Evaluation of myocardial protection by combination of lidoflazine pretreatment and St. Thomas' Hospital cardioplegia in aorto-coronary bypass grafting.

The concept of pretreatment of the myocardium with a pharmacological agent protecting the cell against ischemic and reperfusion injury is very attractive. Lidoflazine, a calcium overload blocker, predominantly membrane stabilizing, is able to prevent cell damage during ischemic arrest and reperfusion. The purpose of this study was to determine whether the combination of lidoflazine pretreatment and St. Thomas' Hospital cardioplegia can provide, in clinical practice, better myocardial protection in aorto-coronary bypass grafting than St. Thomas' Hospital cardioplegia alone. As indices for myocardial protection, recovery of cardiac function, enzyme release, and clinical outcome were registered. Ninety-three patients undergoing aorto-coronary bypass surgery were studied. These patients were randomized into two groups in a double blind fashion. Patients in group A (n = 48) received lidoflazine 1 mg/kg intravenously over a period of 20 min before initiation of cardiopulmonary bypass. Group B (n = 45) receiving placebo, acted as a control group. Myocardial protection consisted of intermittent infusion of cold 4 degrees C St. Thomas' Hospital cardioplegia, topical slush ice, and systemic hypothermia (28 degrees C rectal). No significant differences between the two groups were noted in terms of recovery of cardiac function, enzyme release, incidence of myocardial infarction, low cardiac output, rhythm, and conduction disturbances. In conclusion, our data suggest that the combination of intravenous pretreatment with lidoflazine and St. Thomas' Hospital cardioplegia did not provide significant additional myocardial protection in the clinical situation.


Total cavopulmonary connection for right ventricular endomyocardial fibrosis.

Endomyocardial fibrosis is an endemic problem in tropical countries and is characterised by ventricular cavity obliteration, decreased ventricular compliance, and atrioventricular valve regurgitation. We report on a patient with right ventricular endomyocardial fibrosis resulting in obliteration of the cavity and tricuspid regurgitation treated successfully by total cavopulmonary connection and exclusion of the right ventricle.


Evaluation of peripheral venous disease.

DCI is an excellent method for evaluation of the venous system and has several distinct advantages over other methods. One of the major benefits of DCI, particularly with the addition of capabilities to image slow-flow characteristics of veins, is the ease and rapidity of evaluating the lower extremity veins, including not only the femoral and popliteal system but also the major calf veins. The identification of nonoccluding intraluminal thrombus is enhanced by the additional contrast provided by color-flow imaging. In a similar fashion, flow imaging by scanning through the urine-filled bladder permits excellent visualization of the external iliac veins, and in thin patients the common iliac veins and distal inferior vena cava can be assessed. Thus, DCI permits a more rapid examination with increased diagnostic confidence; it may also permit a more accurate examination. The noninvasive and complication-free nature of the examination recommends it strongly as the primary test, particularly in patients with contraindications to contrast evaluation.


Doppler color imaging. Abdomen.

Abdominal applications of Doppler ultrasonography are becoming increasingly important as familiarity with Doppler principles and instruments grows. The availability of sensitive duplex and DCI instruments specifically adapted for use in the abdomen and pelvis has stimulated interest in the use of Doppler techniques as a complement to conventional imaging. Although the simultaneous display of tissue and flow information has enhanced the ease of evaluation of vascular abnormalities and increased diagnostic confidence, the role of Doppler is only just beginning to be defined. Since blood flow is a fundamental factor in health and disease, it is hoped that the new information provided by Doppler evaluation of the abdomen will continue to advance the role of ultrasound as a primary diagnostic method as Doppler and color imaging technology mature.


Doppler color imaging. Obstetric and gynecologic applications.

The addition of pulsed and color Doppler has greatly added to the diagnostic potential for obstetric and gynecologic ultrasound. In addition to improved morphologic detail inherent in the use of EVUS, new information is available on perfusion and the physiologic changes associated with the menstrual cycle and early pregnancy. The absence of luteal flow strongly predicts unsuccessful pregnancy outcome in patients undergoing therapy for infertility. This introduces the possibility of more economic use of expensive treatments. Later in pregnancy, DCI aids in the efficient and accurate performance of Doppler spectral sampling and contributes to the evaluation of structural and functional abnormalities of the fetus, umbilical cord, and placenta. Applications in the evaluation of patients with suspected ectopic pregnancy, incomplete abortion, and pseudosac are welcome additions for clinical problems that currently result in many malpractice suits. Finally, the recognition of neovascular flow, especially in the ovary, raises hope for improved and earlier diagnosis of ovarian cancer.


Doppler color imaging. Scrotum, breast, thyroid, and extremities.

DCI, when coupled with small-parts gray-scale imaging, has demonstrated great utility in the evaluation of superficial body abnormalities. This technique has rapidly become a primary method of evaluation of suspected testicular torsion, and its results are competitive with those of standard nuclear medicine examinations. DCI evaluation of male impotence, coupled with intracavernous injection of vasoactive substances, is now a leading, noninvasive technique for diagnosis of both arteriogenic and venogenic causes. DCI may provide invaluable information in the evaluation of palpable masses, particularly in the diagnosis of vascular abnormalities such as false aneurysm and arteriovenous fistula. Further studies are needed to corroborate the utility of DCI in the evaluation of focal thyroid and parathyroid abnormalities, breast carcinoma, nodal cancer, and the orbit. Because this technique is applicable to superficial, high-frequency examinations, DCI is rapidly becoming an accepted and frequently necessary part of any small-parts ultrasound study.


Doppler color imaging. Intraoperative and cranial applications.

In infants normal intracranial vessels may be seen in detail by using DCI. This capability is most useful in the initial or follow-up examination of infants with intracerebral AVMs. Aside from this, few clinically important applications of DCI to image the intracranial vessels have been reported.


Doppler color imaging. Carotid and vertebral arteries.

Duplex sonography and DCI have now become standard modalities for imaging of the extracranial carotid and vertebral arteries. They are equivalent in accuracy to arteriography in the evaluation of flow-limiting stenosis. In addition, the newest scanners all appear to have high-resolution imaging systems capable of characterizing plaque properly. DCI currently leads to more rapid scanning and greater ease in evaluating more difficult patients. The most important advance with DCI will come in the future, when there is better understanding of the significance of the Doppler color-flow patterns now being observed. At present, duplex sonography and DCI remain the only imaging modalities that can evaluate the complete spectrum of abnormalities of the extracranial carotid and vertebral vessels, from minimal stenosis to complete occlusion. As a result, they are valuable tools in the diagnosis of disease.


Doppler color imaging. Principles and instrumentation.

DCI acquires Doppler-shifted echoes from a cross-section of tissue scanned by an ultrasound beam. These echoes are then presented in color and superimposed on the gray-scale anatomic image of non-Doppler-shifted echoes received during the scan. The flow echoes are assigned colors according to the color map chosen. Usually red, yellow, or white indicates positive Doppler shifts (approaching flow) and blue, cyan, or white indicates negative shifts (receding flow). Green is added to indicate variance (disturbed or turbulent flow). Several pulses (the number is called the ensemble length) are needed to generate a color scan line. Linear, convex, phased, and annular arrays are used to acquire the gray-scale and color-flow information. Doppler color-flow instruments are pulsed-Doppler instruments and are subject to the same limitations, such as Doppler angle dependence and aliasing, as other Doppler instruments. Color controls include gain, TGC, map selection, variance on/off, persistence, ensemble length, color/gray priority. Nyquist limit (PRF), baseline shift, wall filter, and color window angle, location, and size. Doppler color-flow instruments generally have output intensities intermediate between those of gray-scale imaging and pulsed-Doppler duplex instruments. Although there is no known risk with the use of color-flow instruments, prudent practice dictates that they be used for medical indications and with the minimum exposure time and instrument output required to obtain the needed diagnostic information.


Ultra-high-resolution scanning electron microscopic studies on the sarcoplasmic reticulum and mitochondria of the rat intrafusal muscle fibers. Part II: The extracapsular region.

The three-dimensional structure of the transverse-axial tubular system, sarcoplasmic reticulum (SR) and mitochondria in the extracapsular region of the intrafusal muscle fibers of the rat lumbrical muscle was observed by ultra-high-resolution scanning electron microscopy after removal of the cytoplasmic matrix by the osmium-DMSO-osmium procedure. Nuclear chain fibers possessed thick to moderately sized column-forming mitochondria with occasional I-band branches. The transverse tubules (T-tubules) running at the level of the A-band side of the A-I junction were sandwiched between two large terminal cisternae for most of their length, forming triads. The sarcotubules arising from the terminal cisternae formed single-layered networks at the A-band level, and well developed, double-layered, three-dimensional networks at the I-band level. Nuclear bag1 fibers possessed slender column-forming mitochondria devoid of I-band branches. The T-tubules were located at the level of the A-I junction. Both the T- and the axial-tubules were occasionally coupled with small terminal cisternae, forming dyads or triads. At the I-band level, the SR was well developed and formed single layered networks, but at the A-band level only a few longitudinally arranged sarcotubules and axial tubules were observed. Nuclear bag2 fibers contained medium to large diameter column-forming mitochondria without I-band branches. The T-tubules ran at the level of the A-band adjacent to the A-I junction, and were coupled at some intervals with terminal cisternae of various lengths. Swollen, large terminal cisternae were frequently seen.(ABSTRACT TRUNCATED AT 250 WORDS)


Alveolar bone remodeling in the early stage of experimental apical periodontitis in the rat mandible.

Apical periodontitis was surgically induced in the mandibular first molar of rats and chronological changes in the periapical bone tissue were observed by histochemistry and electron microscopy. On the second postoperative day (Day 2), tartrateresistant acid phosphatase (TRACPase)-positive cells emerged on the bone surface facing the inferior alveolar nerve, whereas alkaline phosphatase (ALPase)-positive cells proliferated on the bone marrow surface of the mandibular canal wall. On Day 3, the active resorption of the mandibular canal wall appeared on the surface facing the inferior alveolar nerve. The bone of the upper wall of the canal was completely resorbed. On Day 4, however, numerous ALPase-positive cells emerged over the bone surface facing the inferior alveolar nerve intermingled with TRACPase-positive cells. On Day 5, repair of the upper wall of the mandibular canal by new bone progressed. Bone formation was also observed on the bone surface facing the inferior alveolar nerve. On Day 6, the upper wall of the mandibular canal was remodeled by the new bone, whereas TRACPase-positive cells had already migrated over the bone surface in the vicinity of ALPase-positive cells. From Days 2 to 5, active trabecular bone formation continued in the bone marrow cavity close to the mandibular canal, while TRACPase-positive cells were found only on Day 6. These demonstrate that inflammatory stimuli activate bone formation coupled with bone resorption, as well as direct trabecular bone formation without a bone resorption phase. A rapid bone turnover in the early stage of apical periodontitis is also suggested. We conclude that bone defects in apical periodontitis are not the result of sole bone resorption but rather, active bone remodeling.


Light and electron microscopic immunocytochemistry of TSH-like cells occurring in the pars tuberalis of the adult male rat pituitary.

Morphological characteristics of TSH-immunoreactive cells (TSH-like cells) in the pars tuberalis (PT) of intact adult male rats were studied by light and electron microscopic immunocytochemistry. TSH-like cells in the rat PT can be classified into three types by light microscopy: 1) cells diffusely stained throughout the cytoplasm, 2) diffusely weak stained cells containing a strongly stained spot in the paranuclear region; 3) cells with a strongly stained spot in the paranuclear region without diffuse reaction. We call the latter two cell types "spot cells". Electron microscopic immunocytochemistry revealed that the latter two cells reacted very strongly in the Golgi apparatus. The spot cells were localized throughout the PT from rostral to caudal extremities as well as the ventral surface area of the pars distalis (PD) which was connected to the PT. The cytoplasm of the TSH-cells in the PD proper was strongly and diffusely stained with anti-TSH serum, while there was no spot-like staining in any cells. The spot cells demonstrated by electron microscopy contained a well developed Golgi apparatus, many microvesicles and a few secretory granules. These immunocytochemical results clearly showed two apparently distinct types of TSH-immunoreactive cells between the PT and PD in the intact adult male rat adenohypophysis. This morphological distinction of TSH-immunoreactive cells suggests functional differences in these cells.


Ultrastructure of the water-clear cell in the rabbit parathyroid gland.

The ultrastructure of water-clear cells has been described in human hyperplastic parathyroid glands. However, previous studies have failed to demonstrate this type of cell in normal human or other vertebrate parathyroid glands. Upon recently recognizing water-clear cells in the parathyroid glands of the golden hamster, we intended to examine the occurrence of these cells in other animals. In the present study the parathyroid glands of about one-year-old rabbits were observed by electron microscopy. Water-clear cells containing numerous vacuoles were demonstrated dispersed among the chief cells. The cells were generally situated close to the basal lamina of perivascular space which lay against the capillary vessel and were attached by desmosomes to the chief cells. Irregularly shaped vacuoles in the water-clear cells resembled dilated cisternae of the granular endoplasmic reticulum in the chief cells. Several ribosomes could be seen attached to the membrane of some of the irregularly shaped vacuoles. It is conceivable that the water-clear cells are transformed from the chief cells.


A light and electron microscopic study on pulpal nerve fibers in the lower incisor of the mouse.

Light and electron microscopic studies were made on pulpal nerve fibers in mouse lower incisors, typical continuously growing teeth. Serial sections, from the apex of the odontogenic sheath to the incisal edge of the apical foramen, were examined by light microscopy to identify myelinated fibers passing through the apical foramen. The fine structure of the pulpal nerves was examined by electron microscopy at three sites: 1) the level at the incisal edge of the apical foramen; 2) a level 5 mm incisal from the apex of the odontogenic sheath; and 3) the level where the incisor comes out of the alveolar bone. No myelinated fibers were found passing through the apical foramen; they were also lacking at the three levels of the pulp. At level 2, unmyelinated axons were seen in close contact with smooth muscle fibers of arterioles. At level 3, nerve fibers were difficult to distinguish from processes of fibroblasts and odontoblasts. Degenerating axons were present in Schwann cells, and fine unmyelinated axons running through the odontoblast cell layer were seen. Various types of unmyelinated axons were observed in the apical region (level 1). These axons were classified into 6 types on the basis of their fine structures: Type I, bundles of unmyelinated axons completely or partly ensheathed by Schwann cell cytoplasm (mature type); Type II, bundles of unmyelinated axons in a space formed by a Schwann cell membrane (regenerating type); Type III, bundles of unmyelinated axons ensheathed not by a Schwann cell, but merely by a basal lamina (regenerating type); Type IV, single axons in direct contact with the basal lamina (regenerating or terminal type); Type V, naked, electron-dense axons with many vesicles and mitochondria (growth cone-like type); and Type VI, electron opaque axons, due to loss of axonal organellae (degenerating type). The significance of these structures is discussed in relation to the continuous growth of the rodent incisor.


Ultrastructural and immunocytochemical studies of enamel tufts in human permanent teeth.

Enamel tufts were exposed after decalcification of the enamel matrix and their fine structures and immunocytochemical characteristics were examined. Under the binocular microscope and the scanning electron microscope (SEM), enamel tufts appeared as corrugated ribbon-like structures located on the dentine parallel to the tooth axis. SEM observation disclosed enamel tufts as bundles of well extended tubular structures with cross striations attributable to hypocalcified enamel sheaths. Plate-like structures were observed at the center of enamel tufts, where they ran parallel to the enamel tufts. Under the transmission electron microscope (TEM), the plates of tufts revealed their origin in the superficial layer of the dentine, penetrating the hypercalcified zone adjacent to the dentine-enamel (D-E) junction, and then reaching the tuft region. The plates of tufts ran mainly along the enamel sheaths and partially across the prisms in the tuft region. THe protein-A-gold technique revealed an intense immunoreactivity for amelogenin over the superficial layer of the dentine, but over the enamel prisms in the tufts nor over the plates of tufts. The immunoreactivity for 13-17 kd protein was detected over the filamentous structures closely associated with the enamel sheaths in the enamel tuft. Thus our study disclosed that enamel tufts consist of both well extended hypocalcified enamel prisms and plates of tufts. The major organic component of the enamel tufts is suggested to be 13-17 kd protein rather than amelogenin.


Changes in subcellular structures of parietal cells in the rat gastric gland after omeprazole.

Omeprazole, an inhibitor of gastric acid secretion, was administered to rats at a dosage of 20 mg/kg/day for 14 and 35 days, and subsequent changes in subcellular structures of parietal cells were analyzed using morphometry and immunocytochemistry. Plasma gastrin levels were also examined, showing two times higher levels in the experimental groups than in the non-treated control. The volume and surface densities significantly decreased in tubulovesicles of the cells in the experimental rats. In the long term treatment of omeprazole (35 days), the volume density of microvilli on the membranes of secretory canaliculi in the cells also decreased significantly, whereas that of lysosomes clearly increased. By electron microscopy, many dense bodies of various shapes often appeared in the cytoplasm of parietal cells after the omeprazole treatment. Immunocytochemistry revealed that large granular immunodeposits for cathepsin B increase in the epithelial cells of the gastric glands after omeprazole treatment. These results suggest that omeprazole induces quantitatively significant decreases in both tubulovesicles and canalicular microvilli. The decreases in these membrane structures may possibly be ascribed to the degradation of the membrane in lysosomes; the proton pump on the membranes bound irreversibly with omeprazole is believed destined to be degraded in lysosomes.


Histochemical and immunohistochemical demonstration of macrophages and dendritic cells in the lingual periodontal ligament of rat incisors.

The distribution of macrophages in the lingual periodontal ligament of rat incisors was surveyed by histochemical and immunohistochemical methods. Numerous macrophages showing intense ACPase reactions were located primarily in the shear zone of the periodontal ligament. Immunostaining with an ED1-monoclonal antibody that recognizes various subpopulations of macrophages revealed plentiful positive cells showing flamelike profiles throughout the periodontal ligament, in addition to regular macrophages associated with sinusoidal blood vessels. A similar distribution of flamelike cells expressing Ia antigens was demonstrable with immunostaining using an OX6-monoclonal antibody. A consecutive staining of sections for ACPase histochemistry followed by immunoreactions for Ia antigens revealed the presence of two types of the flamelike cells in the periodontal ligament: one with and the other without distinct ACPase activity, corresponding to the macrophage and the dendritic cell, respectively. Either type of flamelike cells was located in the bone-related and shear zones, whereas only dendritic cells without ACPase activity were restricted to the tooth-related zone. OX6-immunonegative cells showing ACPase reactions were also found in the periphery of the sinusoidal blood vessels. Our data are the first to demonstrate the abundance of macrophages and dendritic cells expressing Ia antigens throughout the lingual periodontal ligament of rat incisors. In addition to regular macrophages, an exclusive localization of macrophages with flamelike extensions has been demonstrated in the bone-related and shear zones of the ligament. The region-specific arrangement of macrophages and dendritic cells with various histochemical and immunological features suggests that the periodontal ligament of rat incisor is a useful model for analyzing the process of differentiation of antigen-presenting cells.


Health problems and service use by parents of normal infants in the first 6 months of life.

A retrospective descriptive study was carried out on residents of the northern Sydney health area who delivered normal, full term, singleton infants at three large maternity units. A sample population of 1199 was sent a postal questionnaire when their infants reached the age of 6 months, and a 65% response rate was obtained. Problems encountered, with ratings of severity and difficulty of management, were reported in five categories: acute and persistent or recurrent illness, daytime and night-time behaviour problems and feeding problems. Forty-seven per cent of parents reported at least one problem which they rated severe or very difficult to manage, and 19.7% reported two or more, particularly in the areas of behaviour and feeding difficulties. Traditional services such as those provided by general practitioners and specialists were not often helpful for these problems, while baby health services and specialized support services were more helpful. However, a significant number of respondents found no service helpful, representing an area of unmet need.


Pathogenesis of Duchenne muscular dystrophy: the calcium hypothesis revisited.

Rapid advances in the molecular genetics of Duchenne muscular dystrophy (DMD) and the discovery and localization of the gene product dystrophin has brought new hope that successful treatment for this disease may not be too far away. Dystrophin has been postulated to have a mechanical function, helping to resist stress associated with muscle contraction. The presence of dystrophin in low concentrations in muscle cells, its expression in nervous tissue and the observation that hypercontraction of the sarcomeres precedes membrane rupture make the hypothesis unlikely. On the basis of an analogy with a cytoskeletal protein ankyrin, which is associated with the sodium/potassium adenosine triphosphatase (ATPase) in the kidney, it is possible that dystrophin deficiency leads initially to an increased but inefficient calcium-ATPase activity, which pumps calcium out of the cell. Partial failure of the pump would result in intracellular accumulation of calcium, hypercontractions of the sarcomeres, rupture of the cell membrane, massive influx of calcium and cell necrosis.


Parental perception of the effect of venepuncture in preschool children in non-therapeutic research.

Non-therapeutic research in children is said to be justified in part if the risk involved is no more than minimal, but there is little information on the risk of venepuncture to make that judgement. This prospective study was carried out to assess the effect of venepuncture on 425 healthy children aged between 3.6 and 6.6 years old who participated in a non-therapeutic research project. A parental questionnaire was sent out 1 month after the blood was taken. Three hundred and ninety-one parents (92%) returned the questionnaires. Parental responses indicated the risk of complications was of the order considered to be minimal. A large majority of parents (78%) felt this experience would be helpful for the child if blood had to be taken again and a significant proportion (40%) felt the child would be more confident when going to see a doctor or dentist afterwards. Venepuncture in preschool children causes minimal harm and might even have some positive effects.


A review of chest physiotherapy in neonatal intensive care units in Australia.

Clinical techniques and protocols for chest physiotherapy vary greatly from one Neonatal Intensive Care Unit to another. In 1988 a questionnaire designed to investigate differing techniques used was distributed to Neonatal Intensive Care Units (NICU) around Australia. Fourteen of the 15 questionnaires were completed and returned. The results revealed that the methods of chest treatment and the indicators for commencing chest treatment were similar throughout NICU. Both physiotherapists and nursing staff played a role in the performance of chest treatment in all but one unit where it was the responsibility of nursing staff. However, the area in which there was most variability between NICU was the individual treatment protocols employed pre- and postextubation of the neonate. A review of literature over the past 10 years also demonstrates variability in chest physiotherapy. It was concluded that further well-controlled studies with larger sample sizes are needed to validate the use of chest physiotherapy for the neonate, especially in relation to the techniques and specific protocols employed.


Chronic lung disease in very low birthweight infants: a prospective population-based study.

A prospective population-based study of chronic lung disease among all very low birthweight infants (birthweight 500-1499 g) born in New Zealand in 1986 is reported. Of 413 of these infants admitted to neonatal units, 355 (86%) survived to 28 days. An additional 50 infants were recorded as liveborn but died in the labour ward or other place of birth. Both observed survival and survival adjusted for birthweight, gestation and gender were significantly (P less than 0.05) better in larger centres. Oxygen requirement was assessed at 28 days of age, 36 weeks equivalent gestation and 84 days of age, when 38.6, 23.1 and 13.8% of infants, respectively, were being treated with oxygen. To examine the joint effects of predictor variables on oxygen requirement at each age, the data were analysed using multiple logistic regression methods. At 28 days, lower birthweight, shorter gestation, respiratory distress syndrome (all P less than 0.0001), and gender and hospital principally caring for the infant (both P less than 0.05) were significantly associated with treatment with oxygen. In comparison with other studies, New Zealand appears to have a relatively high rate of chronic lung disease. We speculate that a contributing factor may be the small size of some regional neonatal units.


Alcohol burns in the neonate.

The case histories of two infants who sustained chemical burns due to contact with alcoholic skin preparation solutions are presented. The skin permeability of the extremely low birthweight infant renders them susceptible to major burns following relatively brief exposure to such solutions. Care is needed in the selection and use of skin disinfection solutions in the neonatal nursery.


Drug errors in intensive care.

Errors in prescription, administration, delivery and interaction of drugs are likely in children in intensive care units because of the large number of often unfamiliar medications these children receive. We evaluated prospectively the frequency and consequence of drug errors in a large multidisciplinary intensive care unit. There was a mistake in drug prescription, administration, delivery or drug interaction in 2% of medication orders, with 12% of these mistakes causing actual harm to the patient. The frequency of drug errors must be appreciated and due care must be taken in checking and delivering drugs to children in an intensive care unit.


An evaluation of three methods used to assess the gestational age of aboriginal neonates.

Many Aboriginal women do not recall their last menstrual period date, so alternative methods of estimating gestational age are necessary for optimal obstetric and neonatal care. In this retrospective review of 605 Aboriginal infants born at the Royal Darwin Hospital, the gestational age was estimated by the Dubowitz method and compared with available gestational age estimates from first fundal height and first ultrasound measurement. There was good agreement between the Dubowitz and ultrasound estimates of gestational age with best agreement occurring when ultrasound was done in the first trimester and worst agreement in the third trimester. Agreement between fundal height and Dubowitz estimates was poor but the measurement of fundal height was not standardized. When accurate last menstrual period information is absent, these findings suggest that good estimates of gestational age in Aboriginal neonates can be determined from the Dubowitz assessment at birth and from ultrasound measurements taken in the first trimester.


Outcome of infants with birthweight 2000 g or less who undergo major cardiac surgery.

A retrospective study of all neonates with birthweight 2000 g or less undergoing major cardiac surgery at the Royal Children's Hospital, Melbourne over the last 5 years was performed in order to determine outcome and identify subgroups within this population that may have a poor prognosis. The mean length of stay in intensive care following surgery was 32 days, with non-survivors having a significantly longer duration of stay than survivors. Overall mortality was 43%, and for children with congenital heart disease as part of a recognizable syndrome the mortality was 100%. None of the survivors suffered incapacitating cardiac, neurological or respiratory handicap. These children in general have a poor prognosis and utilize significant resources; results of cardiac surgery in this group need to be closely followed in the future.


The prehospital management of children with acute asthma.

Parents of 100 children admitted sequentially to hospital with acute asthma were interviewed in order to determine the frequency of the use of asthma action plans and the intensity of prehospital treatment. The results revealed that 51% of the parents possessed some form of action plan and 84% of this group used their plan prior to the child's admission to hospital. However 79% of those children with more than two prior hospital admissions for asthma had an action plan. Bronchodilator therapy was widely used, with widespread possession of nebulizer units, but tended to be given infrequently prior to hospital admission. Steroid use in the acute attack was inadequate. Despite a concurrent national asthma campaign prehospital management was considered to be suboptimal.


Partial sacral agenesis with constipation: a report of one family.

Seven first degree relatives in three generations of a family with partial sacral agenesis are reported. Anterior sacral meningoceles were found in five cases, four of whom had severe constipation, one with urinary voiding dysfunction, and another without constipation who had low pressure headaches and dyspareunia. The anomalad was transmitted in an autosomal dominant fashion with incomplete penetrance and variable expression. This entity should be considered in all children and adults with severe constipation from birth, a family history of constipation and/or where constipation is refractory to medical therapy.


Failure of allogeneic bone marrow transplantation to benefit HIV infection.

A 16 year old boy underwent allogeneic bone marrow transplantation (BMT) from an human leukocyte antigen (HLA)-identical sibling for severe aplastic anaemia. He was symptomatic for 7 years before transplantation and had received multiple red blood cell and platelet transfusions. Conditioning for BMT consisted of cyclophosphamide, antilymphocyte globulin and total lymphoid irradiation. Engraftment was rapid, there was no evidence of rejection despite the history of multiple blood product transfusions and he did not develop acute or chronic graft versus host disease. He was well for the first 8 months after transplantation but then developed fevers, interstitial pneumonia, herpes simplex infections and cytomegalovirus enteritis. Serological studies revealed antibodies to human immunodeficiency virus (HIV) and he was considered to have acquired immune deficiency syndrome (AIDS). Retrospective analysis of the serum samples showed that he was seronegative for HIV until approximately 10 months before transplantation when his serum became HIV positive. Lymphocyte function studies done after transplantation suggested immunologic recovery at 3 months post-transplant with a brisk though subnormal response to phytohaemagglutinin stimulation. T cell subset analysis performed subsequently showed complete absence of CD4 positive cells indicating immune incompetence which was associated with clinical features of AIDS. Bone marrow transplantation had failed to produce sustained immunologic reconstitution and prevent the progression of HIV to which he ultimately succumbed.


Homozygous pyruvate kinase deficiency in Hong Kong ethnic minorities.

Three cases of pyruvate kinase (PK) deficiency resulting in congenital haemolytic anaemia with transfusion dependency are described. These cases resulted from consanguineous marriages in non-Han Chinese and include a pair of twins. We believe this to be the first documentation of homozygous PK deficiency in the Hong Kong population. The diagnosis was masked due to transfusion dependency in each case stressing the need to take a sample of pretransfusion blood for PK enzyme assay, and for family studies, when this disorder is suspected.


[Long-term results of talus fractures].

In a retrospective study we analysed 29 operative treated fractures of the Talus. The classification of Marti and Weber has been used in this study. The incidence of necrosis was 17% of the group III and IV and that one of arthritis 27%. There was no infection in our series. We doubt that a longterm non weight-bearing with a caliper brace has an effect on the outcome of a necrosis of the Talus. The evidence of the Hawkins' sign on the ap-radiograph at 6-8 weeks is a good and simple parameter of the vitality of the Talus.


[Prevention of medical occupational accidents].

Technical measures are not sufficient to prevent occupational accidents in patients with specific diseases. Since 1984 the Swiss National Accident Insurance Fund (SUVA) has the possibility to clarify the working conditions and medical aspects of patients presumed to suffer a special risk to occupational accidents. The actual situation and the experiences in the medical prevention of occupational accidents in Switzerland since 1984 are described.


[Therapy refractory accident patients and post-traumatic stress disorder].

The appearance of post-traumatic stress disorder (PTSD) is presented and discussed. Three case reports of patients concerned by an accident demonstrate, that not diagnosed PTSD may be the reason of the lack of response to rehabilitation interventions.


[Surgical treatment of radial head fracture].

Fractures of the radial head are often combined with ligament ruptures or subluxations creating instability of the elbow joint. Cartilage avulsions of the capitellum trapped between the fragments are a frequent observation. We advocate ORIF for displaced fractures. The posterolateral approach avoiding compression of the radial nerve may be prolonged proximally with an osteotomy of the humeral epicondyle giving full overview of the circumference of the head. It allows the harvesting of cancellous bone used as a graft to fill in articular depressed areas or metaphyseal defects. The stabilisation is achieved with thin screws of 1.5 mm diameter introduced in different planes, their head slightly sunken in the cartilage. Lately miniplates have been used in cases of neck fractures with surprisingly good functional results. The author reports about the results in 42 of 49 operated patients.


[The medical and insurance technical part of expert assessment].

The expert's demands careful exploration including consideration of psychological factors. Furthermore, to establish their final reports the insurance companies involved need detailed answers to specific questions in regard to the impairment. The medical expert finds himself in an area of conflict between doctor-patient relationship (which requires mutual trust) and his duty as an expert. His task will be made easier if he clearly separates the first part of his report dealing with the medical aspects from the second part referring to the more technical problems of the insurer. It is only after clarification of the medical situation that the questions relating to the insurance as such can be clearly answered. Factors which do not seem to relate directly to the medical aspects of the accidental sequels (e.g. psychosomatic), but which the Swiss Insurance Court does take more and more into account, may be mentioned, however, their evaluation is best left to the insurance company which ordered the expert's report.


The catalytic power of pyruvate decarboxylase. A stochastic model for the molecular evolution of enzymes.

Pyruvate decarboxylase (PDC) catalyzes the decarboxylation of pyruvate anion by a factor of around 10(12), compared with the non-enzymic decarboxylation by thiamine, under standard state conditions of 1 mM pyruvate and thiamine diphosphate (TDP), pH 6.2. Free-energy diagrams constructed on the basis of earlier measurements for the enzymic and non-enzymic reactions give some information on catalysis by PDC. PDC stabilizes the reactant state preceding TDP addition to pyruvate by 76 kJ mol-1 and the transition state for the addition by 83 kJ mol-1. PDC stabilizes the reactant state preceding decarboxylation (presumably alpha-lactyl-TDP) by 27 kJ mol-1 and the transition state for decarboxylation by 68 kJ mol-1. In addition, the free-energy diagrams reveal a leveling of reactant-state free energies in the enzymic reaction compared with the non-enzymic reaction, in that the former are nearly equal to each other. The enzyme-bound transition-state energies are similarly leveled. The energetic leveling of reactant states has been noted by Albery, Knowles and their coworkers in many enzymic reactions and termed 'matched internal thermodynamics.' They showed that the result would arise naturally (and inevitably) in the 'evolution to perfection' of enzymes, when the evolutionary process was treated by a deterministic model. The critical assumption of this model was the validity of a Marcus-type or Brønsted-type linear free-energy relationship between rate and equilibrium constants for reactions occurring wholly within enzyme complexes. Here a completely stochastic simulation of molecular evolution, with no deterministic assumptions, is shown to reproduce both 'matched internal thermodynamics' and the 'matched internal kinetics' or leveling of transition-state energies noted here. The Albery-Knowles result is thus more general than might have been supposed.


The glomerular filterability of polyfructosan-S in immature infants.

Gel chromatography was performed on 21 plasma, 5 urine and 3 spinal fluid samples from pre-term infants who had received intravenous polyfructosan-S (PF-S), in order to investigate whether all sizes of PF-S molecule are filtered at the glomerulus and penetrate deep extra-cellular fluid compartments. Plasma obtained after 24 h continuous infusion of PF-S had identical chromatograms to the aqueous solution, suggesting no glomerular hold-up of the largest molecules. PF-S had a broader chromatogram than inulin, suggesting that it has larger molecules. Urine and plasma samples obtained early after a single injection had an excess of high molecular weight polyfructoside, suggesting that small molecules penetrate deep extracellular fluid compartments more easily. Spinal fluid samples had an excess of low molecular weight polyfructoside, suggesting slow penetration of the largest molecules.


A reappraisal of the measurement of glomerular filtration rate in pre-term infants.

Thirty-seven single-injection polyfructosan-S (PF-S, Inutest) and 98 continuous-infusion PF-S/creatinine clearance studies were performed in 39 sick very low birth weight infants. The single-injection clearance method for measuring glomerular filtration rate has been shown to be a reliable technique if sampling is continued for 8 h or more and the PF-S (Inutest) assay is sensitive, accurate and precise. The continuous-infusion clearance method is also valid if the infusion is continued for more than 24 h and preceded by a loading dose in the form of a double-rate infusion for 8 h. Creatinine clearance is usually less than PF-S clearance, the mean ratio being 0.91, suggesting that there is some creatinine reabsorption in the renal tubule in sick very low birth weight infants.


Renal function following kidney transplantation in children treated with cyclosporine.

The study was performed to evaluate the long-term renal function of children treated with cyclosporine after kidney transplantation. Renal function was determined with clearances of inulin and aminohippurate sodium for evaluating glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Thirty-six children aged 0.4-16.2 (median 6.9) years at transplantation were examined within 5 months of transplantation and then yearly over 0.3-7.1 years. Twenty-five children and young adults, 1.5-20 (median 7.7) years of age, with solitary kidneys because of renal agenesis or nephrectomy, served as controls. The GFR and ERPF within 1 year of transplantation were significantly lower than those of controls (65 +/- 19 and 345 +/- 88 vs 96 +/- 12 and 474 +/- 91 ml/min per 1.73 m2, respectively). GFR remained constant 4 years after transplantation, but ERPF decreased significantly. Significant inverse correlations were found between GFR within 5 months of transplantation and the mean cyclosporine concentration and the number of rejection episodes. The frequency of hypertension decreased from 82% within 5 months of transplantation to 0% after 4 years. The absolute GFR increased during follow-up. In conclusion, kidney transplantation results in a reduced renal function compared with that of solitary native kidneys. The reduction in renal function correlated with the number of rejection episodes and the cyclosporine load. The increase in absolute GFR during follow-up suggests a remaining capacity for growth and/or compensatory hypertrophy.


Amelioration of hypertension and insulin resistance by 1,25-dihydroxycholecalciferol in hemodialysis patients.

The effects of i.v. 1,25-dihydroxycholecalciferol (DHCC) on blood pressure and insulin sensitivity were studied in 7 patients on maintenance hemodialysis and compared with 7 healthy controls. Three days after discontinuing oral 1,25-DHCC, the dialysis patients were evaluated by glucose clamp studies to quantitate insulin sensitivity, with (+D) and without (-D) a prior single dose of i.v. 1,25-DHCC at 2 micrograms/m2. Blood pressure was measured just before the glucose studies. During -D studies, the patients were hypertensive (mean arterial blood pressure 108 +/- 2 mmHg, controls 84 +/- 4 mmHg, P less than 0.02) and insulin resistant (insulin sensitivity index 7.5 +/- 0.4 mg/kg.min per microU per ml, controls 14.2 +/- 0.7, P less than 0.01). i.v. 1,25-DHCC significantly reduced the mean arterial blood pressure (96 +/- 3 mmHg, P less than 0.05) and increased insulin sensitivity (10.9 +/- 0.5 mg/kg.min per microU per ml, P less than 0.02) in the dialysis patients. I.V. 1,25-DHCC did not change blood pressure and insulin sensitivity in the control subjects. During -D studies, serum concentrations of 1,25-DHCC were significantly lower in patients than controls (P less than 0.02). Serum 1,25-DHCC during the +D studies increased to supraphysiological levels in both patients and controls. Serum concentrations of intact parathyroid hormone, total and ionized calcium, magnesium, potassium, urea nitrogen and creatinine were not different between the +D and -D studies in either the dialysis patients or the controls. These results suggest that pharmacological doses of 1,25-DHCC may have therapeutic value in the treatment of hypertension and insulin resistance in dialysis patients.


Mathematical modelling of haemodialysis in children.

The single-pool urea kinetic model (UKM), utilising "Kt/V" (the normalised whole body urea clearance), is widely used to help assess the adequacy of haemodialysis in adults. In the presence of an adequate dietary protein intake, a value of unity is acceptable for thrice weekly dialysis. Children could benefit from this approach but, with their relatively higher protein intakes and dialysis needs, this model may not be applicable. Urea kinetics, studies in six children with chronic renal failure by serial timed blood urea measurements during and after haemodialysis, were compared with the kinetics of a one-pool and a two-pool UKM. The two-pool UKM with intra- and extracellular pools best fitted the observed data, re-equilibration between pools accounting for the marked rebound increase in blood urea seen in the 1st h after dialysis (mu 17%, SD 5). Kt/V calculated using the end-dialysis blood urea was higher (mu 21%, SD 5) than when the more correct equilibrated value was used. The post-dialysis rebound indicates significant disequilibrium between the two pools at the end of dialysis. Dialysis efficiency may be substantially overestimated unless this is allowed for by using the rebounded post-dialysis blood urea when calculating Kt/V.


Cerebral oedema in congenital nephrotic syndrome.

We report an infant with congenital nephrotic syndrome who showed clinical and radiological evidence of cerebral oedema, which resolved during prolonged intravenous albumin therapy. The cerebral oedema in this case can possibly be attributed to the relative immaturity of the blood-brain barrier in early infancy.


Acquired hyperoxaluria and haematuria in children.

Two children with extensive ileal resection are reported. They developed gross haematuria of "non-glomerular origin", without stones or nephrocalcinosis. Previous reports indicate that acquired hyperoxaluria is common in children with a variety of intestinal disorders. Our patients had hyperoxaluria. We think that hyperoxaluria may be the cause of haematuria through a pathogenetic mechanism similar to the one ascribed to haematuria secondary to hypercalciuria and hyperuricosuria.


Aluminum toxicity in childhood.

Aluminum intoxication is an iatrogenic disease caused by the use of aluminum compounds for phosphate binding and by the contamination of parenteral fluids. Although organ aluminum deposition was noted as early as 1880 and toxicity was documented in the 1960s, the inability to accurately measure serum and tissue aluminum prevented delineation of its toxic effects until the 1970s. Aluminum toxicity has now been conclusively shown to cause encephalopathy, metabolic bone disease, and microcytic anemia.


Renal effects of growth hormone. I. Renal function and kidney growth.

Growth hormone (GH) affects renal function and kidney growth. Pituitary-derived or recombinant human GH (rhGH), acting via insulin-like growth factor-1 (IGF-1), increases glomerular filtration rate (GFR) and renal plasma flow (RPF) in GH-deficient as well as in normal adults. Furthermore, GFR and RPF are low in hypopituitarism and elevated in acromegaly. These effects of GH on GFR and RPF have not been demonstrated in moderate renal insufficiency. IGF-1 is implicated in compensatory renal hypertrophy. Markedly elevated levels of serum GH accelerate glomerular sclerosis in rodents, although the significance of these findings for GH treatment in humans is uncertain. rhGH therapy offers great promise to children with short stature from various aetiologies. Preliminary reports on the use of rhGH in children with renal disease and after renal transplantation have not shown any consistent change in kidney function, although follow-up times are short. The long-term impact of rhGH therapy on kidney function in short children needs further evaluation.


Sebaceous gland lipids.

Human sebum contains squalene, wax esters, triglycerides, cholesterol esters, and possibly free cholesterol. The fatty acids of the ester lipids include species with chain branching or with unusual double-bond positions. The alcohol moieties of the wax esters contain unusual chain types similar to those of the fatty acids. Genetic and hormonal factors cause individual differences in sebaceous lipid composition. Genetic factors seem to influence the proportions of the various types of branched-chain fatty acids. Androgenic stimulation of the glands causes an increase in lipid synthesis, and therefore in the ratio of endogenously synthesized lipid to exogenous lipid. Because the endogenously synthesized lipids tend to be different from lipids that are derived exogenously, the overall composition of the secretion changes. Differences in sebum composition are particularly evident when the sebum of prepubertal children is compared with that of young adults. One difference that may be of clinical significance is the different concentrations of linoleate. Higher concentrations of sebum linoleate may protect young children from comedonal acne by preventing an essential fatty acid deficiency from developing in the follicular epithelium.


Epidermal lipids.

Epidermal lipids play important roles in cell structure, in control of growth and differentiation, in determining cohesion and desquamation, and in formation and function of a permeability barrier. Knowledge of the structures and composition of the epidermal lipids is important for understanding these functions. The lipids present in epidermis include phospholipids, monohexosylceramides, ceramides, cholesterol, cholesterol esters, cholesterol sulfate, triglycerides, and fatty acids. The phospholipids are major structural components of the plasma membranes and membranous organelles in the viable and differentiating keratinocytes. In addition, phospholipids serve in several transmembranal signaling processes and as a reservoir for arachidonic acid, the precursor of the eicosanoids. Monohexosylceramides are thought to function in the assembly of lamellar bodies, and in the final stage of differentiation are converted to a structurally heterogenous mixture of ceramides in the intercellular space of the stratum corneum and to a unique ceramide covalently attached to the corneocyte surface. The mixture of lipids in the stratum corneum, composed principally of ceramides, cholesterol, cholesterol esters, and fatty acids, prevents desiccation and limits the penetration of a variety of noxious environmental agents. The stratum corneum lipids represent a major product of epidermal differentiation, and free sphingosine liberated from ceramides in this terminally differentiated compartment may provide a feedback mechanism for the regulation of the differentiation process.


Prostaglandins, leukotrienes, and hydroxy fatty acids in epidermis.

The skin is an organ that displays a highly active metabolism of polyunsaturated fatty acids (PUFA). Deficiency of the 18 carbon (n-6) dietary PUFA (linoleic acid) in epidermis results in scaly dermatoses and disruption of the skin barrier system. The skin possesses the enzyme systems to metabolize and interconvert a variety of lipids. For instance, it metabolizes arachidonic acid (an n-6 PUFA) via the cyclooxygenase pathway into cyclic products, predominantly prostaglandin E2 and prostaglandin F2 alpha. These prostaglandins modulate normal physiological processes at low physiological concentrations. However, at high concentrations, such as result from UV irradiation, they elicit inflammatory reactions. The skin can also metabolize 18-carbon and 20-carbon PUFA (n-6) via the 12- and 15-lipoxygenase pathways to produce predominantly monohydroxy fatty acids: 13-hydroxyoctadecadienoic acid (13-HODE), 12-hydroxyeicosatetraenoic acid (12-HETE), 15-hydroxyeicosatetraenoic acid (15-HETrE), and 15-hydroxyeicosatetraenoic acid (15-HETE). The latter two have potent anti-inflammatory properties. Therefore, it seems possible that elevation of these HETEs in vivo via dietary or topical means could suppress the cutaneous inflammatory reactions elicited by excessive generation of prostaglandins and leukotrienes. Thus, the supplementation of diets with appropriate purified vegetable oil and/or fish oil may serve as a less toxic monotherapy or as an adjunct to standard regimens in the management of skin inflammatory disorders.


Structures formed by epidermal lipids in vitro.

The extracellular membranous structures of stratum corneum constitute the major barrier to percutaneous penetration. These intercellular lipid lamellae are devoid of phospholipids and are unique in their lipid composition. In this article, some of the recent investigations of the structures formed by the stratum corneum lipids in vitro are discussed with relevance to the barrier function of epidermis. These studies have provided some insight into the dramatic physical changes that occur in the membranous structures of the epidermis during the formation of the stratum corneum.


Physical methods for studying stratum corneum lipids.

The skin's barrier to water loss and drug transport is closely related to the biophysical properties of the stratum corneum lipids. A number of in vitro and in vivo methods have been used to evaluate the physical properties of stratum corneum lipids. Two particularly useful techniques, infrared spectroscopy and differential scanning calorimetry, have provided a wealth of information about stratum corneum structure and function. The results of these studies demonstrate that the alteration of stratum corneum lipid packing results in increased skin permeability. Furthermore, the magnitude of increased permeability can be predicted from these physical properties. Therefore, these results provide both insight into the mechanism of transport through the stratum corneum, as well as a useful paradigm for selection of agents that reversibly alter the permeability of the skin.


Epidermal lipids and topical drug delivery.

When a topical formulation is placed on the skin, the active drug is usually required to penetrate through the stratum corneum into the viable tissue. The major control to this process is the slow diffusion through the dead horny layer. The major route of drug penetration through the stratum corneum is via the tortuous intercellular channels. It is therefore important to ascertain the nature of the environment that the drug experiences within the intercellular pathway and how it is affected by the presence of formulation components. The lipids within the intercellular channels are a complex mixture but they are structured into bilayer arrays. Extraction of the lipids by solvents within the formulation will lead to enhanced permeability of the skin. Some penetration enhancers act by creating disorder in the alkyl chains of the lipid bilayers; others modify the solubility characteristics within the stratum corneum. The different interactions that are possible will be discussed in this article.


Model studies of epidermal permeability.

An in vitro physical model approach for describing and predicting transport of molecules and ions across skin is examined. The proposed model is represented by two transport-resistant layers in series: the stratum corneum and the epidermis plus dermis. The stratum corneum is regarded as the principal barrier to transport and is composed of two parallel pathways: the lipoidal pathway and the pore pathway. The epidermis-dermis is treated as a porous membrane. The model predicts three regimes for the transport behavior of permeants, and these predictions have been compared with experimental permeability coefficient data obtained with hairless mouse skin in a two-chamber (aqueous) diffusion cell. The model predicts (1) that extremely lipophilic molecules are rate-limited by the epidermis-dermis and have a limiting permeability coefficient value; (2) that extremely polar permeants are rate-limited by the pore pathway of the stratum corneum with its limiting permeability coefficient; and (3) that permeants with intermediate polarity are transported via the lipoidal pathway and exhibit a lipophilicity-dependent permeability coefficient. Experimental data involving a large number of permeants are found to be consistent with these model predictions. The model approach also has been applied in the study of the mechanism(s) of skin transport enhancement induced by short-chain alkanols in aqueous media. A possible mode of enhancing the lipoidal pathway at low concentrations of the alkanols may involve the polar head region of the lipid bilayer or the region slightly below the polar head plane, or both; alkanols may solvate the lipid-water interface, intercalating and disrupting the interactions of the upper regions of the alkyl chains and the interactions between the polar head groups. This could result in an increase in both diffusivity and partitioning tendency for a permeant in this microenvironment. At higher alkanol concentrations, the pore pathway becomes dominant in controlling the transport of the permeants across the stratum corneum.


Studies of epidermal lipids using electron microscopy.

Ruthenium tetroxide fixation has permitted the electron microscopic visualization of intercellular lipid lamellae in thin sections of stratum corneum. This development complements prior freeze-fracture studies of lipid lamellae and has advanced our knowledge about the ultrastructure of epidermal lipids in several ways. We have demonstrated a continuous lipid envelope that surrounds each differentiated stratum corneum cell and the presence of lipid lamellae throughout the entire stratum corneum of three mammalian species, including humans. Wherever lamellae are seen, they are present in multiples of one, two, or more pairs of bilayers, consistent with their formation from fused, flattened lipid vesicles. A unique pattern of lipid monolayers intervening between each pair of bilayers, based on sharing lipid chains between bilayers, has been proposed. In regions where there are no intercellular lamellae between corneocytes, intervening monolayers are in contact with adjacent lipid envelopes that might be involved in stratum corneum cohesion. However, limitations to the ruthenium technique must be overcome before changes in lamellar patterns can be accurately attributed to, or correlated with, changes in permeability brought about by experimental procedures or in diseased states.


In vivo studies of cutaneous lipid biosynthesis.

The epidermis and the sebaceous glands are both characterized as terminally differentiating tissues in which cells produced by replication in the germinative layer progress during several weeks through a programmed series of biochemical and morphological changes that end in cell death and eventual sloughing of the final metabolic products. Because of these slow changes and the presence of successive anabolic and catabolic regimes in the same tissue, classic methods of biochemistry using cell homogenates have not been widely successful. Much of what is known of the lipid metabolic pathways has therefore been obtained from experiments with biopsy materials or in intact animals. Radiotracer experiments in intact animals have been successful largely because the lipid products into which the radiolabel is incorporated are not lost to the general circulation during the several weeks in which they are retained in the tissue. Nor are they subject to continual degradation and resynthesis that would be the case in most other tissues, but progress steadily through the series of biochemical transformations that occur along with the morphologic changes characteristic of the epidermal and sebaceous tissues. Furthermore, of the radiolabel that enters the general circulation, only an insignificant proportion returns to the cutaneous tissues to obscure the local metabolic activities.


Epidermal lipids and scaling diseases of the skin.

Alterations in epidermal lipid content or metabolism underlie several scaling diseases of the skin in man and experimental animals. The importance of cholesterol to epidermal homeostasis and normal desquamation is demonstrated by the scaling disorder produced by topical applications of lovastatin in experimental animals, and by the imbalance of the cholesterol sulfate:cholesterol ratio in stratum corneum in patients with recessive X-linked ichthyosis. The essential fatty acid-deficient rodent illustrates the importance of linoleic acid to epidermal function. Finally, a defect in lamellar body organellogenesis may underlie harlequin ichthyosis.


Lipids and the epidermal water barrier: metabolism, regulation, and pathophysiology.

In addition to well-known changes in protein composition, epidermal differentiation is associated with dramatic changes in lipid content. A decrease in phospholipids and triglycerides is accompanied by enrichment in ceramides, cholesterol, and free fatty acids in the stratum corneum. The epidermis demonstrates exceptionally high basal levels of lipid synthesis, and regulates its synthetic activity in response to barrier requirements. Not all epidermal lipids are synthesized in parallel; whereas cholesterol and fatty acids are synthesized immediately after barrier disruption, sphingolipids begin to be synthesized later in the course of barrier homeostasis. In addition, with specific inhibitors of the key regulatory enzymes--3-hydroxy-3-methyl-glutaryl coenzyme A reductase (for cholesterol) and serine palmitoyl transferase (for sphingolipids)--it has been possible to demonstrate conclusively a role for these species in the barrier. Furthermore, barrier function not only regulates lipid synthesis, but also epidermal DNA synthesis, perhaps thereby providing an additional pool of lipid biosynthetic factories. These findings have considerable implications for the pathophysiology of skin diseases associated with abnormal barrier function, such as psoriasis and irritant contact dermatitis.


Disorganization is a completely dominant gain-of-function mouse mutation causing sporadic developmental defects.

Disorganization (Ds) is an exceptional mutation because of its diverse and profound developmental effects. Although other mouse mutations produce similar congenital defects, extreme pleiotropism, random occurrence, developmental independence of multiple defects, and type of anomaly make Ds unique. Examples of developmental defects include cranioschisis, rachischisis, thoracoschisis, exencephaly, hamartomas, and anomalies of appendages, digestive, genital and urinary tracts, sense organs, limbs and girdles, tail and pharynx. No other mutation in the mouse has such broad effects. Ds is therefore an important model for studying not only the genetic control of lineage determination and pattern formation, but also the occurrence of sporadic congenital defects. To characterize the effects of gene dosage, we examined the viability and phenotype of Ds homozygotes and the phenotype of +/+/Ds trisomic fetuses. Occurrence of homozygotes was tested by intercrossing Ds/+ heterozygotes, typing genetic markers that flank Ds, and examining homozygotes for morphological abnormalities. Not only were Ds homozygotes found in their expected frequency, homozygotes were not more severely affected than heterozygotes. Trisomies provide a direct test for determining whether Ds is a gain-of-function mutation. Trisomic fetuses were derived by crossing Ds/Ds homozygous mice to hybrid mice that were heterozygous for two related Robertsonian translocations. Two trisomic fetuses had developmental defects characteristic of Ds mice. Together these results demonstrate that Ds is a completely dominant, gain-of-function mutation.


Suboptimal 5' and 3' splice sites regulate alternative splicing of Drosophila melanogaster myosin heavy chain transcripts in vitro.

Using a Drosophila cell-free system, we have analyzed the regulation of alternative splicing of Drosophila muscle myosin heavy chain (MHC) transcripts. Splicing of MHC 3' end transcripts results in exclusion of adult-specific alternative exon 18, as is observed in embryonic and larval muscle in vivo. Mutations that strengthen either the 5' or the 3' splice sites of exon 18 do not promote inclusion of this exon. However, strengthening both splice junctions results in efficient removal of both introns and completely inhibits skip splicing. Our data suggest that the affinity of exons 17 and 19, as well as failure of constitutive splicing factors to recognize exon 18 splice sites, causes the exclusion of exon 18 in wild-type transcripts processed in vitro.


Impaired T cell functions during amphibian metamorphosis: IL-2 receptor expression and endogenous ligand production.

T cell functions are impaired during defined developmental stages of amphibian metamorphosis (Marx et al., 1987). Here we show, using a fluorescent anti-human IL-2 receptor antibody and flow cytometry, that during these stages, the splenocytes of Xenopus laevis, the South African clawed toad, have a progressively diminished capacity to express IL-2 receptors (IL-2R), after in vitro lectin stimulation. Preincubation with human rIL-2 specifically blocks binding of the anti-IL-2R antibody. Separation of an endogenous ligand bound to the IL-2R leads to a substantial increase in available epitope recognized by the anti-IL-2R antibody when pre- and postmetamorphic splenocytes are employed, but not when splenocytes of the prometamorphic stages are treated similarly. Thus, the cells from the prometamorphic stages are not producing significant quantities of the ligand. Finally, we demonstrate that human rIL-2 is not by itself mitogenic in the toad, but it can act as a co-stimulator of antigen-induced mitogenesis. Thus, an absence of an endogenous ligand (autologous IL-2?), coupled with a reduced capacity to express IL-2 receptors may be responsible for impaired T cell clonal expansion in metamorphosing Xenopus. Inhibition of T cell functions during this period is vital, since adult cells forming within the larval body bear surface proteins not found on larval cells (Flajnik et al., 1986).


Differential expression of the msp130 gene among skeletal lineage cells in the sea urchin embryo: a three dimensional in situ hybridization analysis.

In order to examine the ontogeny of tissue-specific expression of the msp130 gene during early embryogenesis of the sea urchin, we have developed a whole-mount, non-radioactive in situ hybridization protocol suitable for these embryos. This protocol is adapted from the existing technology of immunohistochemical localization of digoxygenin-labelled hybridization probes in tissue sections. Transcript distribution patterns in the whole embryo are seen in three dimensions, and at much higher resolution and sensitivity than can be achieved using radioactive probes and sectioned material. We have traced the ontogeny of expression of the skeleton-specific gene, msp130, during the development of Strongylocentrotus purpuratus. Transcripts are first detected at the blastula stage, in micromere-lineage cells just prior to ingression. Appearance of msp130 transcripts remains strictly limited to this lineage through the pluteus stage. Estimated from the relative intensity of staining of the PMCs of an embryo, the relative abundance of msp130 transcripts is uniform among the 32 cells of this lineage in secondary mesenchyme blastulae and in gastrulae, indicating that expression is homogeneous among these cells up to the early prism stage. However, the relative intensity of stain, and therefore abundance of transcripts, changes dramatically and in a consistent pattern among the PMCs of an embryo during prism and pluteus stages, suggesting that these cells switch from an autonomous mode of regulation of the msp130 gene, to an inductive mode. In the pluteus larva, the highest levels of expression occur in those cells associated with the rapidly growing tips of the spicular skeleton.


Pulpal tissue reaction to buffered glutaraldehyde.

Pulpal tissue changes following pulpotomies with 2% w/v buffered glutaraldehyde in primary teeth were observed. A 3 minute single application of 2% w/v buffered glutaraldehyde was able to produce effective surface fixation. Limited penetration of the medicament left the remaining pulp tissue unaffected. The zone of fixation did not proceed apically. With time, macrophages and fibroblasts appear apical to the zone of fixation indicating the onset of replacement resorption.


Lactobacilli from the dentin and saliva in children.

Lactobacilli were detected simultaneously in saliva, dental plaque and carious dentinal plaque in 66 children aged 5 to 15 years. The dentinal plaque samples numbered 15. It was found that Lactobacilli were present in 100% of the dentin samples, 70% of the saliva samples and 29% of the plaque samples. The DMF index and dentinal lactobacilli are systematically linked. The DMF index is weakly linked to salivary and independent of plaque lactobacilli. It is concluded that (1) dentin is responsible for the salivary hypercontamination and (2) the Lactobacillus Count could hardly be a predictive test.


Early eruption and advanced root development of the permanent cuspids in a six-year-old boy.

A case report showing the eruption of the left maxillary and mandibular permanent cuspids in a six-year-old boy, is presented. In addition, the dental age of all the permanent cuspids as seen by the eruption and tooth development suggested that the cuspids are comparable to those seen in a 13 to 14 year-old-boy. A search of the literature has not revealed any such reports.


Hypodontia of the primary and permanent dentition.

The prevalence, possible etiological factors and management of hypodontia was briefly reviewed. A report of a case of hypodontia affecting the primary and permanent lower incisors was described.


Nursing caries in Head Start children, St. Thomas U.S. Virgin Islands: assessed by examiners with different dental backgrounds.

The purposes of this study were to determine the prevalence of nursing caries in 3- to 5-year-old Head Start (HS) children on St. Thomas, U.S. Virgin Islands and to assess the reliability of examiners with different dental backgrounds. A dentist, hygienist, and nondental HS personnel participated in a 1/2 day training session (lecture and workshop) and then independently conducted visual examinations for caries of the maxillary anterior teeth including nursing caries. Twenty-three HS personnel examined a total of 375 children; the dentist and hygienist examined a random sample of 74 and 73 children, respectively. Seventy-one children received all three independent examinations. Reliability was assessed by percent agreement, sensitivity, specificity, and kappa value. The dentist found 41% of the children had caries of the maxillary incisors, which included nursing caries. The percentage of children with nursing caries was 12%. There was strong-to-good diagnostic agreement between the dentist and hygienist. The HS personnel also found that 12% of the children had nursing caries, but the diagnostic agreement between the dentist and HS personnel was only good-to-fair.


Juvenile periodontitis: a review of pathogenesis, diagnosis and treatment.

Juvenile periodontitis (JP) and its treatment has become a critical concern to the practicing dentist. Actinobacillus actinomycetemcomitans has been diagnosed as the prime etiological agent associated with this disease. Decreased chemotaxis and phagocytosis of polymorphonuclear leukocytes have also been described in these patients. The precise treatment regimen must be individualized for each patient. In addition to aggressive antibiotic therapy, root planing, curettage or a surgical approach, with mandatory follow-up care, should be considered. This review discusses the etiology and pathogenesis of JP and recommends treatment regimens, according to patient diagnosis.


Modus operandi of Planas' appliance.

Planas' approach to the management of a distocclusion, as applied by Simoes, is analyzed physiologically by taking into account the Petrovic-Stutzmann's cybernetic vision of facial growth. This scientifically based theorization further strengthens the clinical validity of this orthodontic ideology and procedure. The clinician, the orthodontist, the functional orthopedist or the functional orthodontist are fundamentally dependent on their knowledge about biophysics, biochemistry and mainly physiology. It is important then that they be acquainted with fundamental concepts of basic sciences as applicable to the specialty. In planning the treatment of a malocclusion, it is necessary to select the appliance or the series of them for sequential use in the correction of a intermaxillary malrelation. It is also useful to be able to predict the response to each appliance. In this case it must be considered the input (appliance in the mouth) designed to produce either displacements of the teeth or other modifications within the dentofacial complex and the output (appliance effect). According to Petrovic and Stutzmann there are 6 tissue level growth categories. Previous investigations using Frankel appliance, LSU Activator, Bionator, Chin Cup and Begg techniques, have shown that when going from the growing category number 1 to number 6 it becomes easier to stimulate the growth rate and amount of the condylar cartilage and of the posterior border of the ramus and it becomes more difficult to restrain their growth rate and amount. In other words we have also to test clinically the effectiveness of the Planas Appliance by taking into account the inter-individual variation in the tissue level responsiveness to it. (Fig. 1-4).(ABSTRACT TRUNCATED AT 250 WORDS)


Malocclusion, body posture, and temporomandibular disorder in children with primary and mixed dentition.

Occlusal factors, body posture and TM disorders were examined in forty children with primary dentition and forty children with mixed dentition. The purpose of the study was to test the hypothesis that there is a relationship between TM disorders and malocclusion, as well as that there is a relationship between body posture and TM disorders in the examined population. Clinical examination was done by two investigators, who used a stethoscope to detect TMJ sounds. The results showed that forward head position had a significant relationship to TM disorders in the mixed dentition. Also many of the occlusal factors were closely related to TM disorders in the population examined. The prevalence of TM disorders in primary dentition was 2.5% and in the mixed dentition it was 90% in the population studied.


Space maintenance and endodontic follow-up: case reports.

Early extraction of carious primary teeth may result in functional and/or loss of arch length problems. That is the rationale behind root canal therapy and/or space maintenance after the extraction of pulpally involved primary molars. What follows is a short radiographic and photographic history of unexpected results in well established and routine space therapy treatments.


Delayed retraction utilizing ceramic brackets.

The purpose of this study was to evaluate clinically the delay in retraction utilizing ceramic orthodontic brackets versus stainless steel brackets. Twelve patients with Class II division 1 malocclusions requiring the extraction of maxillary first premolars were employed in the study. The following observations were obtained: 1. Retraction of all cuspids bonded with ceramic brackets displayed delayed retraction when compared to their stainless steel counterparts. 2. Over a 36 week period, teeth bonded with stainless steel brackets travelled 2mm farther or 1.8 times faster than those bonded with ceramic brackets.


Biology and treatment of gliomas.

This review discusses some of the recent advances in glioma research and treatment. Our understanding of the characteristics of these tumors has been strengthened by the application of molecular biologic and genetic techniques to pathologic grading and therapy outcome. Newer attempts to correlate imaging modalities to pathologic grading are also discussed. It is anticipated that these developments will strengthen our ability to design improved treatment strategies, an essential goal inasmuch as current treatment schemes have limited benefit. More work needs to be done to understand the biology of these tumors especially the complex interactions of their cytokine expression, multiplicity of genetic abnormalities, and their local environment. Only then will be able to develop improved therapeutic interventions.


New hormone-related markers of high risk to breast cancer.

New markers of increased risk to breast cancer are examined and related to established risk markers. The following new evidence is highlighted: (1) Increased testosterone secretion by the ovaries is currently the only major steroid abnormality shown to be associated with increased risk of both premenopausal and postmenopausal breast cancer. (2) Upper body-type obesity is a marker for both hyperandrogenaemia and hyperinsulinaemia and is associated with an increased risk of breast cancer. Upper body type obesity may already be recognised in early puberty in caucasian girls and is associated with a characteristic androgen/oestrogen profile. (3) Relative tallness in women is associated with an increased risk of breast cancer. A hypothesis is offered on the significance of these markers in the aetiology of mammary cancer in women, and also a means of testing the hypothesis. The hormonal promotion of mammary carcinogenesis is likely to be greatest between puberty and the first full term pregnancy. The presence of hyperinsulinaemia can increase the ovarian production of androgen, and the abnormal hormonal profile may stimulate proliferative activity in mammary epithelium. This may increase the risk of epithelial atypia and carcinogenesis.


Randomized trial of adjuvant chemotherapy for operable breast cancer comparing i.v. CMF to an epirubicin-containing regimen [see comment].

From January 1985 to December 1987, 228 women with breast cancer smaller than 3 cm were treated by surgery +/- radiotherapy. All of them had axillary node involvement (N+) and/or lacked estrogen and progesterone steroid receptors (EPR-). They were randomized in an adjuvant chemotherapy trial comparing 9 intravenous CMF courses (cyclophosphamide, methotrexate, 5FU)--113 patients--to a polychemotherapy consisting of 3 courses of MTV (mitomycin C, thiotepa, vindesine) plus 3 courses of EVM (epirubicin, vincristine, methotrexate)--115 patients. Prognostic factors were well balanced between the two treatment groups. With a 59-month median follow-up, local breast relapses are more frequent in the CMF group, but regional and metastatic recurrences are the same in the two groups. Overall survival is identical. Toxicity is different: alopecia and neurotoxicity are more frequent in the MTV+EVM group, but general and digestive toxicities are equivalent. Haematologic toxicity is greater in the CMF group, requiring more frequent dosage reductions.


Phase I/II study of liposome-complexed mitoxantrone in patients with advanced breast cancer.

The toxicity of escalating doses of liposome-complexed mitoxantrone (LCM) was evaluated in 22 women with histological/cytological diagnosis of metastatic breast cancer (21 pts) or adenocarcinoma of unknown primary origin (1 pt). All patients but one had been pretreated with chemotherapy. LCM was given IV as a 1h-infusion, repeated every 3 weeks, from a starting dose of 3 mg/m2, corresponding to 1/3 of the MELD10. An intra-patient dose escalation scheme, with an increase per cycle of 3 mg/m2 up to 12 mg/m2, and then by 2 mg/m2 was applied, treatment being continued until tumour progression, or toxicity, or up to a maximum of 6 cycles, whichever occurred first. Granulocytopenia was dose-limiting, with a GNC count of less than 0.5 x 10(3)/microliters after 30%, 28%, 50% and 50% of the cycles given at 16, 18, 20 and 22-24 mg/m2, respectively. The lowest GNC count occurred usually 2 weeks after treatment, with recovery in the following week. Gastro-intestinal toxicity, mucositis and alopecia were rare and of mild degree. Two patients, with a subtotal neoplastic involvement of the liver and a pretreatment grade 4 liver impairment, died because of acute liver failure a few days after treatment. The maximum tolerable dose was defined at 22 mg/m2 and 18 mg/m2, given every 3 weeks for 6 cycles, was the regimen recommended for phase II studies. Seven previously untreated patients with metastatic breast cancer have been so far treated. The pattern of toxicity of LCM (specific, short-lasting granulocytopenia; negligible, non cumulative non hematological toxicity) was confirmed.(ABSTRACT TRUNCATED AT 250 WORDS)


Cancer diagnosis disclosure in a Spanish hospital.

At the Clinic Hospital in Barcelona, Spain, 167 cancer patients and 380 hospital health care workers were interviewed about cancer diagnosis disclosure. Only 25 patients (15%) were correctly informed of their diagnoses. Breast cancer patients were significantly more often informed than patients with other malignancies (p less than 0.05). Two hundred seventy-two of 380 hospital health workers interviewed (71%, p = 0.00) would want to know their own diagnoses should they suffer from cancer in the future, but only 19% (p = 0.00) would want such a diagnosis revealed to their similarly afflicted relatives. This information model, based on cancer taboo, is largely preferred by these healthy people and is followed by doctors, patients and family members. To inform our patients better, the mandatory uniform disclosure of the true diagnosis is not likely to be constructive at present. In our opinion a pragmatic approach is more realistic and humane. Nevertheless, we must hope that more modern cancer education will lead to the gradual elimination of this taboo in our society.


Long-term effects on pulmonary function of mantle radiotherapy in patients with Hodgkin's disease.

Twenty-five patients (21-45 years old) treated for Hodgkin's disease with mantle radiotherapy but no chemotherapy underwent chest radiography and pulmonary testing with spirometry, pulmonary mechanics and exercise test combined with arterial blood gas analysis, lung scintigraphy, assessment of pulmonary artery pressure with Doppler cardiography and vector ECG 10-20 years after treatment. The doses to mediastinum ranged from 35-43 (mean 40) Gy given in 26 fractions with the split-course technique. Radiographic signs of slight to moderate pulmonary fibrosis were seen in 18 patients. Minor restrictive ventilatory defects were found with decreased VC, TLC and lung compliance and increased maximal elastic recoil. Little evidence of airflow obstruction was found. Exercise capacity was decreased in three individuals but the mean value for the study group as a whole was normal. Arterial PO2 at maximum exercise was reduced but no patient had diminished hemoglobin saturation. Lung scintigraphy showed defects in 21 patients, mostly consisting of slight abnormalities at the lung periphery and apices. The perfusion seemed to be more affected than the ventilation, suggesting primary vascular lesions. Twelve patients showed signs of right ventricular hypertrophy in vector ECG and four of these had systolic pulmonary artery pressure greater than or equal to 30 mm Hg. The observed abnormalities were mostly of a minor degree and few clinically significant long-term effects of mantle radiotherapy on pulmonary function were observed.


Feasibility study of high-dose carboplatin and etoposide in the salvage treatment of testicular cancer.

Eleven patients with testicular cancer, either relapsing after or refractory to cisplatin-based chemotherapy, underwent salvage chemotherapy with high-dose carboplatin (800 mg/m2 on day 1) and high-dose etoposide (500 mg/m2 on days 1, 3 and 5). A total of 21 courses were administered. The major toxicity consisted of profound myelosuppression. There were two toxic deaths, both caused by infection during neutropenia. Bone marrow recovery was usually complete around day 26 (range 19-129). Other toxicities included mild mucositis, nausea and vomiting, and alopecia. No significant neurotoxicity or hearing loss were observed and only one patient had a moderate decrease in renal function. Nine of ten evaluable patients responded, with one complete remission, 6 partial remissions with normalization of tumor markers, and two partial remissions with over one log decrease of tumor markers. The duration of these remissions was not evaluable, since only three evaluable and responding patients did not receive additional therapy after HD-CE. All three relapsed after discontinuing chemotherapy. HD-CE has activity in relapsing or refractory testicular cancer and can be administered without bone marrow support. The regimen may thus be suitable to be used as a remission induction regimen prior to consolidation with intensive chemotherapy and autologous bone marrow transplantation.


Prognostic factors for survival in patients with advanced renal cell carcinoma treated with recombinant interleukin-2.

A database of 327 patients with advanced Renal Cell Carcinoma (RCC) has been analyzed in order to identify potential baseline prognostic factors predicting for survival, following recombinant Interleukin-2 treatment (rIL-2). All patients received a continuous infusion (CIV). Eligibility criteria were uniform across studies, and included patients with an ambulatory performance status (PS), measurable disease, no CNS metastases, and no major organ compromise. Multivariate analyses identified baseline PS (ECOG 0 vs. 1), time from diagnosis to treatment (DTI greater than 24 months vs. less than or equal to 24 months), and the number of metastatic sites (1 vs. greater than or equal to 2, where lung, bone and other sites are considered as separate sites) as important predictors for survival. Patients can be classified into 4 subgroups, which are a function of the number of risk factors present. Median survival for each subgroup is 28, 17, 10 and 5 months, respectively. The model was validated in an independent cohort of 125 patients with RCC treated with subcutaneous (s/c) rIL-2, and predicted for survival accurately. By determining in which risk group category patients may fall, treating physicians may be better equipped to decide on patient management. The model may also be of value in order to stratify patients in randomized clinical trials.


Epirubicin/dacarbazine rapidly alternated with ifosfamide in the treatment of metastatic soft tissue sarcomas.

Twenty-eight patients with non-pretreated metastatic soft tissue sarcomas were entered on a treatment protocol of rapidly alternating epirubicin/dacarbazine and ifosfamide: Epirubicin 100 mg/m2 d1, dacarbazine 500 mg/m2 d1 + d2, ifosfamide 6000 mg/m2 24-h infusion d15; repeated d29. Eight patients (30%) achieved partial responses, with a median duration of 8.5 months. The median time to progression was 5.5 months. Myelosuppression was the main toxicity. Only 74% of the planned dose intensity could be administered. This rapidly alternating treatment protocol is not superior to anthracycline single agent therapy.


Double biochemical modulation of 5-fluorouracil by leucovorin and cyclic low dose interferon alpha 2b in advanced colorectal cancer patients.

Because of the different sites and mechanisms of biochemical interaction among 5-fluorouracil (5-FU), leucovorin (LV) and interferon (IFN), we hypothesized that the concomitant use of IFN could increase the activity of the 5-FU/LV combination in colorectal cancer patients. Forty-five patients were included in the study and all were evaluable for response and toxicity. They were treated with 5-FU 370 mg/sqm i.v. d 2-6; LV 200 mg/sqm i.v. d 2-6; IFN alpha 2b 3 million U im d 1-7 every 21 days. Six patients achieved complete responses, 17 partial responses, 14 had stable disease and 8 progressed on therapy for an overall response rate of 51%. Median survival has not been reached. At a median follow-up of 14 months 33 of 45 patients remain alive. Nine patients experienced toxicity grade 3 (6 diarrhea and 3 stomatitis). Our results seem to suggest that IFN could increase 5-FU/LV activity and that this combination is well tolerated.


Towards a molecular basis for tamoxifen resistance in breast cancer.

Breast cancer patients who acquire tamoxifen resistance may respond to second-line hormonal therapy or progress to true endocrine resistance. The biological basis for these processes are poorly understood. Following successful therapy with tamoxifen there is little evidence at relapse for change in either the host endocrine environment or drug metabolic profile to account for the development of acquired resistance. Many tamoxifen resistant tumours still retain a structurally and functionally normal oestrogen receptor (ER) and yet will grow independent of oestrogen. The oestrogen-regulated molecular events which normally govern the growth of hormone-sensitive breast cancer involve a complex autocrine and paracrine interaction between several peptide growth factors (including TGF alpha, IGF-1 and TGF beta), their receptors and signal transduction pathways. Evidence now exists that constitutive activity of many of these mediators of the mitogenic signal can bypass the cell's dependence on oestrogen and provide a mechanism for hormone-independent growth. Research into these molecular mechanisms may result in a better understanding of how to overcome the clinical problem of tamoxifen resistance.


Retinoids in cancer prevention and therapy.

Retinoids are a class of compounds structurally related to vitamin A. In preclinical studies, all-trans retinoic acid (tretinoin), 13-cis retinoic acid (isotretinoin) and the aromatic retinoids etretinate and acitretin have preventive and therapeutic effects on carcinogen-induced premalignant and malignant lesions. Clinically, chemoprevention with isotretinoin and etretinate has been tested with some degree of success in such indications as basal cell carcinomas, squamous cell carcinomas, superficial bladder tumors and second primary tumors in patients with squamous cell carcinoma of the head and neck. Limited therapeutic success has also been achieved with retinoid treatment of precancerous and cancerous conditions of the skin, oral cavity, larynx, lung, bladder and vulva. Dramatic therapeutic effects have been observed in the treatment of acute promyelocytic leukemia with tretinoin, which leads to very high rate of complete remission. Excellent results were recently reported in the treatment of squamous cell carcinomas of the skin and cervix with a combination of isotretinoin and recombinant interferon alfa-2a (rIFN alfa-2a, Roferon-A). The mechanism of action of retinoids is through modulation of cell proliferation and differentiation. Retinoids vary in their capacity to induce differentiation and to inhibit proliferation in a series of human transformed hematopoietic and epithelial cell lines. Some cytokines potentiate the retinoid-induced cell differentiation and act synergistically with retinoids to inhibit cell proliferation. The pattern of synergism is dependent upon the combination and tumor cell line tested. The discovery of nuclear retinoid receptors has contributed substantially to the understanding of the mechanism of action of retinoids at the molecular level. Further understanding of the molecular biology of retinoids is expected to contribute to a rational design of new retinoids in the future, which in turn may result in improvements in the prevention and therapy of cancer.


Randomized trial of chemotherapy versus chemotherapy plus radiotherapy for stage III-IV A & B Hodgkin's disease.

A total of 151 patients with previously untreated Hodgkin's disease, clinical stages III-IV A & B, were randomized to receive CVPP for 6 cycles, or CVPP plus RT 3000 cGy to previously involved areas between the 3rd and 4th cycles. CVPP consists of cyclophosphamide 600 mg/m2/i.v., vinblastine 6 mg/m2/i.v. on day 1, procarbazine 100 mg/m2/p.o. and prednisone 40 mg/m2/p.o. on days 1 to 14. Both groups displayed similar clinical characteristics at diagnosis. Sixty-six were treated with CVPP + RT (52 St III and 14 St IV) and 85 with CVPP alone (68 St III and 17 St IV). Complete remission was obtained in 57 (86%) of 66 patients who received CVPP plus RT, and in 62 (73%) of 85 patients treated with CVPP. Five and sixteen patients, respectively, achieved partial responses, while 2 in each group died during treatment. At 7 years, duration of complete remission and failure-free survival were: 51% and 45% for those treated with CVPP plus RT, and 23% and 21% with CVPP alone (p = 0.0150 and P = 0.0016, respectively). Overall survival at 7 years was 71% and 58%, respectively (p = 0.1488). A dose analysis performed in 84 pts showed that 91% and 88% received full protocol doses of CPM and PCZ, respectively, in the CVPP + RT group, and 95% and 94% for CVPP. The WBC nadir was 3.5 and 3.7 x mm3, respectively. Of 25 pts on CVPP + RT who relapsed, 9 are now disease-free, 5 are alive with disease and 11 have died, and with CVPP, of 37 relapsing pts, 18 are disease-free, 5 are alive with disease and 14 are dead.(ABSTRACT TRUNCATED AT 250 WORDS)


Sequential methotrexate and 5-fluorouracil (FU) vs. FU alone in metastatic colorectal cancer. Results of a randomized multicenter trial. The Association of Medical Oncology (AIO) of the German Cancer Society.

Methotrexate (MTX) modulates 5-fluorouracil (FU) in several in vitro and in vivo experimental systems. Results of phase II studies have suggested improved response rates for the sequential application of MTX and FU in colorectal cancer. In a prospective randomized multicenter study we compared sequential MTX (300 mg/m2) and FU (900 mg/m2) using a seven-hour time interval and leucovorin rescue with FU (450 mg/m2/d for five days) in patients with previously untreated metastatic colorectal cancer. Of 172 patients randomized 159 were eligible for survival analysis and 153 for toxicity and response evaluation. Complete or partial response has been seen in 25.3% of patients receiving sequential MTX and FU and in 17.6% of those receiving FU alone (p = 0.11). There have been two long-term survivors, apparently cured by MTX/FU. Overall toxicity was more pronounced with FU alone, but sequential MTX/FU caused four toxic deaths. Median survival and survival rates at one and two years were not significantly different. It is concluded that this schedule of sequential MTX and FU is no more effective than a dose-intensive treatment with FU alone in metastatic colorectal cancer.


Carboplatin (CBDCA), 5-fluorouracil (5-FU) and mitoxantrone (DHAD): an effective and well tolerated regimen for metastatic breast cancer.

Fifty-five women with metastatic breast cancer were treated with carboplatin (CBDCA), 55 mg/m2 i.v. bolus, daily for 3 days, 5-fluorouracil (5-FU) 900 mg/m2, (max. dose 1,500 mg/day in 24-h infusion (Travenol system) daily for 3 days, and mitoxantrone (DHAD) 8 mg/m2, i.v. bolus on day 1. Cycles were administered every 5 weeks. Objective responses were observed in 25 (44%) patients (95% confidence interval: 28%-60%) with a median duration of remission of 11.5+ months (range 6.5(+)-31+). Toxicity was mild. These results reflect the fact that combination of CBDCA, 5-FU and DHAD is effective and very well tolerated as an outpatient regimen.


Phase II study of edatrexate in chemotherapy-naive patients with metastatic breast cancer.

A phase II trial of the new antifolate edatrexate (10-ethyl-10-deaza-aminopterin) was performed in thirty-eight patients with metastatic breast cancer who had never received chemotherapy. Edatrexate was administered as a weekly intravenous bolus injection at a dose of 80 mg/m2. Sites of metastases included visceral (31%), soft tissue/lymph node/bone (51%), and bone only (18%). Thirty-two patients were evaluable for response; there were 3 complete responses (CR) and 8 partial responses (PR), yielding a response rate (CR plus PR) of 34% (95% confidence limits, 17.9% to 50.9%). Responses were seen in soft tissue metastases, in visceral metastases (liver, lung) and in one patient with bone metastases. Median duration of response was 30 weeks (range 12-66 weeks). Substantial toxicity was observed. The dose-limiting toxicities were mucositis, myelo-suppression and skin toxicity. The general toxicity profile was similar to that usually reported for methotrexate, but mucositis and skin toxicity were more pronounced. Edatrexate appears to be an active drug in the treatment of chemotherapy-native patients with metastatic breast cancer.