.34±0.77 to 0.03±0.19 units (p<0.0001), with no significant difference between the reflux positive and the reflux negative groups.

In view of these findings, it is postulated that anti-reflux therapy may have an additive effect on HRAD severity, beyond that of spontaneous respiratory improvement. We therefore find it appropriate for every severe HRAD patient (frequent exacerbations or high corticosteroid dose) to undergo pH monitoring in order to treat those with proven reflux. In respect to apnea, we cannot attribute any significance to the existence of reflux or to anti-reflux treatment.

Malignant Humoral Hypercalcemia Associated with Angiotropic Large B Cell Lymphoma: Case Report

Boleslaw Knobel, MD;^1,5 Ilan Sommer, MD;¹ Pauline Petchenko, MD;² Dorit Lev, MD; ³ Elimelech Okon, MD;^4,5

¹Department of Medicine "B", ²Department of Hematology, ³Institute of Genetics, Edith Wolfson Medical Center, Holon ⁴Department of Pathology, Rabin Medical Center, Petach Tikva and 5Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Angiotropic large B cell lymphoma (angiotropic LCL) or intravascular large cell lymphoma (IVLCL) was diagnosed by liver and bone marrow biopsies and immunohistochemical studies in a 52 year old Caucasian male.

IVLCL is a very rare disease characterized by widespread intravascular proliferation of lymphoma cells. Although it most commonly affects the central nervous system or skin and occasionally bone marrow, angiotropic LCL may be present without evidence of localized disease, as seen initially in our patient.

To date, only a few cases of intravascular malignant lymphomatosis associated with parathyroid hormone related protein (PTH-rP) induced humoral hypercalcemia have been published.

Our extraordinary case was diagnosed mainly by liver biopsy. The neoplastic lymphoid cells stained diffusely and strongly positive with CD-20 (Pan B) and were negative for CD-3 (Pan T) immunostain.

The most significant, initial clinical finding was severe, unexplained hypercalcemia (until 18.6 mg/dl). Plasma PTH-rP showed a ten-fold increase at 8 pmol/L (normal value less than 0.8 pmol/L). Very unusual cytogenic abnormalities were found.

The patient received the massive third generation combination chemotherapy comprising of Methotrexate, Doxorubicine, Cyclophosphamide, Vincristine, Prednisone and Bleomycin and developed, complete although temporary, clinical, humoral and cytogenetic remission.

בעשור האחרון, פורסמו מספר עבודות, בהן הודגם, כי בקרב חולים עם תחלואה של חלל הפה, ובייחוד דלקת מיסב-השן – דמ"ש (דלקת מיסב השן – periodontitis) ודלקת חניכיים, קיימת היארעות מוגברת באופן משמעותי של טרשת העורקים וביטוייה הקליניים השונים: מחלת לב כלילית, אוטם בשריר הלב ואירוע מוחי. במקביל להצטברות המידע האפידמיולוגי, חלה בשנים האחרונות התקדמות רבה בכל הקשור להבנת התהליכים שביסוד טרשת העורקים.

בתוך הרובד הטרשתי קיימים תהליך דלקתי ותגובה חיסונית פעילה, שבהם נוטלים חלק, בין השאר, לימפוציטים מסוג T ומאקרופאגים משופעלים. מאמץ מחקרי רב נעשה על מנת לאתר את מחוללי הנזק הראשוני בדופן כלי הדם ואותם אנטיגנים, נגד אנטיגנים זרים (ממקור חיידקי, נגיפי וכיו"ב); לחלופין, ייתכן שמדובר בתגובה-צולבת כנגד אנטיגנים עצמוניים.

נסקור את התאוריות השונות לגבי הקשר בין מחלות חלל הפה ומיסב-השן ובין טרשת העורקים. תאוריות אלו מדגימות היטב את מרכזיותו של הגירוי הזיהומי והתגובה החיסונית כלפיו בהתהוות מחלת טרשת העורקים.
 

Newer Diagnostic and Therapeutic Methods in Lung Cancer

R. Rubinstein, R. Breuer, R. Chisin

Dept. of Medical Biophysics and Nuclear Medicine, and Institute of Pulmonology, Hadassah University Hospital, Ein Karem, Jerusalem

Positron emission tomography (PET), when used with F-18 fluoro-deoxyglucose (FDG), contributes to the evaluation of patients with lung cancer. This technique of imaging detects active tumor tissue by showing increased radiopharmaceutical uptake by metabolically active cells.

Thus, PET assists in the early diagnosis of pulmonary malignancies that appear only as non-specific findings on CT-scan or chest X-ray. In addition, it is helpful in staging lung cancer before and after resection, chemotherapy or radiotherapy, or their combined use.

We performed 135 FDG-PET studies between July '97-April '99. and present our preliminary results with examples of the main indications for PET in lung cancer.
 

Antioxidant Profile of Human Saliva and its Biological Significance

R. M. Nagler, A. Z. Reznick

Dept. of Oral and Maxillofacial Surgery, Salivary Clinic and Oral Biochemistry Laboratory; Rambam Medical Center and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa

Saliva is the first biological medium to come in contact with materials entering the body through the oral cavity. These materials are contained in food and drink (or inhaled as volatile ingredients). Accordingly, saliva contains various defense mechanisms which have been thoroughly investigated. They include immunological and enzymatic systems aimed at pathological microorganisms. Saliva also can protect the mucosa against mechanical insults and when required, promote its healing via agents such as the epidermal growth factor.

Another defense mechanism in saliva which has been gaining increased attention and seems to be of paramount importance is its antioxidant system. We discuss both the molecular and enzymatic components of the salivary antioxidant system in respect to mixed, parotid, submandibular and sublingual saliva and under various physiological conditions of secretion.

A Molecular Method of Diagnosis of Congenital Adrenal Hyperplasia

Shoshana Israel, Chaim Brautbar

Tissue Typing Unit, Hadassah Medical Center, Jerusalem

Congenital adrenal hyperplasia (CAH) is caused mainly by deficiency of the 21-hydroxylase enzyme. The disease may appear in the classical salt-losing, simple virilizing forms or as a mild, nonclassical form. 21-hydroxylase is encoded by the CYP21B gene on the short arm of chromosome 6, in the midst of the human leukocyte antigen (HLA) complex, between HLA Class I and Class II regions.

We describe a method for identifying mutations in the CYP21B gene. It is based on amplification of the gene using the polymerase chain reaction and identification of mutations with sequence-specific oligo-probes. The mutations identified were: V281 and P30L responsible for nonclassical CAH, and I2 splice, Q318X, I172N, cluster E6, and a deletion including 8bP in the third exon (8bP del) responsible for the classical form of CAH.

We also analyzed 2 families affected with the classical form of CAH which demonstrate possible complications in genotyping. Typing for HLA haplotypes can be helpful in certain cases, as demonstrated in 1 of the families presented. In this case it was necessary to distinguish between 2 possible genotypes: 1 with the mutations in tandem on 1 chromosome and the other with the mutated genes on both chromosomes. HLA haplotyping enabled the assignment of the mutations to the relevant chromosomes and thus allowed correct genetic counseling.

The other family demonstrated the importance of CYP21B genotyping in individuals with the nonclassical form of CAH. This form may consist of 1 mild and 1 severe mutation, representing a serious potential for transmitting the classical form of CAH.

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.
 

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.

Acipimox as a Secondary Hypolipidemia in Combined Hypertriglyceridemia and Hyperlipidemia

D. Yeshurun, H. Hamood, N. Morad, J. Naschitz

Hyperlipidemia Clinic, Dept. of Medicine A, Bnai-Zion Medical Center, and Rappaport Faculty of Medicine, Technion, Haifa

32 patients with hypertriglyceridemia, excessive hypertri- glyceridemia, and combined hyperlipidemia, were treated with the nicotinic acid derivative acipimox (Olbetam). First line treatment with bezafibrate, or statins in some with combined hyperlipidemia, had failed. In 10 acipimox was discontinued due to side effects or absence of clinical response. The other 22 completed 6 months of treatment with no side effects.

Acipimox caused a significant 54% decrease in triglyceride levels, a 23% decrease in total cholesterol, and a 12% increase in HDL-cholesterol. LDL-cholesterol was difficult to calculate because of the high triglyceride levels, so no results are presented.

Although acipimox was much better tolerated than nicotinic acid, it also had side effects, but fewer. Acipimox can therefor be used as a second-line drug, mainly in those with combined hyperlipidemia and hypertriglyceridemia.

Alopecia Due to Seroxat 

Leonid Umansky, Abraham Dorevitch, Avner Sella

Psychiatry Chronic Dept., Eitanim Mental Health Center, Jerusalem

There are 2 stages of alopecia, anagen and telogen effluvium, both of which may be associated with medication- related alopecia. We describe massive hair loss in a 51-year-old woman during treatment with Seroxat (paroxetine), which remitted after it was discontinued. Pathological mechanisms of drug-associated alopecia are complex and have yet to be fully elucidated.

Carbamazepine Hypersensitivity 

Shimon Ivry, Doobi Shteinmintz, Hava Tabenkin

Dept. of Family Medicine, HaEmek Hospital, Afula and National Residency Institute, Ben-Gurion University of the Negev, Beer Sheba

Carbamazepine (C) can cause a characteristic hypersensitivity reaction (CHS}. This multisystem reaction typically presents as fever, mucocutaneous eruption and lymphadenopathy. The syndrome usually develops between 1 week and 3 months after starting therapy, with involvement of the liver, lung, kidney and inappropriate secretion of ADH. The incidence is less than 0.001% in those treated with C and it is diagnosed clinically. With onset of CHS, the drug must be stopped and if there is no improvement, cortico-steroids should be started. When the diagnosis is in doubt, the patch test, lymphocyte transformation test, macrophage migration inhibitor factor, and other tests can be helpful.

The pathogenesis is not known. Similar syndromes have been described with phenytoin and phenobarbital. There is clinical and in-vitro evidence of cross reactions between C and phenytoin. It is not known whether the CHS syndrome should be considered a premalignant state, with increased risk for the development of malignant lymphoma.

Atypical Mycobacterial Cervical Lymphadenitis in Children

B. Klin, I. Boldur, J. Sandbank, Z. Schpirer, I. Vinograd

Depts. of Pediatric Surgery, Microbiology and Pathology, Assaf Harofeh Medical Center, Zerifin, and Sackler Faculty of Medicine, Tel Aviv University

Scrofula (mycobacterial cervical lymphadenitis) has been well-known for thousands of years. Atypical mycobacteria were first categorized by Timpe and Runyon in 1954. Treatment has varied over the centuries, from exclusion therapy in ancient Greece, through digitalis, iodide, chemotherapy, and surgical excision. The varied differential diagnosis and consequent diagnostic and therapeutic challenges make reassessment of this almost forgotten disease necessary.

21 patients with typical mycobacterial cervical lymphaden„itis seen in over the past 5 years were reviewed. Age distribution ranged from 1-14 years, with peak incidence at 4 years; 9 were boys and 12 girls. Most presented with nontender, palpable neck masses and minimal constitutional complaints. Adenopathy was unilateral in all cases but 2. Mycobacterium avium-intracellulare and M. fortuitum were the main causative organisms. All underwent excision of the affected nodes. Long-term follow-up has been uneventful, except for 1 case of local recurrence requiring re-excision.

This study emphasizes the marked variability in the clinical presentation of scrofula in children, stressing the importance of the differential diagnosis between tuberculous and atypical mycobacterial cervical lymphadenitis. The treatment of choice for the latter is complete excision of the affected nodes. Other treatment is followed by recurrence and unnecessary complications and should be avoided.

Treatment of Hypertension with Losartan

R. Zimlichman

Dept. of Medicine and Hypertension, Wolfson Medical Center, Holon

The efficacy, safety and side-effects of treatment with losartan (Ocsaar) was studied for the first time in Israel in a large group of patients with mild to moderate hypertension in several community clinics. The 421 patients (51% men) aged 30-86 years (mean 58.6) received 50 mg of losartan daily, increased when necessary to 100 mg, and/or a second antihypertensive drug was given. After 4 weeks blood pressure was normalized in 344 and after 12 weeks in 363. Side-effects were minimal and treatment was effective in all age groups.

Use of Unlicensed and Off-Label Drugs in Hospitalized Children

M. Lifshitz, V. Gavrilov, R. Gorodischer

Toxicology Unit, Pediatrics Dept. A, Soroka Medical Center, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba

Many drugs used in children are based on pharmacological data obtained in adults. Therefore, many drugs are either unlicensed for use in children or are prescribed outside the terms of the product license (off-label). This pilot study assessed use of unlicensed or off-label drugs in hospitalized children.

Drug orders of patients admitted to a general pediatric ward were reviewed retrospectively in a random sample. Assessment was based on the data of the Physicians' Desk Reference and the Israel Drug Compendium. 80 different drugs and 278 drug orders were written for 92 patients (0.5 months - 11 years old, mean 26.9 months) in 97 admissions. Of these 52.9% were either off-label or unlicensed. Patients received 1 or more unlicensed or off-label drugs in 64.9% of admissions. They were more often off-label than unlicensed. The main reasons for use of off-label drugs were unusual doses and inappropriate age. The main reason for unlicensed drugs was modification of a particular formulation of a licensed drug.

This pilot study indicates that use of drugs in an off-label or unlicensed manner in children is probably quite frequent in Israel. Our data emphasize the need for licensing a large number of drugs for use in children, based on the same scientific principles as in adults. Further collaborative studies in different pediatric centers in Israel, involving different types of pediatric settings (ambulatory and in-hospital), is required to evaluate comprehensively the magnitude of this preliminary finding.

Extraperitoneal Laparoscopic Adrenalectomy

J. Kuriansky, A. Saenz, D. Rosin, E. Astudillo, L. Fernandez-Cruz

Dept. of General Surgery and Transplantation, Sheba Medical Center, Tel Hashomer, and Dept. of Surgery, Hospital Clinic, Barcelona

Laparoscopic adrenalectomy has recently been shown to be safe and effective for a variety of benign adrenal tumors, such as aldosterone adenoma, pheochromocytoma, nonfunctioning adenoma, Cushing's adenoma and Cushing's syndrome. Recently, laparoscopic surgeons adopted an extraperitoneal approach in which a space is created by the introduction of a trocar with an inflatable balloon tip. This technique with a minimal access procedure provides direct access to the adrenal glands without interfering with intraperitoneal organs.

Laparoscopic adrenalectomy using the extraperitoneal approach was completed in 18/20 consecutive patients. Mean operative time was 95 min (range 80-120) and median hospital stay 3 days. Blood transfusion was not required, and there were no postoperative complications.