Salpingitis isthmica nodosa in infertility and ectopic pregnancy.

Excised tubal segments from 94 infertile women with tubal obstruction, with a mean infertility duration of 5.3 years, and 40 women with ectopic tubal pregnancy were studied histopathologically to evaluate the association with salpingitis isthmica nodosa (SIN). The mean age of the 94 infertile women with tubal obstruction was 24.5 years. Hysterosalpingographies and laparoscopy were performed on all of them. Only the women with ectopic pregnancies we performed salpingectomy on were included in the present study. The incidence of SIN in women with tubal obstruction was 7.4%, in women with ectopic tubal pregnancy 10%, and in the control group the incidence was 0.2%. In 60% of the cases, SIN was present in both of the tubes. Based on this study, we conclude that SIN is significantly associated with infertility and ectopic tubal pregnancy.


Comparison of first trimester serum estradiol levels in aborters versus nonaborters during maintenance of normal progesterone levels.

This study was designed to measure the average serum estradiol (E2) levels in the first trimester for women whose serum progesterone (P) levels were carefully maintained at normal levels by the use of exogenous P, and to compare the mean serum E2 levels in women who aborted with those in women who did not. The study group consisted of 94 pregnant women supported with exogenous natural P therapy from the luteal phase through the first trimester. Beginning at week 5, and continuing through the first trimester, the mean serum E2 levels for nonaborters were significantly higher than those for aborters.


Hemolysis in hypertensive disorders of pregnancy.

The hemolysis markers LDH, haptoglobin, bilirubin (serum, urine), urobilinogen (urine), fragmentocytes and free hemoglobin were compared in 166 patients with various degrees of hypertensive disorders of pregnancy and 179 nonhypertensive pregnant controls in a weekly screening program. Early recognition of hemolysis was limited to a period of 1 week before the actual delivery date. In the diagnostic sensitivity, haptoglobin and to a lesser degree unspecific LDH were clearly superior to the other hemolysis parameters. A decreasing platelet count also has to be taken as an indicator of impending hemolysis. Subclinical hemolysis was associated with poorer fetomaternal outcome. With the aid of haptoglobin, LDH and thrombocytes, an incipient HELLP syndrome could be recognized 1-2 days before the complete clinical picture became apparent.


Obstetrical risk factors and pregnancy outcome in rural Mozambique. A prospective study.

A study of 373 pregnant women in two rural areas of Mozambique indicates that 38% of pregnant women are classified as having high risk factors according to the antenatal card. A postpartum follow-up of 200 women showed that data were available for 85% of the enrolled women. The 10 women (7%) that had suffered perinatal deaths did not have an overrepresentation of high risk factors according to the card. Neither of the 2 women suffering maternal deaths had had any risk criteria according to the card. More efficient risk criteria will presumably be the outcome of further research for an improved antenatal card.


Effect of LHRH and its analogues on the progesterone secretion of human granulosa cells in vitro.

Progesterone secretion of cultured human granulosa cells treated with LHRH or its analogues was measured. Granulosa cells were also stimulated with LH, FSH, cAMP or forskolin. No differences could be observed in the progesterone basal secretion of cultures treated with or without LHRH or its analogues and after the various stimulations. It was concluded that the clinical experience that the sensitivity of ovaries for gonadotropins after LHRH desensitization is decreased could not be explained with the peripheral effects of LHRH on the granulosa cells. From the data obtained, the lack of LHRH receptors in the ovaries are suggested in humans.


Morphological characteristics of spontaneous endometriosis in the baboon (Papio anubis and Papio cynocephalus).

The histopathology of spontaneous endometriosis was studied on 20 pelvic implants biopsied at laparoscopy in 15 healthy baboons. Endometriosis was confirmed by histopathology in 10 of these animals (66%). Typical (n = 3) and subtle (n = 13) endometriotic lesions were confirmed by histopathology in 100 and 61%, respectively. Suspected disease-bearing lesions (n = 4) were confirmed in 50%. Implants could be classified as active (n = 5), inactive (n = 3), atrophic (n = 2) or stromal endometriosis (n = 3). The histological findings for typical and subtle implants were similar to those reported in humans.


Effects of chlorhexidine gluconate douche on normal vaginal flora.

The effects of a 0.5% aqueous chlorhexidine gluconate (CHG) douche on the normal vaginal flora of twenty healthy nonpregnant volunteers were investigated. The douche was applied in a premeasured 180-ml quantity daily for 7 consecutive days. Specimens for aerobic and anaerobic culture of the vaginal flora were obtained on 3 occasions from each volunteer, once before and twice after CHG use. The culture results were analyzed qualitatively and quantitatively. A blood sample was also collected within 24 h of the last CHG application to determine serum CHG concentration. Lactobacillus spp., Gardnerella vaginalis and Staphylococcus epidermidis were the most prevalent aerobic bacteria at all phases of the study and Bacteroides spp. were the most prevalent anaerobes. The composition of the normal flora was essentially the same 30 days after the last dose as the pretreatment flora. Small amounts of CHG were detected in the serum of all but one subject. No untoward effects on the participants were observed. Candida albicans counts were slightly higher, but prevalence was not significantly increased at the end of the study.


Endogenous estrogen levels in postmenopausal women with severe urogenital atrophy.

In order to be able to evaluate the systemic influence of exogenous estrogen therapy in different conditions, it is important to have knowledge of the endogenous estrogen levels. The present study was undertaken to assess the basic levels and possible fluctuations of endogenous estrogen in postmenopausal women with urogenital estrogen deficiency. Plasma concentration levels of unconjugated estrone and estradiol were measured at regular intervals during 24 h in 5 postmenopausal women without estrogen treatment. All women had very low levels of estradiol. No diurnal fluctuation was found. Estrone levels were not measurable with a sensitive RIA technique.


Combined use of progesterone challenge test and endometrium thickness evaluated by transvaginal ultrasonography in the preventive management of postmenopausal women.

Endometrial thickness was evaluated in apparently normal postmenopausal women by transvaginal ultrasonography and the results were compared with the response to the progesterone challenge test (PCT). A positive correlation between amount of withdrawal bleeding after PCT and endometrial thickness was found, also demonstrated by the significative correlation between bleeding length and endometrial thickness. Among women referring withdrawal bleeding, 100 and 22% of cases classified as overt flow and spotting, respectively, were characterized by pathologic histological findings. The combined use of these two procedures is suggested as an effective screening mean in the preventive endometrial management of apparently normal postmenopausal women to select candidates for diagnostic invasive procedures.


Doppler ultrasound studies in pelvic inflammatory disease.

Ten women with tubo-ovarian abscess caused by pelvic inflammatory disease (PID) were investigated by transvaginal Doppler ultrasound during the acute and healing phases of the infection. The pulsatility index (PI) of the uterine arteries was measured and compared with the values obtained from 19 healthy women. Each control patient was investigated three times during a single menstrual cycle. In PID patients, the PI values were significantly lower than in controls in the same phase of the menstrual cycle. When C-reactive protein was > 50, the PI values were lowest and reverted to normal values when the infection subsided. In a case of chronic infection, the PI did not rise to normal despite normal infection parameters. Doppler ultrasound seems to offer a new method of assessing PID.


Early diagnosis of proximal femoral deficiency.

A case of proximal femoral deficiency in a fetus, associated with ventriculomegaly and oligohydramnios is described. Vaginal ultrasonographic diagnosis was made in the 14th week of gestation in a 37-year-old asthmatic woman. Ultrasonic follow-up until termination of pregnancy in the 20th week of gestation was performed. The importance of early diagnosis and the possible roles of oligohydramnios and antiasthmatic medications are discussed.


[Plate osteosynthesis of the radius. Own implant and technique].

In 1989 and 1990, 46 acute distal radius fractures with die-punch compression cavities underwent open reduction and internal fixation using a new compression plate and surgical technique. In 34 of these patients, functional and radiological results after plate removal were studied. Surgical exposure was palmar or dorsal, or combined palmar with a supplementary dorsal incision, depending on the location of the compression cavity and the extent of fracture dislocation. A cortico-cancellous graft from the iliac crest was fitted into the compression cavity, thus supporting the reduced joint surface against the radius shaft. Superior maintenance of the reduction was achieved using cortico-cancellous instead of simple cancellous graft. A new titanius radius reconstruction plate was used for internal fixation. This two-fold support of the fracture allowed for earlier wrist mobilization.


[Step-plasty for therapy of chronic subcutaneous ruptures of extensor tendons of finger end joints].

A new method for secondary operative treatment of subcutaneous ruptures of the extensor tendons in the DIP-joint region is described. A step-cut incision is performed in the area of the regenerative tissue and the adjacent original tendon. The sutures in the longitudinal incision line compensate the tension and give better anchoring. First results show a tendency to an improved relationship between pre- and postoperative extension lag compared to other methods. Also, the method is an improvement from the aesthetical point of view and in operative practicability.


[The importance of arthroscopy for hand surgery today].

Wrist arthroscopy is a new approach to the diagnosis and treatment of chronic wrist pain and pathology, that could not be achieved by conventional diagnostic instruments. The arthroscopy allows detailed assessment to articular surfaces, chronic synovitis, triangular fibro-cartilage tears, lesions of the intercarpal and palmar ligaments, and intraarticular fractures of the radius. The technique is very demanding and should be performed only by experienced surgeons. The dorsal portals are located with relation to the six extensor compartments. Because of the limited space of the wrist joint, an arthroscope with an outermost diameter of 2.5 mm or less is necessary with a high-sensitivity, light-weight microchip video-camera and special mini-instrument. With this equipment, surgery can be performed within the radio-carpal- and midcarpal joint. Only few in Germany are experienced in wrist arthroscopy; looking to the USA, this technique has already shown its great potential.


[Microsurgical and histological observations in schwannoma of peripheral nerves].

From 1986 to 1991, eight patients with benign schwannomas (neurilemomas) of peripheral nerves underwent tumor resection. In six of eight cases, microsurgical dissection revealed one or several nerve fascicles "disappearing" in the center of the schwannoma. Therefore, these fascicles had to be removed along with the tumor. This observation contradicts the current opinion that enucleation of benign schwannomas is usually straightforward and possible without fascicular damage. Interestingly, the resection of fascicles did not create additional neurological deficits. For functional reasons, partial nerve grafts bridging the resulting fascicular defects were considered appropriate in two cases. Tumors of peripheral nerves should be treated by surgeons familiar with microsurgical operative techniques.


[A realistic practice model for learning microneural surgery without experiments on live animals].

The increasing importance of microneurosurgery in hand and plastic surgery makes it necessary for surgeons to familiarize themselves with these techniques. In most training programs, anesthetized rats have been used to learn basic microneurosurgical techniques. Ethical considerations, the costs involved, and the legislation concerning experiments with live animals permit extensive training in microneurosurgery in only a few medical centers. This paper relates our experience with an alternative training program not involving live animals. Instead, we chose the legs of slaughtered pigs. Mono-, oligo-, and poly-fascicular nerves, structurally similar to the configurations found in human extremities, can be found in pig legs. Neurolysis, primary nerve sutures, and nerve transplantations can be practiced.


[Choice of thrombin concentration of common fibrin glue systems for nerve anastomosis].

Although fibrin glue has been used in several areas of surgery with increasing success, it has not become fully established in nerve coaptation. Initially, significant advantages were expected, however, as the fibrin clot dissolved prematurely, gapping occurred and antifibrinolytic substances had to be added to the glue. Following this procedure, fibrosis occurred frequently. This remains a problem. Therefore, the dosage dependent fibrosis-inducing effect of thrombin was investigated in an animal experimental study. Thrombin demonstrates a fibrosis-promoting effect and we therefore recommend 1-1.5 NIH thrombin/ml glue, as lower concentrations increase the clotting time.


[Measuring microcirculation after replantation and revascularization].

Eighty-four patients were evaluated following replantation or revascularization. Extremity function in daily and professional life was altogether satisfactory. Microcirculation investigations in eight patients included thermography, laser-doppler-flowmetry and photoplethysmography. The rewarming period and postocclusive hyperemia after standardized cooling of the upper extremity were determined. In areas of hypesthesia, the rewarming period was clearly delayed. In addition, reactive hyperemia after occlusion of circulation was significantly reduced.


[Laser in surgery of vascular anastomoses].

The disadvantages of present-day microvascular suturing techniques include suture-induced foreign-body granulomas, stenoses and aneurysms. In comparison, argon laser-assisted anastomoses show a more favorable histomorphology and a low rate of stenoses and aneurysms. Laser-assisted anastomoses pass through the same familiar healing phases seen in common wound-healing.


[Chorionic villi sampling: choice of transcervical or transabdominal routes preferable to use of transcervical route exclusively].

Between November 1985 and June 1990 we performed 400 first trimester chorionic villi samplings (CVS). In the first 107 cases only transcervical CVS was performed, regardless of placental location. Later, 163 transcervical and 130 transabdominal CVS were performed, depending on placental location. Anterior and fundal placentas were approached transabdominally and posterior placentas transcervically. Multiple pregnancies were excluded. Successful results were obtained in 394 out of 400 cases. There were 5 failures in the first set of cases and 1 in the second (p < 0.05). In 14 cases (3.5%) fetuses with normal karyotypes were spontaneously aborted, 5 of these in the first period (4.7%) and 9 (3.1%) in the second. The spontaneous abortions in the second period followed transabdominal CVS in 4 cases out of 130 (3.1%) and the transcervical route in 5 cases out of 163 (3.105%). The average attempts per case in the first period was 1.44 (SD 0.66) while in the second it was 1.17 (SD 0.44, p < 0.0001) for the transcervical route and 1.06 (SD 0.2, p < 0.002) for the transabdominal route. In our experience choosing between transabdominal and transcervical CVS according to placental location is preferable to the sole use of transcervical CVS in terms of lower failure rate and fewer attempts per case. Proficiency in both techniques is mandatory for optimal results.


[Limulus amebocyte lysate assay for diagnosing intraamniotic infection].

The value of the Limulus amebocyte lysate assay (LAL) in the diagnosis of intraamniotic infection was determined in amniotic fluid from transabdominal amniocenteses in 51 women in preterm labor with intact membranes. The prevalence of positive amniotic fluid cultures was 21.5% (11/51) in detecting intraamniotic infection. The LAL was positive in 19.6% (10/51), its sensitivity 81.8% (9/11), specificity 97.5% (39/40), positive predictive value 90.0% (9/10), and negative predictive value 95.1% (39/41). Similarly, in detecting women who would fail tocolysis and deliver prematurely, its sensitivity was 27.6% (8/29), specificity 90.9% (20/22), positive predictive value 80% (8/10), and negative predictive value 48.8% (20/41). We conclude that LAL is a simple, rapid and sensitive test for detecting intraamniotic infection in women in preterm labor.


[Laparoscopic hysterectomy].

Abdominal hysterectomy is one of the most common major operations in gynecology. However, it is associated with considerable morbidity and relatively slow recovery. We describe a laparoscopic procedure for removal of the uterus, with or without the adnexa, in women in whom abdominal hysterectomy would otherwise be indicated. Laparoscopy is performed with the 3-puncture technic and an additional incision for the electrocoagulation instrument. The infundibulopelvic and round ligaments are dissected and divided if oophorectomy is to be done. If not, the broad ligament lateral to the uterine body is similarly treated and finally the dissections are extended to the uterine vessels and the uterosacral and upper parts of the transverse cervical ligaments. Surgery is completed vaginally after deflation of the abdomen, as in vaginal hysterectomy. Laparoscopy is repeated when the vagina has been closed, to ensure hemostasis. We have successfully performed laparoscopic hysterectomy, with or without salpingo-oophorectomy, in 7 women, aged 39-57. The procedure lasted 90-160 minutes and postoperative discomfort was minimal. All patients returned to normal activity within 4 weeks and were delighted with the outcome as well as with the cosmetic results. This technique offers an attractive alternative to conventional approaches and has significant advantages. Nevertheless, further studies are necessary to evaluate the true efficacy of the procedure.


[Remission of acute promyelocytic leukemia after all-trans-retinoic acid].

This is the first report in Israel of the successful treatment of acute promyelocytic leukemia (APL; M3) with an active metabolite of vitamin A. In a 42-year-old woman with APL all-trans-retinoic acid (ATRA; tretinoin), 45 mg/m2/day was given per os for 90 days. APL is associated with a distinct cytogenetic abnormality: translocation of a portion of the long arm chromosome 17 onto the long arm chromosome 15t (15; 17) with a breakpoint on chromosome 17 in the region of the retinoic acid receptor-alpha (RAR-alpha), playing a crucial role in the leukemogenesis of APL. In man, the drug induces myeloid and mainly promyelocytic leukemic cells to differentiate, without the development of bone marrow hypoplasia. In our patient it caused complete remission and the disappearance of intravascular disseminated coagulation. The only side-effects were a transient macular rash, gastrointestinal symptoms and mild hypertriglyceridemia. Other principal adverse effects reported in the literature are relatively not very serious and consist of dryness of the skin, occasional headaches and intracranial hypertension, nasal congestion, lymphadenopathy, respiratory distress with infiltrates in the lung, bone pain and increased hepatic aminotransferase. A hyperleukocytosis syndrome seems to be more problematic. ATRA appears to be superior to conventional chemotherapeutic regimens. It is safe and highly effective in inducing clinical, morphologic and karyotypic remission with a marked decrease in the expression of the abnormal RAR-message in APL. There is a possible molecular link between the pathogenesis and treatment of this severe and often fatal coagulopathic disease. This therapy of course does not eradicate the leukemic clone, and consolidation chemotherapy or bone marrow transplantation is necessary.(ABSTRACT TRUNCATED AT 250 WORDS)


[Free-flap reconstruction of the head and neck].

Free-flap microvascular surgery of the head and neck is now an accepted reconstructive technique. Optimal reconstruction of both function and form are achieved in selected patients by this method. We describe our experience with free-flap reconstruction of head and neck defects in 13 patients. In 5 oncologic patients reconstruction was immediate, while in 8 other oncologic and trauma patients it was delayed. The free rectus abdominis myocutaneous flap was used most often. 3 flaps required revision, but only 1 failed.


[Treatment of Pipkin's fracture of the femoral head].

We present 3 cases with Pipkin's fracture of the femoral head, a rare and complicated fracture. 2 were operated on and did well. The third, not operated on, has severe symptoms and most probably will require extensive reconstructive surgery.


[Management of fractures of the face].

During 1985-1989, 371 patients with fractures of the lower two thirds of the facial skeleton were treated. Mean age was 31.2 years and there was a male prevalence of 78%. An equal distribution was found between fractures of the middle and lower third of the face. Our clinical experience has shown that it is preferable to start treatment as early as possible, using an open approach for reduction of fractures and rigid methods of fixation. Rigid internal fixation enables the patient to keep his jaws functional postoperatively and prevents the need for maxillomandibular fixation for 6 weeks. 6-month follow-up showed a low incidence of bone infection (1.5%), although most fractures were exposed to contaminated spaces. The major complication of treatment was impaired sensation of the lips and infraorbital regions (23%). In a follow-up of up to 1 year, the occurrence of this complication decreased to 7%.


[Aortopulmonary fistula due to failed graft for aortic aneurysm].

Hemoptysis originating from an aortobronchial fistula is uncommon. This fistulous connection between the aorta and the lung usually results from a preexisting thoracic-aortic aneurysm, and is uniformly fatal when left untreated. However, with early diagnosis the survival rate exceeds 80%. The case of an aortobronchial fistula in a young alcoholic, 2 years after aortic aneurysmectomy, is presented. He was admitted with symptoms suggesting upper gastrointestinal bleeding, allegedly related to alcohol abuse. He died of a sudden, massive hemoptysis 5 days after admission. An aortobronchial fistula was found on autopsy. To diagnose aortobronchial fistula, a high index of suspicion is necessary. It should be considered in patients with hemoptysis after repair of a thoracic aneurysm.


[Acute systemic side-effects of topical timolol for glaucoma].

Topically-administered ophthalmic medication may reach clinically significant serum concentrations, as evidenced by the variety of systemic side effects reported. These drugs may interact with other drugs administered orally and intravenously, increasing the frequency and severity of their side-effects. We report 4 patients examined in the emergency room because of various systemic manifestations, in whom the symptoms could be attributed either to antiglaucomatous eye drops, or to interaction between these eye drops and systemic medication. Considering the high incidence of glaucoma (0.5-2%), physicians should be aware of the systemic side-effects of antiglaucomatous eye drops and of possible interaction between such treatment and systemic medications.


[The functional treatment of deep bite--the results of a long-term study].

The amount of overbite reduction and the stability of the results three to 14.5 years post-retention were analysed in a follow-up study of 60 patients who had been treated with functional appliances. To establish therapeutic and posttherapeutic changes in dento-facial relationships, plaster casts and lateral cephalograms were evaluated at the beginning, at the end of treatment and at the follow-up examination. Posttherapeutic deepening of the overbite (> 0.8 mm) was found in 54.2% of the cases, while overbite reduction remained stable in 39%. A number of skeletal and dental factors were found to be involved in overbite reduction and posttreatment deepening. In this connection, changes in the ML-NSL angle, the ML-NL angle and the gonion angle were found to be just as important as the therapeutic and posttherapeutic changes in anterior and posterior facial height and changes in the skeletal pattern. It is emphasized that strict application of retention is of the greatest importance to minimize vertical relapse.


[The determinants of wear behavior in treatment with removable orthodontic appliances].

The interplay of significant determinants of patient appliance wear is discussed in terms of a conceptual model reflecting the current state of research in orthodontic compliance. Appliance wear is determined by treatment-related factors such as regimen and perceived comfort, as well as by external factors such as patient personality and parental attitudes. Patient attitudes are the critical link between these influences. In the focus of this article are the patient's experiences and perceptions of treatment and the way they are affected by appliance and prescribed wear. Furthermore, possible measures to enhance compliance are highlighted.


[A contribution to the controversial discussion on a preoperative orthodontic treatment for infants with unilateral cheilognathopalatoschisis].

A longitudinal study of 39 casts of pre-operative orthodontically treated unilateral cleft lip and palate children from birth to palate operation was carried out with a special coordinate measuring technique to quantify changes in the maxilla. A significant reduction in width of the alveolar cleft was found. The anterior alveolar arch width remained constant, while the posterior region slightly increased. These results seem to justify treatment with the infant appliance. After measuring casts from 39 preoperatively treated and casts from 62 untreated patients prior to lip operation, a comparison of the mathematical average values between the two groups revealed few differences. This can be explained by referring to the original morphological findings and the different measurements during the preoperative orthodontic treatment, which lead to different changes in segment position prior to lip operation. In a cross section examination this difference could not be found. A sub-classification of the subject matter in primary and secondary clefts revealed that between both types clear differences in the resulting parameters can be observed. This leaves the question, whether the width of the cleft palate is caused by tissue deficiency or by an embedded tongue. Furthermore, how will the orthodontic appliance therapy influence the growth? A greater dislocation of the segments in secondary clefts may be expected in cases where the rest position of the tongue appears caudal. Improved measuring methods to record cleft morphology and more emphasis on the study of soft tissue reactions may help to understand the differing results after preoperative or orthodontic treatment.


[Sonography--a diagnostic tool for the dynamic functional analysis of the tongue].

The possibility of using ultrasonography to analyse tongue function in the orthodontic setting was investigated in a pilot study involving ten dental students and ten adult, former patients with cleft, lip, jaw and palate. The ultrasonograms were videotaped and the contour of the tongue at rest and during swallowing was analysed in an extremely slow-motion playback mode. Ultrasonography was capable of clearly showing differences in tongue function between both groups. Ultrasonography may therefore be considered a useful technique for visualisation of individual tongue movements. In orthodontics, ultrasonography could be extremely helpful for the long-term documentation of myofunctional treatment, craniofacial anomalies, or in epidemiological research. Standard conditions for investigation and analysis of results still have to be elaborated.


[Transverse expansion with plate appliances--their intermolar stability and significance for gingival recession].

This study was undertaken to investigate if transversal expansion with removable plates is a predisposing factor in the occurrence for buccal recessions in the molar region. In order to clarify a possible causal relationship, it is important to know to what extent the therapeutic expansion remains stable, 58 former patients, ages ten to 15, were studied following transversal expansion and non-extraction therapy with removable appliances. Intermolar expansion and stability, clinical crown length, and the incidence of buccal recessions on the incisors and six-year molars were evaluated. The study revealed that with relatively good intermolar stability (relapse between 13% and 14%), when compared with an untreated control group and with the data contained in the literature, recessions do not increasingly occur.


[The development of the deciduous dentition under the influence of differently shaped pacifiers].

Intending to perform a prospective study after the birth of their children 312 mothers were asked for co-operation and a newly developed preventively shaped pacifier was given them (free of charge) for use. Two years later it was possible to join 202 children and morphologically investigate their primary dentition. On the base of the real behaviour in the meantime the subjects formed five groups: children without sucking habits, finger suckers, user of cherry-shaped pacifiers, so-called health pacifiers and test pacifiers. The findings show specific significant differences. Especially cherry-shaped pacifiers but also medically recommended pacifiers can badly influence the development of the deciduous dentition. However, the harmful results can be minimized by a special preventive shape.


[Complications of and after hysterectomy. Retrospective study of 5,676 patients--guidelines for preoperative patient education].

Over the last three decades, litigation resulting from gynecological operations has risen considerably. This is attributed to no small extent to inadequate preoperative information of the patient by the physician. The medical histories of 5,676 patients submitted to hysterectomy were evaluated retrospectively and all intraoperative and postoperative complications analyzed. In order to be able to give the patient comprehensive information, the physician must be familiar with the nature and incidence of possible complications, on the basis not only of his own personal experience, but also of the data provided by extensive case material. Forensic disputes can be reduced only by ensuring that the patient is fully informed and thus that her agreement to the operation is legally binding.


[Migraine and tension headache. New procedures for objective differentiation].

Presentation of a new questionnaire for headache analysis that supplements a computer-aided scheme for the diagnosis of headaches. The classification scheme of the International Headache Society (IHS) represents an instrument for the classification and identification of headaches that makes use of phenomenological criteria. On this basis, a computer program was developed that permits clearly differentiated analysis of various common types of headache. Both primary forms of headaches and clinically relevant secondary forms are taken into account. Since many--although not all--doctor's offices are equipped with personal computers, a questionnaire has now been developed with the aid of which the two major primary forms of headache, migraine and tension headache, can be distinguished. On average, the patient takes only five minutes to complete the questionnaire. Evaluation is performed simply, with the aid of an evaluation sheet. Types of headache other than those described cannot be excluded on the basis of the questionnaire.


[Different effects of fibrates on the lipoprotein profile. Comparison of the effectiveness of gemfibrozil and bezafibrate in various types of hyperlipoproteinemia].

To compare the efficacy and tolerability of Gemfibrozil and Bezafibrate in patients with hyperlipoproteinemia, types IIa, IIb and IV. In an open, randomized parallel study, the tolerability and efficacy of Gemfibrozil (G) and Bezafibrate (B) were investigated over a period of 12 weeks in 178 hyperlipidemic (HLP) patients first submitted to an 8-week "wash-out" (diet only) phase. In HLP type IIa patients, LDL cholesterol was lowered (G: -13%, B: -10%). In HLP type IIb, a decrease in triglyceride (TG) levels (G: -41%, B: -31%), an increase in HDL-cholesterol (G: +19%, B: +5%), and a decrease in the total cholesterol/HDL cholesterol ratio (G: -32%, B: -9%) predominated. Patients with type IV HLP responded to both fibrates with an appreciable reduction in TG levels (G: -45%, B: -42%). The effects of the preparations differed significantly with respect to the elevation of HDL cholesterol and a decrease in the total cholesterol/HDL cholesterol ratio in HLP type IIb patients. The respective lipid baseline concentration appeared to be of importance for the sense and extent of the changes induced.


Study on the effect of oral administration of carbocysteine on ventilatory parameters in the SO2 inhalation model of bronchitis in the rat.

In order to study the physiological correlates of the beneficial action of carbocisteine (S-carboxy-methyl-cysteine), we have measured the changes occurring in ventilatory parameters in rats made bronchitic by prolonged exposure (2 weeks) to air containing sulfur dioxide (SO2). In animals treated with distilled water (1 ml/100 g/day), statistically significant (P < 0.05) changes in respiratory frequency (-20%) and tidal volume (+31%) were found. As a result of these opposing changes, the ventilation/min was stable. Moreover, the compliance was decreased (33%, P < 0.05) and the resistance was greatly enhanced (+ 99%, P < 0.05). The concomitant administration of carbocisteine (500 mg/kg po/day) with SO2 inhalation significantly (P < 0.05) prevented the development of resistance without effecting significant changes in the other parameters except for a slight improvement in ventilation/min. In conclusion, this improved respiratory resistance in the bronchitic carbocisteine-treated animals tallies with a decrease in mucus retention associated with the return to normal of rheological characteristics of the secreted mucus.


Rolipram inhibits PAF-induced airway microvascular leakage in guinea-pig: a comparison with milrinone and theophylline.

The effects of 3 phosphodiesterase (PDE) inhibitors, rolipram (PDE IV), milrinone (PDE III) and theophylline (non-selective) on PAF (50 ng kg-1; iv)-induced airway vascular leakage have been evaluated in guinea-pigs. Rolipram (3-300 micrograms kg-1; iv) reduced the increase in permeability induced by PAF at all airway levels whereas milrinone (10-1000 micrograms kg-1; iv) and theophylline (30 mg kg-1; iv) were without effects. The anti-leakage activity of rolipram may be of therapeutic value in asthma.


Tolerance and pharmacokinetics of propacetamol, a paracetamol formulation for intravenous use.

In 12 healthy volunteers, paracetamol pharmacokinetics were compared following administration of 1 g propacetamol HCl given intravenously over a 15-min period and 500 mg paracetamol given orally. Mean +/- SD total AUC (microgram/ml.h) following the iv formulation was significantly (P < 0.01) greater than following oral paracetamol (25.53 +/- 4.27 vs 21.04 +/- 4.49) corresponding to a mean oral bioavailability of paracetamol of 82.2 +/- 9.4%. Between 1 and 2 h after administration, paracetamol plasma concentrations became very similar following both formulations. In another study, 2 g propacetamol HCl was given both as a 15-min infusion and as a 2-min bolus injection to six healthy volunteers. Contrary to mild to moderate local discomfort experienced during the 2-min bolus injection, the 15-min infusion was well tolerated without any complaints reported.


Quality of life assessment in therapeutic trials: rationale for and presentation of a more appropriate instrument.

In therapeutic trials, quality of life studies are usually based on a health model which results in a restrictive view. Therefore, it is important to clearly define the concept of the quality of life, since ambiguous concepts can alter the results. The key to this problem is the clear distinction between the two components of the quality of life, ie subjective and objective. This latter component is the only one considered in the current medical approach. The use of the subjective quality of life introduces a number of methodological problems not found when the objective quality of life is assessed, and thus requires a specific model which can be derived from the model of life goals used by sociologists. This model is presented here and illustrated with some results obtained with a new questionnaire, the Subjective Quality of Life Profile (SQLP) questionnaire. We suggest that both subjective and objective quality of life studies should be considered in order to emphasize the humanistic approach to therapeutic indications.


A review of the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency.

Hypoxanthine-guanine phosphoribosyltransferase (HPRT, EC 2.4.2.8) is a purine salvage enzyme that catalyses the conversion of hypoxanthine and guanine to their respective mononucleotides. Partial deficiency of this enzyme can result in the overproduction of uric acid leading to a severe form of gout, whilst a virtual absence of HPRT activity causes the Lesch-Nyhan syndrome which is characterised by hyperuricaemia, mental retardation, choreoathetosis and compulsive self-mutilation. The HPRT-encoding gene is located on the X chromosome in the region q26-q27 and consists of nine exons and eight introns totalling 57 kb. This gene is transcribed to produce an mRNA of 1.6 kb, which contains a protein encoding region of 654 nucleotides. With the advent of increasingly refined techniques of molecular biology, it has been possible to study the HPRT gene of individuals with a deficiency in HPRT activity to determine the genetic basis of the enzyme deficiency. Many different mutations throughout the coding region have been described, but in the absence of precise information on the three-dimensional structure of the HPRT protein, it remains difficult to determine any consistent correlation between the structure and function of the enzyme.


DNA analyses of XX and XX-hypospadiac males.

Fourteen 46,XX "males" were analyzed by Southern blot hybridization with seventeen different Y chromosome-derived DNA probes and by the polymerase chain reaction for an additional two sites on the short arm of Y. Eight 46,XX males possessed various segments of the short arm of the Y chromosome, including the sex determining region. The detected segments ranged from the two most distal loci to nearly the entire length of the short arm, viz., 10 out of 11 loci. None of the eight patients had hypospadia. Five out of the six remaining cases had hypospadia and no Y sequence was detected, suggesting the presence of a causative difference between hypospadiac and non-hypospadiac groups.


The gene encoding human transmembrane secretory component (locus PIGR) is linked to D1S58 on chromosome 1.

The human transmembrane secretory component (SC or poly-Ig receptor, PIGR) is expressed basolaterally on glandular epithelial cells and is responsible for the external translocation of polymeric IgA and IgM. SC is hence a key molecule in antibody protection of mucosal surfaces. The human SC gene (locus PIGR) is located on chromosome 1 (1q31-q41). Here we present the first genetic linkage study of PIGR versus syntenic markers, including D1S58 and F13B, which have been previously regionalized to 1q31-q32 and 1q31-q32.1, respectively. We found that PIGR is closely linked to D1S58 (lods + 5.06 at theta max = 0.06, without sex difference). PIGR versus F13B showed + 1.46 at theta max = 0.25 for both sexes combined. A recombination of 0.06 between F13B and D1S58 (lods + 2.24) was in contrast to a previously published study giving theta max = 0.22 (lods + 3.9), the combined lods being 5.6 at theta max = 0.20. The progeny of a triply heterozygotic female indicated that PIGR is the flanking locus, therefore suggesting a cen-F13B-D1S58-PIGR-qter gene sequence on human chromosome 1. Only negative lod scores to RH, C8@, and PGM1 on 1p, and FY on proximal 1q, were found. Current combined Norwegian allele frequencies were estimated for PIGR to be A1 = 0.63, A2 = 0.37 (370 chromosomes), and for D1S58 to be A1 = 0.44, A2 = 0.56 (218 chromosomes).


Further evidence of a duplication in 17p11.2 in families with recurrence of HMSN Ia (Charcot-Marie-Tooth neuropathy type Ia).

Five Italian families with recurrence of cases of Charcot-Marie-Tooth disease (type Ia) were analysed using three closely linked DNA probes that detect polymorphisms in the region 17p11.2. The probe pVAW409R3 detected the presence of a duplication in all the affected subjects, but not in the subjects with normal electromyographic (EMG) findings. This observation confirms previous data indicating the association of the duplication with the disease, suggesting that, at least in populations of European origin, the duplication might be the molecular feature diagnostic of the pathological trait.


Preparation of a rat brain histidine decarboxylase (HDC) cDNA probe by PCR and assignment of the human HDC gene to chromosome 15.

The formation of histamine from its precursor histidine is catalyzed by histidine decarboxylase (HDC), a pyridoxal phosphate (PLP)-dependent decarboxylase. The knowledge of sequence similarities between various rodent HDCs permitted us to prepare a rat brain HDC cDNA probe. After reverse transcription of rat brain polyA + mRNA, the HDC cDNA obtained was amplified by the polymerase chain reaction using two specific primers. The resulting 1019-bp DNA was cloned in the p-MAL vector. Its sequence corresponds to the published data on rat fetal liver HDC. This 1019-bp rat probe detected two BamHI sequences in man; these were assigned to chromosome 15 by somatic hybrid cell analysis. According to the well-known homology between human chromosome 15 and mouse chromosome 2, the result obtained is in agreement with the published localization of HDC on mouse chromosome 2. The mapping of the human HDC gene on chromosome 15 is an original contribution to the chromosomal assignment of related PLP-dependent decarboxylases.


Absence of Turner stigmata in a 46,XYp-female.

A 46,XY female patient with streak gonads and a large deletion of Yp is described. The deletion included the Y chromosomal genes SRY, ZFY, and RPS4Y. The patient did not display any Turner stigmata, such as webbing of the neck, cardiac or other abnormalities. The findings argue against an important role of RPS4Y in the prevention of Turner stigmata in males and are consistent with a role of SRY in testis differentiation in humans.


Generation and characterization of radiation reduced cell hybrids and isolation of probes from the proximal short arm of the human X chromosome.

Employing a modified Goss-Harris irradiation fusion protocol, we have generated a panel of somatic cell hybrids containing various overlapping fragments of the Xcen-Xp11.4 interval. This region of the human X chromosome is known to carry genes for several hereditary eye diseases including retinitis pigmentosa (RP2), congenital stationary night blindness (CSNB-1) and Norrie disease. These hybrid cell lines were employed to isolate 17 new DNA probes by making use of the Alu polymerase chain reaction (PCR) method and subsequent cloning of the PCR products in a plasmid vector. With these probes, we have characterized two previously described microdeletions spanning the Norrie locus; these deletions have enabled us to subdivide the Xp11.4-p11.3 region into three defined intervals.


A homozygous missense arginine to histidine substitution at position 482 of the beta-galactosidase in an Italian infantile GM1-gangliosidosis patient.

We have studied, by the polymerase chain reaction, the beta-galactosidase cDNA from several Italian patients with infantile GM1-gangliosidosis. One homozygote for a previously undiscovered G > A mutation at position 1479, causing an arginine to histidine change, was detected. The same mutation, in heterozygosis, was identified in 6 unrelated patients, but not in 100 normal chromosomes.


Tissue segregation of a heteroplasmic mtDNA mutation in MERRF (myoclonic epilepsy with ragged red fibers) encephalomyopathy.

The distribution of the causal 8344A-->G mtDNA mutation has been examined in six tissues of a patient with myoclonic epilepsy with ragged red fibers (MERRF), to study the developmental genetics of this type of mitochondrial disorder, and to determine the pathophysiological importance of the mtDNA heteroplasmy generally observed in such patients. Heteroplasmy of the mtDNA was observed in all six tissues (cerebellum, cerebrum, pancreas, liver, muscle, and heart) suggesting that, whereas the mtDNA mutation is relatively new, the mutated population must have existed before the formation of the three primary embryonic layers. The tissue distribution reveals significant variations in the ratio between the mutated and the normal mtDNA species, indicating the randomness of mtDNA segregation during developmental cell division and differentiation events. The result suggests the existence of tissue-specific nuclear factor(s) that determines the expression of the 8344A-->G mutation in various tissues; in MERRF syndrome, expression is mainly in the central nervous system.


Deletions in exon 5 of the human rhodopsin gene causing a shift in the reading frame and autosomal dominant retinitis pigmentosa.

By screening patients with autosomal dominant retinitis pigmentosa for mutations in the rhodopsin gene, two deletions (8 bp and 1 bp) have been identified in exon 5; these deletions cause a shift in the reading frame. The predicted proteins should be radically altered with translation continuing past the normal stop signal and resulting in a rhodopsin molecule that is, respectively, 1 and 10 amino acids longer. The clinical phenotype of the patients is described and is compared with that associated with other mutations in the same region of the gene.


Molecular analysis of type I-A (tyrosinase negative) oculocutaneous albinism.

Type I oculocutaneous albinism (OCA) is caused by the reduction in or absence of activity of tyrosinase in melanocytes in skin, hair, and the eyes, the result of mutations of the tyrosinase gene. To date, a total of 22 unique mutations in the coding region of tyrosinase have been described in the literature. In this report we present 5 additional mutations of the tyrosinase gene associated with type I-A OCA in four individuals, including 2 missense, 1 frameshift and 2 nonsense mutations, and review the relevant literature on all published mutations. Analysis of the distribution of all identified missense mutations (n = 17) shows that most cluster in three areas of the gene and involve amino acids conserved between humans and the mouse. Two clusters involve the copper A and copper B binding sites and may disrupt the metal ion-protein interaction necessary for enzyme function. The third cluster in exon I could represent a functional domain important in enzyme function such as the tyrosine or the dihydroxyphenylalanine (DOPA) binding site of the enzyme. Small deletions or insertions resulting in frameshift mutations and nonsense mutations are distributed throughout the coding region and do not appear to cluster.


Identification of CpG islands around the DXS178 locus in the region of the X-linked agammaglobulinaemia gene locus in Xq22.

The X-linked agammaglobulinaemia (XLA) gene locus has previously been mapped to Xq22. Genetic linkage analysis has shown tight linkage between the disease and the DXS178 locus and that DXS3 and DXS94 are the closet proximal and distal flanking markers, respectively, separated by a genetic distance of 10-12 cM. We attempted to construct a physical map of Xq22 using pulsed field gel electrophoresis (PFGE) and rare-cutting restriction enzymes in order to obtain a finite physical value for the distance between DXS3 and DXS94. However, these attempts were hampered by the large number of rare-cutting restriction enzyme sites around the DXS178 locus, indicative of the presence of CpG rich regions of DNA. We were able to construct a physical map of the sites close to DXS178 that suggests the presence of at least three, and perhaps as many as five, CpG islands. These are arranged on either side of DXS178, extending over about 550kb of genomic DNA. Each of these regions must be considered as being associated with a potential "candidate" gene sequence for the XLA gene and we have initiated a chromosome walk from DXS178 to the nearest of these islands.


A critical analysis of data presented in eight studies favouring X-linkage of bipolar illness with special emphasis on formal genetic aspects.

High lod scores were obtained in several X-linkage studies of bipolar illness under the assumption that a subgroup of manic depression follows an X-linked dominant mode of inheritance. We have previously shown that the segregation patterns do not substantiate this assumption. We now statistically address the lack of evidence for X-linked inheritance by sex-dependently analyzing segregation ratios and clinical data presented in eight positive X-linkage studies. Accordingly, affected males have significantly fewer offspring, a lower mean age and a higher bipolar to unipolar ratio than affected females. There are two possible explanations for these findings: either the X-linked subgroup of bipolar illness has unique features that have not been accounted for clinically, or (more probably) the pedigree structures could also (and might be more likely to) result from ascertaining kindreds following autosomal or multifactorial inheritance only, with exclusion of kindreds encompassing male to male transmission.


Rapid identification of mutations in the glucocerebrosidase gene of Gaucher disease patients by analysis of single-strand conformation polymorphisms.

To detect mutations in the glucocerebrosidase gene in Gaucher disease patients, we used the recently described technique of single-strand conformation polymorphism (SSCP) analysis in combination with selective amplification. We analyzed exon 8, 9, 10 and 11 of the glucocerebrosidase gene; these exons were sequentially amplified using the selectively amplified products as templates. We found variant SSCP patterns corresponding to the presence or absence of the 6433C mutation, which was detected by NciI digestion analysis, in exon 10. Furthermore, we detected four variant SSCP patterns in exon 8, 10 and 11. Sequencing analysis consistently revealed four single-base substitutions in the corresponding exons, three novel missense mutations (5409A, 6375G and 6682T) and one silent polymorphism (6594A). These mutations were found only in one patient; therefore, these findings have confirmed the marked genetic heterogeneity of Gaucher disease. SSCP analysis in combination with selective amplification is a rapid and sensitive procedure for the screening of the mutations in the glucocerebrosidase gene of patients with Gaucher disease.


Characterization and mapping of the 5' portion of von Willebrand factor pseudogene.

A genomic fragment containing the 5' boundary of the von Willebrand factor pseudogene was cloned, partially sequenced and used for in situ hybridization experiments on metaphase spreads from a Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia patient. Data obtained indicate that the von Willebrand factor pseudogenic region is centromeric to the breakpoint cluster region on 22q11.2. This probe could be used for the study of deletions in the DiGeorge syndrome.


The gene for bone morphogenetic protein 2A (BMP2A) is localized to human chromosome 20p12 by radioactive and nonradioactive in situ hybridization.

Bone morphogenetic protein 2A (BMP2A), a member of the decapentaplegic-Vg-related family, belongs to the transforming growth factor beta superfamily and has a striking sequence similarity to the decapentaplegic locus in Drosophila melanogaster, a major determinant of pattern specification during embryogenesis. BMP2A is thought to be involved in cartilage and bone formation during embryogenesis, but may have additional functions in morphogenesis as implied by its expression in various organs and embryonic tissues of mice. Human BMP2A, assigned to chromosome 20 by the use of human-Chinese hamster ovary cell hybrids, is considered to be a reasonable candidate gene for the autosomal dominant disease of fibrodysplasia (myositis) ossificans progressiva. We have confirmed the localization of BMP2A to chromosome 20 and regionally assigned the locus to 20p12 by radioactive and nonradioactive in situ hybridization.


A single-base change at a splice acceptor site in the ornithine aminotransferase gene causes abnormal RNA splicing in gyrate atrophy.

Gyrate atrophy (GA) is an autosomal recessive eye disease involving a progressive loss of vision due to chorioretinal degeneration in which the mitochondrial matrix enzyme ornithine aminotransferase (OAT) is defective. Two sisters with GA are described in this study in whom an A-to-G substitution at the 3' splice acceptor site of intron 4 in one allele of the OAT gene results in a truncated OAT mRNA devoid of exon 5 sequence. The mutation in the other allele was identified to be a mis-sense mutation at codon 318 by denaturing gradient gel electrophoresis and direct sequencing of the polymerase chain reaction (PCR)-amplified DNA. Thus, these GA patients are compound heterozygotes with respect to mutations in the OAT gene that result in inactivation of OAT.


Mutations in the conserved domain of SRY are uncommon in XY gonadal dysgenesis.

In order to evaluate the role of SRY in the determination of the testis, we sequenced the conserved domain of the SRY gene in 8 patients with 46,XY gonadal dysgenesis and 3 patients with related disorders, and compared our data with those obtained in 6 other similar studies. In our study, a 609-bp fragment of SRY was amplified by the polymerase chain reaction and the internal conserved motif was sequenced. SRY sequences did not differ from those in normal males in any of our patients. Overall, 5 de novo mutations have been identified among 56 patients with sporadic XY gonadal dysgenesis (8.9%), and 2 de novo mutations have been identified among 18 patients with related conditions (11%). The unexpectedly low frequency of mutations within the SRY conserved domain in these patients could be caused by undetected Y-linked mutations outside the conserved domain in regions that control transcription during development (e.g., promoter/enhancer regions) or to downstream mutations in other sex-determining genes that need not map to the Y.


Point mutation in the steroid-binding domain of the androgen receptor gene in a family with complete androgen insensitivity syndrome (CAIS).

An exonic single nucleotide substitution in the human androgen receptor gene (hAR) could be detected in an Italian family with two children affected by complete androgen insensitivity syndrome (CAIS), also called testicular feminization. This mutation leads to a guanine to adenine transition in exon 5, changing the sense of the codon from methionine (ATG) to valine (GTG). As this mutation abolishes a NcoI restriction site, a rapid test for the mutation can be performed by digestion of the polymerase chain reaction products with this enzyme. Previous results of indirect gene diagnosis in this family could be confirmed by this method.


Molecular diagnosis of the Prader-Willi and Angelman syndromes by detection of parent-of-origin specific DNA methylation in 15q11-13.

The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are distinct genetic disorders that are caused by a deletion of chromosome region 15q11-13 or by uniparental disomy for chromosome 15. Whereas PWS results from the absence of a paternal copy of 15q11-13, the absence of a maternal copy of 15q11-13 leads to AS. We have found that an MspI/HpaII restriction site at the D15S63 locus in 15q11-13 is methylated on the maternally derived chromosome, but unmethylated on the paternally derived chromosome. Based on this difference, we have devised a rapid diagnostic test for patients suspected of having PWS and AS.


The potassium channel gene HK1 maps to human chromosome 11p14.1, close to the FSHB gene.

Transiently activating (A-type) potassium (K) channels are important regulators of action potential and action potential firing frequencies. HK1 designates the first human cDNA that is highly homologous to the rat RCK4 cDNA that codes for an A-type K-channel. The HK1 channel is expressed in heart. By somatic cell hybrid analysis, the HK1 gene has been assigned to human chromosome 11p13-p14, the WAGR deletion region (Wilms tumor, aniridia, genito-urinary abnormalities and mental retardation). Subsequent pulsed field gel (PFG) analysis and comparison with the well-established PFG map of this region localized the gene to 11p14,200-600 kb telomeric to the FSHB gene.


Investigation of the polymorphic ScaI site by a PCR-based assay at the human atrial natriuretic peptides (hANP) gene locus.

The ScaI polymorphic site within the stop codon of the human atrial natriuretic peptides (hANP) gene was investigated in Mauritian Indian, black African and French Caucasian populations. A distinct distribution pattern is observed in these three populations.


Decreasing incidence of PID in Amsterdam.

To study the incidence of pelvic inflammatory disease (PID) in Amsterdam in the period 1983-1990. Patients diagnosed with PID based on a clinical definition were reported weekly by 30 general practices who covered 11% of the Amsterdam population. Annual age specific incidences were calculated using the number of women in the participating practices as the denominator. The PID incidence was approximately 50 per 10,000 women through 1986, and then started to decrease in 1987 to reach 24 per 10,000 in 1990. The decreasing trend since 1987 was seen in the age-groups 20-24, 25-34 and 35-44 years, but not among teenagers. The moment of decline coincided with extensive attention given in the Dutch media to the risk of heterosexual transmission of the human immunodeficiency virus (HIV). It is plausible that the declining incidence of PID was influenced by a change of heterosexual behaviour under the threat of AIDS.


The dominance of a multiresistant strain of Neisseria gonorrhoeae among prostitutes and STD patients in The Gambia.

To study the epidemiology of antibiotic resistant strains of Neisseria gonorrhoeae from sexually transmitted disease clinics in The Gambia. One hundred and sixty five strains of N gonorrhoeae were tested for their antibiotic susceptibility, auxotype, serotype, and plasmid content. Of the total population 84 (51%) were non-penicillinase producing (nonPPNG) and 81 (49%) penicillinase-producing N gonorrhoeae (PPNG). There were 16 serovars, five auxotypes and 33 auxotype/serovar (A/S) classes in the total population and the nonPPNG. Among PPNG only five serovars, two auxotypes and nine A/S classes were found. One A/S class predominated, NR/IB-7 (86 isolates), of which 66 (77%) were PPNG and the remainder were chromosomally-mediated resistant N gonorrhoeae (CMRNG). These strains also showed reduced susceptibility to ciprofloxacin, ceftriaxone and tetracycline and were evenly distributed among patient groups. We have identified a relatively homogeneous gonococcal population with a core group of isolates exhibiting high levels of antibiotic resistance.


The value of urine specimens in screening for male urethritis and its microbial aetiologies in Tanzania.

To evaluate the first void urine (FVU) specimen in screening for urethritis and its microbial aetiologies in a male African population in which urinary schistosomiasis is also prevalent. Two hundred and forty eight males aged 15-54 years provided FVU specimens: 55 patients from a clinic for sexually transmitted diseases (STD), 151 patients from a medical outpatient clinic and 42 villagers from an area of high endemicity for S haematobium. Specimens were tested for leucocyte esterase (LE) using a dipstick (Nephur-Test+Leuco, Boehringer-Mannheim France SA). Ova of S haematobium were sought in terminal urine samples from all subjects. For all STD patients, and all medical outpatients with a positive LE test, urine and urethral swabs were tested for Chlamydia trachomatis antigen, and urethral swabs were tested for Neisseria gonorrhoeae by gram stain and isolation. The prevalence of LE positivity was 38/41 in STD patients with urethral signs or symptoms (93%), 5/14 among other STD patients (36%), 21/151 among medical outpatients (15%) and 13/42 among villagers (31%). As a screening test for urethral infection (detection of gonorrhoea or chlamydia and/or > or = 5 polymorphs per high power field on gram stain) the LE test had a sensitivity of 94% and a specificity of 53% among STD patients. Of 24 STD patients with gonococcal or chlamydial infection, 23 had a positive LE test (96%). Among general medical outpatients, 12 of 22 with a positive LE test had either conventionally defined urethritis or gonococcal or chlamydial infection, giving a positive predictive value of 55% for the LE test in this group. Of 18 subjects in all groups with urinary schistosomiasis nine had a positive LE test (50%), although three of these also had gonorrhoea. Chlamydial antigen was detected in the FVU specimen of all six subjects in whom it was detected in a urethral swab, and in an additional three subjects in the outpatient group. The FVU, which is an easily collected and non-invasive specimen, can provide valuable information on the prevalence of urethritis and on its microbial aetiology among the general male population in African countries.


Trends in reported cases of donovanosis in Durban, South Africa.

To investigate recent trends in reported cases of donovanosis (granuloma inguinale) in Durban, South Africa. The annual reports of the Medical Officer of Health for Durban 1958-1988 were reviewed to identify cases of donovanosis, genital ulcer disease (GUD) and new patients with sexually transmitted diseases (STD). A rapid staining technique for the detection of Donovan bodies was introduced in 1988. City Health STD Clinic, King Edward VIII Hospital, Durban. An initial peak was identified in men 1969-1974. A second peak was recorded in 1988 when reported cases of donovanosis (313) were the highest since records commenced. Both peaks were unrelated to either increases in the numbers of new attenders with STD or patients with GUD. The recent increase in donovanosis in Durban may reflect either a new epidemic or under-reporting of a disease previously diagnosed on clinical grounds. Improved control of donovanosis, a condition sometimes causing extensive GUD, and which has been implicated in HIV-1 transmission in local men, should be targeted in HIV control programmes.


Unique patterns of bereavement in HIV: implications for counselling.

The aim of this study was to examine the nature and extent of bereavement problems in HIV + ve clients and the counselling input required. Ninety individuals referred consecutively for counselling by the medical teams after HIV diagnoses were included in the study. Specific bereavement data was gathered by each counsellor according to schedule and semi-structured interviews for all 90 subjects. These data were analysed in conjunction with medical referral letters. HIV positive clients attending for treatment at an inner London Hospital. The subjects were 91% males and 9% females, mean age 33.82 years (SD 7.2, range 15 to 50 years, mode 28). 44.8% were diagnosed as HIV + ve (asymptomatic), 42.5% had an AIDS diagnosis and the remainder were coded as AIDS Related Complex or unclear. The subjects were monitored for the presence or absence of bereavement issues, the nature and extent of the reactions and counselling input. The occurrence of single and multiple bereavements was monitored, as were the relationship to the index patient and the health status of the bereaved. Bereavement was mentioned in 28.2% of referrals from medical practitioners yet 43.1% of the patients had been bereaved and used bereavement counselling. 43% spontaneously commenced the session with bereavement issues. They had lost 348 people (average of 12.9 deaths per person reporting). These were overwhelmingly due to AIDS with only 12 (5.6%) not HIV related. 65% linked the bereavement to their own death. Emotional reaction seemed to be independent of the relationship with the deceased but linked with the diagnosis status of the bereaved. The emotional consequences of a loss can be severe and long term. The advent of AIDS/HIV has revealed a wave of deaths in a population unused to facing traumatic loss to this extent. There are particular features surrounding AIDS and HIV infection which may differ dramatically from other sorts of loss and challenge previously held notions of bereavement such as the age of the clients, the fact that bereavements are often multiple the illness state of the bereaved person, the taboo surrounding AIDS which often presents barriers to wider social support and the catalogue of losses which any individual has to face. The frequency and high rate of bereavement, often not noted by referrers, suggests similarity with disaster literature in terms of counselling demand.


Social care services for patients with HIV at a London teaching hospital; an evaluation.

To investigate outpatients' use of, and satisfaction with social care services in an HIV unit. Survey of patients with HIV infection using self administered questionnaire. Outpatient HIV clinics at the Royal Free Hospital, London, March-April 1991. Patients' social circumstances, use or intended use of social care services and satisfaction with social care services. The greatest demand was for counselling about coping with HIV (38% of respondents), available medical treatment (24%), counselling for the HIV test (33%), psychological support for emotional (24%) or relationship problems (16%), advice about housing (24%) and financial matters (20%). In general, the use of social care services by men and women was similar. Twice as many men, however, sought help with payment of domestic bills, compared with women. Women were more likely to seek advice about financial benefits, obtaining sterile injecting equipment and discuss sleep and relationship problems. Thirty eight percent of patients were unemployed. Overall, 84% thought the service was good or excellent. Although less than 40% of patients currently used any one service, 60% thought they would use these services in the future. The greatest demand for social care services was for coping with HIV, housing and financial matters, and HIV test counselling. More than half the patients stated that they would probably need social care services in future.


A women-only clinic for HIV, genitourinary medicine and substance misuse.

To evaluate a multidisciplinary women-only clinic (WOC) providing HIV testing, HIV follow-up, genitourinary screening and a substance misuse service. The clinic is designed to attract women who are at risk of acquiring sexually transmitted infections, including HIV, yet are not using existing medical services. A questionnaire survey and review of the case notes of women attending the WOC during the first seven months (April to October 1991) and comparison with a mixed-sex, daytime genitourinary clinic (John Hunter Clinic), and a HIV out-patients clinic (Kobler Centre) all within St Stephen's Clinic. One hundred and twenty-nine women attended the WOC over the seven month period and 113 completed a questionnaire. The main reasons for attendance included a preference to be seen by a female doctor and staff, the presence of female patients in the waiting area, and the greater convenience of an evening clinic. In the absence of the WOC over half the patients (56%) indicated that they would not have attended a genitourinary medicine (GUM) clinic. The WOC attracted significantly more new patients than in the JHC (31.5% vs 15% p < 0.001). One hundred and four women (81%) were screened for genitourinary infection. Compared with the JHC there were significantly more cases of genital warts (33.9% vs 16.1% p < 0.001) and candidosis (41.5% vs 22.3% p < 0.001). A greater number of HIV tests were also performed (19% vs 9% p < 0.01). Sixteen (12.4%) women were HIV positive. Their attendance record at both first appointment (88% vs 64% p < 0.05) and subsequent follow-up appointments (81% vs 43% p < 0.05) was significantly higher than a comparable group of women seen by the same doctor (FB) in the Kobler Centre. The women also saw the health adviser more frequently. Although the number of injecting drug users was small (eight), all women currently injecting drugs entered a detoxification programme. The WOC has become an established and popular service at St Stephen's. Women not previously using medical services are attending. The multidisciplinary nature of the clinic encourages a wider use of medical and paramedical services. Attendance record for HIV positive women has improved significantly. Whether these factors will lead to improved standards of sexual health will require a longer period of audit. Seventy-nine per cent of women indicated they would use a family planning service if available. An integrated family planning clinic was introduced after the audit period.


Auditing AIDS reporting. Experience from a central London district 1982-1991.

To evaluate completeness of reporting of cases of AIDS to the Communicable Disease Surveillance Centre (CDSC) between 1982-1991. Southside of the Bloomsbury and Islington District Health Authority. Reconciliation exercise with CDSC of cases reported with those known to have received treatment in the district from 1982 to March 1990. Case note review of unreported cases and follow-up at March 1991. Delayed and non-reporting of cases. Cumulatively 13% (46/351) of patients whose initial AIDS illness was diagnosed in the District remained unreported by March 1991. Non-reporting increased from 9% (2/23) of cases diagnosed prior to 1985 to 28% (26/92) of cases diagnosed between 1989 and 1990. After September 1987 the proportion of patients with a diagnosis of Pneumocystis carinii pneumonia or Kaposi's sarcoma was significantly higher in the reported group than in the non-reported group: 78% (124/158) v 51% (24/49) p < 0.001. Nine of 19 (47%) cases of AIDS transferring their care into the district had not been reported by their previous District Health Authority. Within the district non-reporting of cases of AIDS has risen over time as the numbers of patients treated has increased. The physician must be aware of the full AIDS case definition for surveillance purposes and the implications of non-reporting for the allocation of special "ring-fenced" resources for AIDS care. Adequate investment in information and reporting systems would seem essential.


Determinants of sexual habits in Italian females.

To identify characteristics of women reporting multiple sexual partners and early age at first intercourse in Italy. Information on 1139 control women (median age 54 years) interviewed as part of a case-control study of cervical neoplasia conducted in the greater Milan area, Northern Italy were analysed using stratified analysis and multiple logistic regression. Overall, 81% of the study sample reported no more than one sexual partner, 10% two and 9% three or more. The proportion reporting multiple sexual partners tended to be higher among younger and more educated women (4% vs 19% of women with respectively less than 7 and 12 or more years of education reported three or more partners). Ever smokers reported a higher number of sexual partners than never smokers. The proportion of nulliparae reporting three or more sexual partners was higher than that of parous women. These findings were confirmed after taking into account in a multivariate analysis the role of potential confounding factors. Furthermore similar findings emerged from an analysis restricted to women aged 40 years or less. Always considering number of sexual partners, no relationship emerged with marital status, spontaneous or induced abortions, lifetime number of reported Pap smears and contraceptive habits. With reference to age at first intercourse, 25% of the study population reported their first intercourse at age 18 or before, 34% between 19 and 22 years, and 41% at age 23 or later. Younger women (that is, more recent cohorts) more frequently reported earlier age at first intercourse and the proportion of never married women reporting early intercourse was higher (51% vs 22% of never married vs married women). No relationship emerged between education, smoking habits, parity, history of spontaneous or induced abortions, number of Pap smears, contraceptive habits, and age at first intercourse. This study documents conservative sexual habits in Northern Italian females (at least on the basis of self reporting) but indicates that any educational compaigns towards safe sex should be focused towards younger women, particularly smokers, unmarried and nulliparae.


Mechanical urethritis and ascendent genitourinary infections due to sexual stimulation of the urethra by inserted foreign bodies.

The cases of 23 men with mechanical urethritis due to insertion of foreign bodies into the urethra are presented. Seven patients had upper urinary tract infections and one died with gangrene of the genitalia and septicaemia.


Staghorn calculus presenting as sterile pyuria.

Urinary tract calculi are relatively common and usually symptomatic. We describe a patient who had several very unusual features with regard to his urinary tract calculus disease.


A physiologic regurgitant cardiac valve phantom for magnetic resonance imaging or color Doppler ultrasound study.

Noninvasive imaging has proven successful in the evaluation of valvular heart disease; primarily with magnetic resonance imaging (MRI) and color Doppler ultrasound (CFM). However, the relationship between the morphology of regurgitant flow in MRI and CFM, as a function of hemodynamic parameters (chamber pressure difference, lesion size, compliance, etc.) is not understood. The goals for this work were: 1) to develop a computer-controlled regurgitant cardiac valve phantom, compatible with artifact-free CFM and MR imaging, 2) to create regurgitant lesions in the phantom which appear similar to those detected clinically, 3) to produce and measure physiologic pressure differences between chambers, compliances, and regurgitant fractions as seen in mild, moderate, and severe regurgitation. Mean chamber pressure differences ranged from 43-142 mmHg over the range of diseases simulated. Similarly, regurgitant flow rates ranged from approximately 0.54-18.6 L/min. Compliance values ranged from 0.83 to 21.95 cc/mmHg. No coherent or incoherent artifacts were observed in MRI or CFM images. Images show a high degree of similarity to regurgitant lesions detected with each modality, confirming that all design goals were met. The system should allow extensive comparative analysis of Doppler ultrasound and MRI flow jets under a wide range of controllable hemodynamic conditions in future experiments.


A flexible blood flow phantom capable of independently producing constant and pulsatile flow with a predictable spatial flow profile for ultrasound flow measurement validations.

The validation of the ultrasound time-domain correlation method of measuring blood flow has required the development of a flexible blood flow phantom capable of generating predictable flow profiles under a wide variety of conditions. The purpose of the phantom is to generate flow with well-known flow properties and not to mimic actual in vivo vessels. This paper describes a flow phantom which can independently generate both constant and pulsatile flow over a wide range of flow rates with a spatially fully developed laminar flow profile. It incorporates a computer-controlled pulsatile pump, which can produce different temporal pulsatile waveforms. The flow phantom also supports multiple vessels, different vessel sizes, as well as different attenuating media. The fluid most commonly used in the phantom is Sephadex mixed with water, and the probability density function of ultrasound reflected from Sephadex is experimentally determined and compared with that of blood. Examples of different constant and pulsatile flow experiments using the phantom are presented.


Comparison of impedance at the microelectrode-saline and microelectrode-culture medium interface.

The impedance characteristics of gold-plated indium-tin-oxide microelectrodes immersed in culture medium (MEM) are described and compared with the impedance characteristics observed when those microelectrodes are immersed in isotonic saline. For microelectrode areas of approximately 100 microns2, applied voltage levels of 5, 50, and 100 mV, and for frequencies of from 100 Hz to 10 kHz the resistance, capacitance, capacitive reactance, and total impedance are given as a function of frequency both in culture medium and in saline. The results, which hold for current densities ranging from 0.45 to 700 pA/microns2, are compared. Also given are the alpha and K values determining the frequency characteristics of the interface resistance and capacitance in medium and in saline.


The electrode system in impedance-based ventilation measurement.

In this paper, we determined which electrode types, sizes, and locations were best suited for impedance-based ventilation measurement. Optimal electrodes provide high signal-to-(motion) artifact ratio (SAR) and reliability by meeting the following criteria: 1) low baseline impedance, 2) high adhesion, 3) good physical stability, 4) large effective area, 5) thin with high flexibility. We compared 14 electrodes from two main groups: adhesive-gel and conductive rubber electrodes. Adhesive-gel electrodes are easy to apply, make good body contact, and do not slip during the course of an experiment. We found that higher SAR's are obtained when electrode area is increased by connecting several small electrodes together rather than by using a single electrode with a larger area. The peak SAR is achieved when two electrode arrays (area = 70 cm2) are centered at the 8th intercostal spaces on opposite midaxillary lines. To determine the optimal electrode locations, we placed 32 electrodes on the trunk and recorded impedance between 171 electrode combinations on ten normal adult subjects. Based on these data, we conclude that the SAR's are highest when one electrode is placed on the midpoint between the left and right second intercostal spaces on the sternum and the other electrode is placed in the opposite position on the back.


Pseudorandom signals to estimate apparent transfer and coherence functions of nonlinear systems: applications to respiratory mechanics.

There is an increasing need in physiology to estimate nonparametric linear transfer functions from data originating from biological systems which are invariably nonlinear. For pseudorandom (PRN) input stimuli, we derive general expressions for the apparent transfer (Z) and coherence (gamma 2) functions of nonlinear systems that can be represented by a Volterra series. It is shown that in the case of PRN signals in which the frequency components are integer multiples of other components the estimates of Z are seriously biased due to harmonic distortion and crosstalk among frequency components of the input. When the PRN signal includes components that are not integer multiples of other components harmonic distortion is avoided, but not necessarily cross talk. Here the estimates of Z remain poor without a noticeable influence on gamma 2. To avoid the problems associated with harmonic distortions and minimize the influence of crosstalk, a family of pseudorandom signals is proposed which are especially suited for the estimation of Z and gamma 2 in mechanical measurements of physiological systems at low frequencies. The components in the signals cannot be reproduced as linear combinations of two or more frequency components of the input. In a second-order system, this completely eliminates the bias, while in higher-order, but not strongly nonlinear systems, the interactions among the components are reduced to a level that the response can be considered as if it was measured with independent sine waves of an equivalent amplitude. It is also shown that the values of gamma 2 are not appropriate to assess linearity of the system. The theory is supported by simulation results and experimental examples brought from the field of respiratory mechanics by comparing the input impedance of the respiratory system of a dog measured with various PRN signals.


Chaotic activity during iron-induced "epileptiform" discharge in rat hippocampal slices.

Low-dimensional chaotic dynamics have been suggested in the rat hippocampal slice during iron-induced epileptiform activity. The dimensionality of this chaotic activity has been found to be similar in slices bathed in the same ionic extracellular medium. Some slices also displayed a drop in dimensionality prior to the onset of seizure-like activity. We suggest that techniques of nonlinear dynamical analysis are a useful reverse-engineering tool for studying the in vitro brain slice. We further conclude that neuronal circuits capable of displaying chaotic activity could exist at the level of the in vitro brain slice.


The spatial integration effect of surface electrode detecting myoelectric signal.

The spectral properties of surface electrodes used for myoelectric signal detection were investigated using both a theoretical and an experimental approach. On the basis of the theoretical model, the single surface electrode was found to act as a low pass filter depending on the electrode diameter (d) and the fiber conduction velocities (CV). Several dips in the power spectrum were also predicted for varying frequencies depending on d and CV. The mathematical expression of the surface electrode filter was highly consistent with previously demonstrated properties of the single fiber power spectrum. An experimental comparison between myoelectric signals from the vastus lateralis muscle recorded using two electrode pairs with different diameters confirmed this low pass filter effect. However, the dip phenomenon was not observed from experimental data. The practical consequences of the electrode filter effect are discussed with respect to the interpretation of changes in surface myoelectric signal spectrum, particularly when a shift toward the high frequencies is observed.


Field distributions in the rat tibia with and without a porous implant during electrical stimulation: a parametric modeling.

Expeditious post-operative ingrowth of bone is necessary for clinically successful fixation of porous joint prostheses. Electrical or electromagnetic fields to stimulate bone growth into porous implants have been used; however, they produced nonconvincing data. This was partially attributable to the lack of quantification of the localized electric fields produced in the pores of the implants. Therefore, this study set out: i) to quantify the local electric field values induced into the surface pores of nonconducting implants by "capacitive" coupling and to determine the magnitude of the macroscopically applied capacitively coupled electrical currents to induce specific electric field amplitudes in the pores, ii) to identify the important dielectric properties of the implant-tissue interface, and iii) to create the basis for successfully applying electrical fields in an animal model to stimulate bone ingrowth. A finite element method was used to calculate the electric field gradients and current densities present in a rat tibia modeled with a porous intramedullary implant when capacitively stimulated. Results indicated that while the current density in the pores are reduced in comparison to the region just outside the pore by about one order of magnitude, a significant current density still exists in the pore region. Furthermore, the presence of the implant increases the current densities in the trabecular bone while decreasing these values in the cortical bone. Replacing the trabecular bone in the pore by saline increases the current density in the pore by three-fold, but decreases the voltage gradient by a similar factor.


Body surface Laplacian ECG mapping.

A new noninvasive approach has been developed to resolve spatially distributed cardiac electrical activity by measuring the surface Laplacian of the body surface potential. Computer simulations demonstrate the ability of the Laplacian map compared with the potential map to image spatially distributed dipole sources embedded in a semi-infinite volume conductor. Body surface Laplacian mapping has been implemented in human subjects utilizing dry bipolar Laplacian electrodes and compared with potential maps obtained using the central terminal of each bipolar Laplacian electrode. The body surface Laplacian ECG distribution was found to provide better spatial resolution than the body surface potential distribution. The body surface Laplacian map appears to resolve depolarization and repolarization of different regions of the heart. Further improvements of the body surface Laplacian mapping may permit noninvasive mapping of spatially distributed intracardiac events.


A comparison of measured and calculated intracavitary potentials for electrical stimuli in the exposed dog heart.

The objective of this paper is to test the feasibility of using a multielectrode, intracavitary probe to solve a forward problem in which measured intracavitary potentials are compared to those calculated from subendocardial potentials and left ventricular (LV) cavity geometry. Intracavitary potentials and subendocardial potentials are measured simultaneously during electrical pacing stimuli from the LV apex, LV anterior base, LV posterior base, and right ventricular (RV) outflow tract of three exposed dog hearts. The LV cavity geometry is measured from postmortem magnetic resonance microscopy images of fixed hearts. Boundary integrals are approximated using a boundary element method and solved for intracavitary potentials. Correlation coefficients for LV apical pacing episodes are 0.989 +/- 0.002 while those for nonapical pacing episodes are 0.873 +/- 0.092. These results indicate that for electrical pacing from the apex, intracavitary stimulus potentials can be calculated with a high degree of accuracy. For nonapical pacing locations, the accuracy decreases since the calculations are more sensitive to errors in measuring probe position and LV cavity geometry near the septum. These results show that accurate geometric measurements of the intracavitary probe position and subendocardial surface are the primary concerns in solving future forward and inverse problems using an intracavitary probe.


The activating function for magnetic stimulation derived from a three-dimensional volume conductor model.

A three-dimensional volume conductor model of magnetic stimulation is proposed that relates transmembrane potential of an axon to the induced electric field in a uniform volume conductor. This model validates assumptions used to derive a one-dimensional cable model of magnetic stimulation (Roth & Basser, IEEE Trans. Biomed. Eng., vol. 37, pp. 588-597, 1990) of unmyelinated axons. The three-dimensional volume conductor model reduces to this one-dimensional cable equation forced by the activating function, -delta EzA/delta z.


Identification of time-varying biological systems from ensemble data.

The theory underlying a new method for the identification of time-varying systems is described. The method uses singular value decomposition to obtain least-squares estimates of time-varying impulse response functions from an ensemble of input-output realizations. No a priori assumptions regarding the system structure or form of the time-variation are required and there are few restrictions on the input signal. Simulation studies, using a model of time-varying joint dynamics, show that the method can track rapid changes in system dynamics accurately and is robust in the presence of output noise. An application of the method is demonstrated by using it to track dynamic ankle stiffness during a rapid, voluntary, isometric contraction. During the transient phase of the contraction, low-frequency ankle stiffness gain decreased in a manner which could not be described with the second-order model of joint dynamics often used under stationary conditions.


Interactive image-guided neurosurgery.

Interactive image-guided (IIG) surgery involves the synchronal display of the tip of a surgical device on preoperative scans. This display allows the surgeon to locate the present surgical position relative to the final site of surgical interest. We have developed a technique for IIG surgery device based on a six-degree-of-freedom articulated arm. Design accuracy for the arm is less than 0.1 mm and the present implementation has a submillimetric accuracy. The display can show the surgical position on any tomographic image set with simultaneous display on up to three image sets. Laboratory results and clinical applications are discussed.


A model study of electric field interactions between cardiac myocytes.

The transmission of excitation via electric field coupling was studied in a model comprising two myocytes abutted end-to-end and placed in an unbounded volume conductor. Each myocyte was modeled as a small cylinder of membrane (10 microns in diameter and 100 microns in length) capped at both ends. A Beeler-Reuter model modified for the Na+ current dynamics served to simulate the membrane ionic current. There was no resistive coupling between the myocytes and the intercellular junction consisted of closely apposed pre- and post-junctional membranes, separated by a uniform cleft distance. The membrane current crossing the prejunctional membrane during the action potential upstroke tends to flow out of the cleft, but it is partly prevented from doing so by the shunt resistance constituted by the cleft volume conductor. The prejunctional upstroke gives rise to a pulse of positive potential within the cleft which induces a small capacitive current across the post-junctional membrane to yield a small positive change in the intracellular potential in the post-junctional cell. The net result is an hyperpolarization of the post-junctional cleft membrane and a slight depolarization of the rest of the cell membrane since the extracellular potential outside of the cell is zero. The magnitude of this depolarization is quite small for a flat junctional membrane and it can be increased by membrane folding and interdigitation, so as to increase the junctional membrane area by a factor of 10 or more. Even then the post-junctional depolarization does not reach threshold when the extracellular potential around the post-junctional cell is effectively zero. Threshold depolarization occurs in the presence of a large decrease of post-junctional load, by increasing the junctional membrane capacitance and/or decreasing the volume of the post-junctional cell. Assuming that the normal resistive coupling between two cardiac myocytes is 1-4 M omega, our model study indicates that electric field coupling would then be about two orders of magnitude smaller. However, substantial enhancement of the efficacy of electric field transmission was observed in the case of cells with substantial junctional membrane folding.


Modeling the effects of electric fields on nerve fibers: determination of excitation thresholds.

We have developed a method to predict excitation of axons based on the response of passive models. An expression describing the transmembrane potential induced in passive models to an applied electric field is presented. Two terms were found to drive the polarization of each node. The first was a source term described by the activating function at the node, and the other was an ohmic term resulting from redistribution of current from sources at other nodes. A total equivalent driving function including both terms was then defined. We found that the total equivalent driving function can be used to provide accurate predictions of excitation thresholds for any applied field. The method requires only knowledge of the intracellular strength-duration relationship of the axon, the passive step response of the axon to an intracellular current, and the values of the extracellular potentials. Excitation thresholds for any given applied field can then be calculated using a simple algebraic expression. This method eliminates the errors associated with use of the activating function alone, and greatly reduces the computation required to determine fiber response to applied extracellular fields.


A three-dimensional iterative scheme for an electromagnetic inductive applicator.

An efficient iterative method for solving quasi-static electromagnetic field problems is presented. The electromagnetic field is generated by an inductive applicator and is represented as a superposition of two constituents, viz. a primary field in absence of the tissue configuration and a secondary field generated by the presence of the tissue. Then, for the secondary field a quasi-static approximation is employed. In the quasi-static field equations a relaxation function is introduced, such that the resulting equations can be solved iteratively. For a realistic three-dimensional model of a human hand numerical results are presented.


Reduced-order modeling for hyperthermia control.

This paper analyzes the feasibility of using reduced-order modeling techniques in the design of multiple-input, multiple-output (MIMO) hyperthermia temperature controllers. State space thermal models are created based upon a finite difference expansion of the bioheat transfer equation model of a scanned focused ultrasound system (SFUS). These thermal state space models are reduced using the balanced realization technique, and an order reduction criterion is tabulated. Results show that a drastic reduction in model dimension can be achieved using the balanced realization. The reduced-order model is then used to design a reduced-order optimal servomechanism controller for a two-scan input, two thermocouple output tissue model. In addition, a full-order optimal servomechanism controller is designed for comparison and validation purposes. These two controllers are applied to a variety of perturbed tissue thermal models to test the robust nature of the reduced-order controller. A comparison of the two controllers validates the use of open-loop balanced reduced-order models in the design of MIMO hyperthermia controllers.


Ambulatory oxygen uptake measurement system.

An apparatus for monitoring prolonged measurement of oxygen uptake without discomfort has been developed. The system is based on the open flow-through principle. The subject wears a hood through which air is drawn by an exhaust blower. Oxygen concentration is kept constant by a servo-controlled blower, so that flow rate is essentially proportional to oxygen uptake. The flow rate of the main stream is measured by a time-of-flight flowmeter located in the exhaust hose. Oxygen concentration is measured by a limiting-current oxygen sensor. The signals representing flow rate and oxygen concentration are digitized and stored in a memory. All of the equipment is assembled in a small package (wt = 3 kg) which the subject carries on his back. The memory chip is removed from the portable device after each experiment. Data are transferred from the memory to a microcomputer and then an oxygen uptake trend is estimated. Response of the system to a step input is about 30 s. Compared with a commercially available oxygen monitoring system (Magna 88, P. K. Morgan Ltd., Rainham, UK), the maximum difference was 0.15 L/min within an oxygen uptake range of 0.25-2.3 L/min. Thus, the measurements made with our portable device agree with the results obtained using the conventional method.


A microfluorometer for measuring diffusion of fluorophores across the cornea.

A microscope has been modified to a confocal spatially scanning fluorometer so that the concentration profile of a fluorophore across an isolated cornea can be measured. A slit of light is focused through one half of the objective to excite fluorescence. A confocal slit is placed at the image-plane of the microscope to collect the fluorescent light from the tissue which passes through the other half of the objective. The fluorescent light falls on to the cathode of a photomultiplier whose output is amplified by a lock-in amplifier. Scanning across the cornea is achieved by a stepper motor coupled to the fine focus of the microscope. The performance of the instrument has been assessed by studying the transport of fluorescein, carboxyfluorescein, and rhodamine B through intact rabbit corneas. A depth resolution of about 10 microns has been achieved with a 40x objective. This resolution is sufficient to determine concentration gradients in the epithelium as well as the stroma and to partially resolve the endothelium. The potential errors in the technique, resulting from limited resolution, light scattering and absorption, quenching of fluorescence, and binding of the fluorophores, are discussed.