Vagally mediated modification of inspiratory activity by changes in airway pressure.

The impact of varying the end-expiratory transpulmonary pressure (PE'tp) on phrenic (Phr) and parasternal intercostal (IC) activity early in inspiration was studied in 12 spontaneously breathing, anaesthetized cats. PE'tp was varied in a stepwise fashion by rapidly changing the tracheal pressure (Ptr) from ambient pressure to a pressure in the range between -1.2 and +1.2 kPa relative to ambient pressure, and vice versa. The amplitudes of integrated Phr and IC activity were determined in each breath at three particular points in time (t), corresponding to 0.1, 0.2 and 0.3 sec after the onset of Phr activity, respectively. For all three values of t, Phr and IC activity increased with a decrease in Ptr and decreased with an increase in Ptr. The relationships between Phr activity and PE'tp and between IC activity and PE'tp could be described satisfactorily by mono-exponential functions. An increase in PE'tp of 0.1 kPa resulted in a decrease in Phr activity of 16%, 13% and 12% for the 3 aforementioned values of t, respectively. For IC activity the corresponding values were 42%, 42% and 36%, respectively. After bilateral vagotomy no changes in Phr activity in response to changes in Ptr were observed any more, whereas the changes in IC activity had decreased to about one tenth of the corresponding values obtained before vagotomy. Apparently, extra-vagal mechanisms contribute for a small part to the effect of changes in PE'tp on IC activity. Our results indicate that relatively small changes in PE'tp may have a large impact on central inspiratory output.


Dual responses of carotid chemosensory afferents to dopamine in the newborn kitten.

The effects of dopamine and of dopamine D2 receptor blocker haloperidol on the activity of carotid chemoreceptors were studied in 24 anesthetized, paralyzed and artificially ventilated newborn kittens aged 0-17 days. Single or few fiber preparations of chemoreceptors were made from one carotid sinus nerve. The responses of the chemosensory afferents to intravenous injections of dopamine (5-50 micrograms.kg-1) were studied in kittens breathing air and 8% O2 in N2. The effects of haloperidol on the chemosensory activity in air or 100% O2 and on the chemosensory response to hypoxia were studied. Dopamine inhibited the chemosensory discharge in 25/44 studies in normoxia. Of the 9 studies performed in hypoxia, dopamine was excitatory in 5 or had no effect in 4 (P < 0.05 vs normoxia). Inhibition of the chemosensory discharge was observed in 24/37 studies performed in kittens aged more than 3 days and was predominantly excitatory in 6/7 studies in kittens aged 0-3 days (P < 0.01). One minute after haloperidol, the chemosensory discharge had increased significantly in all experiments. The biphasic pattern of chemosensory response to hypoxia (Marchal et al., Respir. Physiol. 87: 183-193, 1992) was not changed by haloperidol. The steady-state chemosensory activity was significantly increased after haloperidol, respectively from 3.9 +/- 0.7 impulses.sec-1 to 9.8 +/- 1.2 impulses.sec-1 in air, and from 13.1 +/- 1.4 impulses.sec-1 to 17.8 +/- 2.4 impulses.sec-1 in hypoxia (mean +/- SEM, P < 0.03). It is concluded that the dopaminergic mechanisms are active in the carotid body of the kitten, and the observed responses to dopamine and haloperidol are qualitatively similar to those reported in the adult cat.


Response of roosters to resistive loads at constant chemical drive to breathe.

This study investigated the role of mechanoreceptors in the respiratory responses to resistive loading in roosters. Adult roosters were unidirectionally ventilated (maintaining a constant chemical drive to breathe). Electrical circuits assessed the respiratory muscle pressure (Pmus) and controlled the relationship between Pmus and the respiratory volume changes. Respiratory volume changes similar to those achieved by flow-resistive unloading or loading were produced by the circuits, imposing a 'virtual' resistance (Rv). When Rv was doubled (decreased rate of volume change, n = 6), tidal volume (VT, measured by whole body plethysmography) decreased significantly (28%), while thoracic volume (VRIP, measured by respiratory inductance plethysmography) did not change. When RV was quadrupled (n = 4) VT and VRIP decreased significantly (53% and 24%, respectively). Changing RV to one half the normal value (n = 5) did not affect these parameters. Inspiratory time and Pmus were not significantly altered at any RV. It is concluded that, at constant chemical drive, mechanoreceptors play a minimal role in maintaining tidal volume during impeded breathing in roosters. Comparative differences which may explain these results are discussed.


Effects of exercise modality on patterns of ventilation and respiratory timing.

Ventilatory patterns and respiratory timing were measured in 14 subjects during cycling (CYC) and treadmill exercise (TM) at similar leg frequencies (fLEG) to determine if mode of exercise affects patterns of ventilation and respiratory timing. Measurements of breathing frequency (fR), tidal volume (VT), expired ventilation (VE), and inspiratory (TI) and expiratory (TE) time were obtained at fLEG of 50, 70, and 90 rev.min-1 (rpm) for CYC and at similar incremental fLEG (strides.min-1; spm) during TM achieved by increasing belt speed at 0% grade. CYC exercise intensity was approximately 50% VO2,max at all fLEG, whereas VO2 increased progressively with TM. fR increased significantly (P < 0.001) with increasing fLEG of TM (20.5 +/- 4.6, 25.4 +/- 5.8, and 36.3 +/- 7.6 breaths.min-1; mean +/- SD), but during CYC fR changed significantly (P < 0.05) only between fLEG of 70 and 90 rpm (25.0 +/- 5.9 vs 28.5 +/- 6.9 breaths.min-1). Both average breath TI and TE obtained by grouping into incremental ranges of fR decreased significantly (P < 0.05) with increasing fR up to 36 breaths.min-1 and the relationships of TI and TE to fR, TI to TE, and central inspiratory drive (VT/TI) to VE were the same for CYC and TM. Group average fR and fLEG were synchronized during TM, but individual subjects did not exhibit a high degree of entrainment. This study shows respiratory timing patterns to be independent of mode of exercise over the range of fR observed when describing patterns by grouping into incremental ranges of fR.


Fatigue-induced changes in diaphragmatic afferents and cortical activity in the cat.

The rationale for the present study was to test the hypothesis that changes in phrenic sensory activity during diaphragmatic fatigue may modify the transmission of phrenic afferent action potentials to the cortex and also the spontaneous EEG activity. This was performed in anesthetized cats. Diaphragmatic fatigue was produced by intermittent direct muscle stimulation for a 30 min period. Diaphragmatic metaboreceptors (tonically active afferents) and mechanoreceptors (phasic phrenic activity) were identified by their activation by intraarterial lactic acid injection or their discharge in phase with diaphragmatic contraction, respectively. Cortical phrenic evoked potentials (CPEPs) and spontaneous EEG activity were recorded from the left sensorimotor area. Diaphragmatic failure was shown from the 10th minute of stimulation. Then, the activity of tonic phrenic afferents increased markedly whereas, in parallel, the phasic discharge of mechanoreceptors decreased progressively. This was associated with progressive lengthening in onset and peak latencies of CPEPs. The main EEG changes (visual and fast Fourier transform analysis) were characterized by a transient increased energy in the delta frequency band during the first minutes of the fatigue run, followed by decreased energy in the theta frequency band after 11-25 min of stimulation. Denervation of the diaphragm suppressed the EEG changes during the fatigue run. The present observations suggest that the cortical integration of sensory information from the diaphragm may be altered during fatigue.


Tissue PO2 and growth rate in early chick embryos.

We determined dry mass, frequency distribution of tissue PO2 and microvascular density of head and trunk of early chick embryos between day 4 and day 6 of incubation. During this period the percentage of the dry mass of the head on total dry mass increased from 31% to 48% indicating that the head grows faster than the trunk. Tissue PO2 values ranged between zero and arterial PO2. About half of the numbers were less than 5 Torr. Mean tissue PO2 was significantly higher in the head than in the trunk. This was paralleled by a significantly higher microvascular density in the head. The high frequency of low tissue PO2 values found at each day at all measuring sites suggests that the embryonic tissue of both head and trunk extracts as much oxygen from the capillary blood as possible. Consequently, growth rate strongly depends on oxygen availability. Since the arterial PO2 is the same in the head and in the trunk (Meuer and Baumann, 1988), the diversity of tissue PO2 and growth rate found in this study is probably caused by differences in the structure of the microvascular bed resulting in variations of tissue blood perfusion, capillary transit time and diffusion distance.


Responsiveness to histamine in human sensitized airway smooth muscle.

Passive sensitization of human isolated airway smooth muscle increases contractile responses to histamine. We looked to see whether this increase was due to an alteration in the relative role of histamine H1 and H2 receptors. Human bronchial spiral strips obtained at thoracotomy were passively sensitized by incubation in serum from atopic asthmatic patients to Dermatophagoïdes pteronyssinus and control strips were incubated in serum from healthy non-allergic non-atopic subjects. We also studied spiral strips dissected from two spontaneously sensitized human lung specimens. Cumulative concentration-response curves (CCRC) to Ca2+ (10(-5) -3 x 10(-2) M) were constructed either in the presence of 10(-5) M histamine alone or in that of the combination histamine and the H2 antagonist cimetidine (10(-5) M). Unlike in the absence of histamine, Ca2+ CCRC in the presence of histamine alone were significantly shifted to the left in the passively sensitized tissues (mean EC50: 5.7 x 10(-4) M) compared to control ones (mean EC50: 9.3 x 10(-4) M, n = 6, P < 0.05). Addition of cimetidine to histamine did not alter the Ca2+ CCRC either in the control or in passively or spontaneously sensitized airway smooth muscle. These results suggest that (i) passive sensitization increases contractile response to Ca2+ of human bronchial smooth muscle in the presence of histamine; (ii) this increase is not due to a difference in the H1- vs H2-mediated response; and (iii) H2-mediated effects do not play a significant role in spontaneously sensitized human lung as both in the non-sensitized and passively sensitized lung.


[Cerebrotendinous xanthomatosis. 2 cases with magnetic resonance imaging].

A 40-year-old woman presented with bilateral juvenile cataract, tendinous xanthomas, intellectual deterioration, spastic tetraparesis, proprioceptive deficit and parkinsonian syndrome. A younger sister's clinical picture differed by the absence of xanthomas and the presence of a cerebellar syndrome. The diagnosis of cerebrotendinous xanthomatosis was confirmed by a high concentration of plasma cholestanol and by urinary chromatography. Magnetic resonance imaging displayed some abnormalities in the hemispheric and cerebellar white matter. Under chenodesoxycholic therapy the biological abnormalities decreased while the clinical disturbances were unchanged.


[Neurological, dermatological and biological manifestations of porphyria variegata. A study of 3 families of Italian origin in Marseilles area].

Three kindreds of Italian descent with variegate porphyria are described. These families are now living in Marseilles and surrounding regions. The first kindred originating from Torre del Greco, near Naples, is living in Arles. This family includes two propositi who experienced an acute attack with visceral and neuropsychiatric manifestations. The family's survey was carried out by measuring protoporphyrogen oxidase (PO) activity in lymphocytes (normal values = 4.8 +/- 1.2). Seven of the 20 subjects tested, beside the two propositi, were found to be asymptomatic carriers (PO < 3.6). The first index patient, a 41-year old man, was first observed at the age of 31 with acute and psychiatric manifestations after rifampicin treatment; the cutaneous symptoms appeared one year later. For the second propositus, a woman presenting with abdominal and psychiatric manifestations, the age of onset was 38 years; the acute attack had no recognizable cause; she had mild skin lesions and initially was incorrectly diagnosed as intermittent acute porphyria; the diagnosis of variegate porphyria was only established at the age of 50 years. The second family, originating from la Spezia and Vernazza, is living in Marseilles. The propositus, a 50-year old man, developed cutaneous symptoms at the age of 30. A diagnosis of porphyria cutanea tarda was initially made. The first and unique acute attack with abdominal and neurological manifestations recurred at the age of 41. The diagnosis of variegate porphyria was established on laboratory data. Physical stress was probably the cause of the acute attack. Beside the propositus, out of 9 subjects tested 6 were asymptomatic carriers.(ABSTRACT TRUNCATED AT 250 WORDS)


[Rademaker and Garcin syndrome associated with pallidal calcifications].

We report gait abnormalities with exaggerated support against gravity in a 76 year-old woman. This exaggeration, and its demonstration by ankle dorsiflexion in supine position, was first described by Rademaker and Garcin (1933) as probably resulting from cerebellar and brainstem lesions. In the present case, quantitative analysis of locomotion showed a strong reduction in both stride duration and stride length. There was an increased variability between two consecutive locomotor cycles and a large increase in both stance duration and relative double-support duration. Electromyography clearly showed leg hypertension following ankle dorsiflexion, contrasting with normal leg mobility in the supine patient. This suggested that reflexive antigravity support abnormalities could explain this pattern of locomotor disabilities, differentiating them from other kinds of "marche à petits pas". The present case was associated with bilateral pallidal calcifications, suggesting an involvement of the basal ganglia in support reaction against gravity and in control of adequate postural muscle tone necessary for locomotion.


[Cerebrovascular disorders in young adults in Saudi Arabia. A study of 136 cases].

We report our experience of stroke in 136 young adults aged from 18 to 45 years seen in the Eastern Province of Saudi Arabia over a 10-year period. They constituted 25% of all our stroke cases. Thirty-eight percent were Saudi nationals and 62% expatriates. Males largely outnumbered females. The frequency of cerebral infarction (54%) was not very different from that of intracranial hemorrhage (45%). Atherosclerosis and embolism of cardiac origin were the major causes of infarction. The main causes of intracranial bleeding were arterial aneurysms, arteriovenous malformations and hypertension. However, the causes of 29% of ischemic strokes and 44% of hemorrhagic ones remained undetermined. Interethnic comparison of the causes showed that hemorrhages were significantly more frequent in Far East immigrants. Sixty five percent of cerebral infarctions in Asiatic patients remained of undetermined origin. The local variant of sickle cell gene did not seem to play a major role in the pathogenesis of stroke in the Saudi young adult. These data are commented and compared with similar reported data. The influence of the demographic structures of the Saudi population and immigrants communities is analyzed.


[Carotid artery obstruction caused by vagal paraganglioma].

A 72 year-old-man presented with right hemiparesis and global aphasia related to a large infarct in the left middle cerebral artery territory. A left carotid angiography revealed internal carotid artery occlusion and vascular blush just below the base of the skull. The blush was supplied by branches from the external carotid artery. Cervical CT-scan showed a large tumor centered by the left internal carotid artery. At cervical surgery, the internal carotid artery was compressed and infiltrated by the tumoral process: a benign paraganglioma. The site below the base of the skull and the connection between tumor and vagal nerve suggested a vagal paraganglioma. To our knowledge, this is the first case of cerebral infarction and internal carotid artery occlusion revealing a vagal paraganglioma.


[Facio-linguo-masticatory diplegia and epilepsy. Cortical dysplasia].

Neuronal migration anomalies are caused by insults occurring during the third to fifth gestational months when neuroblasts migrate from the germinal zone to the cortical plate. They lead to several cerebral malformations such as macrogyria, identified nowadays by MRI. We describe a case of bilateral parieto-rolandic macrogyria responsible for a bi-opercular syndrome resulting in a facio-linguo-masticatory diplegia associated with mental retardation and severe epilepsy.


[Left prerolandic infarction with initial epilepsy. Development of chronic hallucination psychosis].

A 34-year-old woman had three tonico-clonic seizures and aphasia revealing a left prerolandic infarct. Three weeks later, she began to develop psychiatric symptoms leading to the diagnosis of chronic hallucination psychosis. These symptoms were probably related to epilepsy and their cause was compatible with the diagnosis of interictal psychosis. It has been suggested that kindling of the mesolimbic system could account for psychosis in epilepsy. In our case, however, the sort time interval between the onset of epilepsy and the appearance of psychosis is not in favour of this mechanism.


[Systematized cavernous angiomatosis with multiple cerebral and cutaneous localizations].

A 45 year-old woman with no history of familial disease presented with multiple cutaneous and cerebral cavernous angiomas. The diagnosis rested on biopsy for cutaneous angiomas and on MRI for cerebral angiomas. The clinical manifestations of cerebral angiomas were headaches and a cerebellar syndrome, the latter most probably due to progressive growth of cerebellar angiomas. Systematized cavernous angiomatosis is characterized by multiple angiomas of the brain and other viscera and is considered to be a phacomatosis.


[Unilateral scapulohumeral amyotrophy. Contribution of imaging].

A case of right scapulohumeral muscular atrophy stable after a 6 month progressive course is reported. Cervical metrizamide CT and MRI showed a flattened right cervical spinal cord regarded as a segmental atrophy. The case could belong to the Kaeser type of sporadic chronic spinal amyotrophy, or perhaps corresponds to a benign focal amyotrophy.


[Acute renal failure complicating carbamazepine hypersensitivity].

A case of acute renal failure occurring during treatment with carbamazepine is reported. The clinical signs and biological abnormalities strongly supported the diagnosis of acute interstitial nephritis of immunoallergic origin. The outcome was favourable after drug withdrawal. We review the cases of carbamazepine-induced acute renal failure.


[Prognosis of transient ischemic accidents disclosing infarction].

In a prospective study, thirty six out of 175 consecutive patients (21%) with transient ischemic attack (TIA), had cerebral infarction on CT-scan. This group of patients differed from the group without cerebral infarction by a higher age, a longer duration of neurological deficit, a greater frequency of neurological history, vertebro-basilar TIAs, cephalagia and, cardiac arrhythmia, and by a higher 2-year mortality rate. Due to their difference in etiological factors and prognosis, TIAs with cerebral infarction on CT-scan should be differentiated from those without cerebral infarction.


[Investigation of phosphorus calcium metabolism after oral phosphorus supplementation].

Effects of oral administration of phosphorus on phosphorus and calcium parameters and on bone metabolism hormones were investigated in two studies: in the first, 12 young female adults and 8 females over 50 years of age took a single oral load dose of 780 mg elemental phosphorus, whereas in the second study assays were performed 5 and 15 days after initiation of twice-daily phosphorus supplements in 19 young adults, 14 subjects above 50 years of age who were free of osteoporosis, and 12 patients with osteoporosis also over 50 years of age. The phosphorus load was associated with an increase in intact parathyroid hormone levels (iPTH 1-84), which was more marked in subjects above 50 years of age than in younger adults. On the 15th day of phosphorus supplementation, there was no significant increase in baseline iPTH and no change in baseline dihydroxyvitamin D or osteocalcin levels; during the Nordin tests, the fractional calcium excretion index (CaU/CrU) and the fractional hydroxyproline excretion index (OH Pro/CrU) remained unchanged. In contrast, the phosphorus load was followed by a decrease in the maximum phosphorus reabsorption threshold (TMP/DFG), which was more marked on the 5th day than on the 15th day; a slight fall in serum phosphorus levels was also seen on the 15th day. These findings suggest that phosphorus supplementation should be intermittent rather than continuous. Analysis of subjects aged 50 to 69 years failed to disclose any significant differences between patients with and without osteoporosis.


Correlation between knee roentgenogram changes and clinical symptoms in osteoarthritis.

The main purpose of this study was to analyze the relationship between clinical symptoms and roentgenographic changes in patients with incipient osteoarthritis of the knees (OA). One hundred and sixty-two patients (126 women, 36 men, mean age 59 years) with established osteoarthritis of the knee were examined. Patients performed subjective self-assessment using Lequesne's questionnaire (index of severity for OA of the knee) and had frontal and lateral roentgenograms of both knees. Validity of the indices as reflections of individual symptoms was documented. A statistically significant correlation was found between clinical and patient indices (r = 0.327, p < 0.0001) as well as a very weak correlation between the clinical and roentgenogram indices (r = 0.196, p = 0.286). However, there was no correlation between the patient index and roentgenogram index (r = 0.065, p = 0.47). For the assessment of severity and progression of the disease, items reflecting acute irritation (swelling, effusion, increased joint temperature, pain during passive motion) were more reliable than items reflecting chronicity (muscular atrophy, decreased range of motion, crepitus). This study confirmed that Lequesne's questionnaire is a suitable tool for assessing subjective symptoms as well as for generating a condensed measure of disease severity. In addition, sclerosis, narrowing and osteophytes were proved to be important features characterizing the OA process.


[Severe hypocalcemia complicating outbreaks of renal failure in 2 uremic patients].

Hypocalcemia has many causes of which several often occur in combination in intensive care unit patients. Two cases (a 78-year-old male and a 63-year-old female) of severe hypocalcemia (corrected serum calcium 1.2 mmol/l in both cases) in patients hospitalized for acute decompensation of chronic renal failure are reported herein. Both subjects had a history of chronic hypocalcemia due to vitamin-calcium deficiencies and chronic renal failure. The lack of adverse clinical consequences of the low serum calcium levels can be explained by the fact that both patients also had severe metabolic acidosis, a disorder which increased the ionized fraction of total serum calcium. Serum calcium returned to normal slowly and gradually despite parenteral administration of large amounts of calcium and vitamin D or vitamin D derivatives.


[Sciatic radiculalgia with muscular hypertrophy].

A 52-year-old male developed hypertrophy of the right calf after several bouts of right lumbar pain with sciatica. Electromyography disclosed evidence of demyelination in the territories of the right S1 and S2 roots. Microscopic studies showed both atrophic muscle fibers scattered among fibers of normal caliber and a large number of hypertrophic fibers. Post-sciatica hypertrophy of the calf is a true muscle hypertrophy with muscle weakness. Electromyography may show unusual tracings with repeated complex bursts or continuous activity of motor units. Muscle enzyme levels may be elevated. The size of hypertrophied fibers varies across cases. The cause of the muscle fiber hypertrophy may be either stretching due to the action of antagonists or unusual electrical activity.


[Rheumatoid aortic insufficiencies: severity of the prognosis].

Rheumatoid aortic incompetence is infrequent, with only 43 cases published in the literature. Seven additional patients (5 females and 2 males) with rheumatoid arthritis (RA) and aortic incompetence are reported herein. All seven patients had seropositive RA with severe joint disease and extraarticular manifestations (nodules, cutaneous vasculitis, multiple neuritis). Development of aortic incompetence was unrelated to age or duration of RA. The aortic disease was diagnosed upon the development of sudden heart failure (pulmonary edema) in three patients and during a routine evaluation in the other four. The course was extremely severe with a fatal outcome in five patients, of whom the youngest was only 24. Only one patient had valve replacement surgery; however, this patient died 8 days after the procedure. Mean survival in the seven patients was 20 months (range 7-56) from diagnosis and 11 months (range 1-28) from the first manifestation of heart failure. Histologic studies done in the only patient who had surgery demonstrated a rheumatoid granuloma in the pericardium and lymphocytic infiltrates in the pericardium and aortic valve.


[Chronic sarcoidosis-polyarthritis with infantile onset. Persistent synovial granulomas under corticotherapy].

The case of a patient who developed sarcoidosis with chronic joint symptoms at the age of four and still has active disease twenty years later despite three years of corticosteroid therapy is reported. During the course of the disease, specific histologic features of sarcoidosis were evidenced twice in synovial specimens, twice in skin biopsy specimens, and once in bronchial tissue. Deformations and joint lesions developed in the hands and feet. The combination of arthritis, skin lesions, and uveitis occurs both in juvenile-onset sarcoidosis and in chronic juvenile joint diseases, raising significant diagnostic problems which can be solved by histologic studies of synovial or skin biopsy specimens.


[Bone condensation and enterocolitis: SAPHO syndrome. Apropos of a case].

A new case of SAPHO syndrome with lesions confined to the spine and concomitant enterocolitis reported. Only eight cases of this rare combination have been published to date. Bone involvement consisted in sclerosis of vertebral bodies of T10 and T11, raggedness of the vertebral plateaux from T7 to T10, and thick syndesmophytes bridging the vertebrae from T7 to T11. Erythrocyte sedimentation rate was 108 in one hour. Systemic corticosteroids were given after failure of nonsteroidal antiinflammatory agents and recurrence of iritis. Pain resolved promptly and the erythrocyte sedimentation rate returned to normal. This case is unusual both because this combination of diseases is rare and because virtually complete resolution of vertebral sclerosis was noted after one year of corticosteroid therapy. Possible relationships between the SAPHO syndrome and the group of spondylarthropathies are suggested and discussed.


[Effects of methotrexate on leukotriene and derivated lipoxygenase synthesis in polynuclear neutrophils in rheumatoid polyarthritis].

Methotrexate (MTX) has been proved to be effective in rheumatoid arthritis (RA). The mechanism of action of MTX in this disease remains unelucidated but may involve inhibition of the enzyme 5-lipoxygenase. Arachidonic acid metabolites were studied in eight patients with active RA immediately prior to and 24 hours after the first intramuscular injection of 10 mg MTX. None of the patients were taking corticosteroids. Nonsteroidal antiinflammatory drugs were withdrawn four days before the study. Reverse phase high-performance liquid chromatography was used to quantitate metabolites produced by 5-lipoxygenase (5-LO) and 12-LO in plasma (full spectrum of blood cells) and purified neutrophils (PN) after stimulation with calcium ionophore A 21387 (50 microM for 30 minutes and 5 microM for 5 minutes, respectively). LTB4 production by PNs was significantly decreased (-32%, p < 0.01) 24 hours after MTX administration. A moderate (-17%), nonsignificant (NS) fall in LTB4 omega-oxidation products (wP) was seen. Production of 5-HETE was also slightly decreased (-15%, NS). Findings in plasma were comparable, with a significant decrease in total LTB4 (-29.8%, p < 0.01) and moderate falls in wP (-18.8%, NS) and in 5-HETE production (-17%, NS). Production of 12-HETE was unchanged. These findings suggest that MTX in a single dose is responsible for a decrease in the synthesis of LTB4 and 5-LO products in neutrophils and other blood cells in RA patients but does not affect 12-LO activity.


[The value of epidemiologic studies of ski injuries].

The Garmisch-Partenkirchen experience--15,513 skiing injuries between 1972 and 1990--was compared to the results of an inquiry into the skiing injuries among 565 persons of the medical profession, that were active skiers over an average of 18 years. The parameter injuries per 1000 skiing days was calculated from the outpatient clinic data as well as from all skiing injuries that had happened in the interview group and those that required surgical treatment. The mean value of 2.7 injuries/1000 skiing days--corrected for the number of patients--from the literature and the clinical data with 2.1 is comparable to the 1.8 injuries/1000 skiing days (injuries that required surgical treatment) but stands sharply against the 4.2 arising from the total number of injuries in the inquiry group.--Thus, every epidemiological study clearly underestimates the actual rate of skiing injuries. This fact may be defined as the "bypass-effect". The comparison between clinical setting and inquiry allowed for a quantification: Depending on the type of injury and the study design, a true prevalence of skiing injuries that is between 10% and 200% higher than the published data has to be expected.--Descriptive, not controlled epidemiologic studies on skiing injuries are justified and give valid trends on which therapeutic and prophylactic measures can be based--but exclusively under the following prerequisite conditions: 1. a standardized study protocol; 2. an observation.


[The spine--a problem area in high performance artistic gymnastics. A retrospective analysis of 24 former artistic gymnasts of the German A team].

24 former female artistic gymnasts of the German national team were examined for spinal deformities after the end of their athletic career. In 3 cases we found osseous lesions of the spine without neurological complications. However, emphasis was on spinal changes due to stress. During their athletic career 15 gymnasts complained of low back pain which persisted in 7 of them after finishing their athletic activities. The lumbar radiographs revealed bilateral spondylolysis at L5 in 6, unilateral spondylolysis in 1, spondylolisthesis at L5/S1 in 3, degenerative changes of the intervertebral joints in 5, retrolisthesis at L5/S1 in 2, and scoliosis in 6 cases.


[Structure of the palmar plate of the proximal interphalangeal joint with reference to the typical injury pattern in hyperextension trauma of the finger. A morphometric, densitometry and histologic study].

The palmar plates of the PIP of the fingers are examined in 43 hands. Apart from macroscopic morphometric studies special attention is paid to the density of bone in the areas of insertion, measured with the help of a computerized image analysing system. Especially the distal area of insertion in the basis of the medial phalanx shows a low density of bone. The consequent low adaptation to stress explains clinical findings, describing most frequent osseous ruptures of the palmar plates in case of hyperextension injuries to the fingers. The fibrous structure of the palmar plate is studied in histological sections. A palmar layer of transversally running collagenous fibres, as well as a medial layer of diagonally and a dorsal layer of longitudinally running fibres can be differentiated. The distal area of the palmar plate mostly consists of transversal, the proximal area of longitudinal collagenous fibres. Therefore a hyperextension stress, hitting the fibres in a right angle distally, cannot be neutralized sufficiently. This result is closely linked to clinical observations describing mostly distal ruptures of the palmar plate in spite of its proximal region being of weaker structure.


[Diagnosis and treatment of ligament injury of the thumb base joint. Results within the scope of follow-up].

Distortions and ruptures of the ulnar collateral ligament of the metacarpophalangeal joint of the thumb represent 6% of hand injuries in alpine skiing and 8% in ski-skating. 155 patients who had been treated for ligamentous rupture (88), for osseous rupture with dislocation of the fragment (42) and for osseous rupture without any dislocation (25) wer reviewed: in 106 patients with conservative treatment 64 had stable joints and 42 showed a ligamentous instability. After surgical treatment in 49 patients 44 had ligamentous stability; 5 joints (10%) showed a radial instability. Summarizing the results we found instability after conservative treatment in 40%, but only in 10% of surgically treated patients. Recommendations for the treatment of this frequent hand injury are given.


[Importance of the subchondral space for development of chondromalacia patellae--morphologic study of joint cartilage of the rabbit patella after experimental ischemia].

The aetiology of chondromalacia patellae and especially the importance of the subchondral space have not been clarified to date. However, clinical findings yielded pointers to a connection between degenerative changes of the articular cartilage and an influence exercised by the subchondral space. In our experiments we performed an operative ischaemia of the patella with interruption of the vascular inflow and outflow on 40 adult rabbits for exactly defined times (2 weeks, 6 weeks, 3 months, 6 months). The examinations were carried out using the plastination method, histology, transmission electron microscopy, and scanning electron microscopy. Marked changes can be seen from the third month onwards: disappearance of the tidemark, degeneration of the cartilaginous cells (formation of clusters) and onset of trachomatous keratitis. These degenerative changes progress further in the animals of 6 months of age. The results indicate that metaplasia of the tidemark plays a significant part in the pathogenesis of degenerative changes of the cartilage. Hence, chondromalacia patellae can be caused by subchondral vascularisation disorders.--This is, therefore, a new concept for the aetiopathogenesis of chondromalacia patellae, a disease pattern that is of great importance in sports orthopaedics.


[Securing the syndesmosis suture by syndesmosis hook in extreme stress caused by long-distance running. A case report].

The elastic fixation of the distal tibiofibulary syndesmosis by means of Engelbrecht's hook allows weight bearing and free dorsal flexion. The example of an 40-year-old long distance runner (and surgeon) shows that this system can endure extreme stress: during the 9 months until the metal was removed, he took part in 14 contests with excellent results. He ran at least 100 km per week, together more than 3700 and classical marathons, 100 km runs and mountain marathons. When the metal was removed there was no sign of metallotic changes of the tissue at the interface between hook and plate.


Diagnosis of Pneumocystis carinii pneumonia in HIV antibody positive patients by simple outpatient assessments.

As increasing numbers of patients with immunosuppression induced by the human immunodeficiency virus (HIV) present with respiratory symptoms it is important to differentiate Pneumocystis carinii pneumonia from other chest diseases rapidly and start treatment early. The management of pneumocystis pneumonia could be improved if clinicians could diagnose this condition confidently on the basis of simple clinical assessments. Three hundred and eighteen patients with evidence of immunosuppression due to HIV infection and suspected pneumocystis pneumonia were investigated. A clinical history was taken and arterial blood gas analysis, chest radiography, oximetry during exercise, and sputum induction or bronchoscopy (or both) were performed. Pneumocystis pneumonia was confirmed microscopically from induced sputum or bronchoalveolar lavage fluid in 154 patients; 118 had other chest disease. The remaining 46 patients had no definitive diagnosis. The best single independent predictors of a diagnosis of pneumocystis pneumonia were exercise induced oxygen desaturation and obvious interstitial infiltrates on the chest radiograph (odds ratios of 4.88 and 5.44 respectively). The symptom triad of exertional dyspnoea, cough, and fevers; the absence of pneumocystis pneumonia prophylaxis; and resting arterial hypoxaemia were less predictive (odds ratio 2.07, 3.72, and 0.69). An algorithm was developed that gave a positive predictive value for confirmed pneumocystis pneumonia of 95% and also identified those patients with a very small chance of having pneumocystis pneumonia (negative predictive value 85%). The diagnosis of an initial episode of pneumocystis pneumonia can be confidently made in a large proportion of immunosuppressed patients with respiratory symptoms on the basis of clinical symptoms, the absence of prophylaxis, chest radiographic appearances, and oxygen desaturation during exercise as shown by oximetry. Using these simple features clinicians can rapidly assign patients to the appropriate type of management at presentation.


Bioelectric properties of cystic fibrosis airways obtained at heart-lung transplantation.

The basic defect in cystic fibrosis centres on abnormal ion transport in affected tissues such as the respiratory tract. Heart-lung transplantation provides a limited supply of native lower airways from these patients. The feasibility of in vitro studies of bioelectric properties and ion fluxes in lower airways, obtained at heart-lung transplantation from patients with cystic fibrosis, has been assessed. Comparison was made with airways from patients without cystic fibrosis. Tissue segments were mounted in Ussing chambers under open circuit conditions. The basal potential difference in tissues from nine patients with cystic fibrosis was -3.6 mV (SE 0.3 mV), not different from tissues from 12 patients without cystic fibrosis of -3.6 mV (0.5 mV). Amiloride (10 microM) caused a significantly greater fall in potential difference in bronchi from patients with cystic fibrosis (83.5% (SE 2.9%)) than in those from controls (55.1% (7.1%)). Isoprenaline (100 microM) produced no significant change in bioelectric properties in non-cystic fibrosis tissues, but induced a 26.2% (6.3%) increase in potential difference in cystic fibrosis airways. The latter response was reduced by amiloride pretreatment. Mucosal chloride substituted Krebs-Henseleit solution caused no change in bioelectric properties in cystic fibrosis airways. Sodium substituted Krebs solution produced a substantial fall in potential difference similar in magnitude to that seen after amiloride. Isotropic flux measurements showed no significant differences between non-cystic fibrosis and cystic fibrosis airways. No net movement of Na+ or Cl- was detected under open circuit conditions in either group. Cystic fibrosis bronchi obtained at heart-lung transplantation provide a viable source of tissue for in vitro studies of bioelectric properties. The increased response to amiloride characteristic of the upper airways in cystic fibrosis is retained in these tissues, as is the reduced chloride conductance. Although no differences in isotopic fluxes were seen between non-cystic fibrosis and cystic fibrosis tissues, heavily infected airways from patients with cystic fibrosis may not be suitable for ion flux measurements.


Notification of tuberculosis: how many cases are never reported?

Notification of tuberculosis is essential for local contact tracing and for assessing the national incidence of tuberculosis. The accuracy of notification figures is uncertain. This study examined the notification rates of all patients diagnosed as having tuberculosis at two hospitals in the East End of London over five years. In a retrospective survey of all patients aged 16 years or more presenting with tuberculosis to the London Chest Hospital or the Royal London Hospital from 1 January 1985 to 31 December 1989, cases of tuberculosis were identified from microbiology and histology records, statutory notifications, necropsy reports, coroners' records, hospital activity data, and death certificates. Clinical data were obtained from case notes and notification was determined from the local authority notification lists. Six hundred and nine adult patients with tuberculosis were identified. Notes were available for 580 cases (95%), of which 426 (73%) had been notified. The proportion of cases notified varied according to the specialty of the clinician in charge of the patient at diagnosis. Patients with a past history of tuberculosis and those who died within one year were less likely to have had their tuberculosis notified. Age, race, and lack of microbial or histological confirmation of diagnosis did not influence the proportion of cases notified. One hundred and eighty five patients had smear positive sputum, but 25 of these cases (14%) were not notified. Eighty five patients who had presented with pulmonary tuberculosis did not have their disease notified; 20 (24%) had smear positive sputum. Many cases of tuberculosis are not notified (27%). Fourteen per cent of all sputum smear positive cases of tuberculosis were not notified, and these patients are a considerable public health risk. The true incidence of tuberculosis in the area studied is at least one third higher than current notification figures suggest.


Development of a shuttle walking test of disability in patients with chronic airways obstruction.

The aim was to develop a standardised and externally paced field walking test, incorporating an incremental and progressive structure, to assess functional capacity in patients with chronic airways obstruction. The usefulness of two different shuttle walking test protocols was examined in two separate groups of patients. The initial 10 level protocol (group A, n = 10) and a subsequent, modified, 12 level protocol (group B, n = 10) differed in the number of increments and in the speeds of walking. Patients performed three shuttle walking tests one week apart. Then the performance of patients (group C, n = 15) in the six minute walking test was compared with that in the second (modified) shuttle walking test protocol. Heart rate was recorded during all the exercise tests with a short range telemetry device. The 12 level modified protocol provided a measure of functional capacity in patients with a wide range of disability and was reproducible after just one practice walk; the mean difference between trial 2 v 3 was -2.0 (95% CI -21.9 to 17.9) m. There was a significant relation between the distance walked in the six minute walking test and the shuttle walking test (rho = 0.68) but the six minute walking test appeared to overestimate the extent of disability in some patients. The shuttle test provoked a graded cardiovascular response not evident in the six minute test. Moreover, the maximal heart rates attained were significantly higher for the shuttle walking test than for the six minute test. The shuttle walking test constitutes a standardised incremental field walking test that provokes a symptom limited maximal performance. It provides an objective measurement of disability and allows direct comparison of patients' performance.


Effect of aminophylline on brain tissue oxygenation in patients with chronic obstructive lung disease.

It is known that theophylline reduces cerebral blood flow in humans. To quantitatively assess the possible adverse effect of theophylline on brain tissue oxygen tension (PO2) due to decreased cerebral blood flow, two sets of experiments were conducted in mildly hypoxaemic patients with chronic obstructive lung disease. Firstly, internal jugular venous PO2 (PjO2) was measured simultaneously with arterial and mixed venous blood PO2 (PaO2 and PvO2) during right heart catheterisation in 10 subjects (mean PaO2 73 mm Hg; conversion factor: 10 mm Hg = 1.33 kPa)) before and after intravenous infusion of aminophylline (6 mg/kg). The PjO2 and PvO2 were considered to reflect the average tissue PO2 for the brain and for the whole body respectively. Secondly, the relation between PaO2 and PjO2 over a wide range, with the PaCO2 similar to that in the first study, was investigated in a different group of 12 subjects by stepwise changes in inspiratory gas composition. The mean PjO2 decreased by as much as 6 mm Hg 15 minutes after an infusion of aminophylline, whereas PaO2 stayed at the same level and PvO2 showed only a small decrease. The low PjO2 value of 29 (SD 6) mm Hg with aminophylline in the first study was similar to the PjO2 value of 30 (2) mm Hg obtained during severe hypoxia (PaO2 45 mm Hg) in the second study. The coefficient of oxygen delivery for the brain decreased by 29% with aminophylline treatment, but did not change significantly during severe hypoxic challenge. These data suggest that an infusion of aminophylline lowers brain tissue PO2 appreciably when given to mildly hypoxaemic patients with chronic obstructive lung disease.


Lung function abnormalities in repaired oesophageal atresia and tracheo-oesophageal fistula.

Respiratory complications are common after neonatal repair of oesophageal atresia and tracheo-oesophageal fistula. The prevalence of lung function abnormalities and the relation between gastrointestinal complications and lung function has not been studied in a large number of patients. Lung volumes and flow-volume loops were measured in 155 patients without spinal curvature aged 6-37 years who had undergone surgery for oesophageal atresia and tracheo-oesophageal fistula. Sixty four of the 155 patients had evidence of mild lower airways disease, with values for FEV1 more than two standardised scores below the predicted value in 39 (25%) and above 2 standardised scores for the residual volume (RV)/total lung capacity (TLC) ratio in 64 (41%). Restrictive lung disease (TLC more than 2 standardised scores below predicted) was present in 28 (18%). Severe lung function abnormalities were present in under 10% of the 155. Half the subjects had some evidence of extra-thoracic tracheal obstruction, with a high ratio of expiratory to inspiratory flow for peak flow in 76 (50%) and at 50% of vital capacity in 59 (38%). Patients with radiological gastro-oesophageal reflux in early childhood had more airways obstruction and smaller lung volumes. Patients with current gastrointestinal symptoms were similar in their lung function to symptom free patients. Minor lung function abnormalities are common in patients after repair of oesophageal atresia. Early diagnosis and management of gastro-oesophageal reflux may help to minimise these lung function abnormalities.


Alveolar atypical hyperplasia in association with primary pulmonary adenocarcinoma: a clinicopathological study of 10 cases.

A distinctive cytologically atypical lesion has been found in patients with primary adenocarcinoma of the lung. The aim of this study was to characterise the lesion and assess its role in tumour pathogenesis. Lung parenchyma from 175 consecutive resection specimens for primary pulmonary adenocarcinoma were examined. Foci of atypical hyperplasia were identified. Cell proliferation state and expression of S100 and carcinoembryonic antigens were evaluated by immunohistochemistry. Clinical data on cigarette smoking and occupational exposure to carcinogens were abstracted from inpatient case notes. Ten cases (5.7%) with these distinctive cytologically atypical lesions were identified. The lesions showed immunohistochemical evidence of increased cell proliferation and focal carcinoembryonic antigen expression. The associated adenocarcinomas were of peripheral (parenchymal) type. There was an association with cigarette smoking and two of the 10 patients had synchronous carcinomas elsewhere in the lung. The clinical and pathological associations of these lesions suggest that they may be important in the histogenesis of primary pulmonary adenocarcinoma.


Interstitial pulmonary fibrosis with and without associated collagen vascular disease: results of a two year follow up.

Interstitial pulmonary fibrosis is a disease with a highly variable clinical course. To ascertain if an inadequate selection of patients might explain part of this variability, two different groups of patients with interstitial pulmonary fibrosis, those with the "lone" form of the disease (LIPF) and those with associated collagen vascular disorders (AIPF), were studied separately. Twenty consecutive patients (nine with LIPF and 11 with AIPF) were included. Their clinical and radiographic findings and results of pulmonary function tests, gallium-67 lung scanning, and cellular analysis of bronchoalveolar lavage fluid were compared at diagnosis. Moreover, the evolution of LIPF and AIPF was contrasted after a follow up of two years, both groups having received a similar treatment regimen of corticosteroids. At enrollment, patients with LIPF and AIPF were of similar age, and had similar symptoms and derangement of lung function, but patients with LIPF presented with finger clubbing, more obvious radiographic abnormalities, and a greater percentage of eosinophils in bronchoalveolar lavage fluid. Two years later, patients with LIPF had significantly decreased FVC, FEV1, TLC, TLCO, and PaO2. By contrast, lung function remained unaltered in patients with AIPF. Similarly, when the percentage change from entry to the study was compared, patients with LIPF showed a significant decrease in FVC, FEV1, and PaO2. Unlike the patients with AIPF, those with LIPF showed a deterioration in lung function and developed further restrictive impairment and poorer gas exchange. This has implications in their clinical management.


Immune responses to colophony, an agent causing occupational asthma.

Inhalation of fumes from heated colophony (pine resin) is a recognised cause of occupational asthma, although the mechanisms by which colophony produces symptoms are unclear and specific immune responses to colophony have not been reported in sensitised workers. A study was carried out to determine whether colophony is antigenic. The immune responses to colophony were studied in C57BL/6 mice and Dunkin Hartley guinea pigs after intraperitoneal injection of colophony conjugated to bovine serum albumin (BSA) or human IgG by a mixed anhydride procedure. Colophony and dinitrofluorobenzene were also compared in an assay of dermal sensitisation. Mice immunised with the colophony conjugates produced antibodies which recognised conjugates of both BSA and human IgG irrespective of which had been used as the immunogen. Solutions of unconjugated colophony inhibited the binding of antibodies to the BSA-colophony and BSA-abietic acid conjugates, confirming that the antibodies recognised one or more components in the colophony. Portuguese colophony also abrogated the antigen binding of serum from guinea pigs immunised with the BSA-colophony conjugate. Spleen cells from immunised mice proliferated in the presence of the conjugates. Although there was some cross reactivity in these responses, it was not as marked as in the antibody assays. Unconjugated colophony failed to induce an immune response when injected intraperitoneally with adjuvant. Skin sensitisation could not be induced in mice by topical application, or by subcutaneous or intradermal injection of unconjugated colophony. Colophony components have the potential to act as haptens and an immune component could be involved in the pathogenesis of occupational asthma in workers exposed to colophony. Colophony is not readily immunogenic unless conjugated ex vivo to proteins.


Sex differences in hypokalaemic and electrocardiographic effects of inhaled terbutaline.

Gender differences in the chronotropic effects of infused isoprenaline have previously been described. The aim of the present study was to investigate possible gender differences in hypokalaemic, chronotropic, and electrocardiographic effects of inhaled terbutaline. Twenty healthy volunteers (10 female) were recruited (mean age 24 years for women (F) and 22 years for men (M). Subjects were given either inhaled terbutaline 5 mg or placebo in single blind, randomised crossover fashion and the following measurements were made for four hours after inhalation: (a) serum potassium concentration; (b) heart rate; (c) electrocardiographic sequelae (T wave amplitude, Q-Tc interval). The effects of terbutaline on serum potassium was chosen as the primary end point for detecting a 0.3 mmol/l difference between sexes, with a beta error of 0.2 and alpha set at 0.05. The hypokalaemic effects of terbutaline were significantly greater in women, the potassium results (means and 95% CI) being as follows: lowest potassium concentration--F 3.12 (2.96-3.28) mmol/l v M 3.65 (3.49-3.81) mmol/l; percentage change from baseline at one hour--F 15.4% (11.5-19.3%) v M 8.5% (4.6-12.3%); average potassium concentration during the four hours--F 3.39 (3.33-3.46) mmol/l v M 3.78 (3.72-3.85) mmol/l. There was no significant regression between body weight and the potassium response to terbutaline. There were also significant sex differences for T wave, Q-Tc, and heart rate response. The percentage fall in T wave amplitude 30 minutes after terbutaline was: F 44.6% (32.1-57.0%) v M 22.4% (9.9-34.8%). Women are more sensitive to the hypokalaemic, chronotropic, and electrocardiographic sequelae of inhaled terbutaline.


Use of jet mixing devices with an oxygen concentrator.

Jet mixing devices ("Venturi" devices) can be used in conjunction with domiciliary oxygen concentrators and provide delivered oxygen concentrations similar to those obtained with medical oxygen, though with the devices delivering higher concentrations (above 30% oxygen) the total flow is substantially reduced. A jet mixing device driven by a domiciliary concentrator would be valuable in various circumstances, especially in developing countries and also for infants and for patients with upper respiratory tract infections who are breathing through the mouth.


Preoperative laser therapy in a patient with resectable bronchogenic carcinoma and severe coronary artery disease.

A 67 year old man with severe coronary artery disease was found to have a resectable bronchogenic carcinoma. Myocardial revascularisation and lung resection were considered to be unduly hazardous as either separate or combined operations. Preoperative laser therapy, however, enabled the two procedures to be performed in greater safety in the most appropriate sequence.


Multiple cystic pulmonary hamartomas.

A patient with multiple cystic hamartomas presented with a pneumothorax and later developed a cystic myxomatous vaginal polyp. This and three of the cysts were resected. She remains well 13 years later. Multiple cystic hamartomas are uncommon and may be misdiagnosed as pulmonary metastases.


New perspectives on basic mechanisms in lung disease. 1. Lung injury, inflammatory mediators, and fibroblast activation in fibrosing alveolitis.

It is over 25 years since Scadding first defined the term fibrosing alveolitis. It has since been established that complex mechanisms underlie its pathogenesis, including epithelial and endothelial injury, vascular leakage, production of inflammatory cells and their mediators, and fibroblast activation. Only through a detailed knowledge of how these cellular and molecular events are interlinked will we learn how to combat this disease, which is notoriously resistant to present treatments. So far the only therapeutic advances have been refinements in immunosuppression, and even these treatments are frequently disappointing. We believe that future advances in treatment will come from the development of agents that protect endothelial and epithelial cells from further injury and agents that can inhibit release of inflammatory mediators. A better knowledge of the mechanisms of collagen gene activation and the biochemical pathways of collagen production may also allow the identification of vulnerable sites at which new treatments may be directed. A combined approach to modifying appropriate parts of both the inflammatory component and the fibroblast/collagen component should provide a new stimulus to research. Further epidemiological studies are also needed to identify the environmental causes of lung injury that initiate the cascade of events leading to interstitial fibrosis.


Pneumothorax secondary to septic pulmonary emboli in tricuspid endocarditis.

Two cases of pneumothorax secondary to pulmonary septic infarctions occurred in the course of tricuspid endocarditis in intravenous drug misusers. This unusual complication must be considered in patients with right sided endocarditis who develop pleuritic chest pain, haemoptysis, or breathlessness.


Congenital bronchial atresia with regional emphysema associated with pectus excavatum.

Two cases of congenital bronchial atresia with pectus excavatum are reported. Costosternal retraction during the efforts to overcome the airway obstruction due to encroachment on normal lung tissue by the hyperinflated segments may play a part in causing pectus excavatum.


Methodological problems relating to the evaluation of anti-rejection treatments.

The evaluation of anti-rejection treatments raises a variety of methodological problems depending on the clinical phase of development. The first administrations in man are carried out in order to study the profile of a drug and are sometimes performed in healthy volunteers, but more frequently in transplanted patients. It is then necessary to select and evaluate the assessment criteria which will be used in comparative studies to demonstrate the efficacy and safety of the new treatments compared with reference drugs. Factors responsible for variation may be related to the nature of the organ transplanted, the clinical condition of the donor and host and their immune compatibilities. Associated treatments and the multidisciplinary environment in which an organ transplant takes place should also be taken into consideration. After registration, knowledge about the new anti-rejection drug continues in order to identify the optimum conditions for its use, its true therapeutic efficacy and to determine possible new indications.


[Hepatic allograft rejection. Diagnostic and therapeutic aspects].

Rejection is still a major problem in liver transplantation: 50-70% of patients present at least one acute episode, while 5-15% develop chronic rejection. Acute rejection is suggested by clinical signs and abnormal laboratory test results, but only histological signs on biopsy specimens are adequately specific. The three most frequent elementary lesions are a portal infiltrate, bile duct alterations and endothelial inflammation. Several systems have been forwarded to classify the degree of rejection. Chronic rejection is characterized by a progressive reduction in the number of interlobular bile ducts. It does not respond to available immunosuppressive drugs and thus requires retransplantation. Prophylactic immunosuppression is usually based on the triple-drug combination cyclosporine/azathioprine/corticosteroids. The orthoclone OKT3 and FK506 have recently been proposed for prophylactic use in this setting. Treatment of liver graft recipients with cyclosporine carries a number of specific disadvantages, particularly with regard to gastrointestinal interactions (delayed intestinal absorption in patients with cholestasis, bile derivation, diarrhea or receiving cholestyramine; possibility of a sharp increase in blood cyclosporine levels when the Kehr drain is clamped), and drug interactions (cyclosporine metabolization of CP450-IIIA accounts for most such interactions). The results of radioimmunoassay and TDx must be interpreted with care, and HPLC remains the reference technique in borderline cases. Cyclosporine is hepatotoxic in about 20% of cases, generally giving rise to cholestasis. This toxicity is dose-dependent and therefore diminishes when the dosage is reduced. Most groups initially treat rejection with corticosteroids. The response to treatment is generally evaluated in terms of liver function tests.(ABSTRACT TRUNCATED AT 250 WORDS)


[Rejection reaction. Elements of diagnosis, monitoring, therapeutic attitude in the case of kidney].

Allograft rejection reaction must be integrated in the broader sense of alloreactivity, i.e. involving a huge T cell repertoire with a high number of alloreactive precursors. This reaction is modulated by the particular immunological state induced by chronic renal insufficiency, by haemodialysis and by the primary kidney disease. The imperfect effect of current immunosuppressive drugs is illustrated by a sizeable proportion of grafts undergoing a chronic rejection process where many growth factors are involved. It has to be noted that allostimulating cells are different from target cells. At present, the therapeutical rejection involves corticosteroids and serotherapy, but it is hoped that new immunosuppressive drugs will increase the efficacy of the rejection crisis treatment.


[Acute cardiac graft rejection after orthotopic cardiac transplantation. Elements of diagnosis and monitoring, therapeutic attitude].

The diagnosis of acute rejection in heart allograft recipients receiving cyclosporine is still an important challenge. The poor diagnostic value of clinical signs and the ECG means that regular endomyocardial biopsies must be performed. Despite their diagnostic value during the first year after transplantation, endomyocardial biopsies are less sensitive there after and currently suffer from the lack of a universally accepted histological classification. Doppler echocardiography can be used for routine surveillance and has proven reliable for the diagnosis of acute rejection with various clinical presentations when used in conjunction with endomyocardial biopsies. Immunohistological examination of myocardial specimens can further increase the sensitivity of histological diagnosis. Similarly, immunoscintigraphy with indium 111-labelled antimyosin antibodies is of value for the prediction of acute rejection after the first year. Therapeutic approaches have been standardized, but must still be tailored to the individual patient according to the severity of the rejection and the presence of associated infection and/or metabolic disturbances.


Monoclonal antibodies in human organ transplantation and auto-immune diseases.

The usefulness of monoclonal antibodies (mAbs) in the transplantation field has become evident over the last couple of years. Different mAbs have been used as a prophylactic treatment after transplantation, in a therapeutic way against acute organ rejection and new diagnostic tools to predict clinical rejection immerge. One can even hope that with humanised mAbs or human mAbs obtained by repertoire cloning the formation of human anti-mouse antibodies will be solved although on the one hand this appeared not to be a big problem and on the other hand anti-idiotypic antibodies can still be expected. However, the most puzzling question is how the mAbs modulates the immuno-response and this not only in organ rejection but also in auto-immune diseases. Only one out of many CD25 mAbs with seemingly similar epitope recognition can be used in therapeutical treatment of acute Graft versus Host Disease. The same mAb is not, however, very efficient in the prophylactic treatment of kidney transplantation without association of suboptimal doses of cyclosporin A. Another example is a CD4 mAb which is efficient in the treatment of polyarthritis with no side effects but which provokes transient but clear side effects when used in psoriasis or multiple sclerosis patients. A second CD4 mAb with high inhibitory activity in several bioassays compared to the first CD4 mAb has no beneficial effect at all on polyarthritis. Also the question why there is a percentage of "no response" patients among apparently identical "good response" patients remains unanswered. However it becomes clear from these experiences that: 1) mAbs recognizing a similar epitope and being of the same isotype will not automatically have the same effect in therapy. 2) side effects may be depending of the disease treated. 3) the activities of mAbs in bioassays and even animal models very often do not reflect the in vivo situation in human. 4) efficiency of the treatment with mAbs can be increased by a better understanding of the mode of action and increased efficiency can be expected by association of several mAb or mAb with drugs for the "no response" patients and should be the next step in the therapeutical use of mAbs.


[Modalities of therapeutic follow-up of cyclosporine].

The therapeutic use of cyclosporine (CsA) requires total blood levels to be monitored with a specific assay, since this drug is nephrotoxic, has a narrow therapeutic index, shows wide intra- and inter-individual differences in its pharmacokinetic behaviour and can interact with other drugs. The parameter generally measured is the residual blood concentration at equilibrium; levels are occasionally again measured four or six hours after CsA administration. Patients are monitored every two days during the first two weeks following organ transplantation, a frequency which gradually declines to monthly determinations at four to six months in the absence of complications. The therapeutic range of blood CsA concentrations is still poorly defined. In renal, liver, heart and bone marrow transplantation most authors recommend concentrations of 100-250 ng/ml for the first three months when renal function is satisfactory. Ways of administration (i.e. continuous infusion or dividing up of the daily dose) must be taken into consideration to assess values of blood concentration of CsA.


[Lymphocytic molecules implicated in rosette phenomenon. Differential effect of antilymphocyte serum on T (CD2+E2+) and B (CD2-E2+) lymphocytes].

The molecule E2 is present on T lymphocytes and thymocytes and is implicated in rosette phenomenon most probably via interaction with CD2. The discrepancy observed between rosette levels and lymphocyte phenotypes in the follow-up of kidney-transplanted patients treated with antilymphocyte globulins (ALG), methylprednisolone and azathioprine leaded us to study the effect of ALG on E2 molecule.


[Circulating forms of cyclosporin A].

The major circulating blood fraction of cyclosporin is localized in red blood cells. It is 58% for blood levels of less than 1,000 ng/ml. Beyond this concentration, a fall of this percentage is noticed which is related to a saturation phenomenon which occurs in its binding on an intracytosol protein, cyclophilin. Other fractions are distributed in the following manner: 27.5% on lipoproteins, 5% on albumin, 4% on polymorphonuclears, 5% on lymphocytes and 0.5% in the free state. There are various binding sites in the lymphocyte: in the membrane, cytosol on cyclophilin, and on the nucleus. The manner of binding on various plasma proteins, blood cells and platelets results in manifold pharmacological, pharmacokinetical, and toxicological results which are discussed here.


[Methods of cyclosporine determination in biological media].

Cyclosporine is an immunosuppressive medicine widely used in all grafts and organ transplantations. Its pharmacokinetic characteristics, especially its intensive metabolism, result in great variability potential between and within patients justifying blood levels' determination in patients treated with this drug. If the biological medium (whole blood) selection is of the utmost importance regarding the quality of the result and its validity, the accuracy of the result compared to the blood levels of the drug will depend on the selection of the determination technic involved. At present, various analytical methodologics are available: the immunological technics involving radioactive or non-radioactive tracers, and HPLC (High Performance Liquid Chromatography) technic. The latter requires good chromatography experience; it takes more time to be implemented due prior extraction of cyclosporine from the biological media. This extraction can be effected with organic solvents or by column chromatography: these various technics will be discussed and compared. This methodology enables one to determine metabolite concentrations. Regarding immunological technics, multiclonal or monoclonal antibodies are available for technics involving fluorescence polarization. However, for radioactive tracings and enzymic tracers, only one specific antibody is available. It is important to take into account the specificity of these antibodies relative to the various metabolites regarding results interpretation, their crossing rate being altered in accordance with antibodies and related pathologies. The validity of these technics will be discussed in words of accuracy and exactitude. The laboratory arrangement, the feasability and cost of the technic are also factors to be taken into consideration. At present selection tends towards to most specific technics.


[Critical analysis of the immunosuppressive activity and of the toxicity of cyclosporine metabolites].

Cyclosporin A (CyA) is intensively metabolized by the hepatic cytochrome P450 III monooxygenases A systems in the human liver. Among about twenty metabolites, only twelve of which have been identified, and found in the blood of treated patients. The major metabolic pathways are hydroxylation and N-demethylation of the various amino-acids of the parent compound. Quantitatively, and although there are some differences depending on whether one refers to the residual concentration or to the Area Under Curve (AUC), major metabolites are always, in decreasing significance, M17, M1, M18, and M21. Metabolite/CyA ratio is subjected to numerous variations from one patient to another which can be explained by pharmacogenetics, but can also be affected by the type of graft, the hepatic performance status, and related treatments. Be that as it may, it is metabolites 17 and 1 which are especially present in the blood in large quantities. In fact, if one considers the relative percentage of metabolites in comparison with CyA, expressed in blood AUC, values of 79, 39, 21 and 15% are noticed for M17, M1, M18, and M21, respectively. These percentage become 170, 65, 16 and 10% if one refers to residual concentration. In the aggregate, these results may be extrapolated to the tissues and it has been shown that, excepting the liver which contains high M17 concentrations, metabolites overall appear in equal or lower levels than CyA. They are widely diffused throughout the tissues and the highest levels are found in the liver and kidneys, then in fats and pancreata.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical usefulness of estrogen receptor immunocytochemistry in human breast cancer.

We assessed the reliability of the immunocytochemical assay of estrogen receptor (ER-ICA) as a marker of clinical outcome. Relapse-free interval (RFI) and overall survival (OS) according to ER-ICA status were retrospectively evaluated on a series of 210 patients who had undergone surgery for primary breast cancer between January 1985 and December 1988. ER assay by the dextran-coated charcoal method (DCC) was also performed in 189 tumors. A significant positive correlation was found between the DCC and ER-ICA assays, with an overall agreement of 79%. ER-ICA status showed a prognostic predictive power with respect to OS and RFI in the whole series of patients and in the subset of node-positive patients. It was also a marker of outcome with respect to OS in the subsets of node-negative patients and patients with tumors < or = 2 cm in diameter. Moreover, the predictive value of the ER-ICA assay was higher than that of the DCC assay in the present study. These findings emphasize the clinical usefulness of the ER-ICA assay as a measure for prognosis.


Quality control for colposcopy in the Florence screening program for cervical cancer.

The authors report on the quality control for colposcopy adopted in the Florence District screening program. The sensitivity of colposcopy was determined on all cases of CIN III recorded in the local cancer registry in a four-year period. However although this showed that a centralized colposcopic clinic employing a limited number of expert operators is superior to the performance of colposcopy in private practice, such a parameter was impractical for further routine quality control since differences among operators were too small and statistically insignificant. Other parameters for quality control were chosen, namely a) the rate of colposcopically directed biopsies performed, b) the detection rate of CIN II or more severe lesions, and c) the positive predictive value of a directed biopsy for CIN II or more severe lesions. Analysis of these indicators after stratification by cytologic report allows the identification of those operators who need additional training and provides useful information for colposcopists to optimize their diagnostic and operative criteria.


[Therapeutic follow-up of cyclosporine. Main factors involved in the interpretation of results].

The therapeutic drug monitoring of cyclosporine (CsA) requires not only correct methodological conditions but also taking into consideration of numerous other factors involved in the value of blood drug concentrations. Main factors concern: the clinical state of patients. Liver function and bile flow act predominantly on drug clearance; the choice of monitoring parameters and of sampling time. Comparison was done of information given respectively by area under the curve and different sampling times. Usually blood concentration is monitored with trough level plus eventually another concentration measured 4-6 h after drug administration; the time-table. Blood concentrations are measured at steady-state period. Bioavailability of CsA increases in the immediate postoperative period after transplantation; ways of CsA administration. Trough level is influenced by dividing up of the daily dose. In case of continuous i.v. infusion mean blood concentration, but not trough concentration, is measured; drug interactions. Several drugs modify blood concentrations of CsA. Others induce an additive nephrotoxicity or immunosuppressive effect. Recommended blood trough concentrations vary with clinical indications, experience and therapeutic habits of each transplant center. Currently recommended values (CsA whole blood concentration determined by specific method) are 150-250 ng/ml in renal, heart, liver and bone marrow grafts, during the 3 months after transplantation, with good renal function. Concentrations are often higher for lung transplantation.


The effect of cytological screening on cervical neoplasia in the Italian province of Varese.

In the Varese province (409,142 female inhabitants in 1981), which has been covered by a cancer registry since 1976, cytologic screening for cervical cancer began in the early sixties in the municipality of Busto Arsizio (41,818 female inhabitants in 1981) and subsequently spread to the rest of the province. The distribution by age of cytologic smears and of detected in situ cancer reveals a more frequent attitude to be screened for women aged between 25 and 54 years. Overall, the incidence rate (world standardized) for invasive cancer in the province decreased from 10.3/100,000 women-year in the period 1976-81 to 7.5/100,000 in 1982-87. In Busto Arsizio a survey of the hospital archives has been carried out to identify the cases of cervical cancer diagnosed from 1966 to 1985: in this 20-year period, the incidence of cervical cancer decreased markedly, but only in those ages frequently screened. In the rest of the province, for the first period of cancer registration (1976-81), the incidence was significantly higher than in Busto Arsizio, especially for ages 35-64. Subsequently, between 1982-87, the cervical cancer incidence was low in both areas. For the period 1976-87, no difference for carcinoma in situ registration rates was observed between the two populations studied. Actually by 1976, when the Lombardy Cander Registry began its activity, the screening was diffuse throughout the province. These observations are consistent with the preventive effect of screening activity.


[Critical analysis of drug interactions with cyclosporine. Evaluation of interactions with cyclosporine].

Cyclosporine A is a potent immunosuppressive agent, widely used in organ transplantation, in bone marrow transplantation and in the treatment of some autoimmune diseases. Changes of its absorption, a metabolism mainly processed by the liver and a concentration-related nephrotoxicity lead to the need of a careful drug monitoring, allowing to obtain blood levels that must be low and nevertheless sufficiently efficient. Cyclosporin A may additionally yield some numerous drug interactions. Those with potentially serious issue must be mandatory avoided and distinguished from those less severe that only have to be followed up. The strategy differs according to the nature of the interaction (i.e. pharmacokinetic/pharmacodynamic): the posology will have either to be adjusted or the risk/benefit ratio will have to be taken into account to decide any change in the dosage regimen.


Altered fractionation schedules in radiotherapy of head and neck cancer. A review.

The authors review the main contributions of international literature to show the current status in clinical trials on unconventional fractionations of the dose in radiotherapy of head and neck cancers. Several clinical (but only a few randomized) trials have been conducted over the last 15 years using hyperfractionated (HF), accelerated (AF) or mixed (HF-AF) schedules. HF schedules have obtained promising results in terms of local control in comparison with conventional fractionation (CF) of the dose. Improvement in survival was also obtained by the random trials of Pinto and Sanchiz, whereas in EORTC trial no. 22791, the improvement in survival rate was only marginal. A significant increase in local control and, less frequently, in survival has been claimed in several studies using HF-AF. Such data still need to be confirmed by a random study, since EORTC trial 22811 showed superimposable results in comparison with CF. Selection of the most suitable cases for altered fractionation schemes is also being studied in ongoing trials of the EORTC (22851) and RTOG (90-03). As regards acute reactions during and after altered fractionation, they are more severe than after CF. Only pure HF with a dose intensity approximately comparable to CF seems to produce similar acute reactions. Several factors have been found to influence the severity of acute mucosal reactions: interfraction interval, overall treatment time, total dose, and field size. As regards late damage, genuine HF schemes seem to cause roughly equivalent late damage in comparison to CF, whereas high-dose intensity schedules have a higher rate of complications. Interfraction interval, overall treatment time, total dose, fraction size and field size can influence the risk of late sequelae. Before altered fractionations can be considered standard therapy, more data are needed, which should be provided by multicentric randomized trials, some of which are already in progress.


[Monitoring of clinical trials and interim analysis. 1. Monitoring committee].

In order to fulfil the ethical principles linked to the protection of patients randomized in a controlled clinical trial, monitoring procedures need to be set up. In this context, a committee of experts, called the data monitoring committee is in charge of reviewing regularly unblinded data to assess the quality and the relevance of the trial, to evaluate the evidence of an emerging treatment difference and to control the rate of occurrence of serious adverse events. After each meeting, the monitoring committee reports to the steering committee its recommendation to continue or to stop the trial prematurely. Protocol modifications might be proposed as well. Illustrated with several examples, this article reviews different situations a monitoring committee might have to tackle with.


Accelerated hyperfractionation of radiotherapy for rapidly growing inoperable breast cancer unresponsive to chemotherapy.

Eleven patients with rapidly growing inoperable breast carcinoma were treated with a thrice-a-day fractionation of 1.2 Gy per fraction (5-h intervals, 15 fractions per week). Nine of them had been considered as non-responders to previous aggressive multidrug chemotherapy. A split of 2 weeks was inserted after 54 Gy, and radiation fields were then restricted to the clinical positive area up to a total tumor dose of 90 Gy. Nine of 11 patients completed their treatment, and 7 of them were considered as complete responders. Acute toxicity was surprisingly low (grade I-II). Four patients surviving 12-18 months after radiotherapy did not relapse and did not present any late complications. A favorably improved quality of life was obtained for all 9 patients.


[Cyclosporine. Obscure sides of cardiac and pulmonary transplantations].

Cyclosporine therapy after heart and lung transplantation implies a number of specific aspects such as: kidney deficiency associated to heart failure, which delays its use as for cardiac transplantation; intestinal absorption disturbances that could be linked to the cystic fibrosis disease for lung transplantation. For both types of transplantation, local efficiency could indicate an interesting, but still unexplored therapeutic effect. Finally, it seems that the immunosuppressive effect could be linked to important pharmacological effect on calcium and could explain the specific aspects of rejection of patients under cyclosporine.


Weekly first-line chemotherapy of metastatic breast cancer with cyclophosphamide and epirubicin.

Forty-six patients with metastatic breast cancer who had not received previous chemotherapy for advanced disease entered a phase II trial of weekly chemotherapy with cyclophosphamide (250 mg/m2) + epirubicin (25 mg/m2) for 16 weeks. The overall response rate was 61% (95% confidence limits, 47-75%), with 10 complete and 17 partial responses. Toxicity was mild and confined to nausea and vomiting and asymptomatic neutropenia (except in 2 cases). Sixty-three per cent of patients had no side effects. Weekly cyclophosphamide + epirubicin is an active and nontoxic regimen for patients with metastatic breast cancer who have had no prior anthracycline-containing adjuvant chemotherapy.


Phase I study of FUDR continuous infusion with circadian variability in advanced cancer patients.

A phase I study of floxuridine circadian infusion was performed in 14 patients with advanced solid tumors (9 colonic, 1 gastric, 4 renal). The starting dose was 0.15 mg/kg/day for 14 days followed by a 14-day therapy-free interval. Sixty-eight percent of the daily dose was infused between 3pm and 9pm. The dose was increased by 0.025 mg/kg/day for each successive course. Eighty-one cycles of therapy were given for a total of 1134 days of treatment. The mean dose intensity was 0.868 mg/kg/day for the entire group. The highest dose achieved (maximum tolerated dose) was 0.325 mg/kg/day. The most frequent toxicity was diarrhea (4.9% of all courses) and nausea-vomiting (3.7% of all courses). These side effects were of a low grade and all were resolved without hospitalization. Our results suggest the circadian modulation of floxuridine infusion.


[Therapeutic follow-up of cyclosporine: specific problems in kidney, liver, bone marrow grafts and in the treatment of autoimmune diseases].

In transplantation, the advantage of therapeutical follow-up of immunosuppressive treatment involving cyclosporine is generally recognized, even though the ideal therapeutic index has as yet not been perfectly defined. Cyclosporine blood level determination is merely one factor among many others in therapeutical success, but if replaced in its context, can provide valuable and relevant information. A certain number of rules exist regarding the use, and pharmacological surveillance, of cyclosporine in all patients treated with this medicine. These rules take into consideration the patients immunological responsivity, the length of time since transplantation, the position of cyclosporine in immunosuppressive treatment, related pathologies and medicines. However, it is of special interest to consider a few points according to the nature of the indication. In kidney transplantation, and nephrotoxicity, determination of cyclosporine blood level will help differential diagnosis between an immunological origin (graft rejection) and an iatrogenic origin; in liver transplantation the consideration of metabolite determination, and study of metabolite ratio, will enable the gathering of information on performance status and toxicity hazards. In some cases, the necessity to administer intravenous cyclosporine, and the special weakness of some patients as in bone marrow transplantation, treatment surveillance patterns will be altered. Finally in spite of our lack of background information, the use of cyclosporine in autoimmune diseases has shown that principles of treatment and surveillance differed from one pathology to another, this being increased in some cases (juvenile diabetes), or occasional and even non-essential (psoriasis).


Favorable response of metastatic adrenocortical carcinoma to etoposide, adriamycin and cisplatin (EAP) chemotherapy. Report of two cases.

The usefulness of non-specific chemotherapy for advanced adrenocortical carcinoma (ACC) is controversial. We report on 2 young female patients (25 and 19 yr) who presented with a clinical picture of Cushing's syndrome due to histologically confirmed ACC. The first patient underwent radical surgery, but after a disease-free interval of 6 months a local recurrence was apparent. She was reoperated and treated with 6 courses of cisplatin and etoposide chemotherapy. Mitotane (8 g daily) was begun, but 2 months later debulking surgery was again performed. A second-line chemotherapy with the etoposide, adriamycin, cisplatin (EAP) scheme attained a partial remission lasting 7 months, then metastatic spread to the brain led to death of the patient. The survival time was 30 months. The second patient underwent radical surgery and adjuvant mitotane (4 g daily), but multiple lung and mediastinal metastases were diagnosed after an interval of 29 months. Chemotherapy with the EAP regimen (6 courses) without interrupting mitotane attained a partial remission lasting 21+ months. We suggest that the EAP scheme is active in advanced ACC and that its association with mitotane is feasible.


Weekly doxorubicin chemotherapy for breast cancer in pregnancy. A case report.

The simultaneous occurrence of breast cancer and pregnancy is rare. Little data are available about cytostatic treatment in patients with breast cancer during pregnancy. We report on a 31-year-old woman with a 28-week pregnancy and a T3 N+ Mx breast cancer treated with weekly doxorubicin chemotherapy. This was a well tolerated treatment without toxicity or complications for the mother. A partial response of the tumor was observed after 4 treatment courses. A normal baby was delivered. Doxorubicin and its metabolites were not detected in amniotic fluid collected through amniocentesis. Macroscopic and pathologic examinations of the placenta were normal. Although larger experiences are needed, weekly doxorubicin seems to yield satisfactory results without additional risks of fetal distress or malformations when given in women during the second and third trimester of pregnancy.


[Monitoring of clinical trials and interim analysis. 2. Statistic methods].

Although the decision to continue or to stop prematurely a clinical trial is not solely based on statistical tests, they bring useful objective arguments to the data monitoring board. However, the multiple use of statistical tests leads to increase the risk of false positive conclusions in favor of one of the treatments, and several methods have been developed to address this problem. This article presents the four major strategies that are being used for monitoring clinical trials, as well as the rationale for planning and using such statistical monitoring procedures.


A case of malignant phyllodes tumor with muscular and fatty differentiations.

A 50-year-old female underwent surgical removal of a mammary phyllodes tumor, whose peculiar histologic feature was the coexistence of areas of liposarcoma and leiomyosarcoma. The morphologic differential diagnosis is briefly discussed.


Hypertriglyceridemia during long-term interferon-alpha therapy: efficacy of diet and gemfibrosil treatment. A case report.

Interferon-alpha might increase triglyceride serum levels through the enhancement of hepatic lipogenesis and/or inhibition of the peripheral lipoprotein lipase. Hypertriglyceridemia during interferon-alpha therapy has been only recently described, mostly in patients with previous abnormalities of lipid metabolism. The authors report here a case of a 65-year-old male bearing advanced colon carcinoma who developed hypertriglyceridemia during long-term interferon-alpha treatment in association with 5 fluorouracil administration. Hypertriglyceridemia was maintained within acceptable levels, without adjusting the treatment plan, by an appropriate diet and gemfibrosil administration.


Acute myelocytic leukemia and chronic myelomonocytic leukemia simultaneously with resectable breast cancer: a report of two cases.

This report describes 2 patients who developed acute myelocytic leukemia (AML) type M2 and chronic myelomonocytic leukemia (CMML) of the FAB classification, respectively 2 months and 2 weeks after diagnosis of operable breast cancer. The patient with AML showed pancytopenia 2 months before the diagnosis of AML, had a normal karyotype, and showed a good response to chemotherapy. The patient with CMML had a normal karyotype, and she was treated with hydroxyurea and supportive therapy. The 2 patients had no previous exposure to irradiation or cytotoxic therapy. These cases show that breast cancer and either leukemia or myelodysplastic syndrome may be associated even without previous irradiation or combination chemotherapy.


Progression and regression of partial corneal involvement in the iridocorneal endothelial syndrome.

We have observed three women with partial corneal involvement in the ICE syndrome for over 10 years. During this time, the peripheral anterior synechiae progressed in all three, with glaucoma developing in one patient. In two patients, the abnormal endothelial cells spread to cover the entire posterior corneal surface; in the third, they disappeared entirely (ie, "the ICE melted"). The endothelial permeability to fluorescein remained abnormally low only in the two eyes with diffusely abnormal endothelium, increasing to normal in the third eye as the abnormal endothelium disappeared. The permeability in that eye had been abnormally low only in the superior half of the cornea, where the abnormal endothelium was. As the abnormal endothelium regressed, it was replaced by normal endothelium with a normal cell density similar to that of the opposite, uninvolved eye. Thus, over a 10-year period the partial endothelial involvement associated with the ICE syndrome progressed substantially in two patients and regressed dramatically in a third.


The study of malformations "by the company they keep".

Our study of individuals with thalidomide embryopathy reaffirms many of the principles of clinical teratology concerning sensitivity of developing structures and specificity of action. It also highlights important features of ocular teratology that differ from those of other organ systems. Because malformations of the eye and associated structures do not significantly threaten the survival of the embryo, fetus, or neonate, any variation in prevalence in older individuals is not due to the nature of the ocular malformation but may be significantly modified by "the company they keep," the systemic malformations occurring at the same time as the original insult, whether it be an environmental, a genetic, or a local disturbance. Additionally, the presence of clusters of malformations caused by a teratogen at a specific time supports the concept of a common pathogenic mechanism and provides suggested avenues for further research into the cause of these malformations.


Botulinum alignment for congenital esotropia.

This is the first report of a group of patients with congenital esotropia examined for motor and sensory evidence of binocularity a minimum of 3 years after alignment by botulinum. Evidence for binocularity was clearly present in approximately one half of the patients. Lag time to satisfactory alignment was at least 1 month (average, 5 months) following the initial botulinum injection. The results must be considered preliminary. However, when these results are compared with those of patients with congenital esotropia aligned by incisional surgery by age 2 years and examined with the same testing devices by this same investigator, botulinum alignment appears to be less effective than surgical alignment in establishing evidence for binocularity (P < 0.005).


The four-meter confrontation visual field test.

The 4-m confrontation visual field test has been successfully used at the Mayo Clinic for many years in addition to the standard 0.5-m confrontation visual field test. The 4-m confrontation visual field test is a test of macular function and can identify small central or paracentral scotomas that the examiner may not find when the patient is tested only at 0.5 m. Also, macular sparing in homonymous hemianopias and quadrantanopias may be identified with the 4-m confrontation visual field test. We recommend use of this confrontation visual field test, in addition to the standard 0.5-m confrontation visual field test, on appropriately selected patients to obtain the most information possible by confrontation visual field tests.


The ocular manifestations of sickle-cell disease: a prevalence and natural history study.

Prophylactic photocoagulation may have a role in the treatment of proliferative sickle retinopathy in selected patients with SC disease, but none of the studies reported to date have established that such treatment of these eyes improves the long-term visual outcome as compared with the natural history as documented in this study. The similar visual outcomes in the eyes reviewed in this natural history study as compared with those that have been treated with photocoagulation should not be unexpected, because there is greater predilection for spontaneous involution or autoinfarction of the neovascular tissue in SC disease as opposed to the neovascularization that develops in other retinal vascular disease. A controlled, multicenter clinical trial designed to study those eyes at greatest risk should be considered. Such a trial should specify patient age (15 to 30 years), hemoglobin type (SC disease), and a minimum threshold of active proliferative disease (60 degrees or greater). Such criteria have been suggested by others. By comparing the outcome of eligible eyes randomly assigned to treatment or observation and followed for an extended period, it will be possible to learn whether laser photocoagulation offers a better prognosis than the natural history of proliferative sickle retinopathy. There is no question that in some eyes with proliferative sickle retinopathy, nonclearing vitreous hemorrhage and/or retinal detachment will develop. Clear definition of the risk factors leading to these advanced stages, however, is lacking, and the value of treatment is uncertain.


Experimental postoperative endophthalmitis.

Various inocula of vancomycin-sensitive E faecalis (EF01), S aureus (SA02), S epidermidis (SE03), and B cereus (BC04), were intravitreally inoculated into an aphakic rabbit model with and without vancomycin, with or without vitrectomy. A summation average of the clinical response mean scores of various inocula (10(3), 10(5), 10(7) cfu) in the absence of therapy ranked these etiologic agents in the order of severity as SE03 (1.4), BC04 (1.8), EF01 (2.3), and SA02 (2.8). These favorably compared with the histopathology cavitary/noncavitary mean scores in increasing order of severity: SE03 (1.7/0.6), BC04 (1.7/0.9), EF01 (2.4/1.1), and SA02 (2.5/1.5), compared with control eyes (1.1/0.4). If the inoculum was increased to 10(7) cfu, SE03 (2.4/0.9) and BC04 (2.8/2.0) could equate EF01 and SA02. Treatment with 1 mg of vancomycin, with or without vitrectomy, did not significantly alter the overall inflammatory response to these four endophthalmitis isolates. No treatment was necessary to achieve > 99.9% killing effect by 72 hours when testing BC04, while any of the treatment modalities during 72 hours achieved 99.9% killing effect when testing SE03. No treatment modality achieved a 99.9% killing effect when testing EF01 or SA02. No single in vitro result could predict the in vivo microbiologic behavior of this model. Further research is needed to better understand the role of antiinflammatory agents, multiple drug therapy, and multiple-injection single-drug therapy with or without vitrectomy, and their impact on the inflammatory response in the aphakic model, to better treat endophthalmitis and thus improve visual prognosis.