Effect of intravenous flumazenil on reversal of the central effects of midazolam used with short-acting opioids for general anesthesia in hospitalized patients: report of a multicenter, double-blind clinical study. The Flumazenil in General Anesthesia in Hospitalized Patients Study Group I.

Midazolam, a short-acting benzodiazepine central nervous system (CNS) depressant widely used for the induction and maintenance of general anesthesia, is often supplemented with short-acting opioids for general anesthesia. Administered postoperatively, flumazenil, a specific benzodiazepine antagonist, reverses the CNS sedative effects of midazolam. In a double-blind clinical trial in hospitalized patients, flumazenil, administered postoperatively at an average intravenous dose of 0.89 mg (range: 0.4 mg to 1 mg), was more effective than placebo in reversing sedation and other residual effects of benzodiazepines in patients recovering from general anesthesia induced by midazolam (mean dose 29 mg) in conjunction with fentanyl (mean dose 0.4 mg) or sufentanil (mean dose 0.056 mg). Five minutes posttreatment, 87 (83%) of 124 flumazenil-treated patients and 6 (10%) of 60 placebo-treated patients had attained the criterion response for reversal of sedation. Of these patients, 60% in the flumazenil group, compared with 100% in the placebo group, retained their degree of alertness throughout the 3-hour observation period. Between-group differences were significant until 60 minutes posttreatment, when the effect of the benzodiazepines had spontaneously waned in the placebo group. The Physician's Global Efficacy Rating, providing an overall measure of efficacy 5 minutes after test drug administration, was good or excellent for 86% of the flumazenil-treated patients, as compared with 7% of the placebo-treated patients evaluated. Measurements of psychomotor function and memory also showed significant between-group differences. Flumazenil, compared with placebo, was not associated with a substantially greater frequency of operative-site pain. These results demonstrate that the efficacy and safety of flumazenil were not compromised by the addition of a short-acting opioid to the anesthetic regimen.


Reversal of the central effects of midazolam by intravenous flumazenil after general anesthesia and use of a long-acting opioid in hospitalized patients: report of a multicenter double-blind clinical study. The Flumazenil in General Anesthesia in Hospitalized Patients Study Group II.

A double-blind clinical trial was conducted to evaluate the efficacy and safety of flumazenil, a benzodiazepine antagonist, in 146 hospitalized patients, who had had general anesthesia induced by midazolam and a long-acting opioid. Ninety-eight patients received flumazenil and 48 received placebo. Administered postoperatively at a mean intravenous dose of 0.84 mg (range: 0.2 mg to 1 mg), flumazenil reversed benzodiazepine-induced sedation to a greater extent than did placebo. At 5 minutes posttreatment, 61 (76%) of 80 flumazenil-treated patients and 7 (18%) of 40 placebo-treated patients had attained a score of 4 or 5 on the Observer's Assessment of Alertness/Sedation Scale, indicating that they were drowsy or fully awake and alert. This level of arousal was maintained for the full 180-minute posttreatment assessment period in 79% of flumazenil-treated patients. Between-group differences in mean change from baseline in level of alertness were statistically significant (P < 0.01) until 60 minutes posttreatment, when the spontaneous recovery of placebo-treated patients resulted in declining intergroup differences. The global efficacy rating (based on the physician's general impression of the effectiveness of the reversal of sedation 5 minutes after test drug administration) was good or excellent in 64 (80%) of the 80 flumazenil-treated patients and 5 (13%) of the 40 placebo-treated patients evaluated. Flumazenil, compared with placebo, was not associated with an increased frequency of operative-site pain, and no serious adverse effects of this benzodiazepine antagonist were reported. The most frequent adverse experiences in both treatment groups were nausea, shivering, and operative-site pain. Vomiting, dizziness, and injection-site reactions were also reported in > or = 5% of patients treated with flumazenil.


Reversal of central benzodiazepine effects by flumazenil after intravenous conscious sedation with diazepam and opioids: report of a double-blind multicenter study. The Flumazenil in Intravenous Conscious Sedation with Diazepam Multicenter Study Group II.

The efficacy and safety of a new benzodiazepine antagonist, flumazenil, were assessed in a double-blind multicenter study. Flumazenil (mean dose, 0.76 mg) or placebo (mean dose, 8.9 ml) was administered intravenously to 130 and 67 patients, respectively, who had been given diazepam in conjunction with an opioid (fentanyl, meperidine, or morphine) for the induction and maintenance of intravenous conscious sedation for diagnostic or therapeutic surgical procedures. The group assessable for efficacy comprised 122 patients treated with flumazenil and 64 patients given placebo. After 5 minutes, 80/115 (70%) flumazenil-treated patients, compared with 21/63 (33%) placebo-treated patients, were completely awake and alert, as indicated by a score of 5 on the Observer's Assessment of Alertness/Sedation Scale. Ninety-five percent of patients in each group who attained a score of 5 at the 5-minute assessment showed no loss of alertness throughout the 180-minute assessment period. Flumazenil-treated patients also performed significantly better on the Finger-to-Nose Test and the recall of pictures shown at the 5-minute assessment. Flumazenil was well tolerated, with no serious adverse effects reported. Thirty-nine (30%) of flumazenil-treated patients, compared with 17 (25%) of placebo-treated patients had one or more drug-related adverse experiences. The most common adverse effects were nausea and vomiting in the flumazenil group and nausea and injection-site pain in the placebo group. Flumazenil was found to promptly reverse sedation induced by diazepam in the presence of opioids.


Reversal of the central effects of midazolam by intravenous flumazenil after general anesthesia in outpatients premedicated with an opioid and a muscle relaxant: report of a multicenter double-blind clinical study. The Flumazenil in General Anesthesia in Outpatients Study Group II.

Flumazenil was studied in a double-blind multicenter trial to confirm its efficacy and safety in antagonizing the central effects of benzodiazepines after general anesthesia (midazolam, short-acting narcotic, nitrous oxide) with muscle relaxants and selected potent volatile anesthetics as needed. One hundred seventy-two outpatients were randomly assigned to receive either flumazenil or placebo titrated to the point of reversal of sedation or a maximum dose of 1 mg of flumazenil or 10 ml of placebo. The test drug was given intravenously (0.2 mg flumazenil or 2 ml placebo) at 1-minute intervals. Tests of alertness, psychomotor function, and memory were conducted prestudy and at baseline before the administration of flumazenil and at 5-, 15-, 30-, 60-, 120-, and 180-minute intervals after administration. The changes from prestudy or baseline scores were analyzed to compare differences between treatment groups. Seventy-five percent of the 105 flumazenil-treated patients and 14% of the 55 placebo-treated patients who met the qualifications for efficacy evaluations obtained a criterion level of response as measured by the Observer's Assessment of Alertness/Sedation Scale. Most (76%) patients who were alert at 5 minutes maintained their level of wakefulness throughout the 180-minute observation period. All 172 patients were included in evaluations of safety. Fifty percent of 113 flumazenil-treated patients and 31% of 59 placebo-treated patients reported one or more adverse experiences. The most frequently reported were nausea, vomiting, and dizziness. Only 6 adverse effects in the flumazenil group and 1 in the placebo group were considered severe; the remainder were mild or moderate. None were considered serious or potentially serious. Postoperative administration of flumazenil (mean dose, 0.85 mg) safely provided a prompt, controlled reversal of the sedative and psychomotor effects of midazolam in most patients.


Reversal of the central effects of midazolam by intravenous flumazenil after general anesthesia in outpatients: a multicenter double-blind clinical study. The Flumazenil in General Anesthesia in Outpatients Study Group I.

In a US double-blind, multicenter study, flumazenil, a benzodiazepine antagonist, administered postoperatively in a mean intravenous dose of 0.67 mg (range, 0.2 to 1 mg), was superior to placebo in reversing sedation and other central nervous system effects of benzodiazepines in outpatients recovering from general anesthesia induced by midazolam, fentanyl or sufentanil, and nitrous oxide. Within 5 minutes after administration of flumazenil, sedation was reversed in 94% (87 of 93) of flumazenil-treated patients, compared with 13% (6 of 46) of placebo-treated patients. The criterion response (Observer's Assessment of Alertness/Sedation Scale score of 4 or 5) that was achieved at 5 minutes was maintained in 79 (93%) of 85 patients throughout the 180-minute observation period. Psychomotor performance, measured by the Finger-to-Nose Test, was rated as normal at 5 minutes posttreatment for 77% (71 of 92) of flumazenil-treated patients, and 4% (2 of 46) of placebo-treated patients. The reversal of amnesia, as determined by the Picture Recall Test was less consistent. Patients given flumazenil did not experience more pain at the operative site or require more analgesic medication than did those given placebo. Nausea (flumazenil 24%; placebo 15%), dizziness (flumazenil 12%; placebo 2%), and vomiting (flumazenil 10%; placebo 9%) were the most frequent adverse effects in each group. In conclusion, flumazenil provided prompt arousal from benzodiazepine-induced sedation and was well tolerated.


Cellular origin of the rapidly exchangeable calcium pool in the cultured neonatal rat heart cell.

Calcium in the myocardial cell is highly compartmentalized and in the cultured neonatal rat heart cells over 66% of the exchangeable calcium exchanges extremely fast (t1/2 < 1 s). The goal of the present study was to investigate, in the intact cell, the locus of this pool. By comparing myoblasts and fibroblasts and their respective plasma membranes, it is concluded that in the intact myocyte a significant fraction of the large lanthanum displaceable calcium pool is attributable to intracellular components, not present in the fibroblast. At least 30% of the lanthanum displaceable pool resides intracellularly, as is shown with the use of the drugs nifedipine, ryanodine and thapsigargin. It is proposed that the diadic subsarcolemmal junctional region represents a significant locus for the pool.


Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group.

Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose. Thirteen emergency departments enrolled 326 patients in this double-blind, placebo-controlled trial; 162 patients were randomly allocated to receive flumazenil (maximum dose, 30 ml, providing 3 mg of flumazenil), and 164 were allocated to receive placebo (maximum dose, 30 ml). A successful response was the attainment of a score of 1 or 2 on the Clinical Global Impression Scale (CGIS), denoting a very much improved or much improved status, 10 minutes after the start of intravenous administration of the test drug. Among those patients whose drug screen revealed the presence of benzodiazepines, 75 (77%) of 97 patients given flumazenil and 13 (16%) of 83 given placebo attained such a response. The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo. As determined by the Neurobehavioral Assessment Scale, 61% of patients who initially responded became resedated; in these patients, the effect of flumazenil lasted a median of 90 minutes. At the investigator's discretion, patients who did not achieve a criterion response in the double-blind trial could receive open-label flumazenil, titrated as in the double-blind phase. Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded. Safety was assessed in all 326 patients given the test drug. The most frequent adverse experiences after the administration of flumazenil were agitation (7%), vomiting (7%), abnormal crying (4%), and nausea (4%); these effects were observed with a lower frequency in the placebo group. Serious adverse experiences were reported in 4 patients; these included seizures and cardiac arrhythmias. Of the 3 patients with seizures, 2 had ingested large doses of cyclic antidepressants in addition to the benzodiazepine. The toxicology screen for 1 of the 2 showed 1900 ng/ml of amoxapine and 900 ng/ml of nortriptyline; the toxicology screen for the other, who also had ventricular tachycardia, showed 1928 ng/ml of loxapine and 301 ng/ml of amoxapine. The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose. This was accomplished irrespective of the presence of coingested drugs. Flumazenil is not recommended for patients with serious cyclic antidepressant poisoning or those who use benzodiazepines therapeutically to control seizure disorders. When used as recommended, however, flumazenil has been shown to have an acceptable safety level.


Hormonal management of prostate cancer.

In advanced disease, androgen deprivation remains the usual treatment. The completion of current trials is awaited to confirm whether total androgen blockade will prolong survival. To make further advances in treatment the fundamental biology of the prostate cell, benign or malignant, and its relationship to endocrine manipulation, must be understood. This may then lead to an understanding of clonal escape mechanisms in transformed cells and the clinical correlate of escape, relapse.


Morbidity in patients on L-thyroxine: a comparison of those with a normal TSH to those with a suppressed TSH.

Patients on L-thyroxine with a 'suppressed' TSH (< 0.05 mU/l) were compared to those in whom TSH was detectable but not elevated (0.05-4.0 mU/l), with regard to morbidity data. Biochemical data from Tayside Thyroid Register was matched to hospital admissions data obtained from Health Board Statistics. The patients were identified from those registered on the computerized Tayside Register. Serum T4 and TSH assays, clinical assessment scores, and admission records with regard to ischaemic heart disease, overall fractures, fractured neck of femur and breast carcinoma. Over one year, 1180 patients on thyroxine replacement had clinical and biochemical assessment; 59% had a suppressed TSH and 38% 'normal' TSH. Patients with a suppressed TSH exhibited higher median serum thyroxine levels (146 nmol/l, range 77-252 vs 119 nmol/l, 58-224; P < 0.001). Patients under the age of 65 years on L-thyroxine had an increased risk of ischaemic heart disease compared to the general population (female 2.7 vs 0.7%, P < 0.001; male 6.4 vs 1.7%, P < 0.01), but the risk was no different between those with suppressed and normal TSH. There was no increase in risk for overall fracture, fractured neck of femur or breast carcinoma in those on thyroxine with suppressed or normal TSH. Patients under the age of 65 years on L-thyroxine had an increased risk of ischaemic heart disease. There was no excess of fractures in patients on L-thyroxine even if the TSH is suppressed.


Circadian changes in pulsatile TSH release in primary hypothyroidism.

We evaluated pulsatile and circadian TSH secretion in primary hypothyroidism. In a prospective study, blood was sampled every 10 minutes during 24 hours for assay of TSH (IRMA). Thyroid hormones and TSH responsiveness to TRH were then measured. Nine patients with overt primary hypothyroidism, seven patients with subclinical hypothyroidism and 16 healthy controls. Computer-assisted analysis by the Desade and Cluster programs. Both computer-assisted programs revealed an increased TSH pulse amplitude in both overt and subclinical hypothyroidism versus controls (Desade: 36.9 +/- 31.4 (mean +/- SD) (P < 0.001) and 2.8 +/- 1.9 (P < 0.001) vs 0.4 +/- 0.2 mU/l; Cluster: 25.6 +/- 25.1 (P < 0.001) and 2.4 +/- 1.4 (P < 0.001) vs 0.4 +/- 0.2 mU/l). TSH pulse frequency remained unchanged with approximately 10 pulses/24 hours. A highly significant correlation was found between the mean 24-hour TSH concentration and the TSH pulse amplitude in all controls and patients but not to TSH pulse frequency. The nocturnal TSH surge was absent in six out of nine patients with overt primary hypothyroidism. The deficient nocturnal rise of TSH in primary hypothyroidism vs controls (22 +/- 51 vs 82 +/- 41%, P < 0.001), was associated with a loss of the usual nocturnal increase in TSH pulse amplitude and frequency. Mean 24-hour TSH pulse amplitude is increased in primary hypothyroidism, but TSH pulse frequency remains unchanged. The decrease of the nocturnal TSH increase in primary hypothyroidism is associated with a loss of the usual nocturnal increase in TSH pulse amplitude and frequency.


Circadian rhythm and pulsatility of parathyroid hormone secretion in man.

We wished to investigate the circadian rhythm and pulsatility of parathyroid hormone (PTH) secretion in man, as conflicting results have been published. To investigate the circadian rhythm during daytime, we sampled (a) peripheral blood at hourly intervals in 12 healthy young men from 0900 h until 1700 h. For observation of pulsatility, we sampled (b) peripheral blood at 1-minute intervals for 1 hour in three healthy men and three healthy women (mean 27.7 years, range 21-56 years) and (c) at 1-minute intervals for 30 minutes in 21 patients with surgically confirmed primary hyperparathyroidism (pHPT). The serum levels of intact PTH were measured by two-site immunoradiometric assay and special care was taken to reduce intra-assay variability, especially at the normal PTH concentration. In series (a), ionized calcium, total calcium and phosphate were also determined. A circadian rhythm during daytime was found for intact PTH in healthy men and women with a nadir at 0930 h and a peak in the afternoon. Ionized calcium and total calcium (protein-adjusted) decreased and phosphate increased in the afternoon. These changes were all statistically significant (P < 0.02). Pulsatility of PTH: Statistical cluster analysis of the data showed no pulsatility either in healthy persons or in patients with primary hyperparathyroidism. In two healthy women and one healthy man slight changes of longer duration were discovered, but no complete pulses. In five patients with primary hyperparathyroidism, larger differences between the highest and lowest concentrations of intact PTH were found, but no complete pulses. Our data show a significant circadian rhythm during daytime of intact PTH and only minor changes from minute to minute. The alterations in PTH-levels occurred at longer time intervals in healthy persons. In some patients with primary hyperparathyroidism, decreases of PTH-levels were found. The circadian rhythm of PTH may be due to slight changes in calcium or phosphate concentration.


The effects of opioid blockade and GnRH administration upon luteinizing hormone secretion in patients with anorexia nervosa during the stages of weight loss and weight recovery.

We examined the functional status of the hypothalamic-opioid system involved in LH secretion and the pituitary LH sensitivity and reserve in patients with anorexia nervosa were studied during body weight loss and weight recovery. We measured the temporal relationship between weight recovery, expression of hypothalamic-opioid activity and pituitary GnRH responsiveness, and resumption of ovulatory cycles. Five patients with anorexia nervosa were prospectively studied during weight loss and amenorrhoea, subsequently when they reached their ideal body weight but still remained amenorrhoeic and thereafter every 6 months until resumption of ovulatory cycles; one patient was studied only during weight loss, two during ideal body weight and amenorrhoea and one during ideal body weight and ovulatory cycles. Blood was sampled every 10 minutes over a 16-hour period on two alternate days. On study day 1 (control day), patients received two sets of saline infusion every 6 hours and one saline bolus at the beginning of the seventh hour; on study day 3 (experimental day), they received a saline infusion during the first 6 hours, an intravenous bolus of naloxone (20 mg) at the beginning of the seventh hour and then a continuous naloxone infusion (1.6 mg per hour) during the ensuing 6 hours. Pituitary LH sensitivity and reserve were assessed on both study days by the subsequent administration of 5 and 95 micrograms of GnRH 4 hours before the completion of each sampling period. Patients in ideal body weight and ovulatory cycles as well as five normal menstruating women included in the study for comparative purposes, were studied during the midluteal phase of a cycle. LH, oestradiol and progesterone were determined by radioimmunoassay. Areas under the LH curve were calculated by the trapezoid method; LH pulse detection was carried out by the program Cluster. Naloxone administration to patients with anorexia nervosa in the weight loss phase, did not significantly modify their serum LH levels nor the characteristics of its pulsatile secretion. Administration of the opioid blocker induced a significant increase in serum LH concentrations only in those patients in ideal body weight and amenorrhoea who resumed ovulatory cycles within the 6 months following the last study as well as in patients with an ideal body weight and ovulatory cycles and in normal controls. All patients and subjects who responded to naloxone administration exhibited significant increases in the area under the LH curve, mean LH pulse amplitude and peak area. Patients in ideal body weight and amenorrhoea who did not resume ovulatory cycles within the 6 months following the study days, did not respond to naloxone administration. There were no significant correlations between the magnitude of LH response to naloxone administration and the baseline levels of serum oestradiol and progesterone. All patients exhibited significant pituitary LH responses to both GnRH doses, regardless of the stage of the disease; however, the pituitary responsiveness shown by patients in ideal body weight was significantly higher than that presented by patients in weight loss. There were no significant differences between the responses to GnRH exhibited by patients in ideal body weight and amenorrhoea who responded to naloxone administration and those shown by patients in the same clinical condition but who were insensitive to opioid blockade. The re-establishment of hypothalamic-opioid inhibitory activity involved in LH secretion in patients with anorexia nervosa during the phase of weight gain predicts imminent restoration of ovulatory cycles. Pituitary LH response to exogenous GnRH during weight recovery does not accurately predict the outcome of the disease regarding reinitiation of menstrual cycles; however, it might be an indicator that the normal function of the hypothalamic-pituitary axis is being restored.


The empty sella: results of treatment in 76 successive cases and high frequency of endocrine and neurological disturbances.

We assessed the frequency of endocrine or neurological disturbances and the results of surgery in patients with empty sella, diagnosed with cisternography and/or computerized tomography scanning. Analysis of hospital records of 76 successive patients (73 primary, three secondary empty sella) from a single institution. Clinical and neuro-ophthalmological evaluation. Serum PRL, GH, TSH, LH, FSH, T4, T3 by radioimmunoassay. Diagnosis of empty sella with cisternography and/or computerized tomography scanning (n = 69), or discovered at surgery (n = 7). Patients with empty sella had: headache (69.7%), visual disturbances (34.2%), cerebrospinal fluid rhinorrhoea (11.8%), endocrine disturbances (51.4%, including hyperprolactinaemia, acromegaly, Cushing's syndrome). A pituitary tumour was discovered in two patients, in seven other ones it was suspected but not found at surgery. Transsphenoidal packing of empty sellas was done in 56 cases, with 7.1% post-operative complications. With surgery there was improvement of headache in 71%, of visual disturbances in 46%. Cerebrospinal fluid rhinorrhoea (discovered at surgery in four other patients) was not resolved by the first operation in six out of 13 patients. In 20 patients without surgery, headache improved in 64.6%. The empty sella is frequently associated with a variety of neurological and endocrine disturbances, which is contrary to conventional belief. Cerebrospinal fluid rhinorrhoea is not a rare complication and it may be difficult to treat. Some cases of empty sella may be due to partial pituitary apoplexy. Autoimmunity may have existed in other cases. Surgery may be useful in many patients, but a judicious selection is needed because it entails complications and non-operated patients may improve spontaneously.


Dose-dependent suppression of serum prolactin by cabergoline in hyperprolactinaemia: a placebo controlled, double blind, multicentre study. European Multicentre Cabergoline Dose-finding Study Group.

Dopamine agonists have a well established place in the treatment of hyperprolactinaemic disorders but their use is associated with a high incidence of adverse effects. We have investigated the biochemical efficacy and side-effect profile of a range of doses of the novel, long-acting dopamine agonist, cabergoline, in suppressing prolactin (PRL) in hyperprolactinaemic women. Multicentre, prospective, randomized, placebo controlled and double blind. One hundred and eighty-eight women with hyperprolactinaemia secondary to microprolactinoma (n = 113), idiopathic disease (n = 67), empty sella syndrome (n = 7) or following failed surgery for a macroprolactinoma (n = 1). Weekly assessment of adverse symptoms, blood pressure and pulse, serum PRL, blood count, liver and renal function. Patients received either placebo (n = 20) or cabergoline 0.125 (n = 43), 0.5 (n = 42), 0.75 (n = 42) or 1.0 mg (n = 41) twice weekly for 4 weeks. The five treatment groups were comparable in age (mean 31.8, range 16-46 years), diagnosis, previous therapy, and pretreatment serum PRL. PRL was suppressed to below half the pretreatment level in 5, 60, 90, 95 and 98% and normalized in 0, 30, 74, 74 and 95% of patients taking placebo or cabergoline 0.125, 0.5, 0.75 or 1.0 mg twice weekly respectively (Armitage's test, chi 2 = 39.3, P < 0.01). Cabergoline therapy (all doses) restored menses in 82% of the amenorrhoeic women not previously treated with dopamine agonists. Adverse events were recorded in 45% of patients in the placebo group and in 44, 50, 50 and 58% of those taking 0.125, 0.5, 0.75 and 1.0 mg cabergoline twice weekly (Armitage's test, P > 0.05). Over 95% of reported symptoms were relatively trivial, most frequently transient nausea, headache, dizziness, fatigue and constipation. More severe adverse events, interfering significantly with the patients' lifestyle, occurred in 13 (7.7%) patients taking cabergoline; treatment withdrawal was necessary in only one case. No adverse effects were detected on blood pressure or haematological or biochemical parameters. We have shown a linear dose-response relationship for cabergoline in the treatment of hyperprolactinaemia in the range 0.125-1.0 mg twice weekly, with normalization of PRL in up to 95% of cases and acceptable tolerability throughout the dose range.


Immunoreactive inhibin levels during ovarian stimulation may predict granulosa cell maturity.

The aim of the study was to assess whether the immunoreactive inhibin response to ovarian stimulation in polycystic ovarian syndrome was of predictive value for the outcome of ovulation induction. Daily injections of purified FSH (Metrodin, Serono Laboratories, UK) were administered for the purpose of inducing development and ovulation of a single follicle. All patients had anovulatory infertility secondary to polycystic ovarian syndrome and were resistant to clomiphene citrate. Alternate day serum samples were obtained for measurement of gonadotrophins, sex steroids and inhibin by radioimmunoassay. Alternate day ovarian ultrasound scans were carried out to monitor follicular development. There was a high incidence of multiple follicular development (MFD) (10.2 +/- 7.1 (standard deviation) follicles). There was a close relationship between the number of follicles on the day of the ovulatory trigger and serum oestradiol (E2) levels (R = 0.97, P < 0.001). This relationship was not seen with serum immunoreactive inhibin levels (R = 0.31). The cycles were divided into two groups depending whether there was or was not MFD (more than five follicles > 7 mm in diameter on day of hCG administration). The MFD group had 15.6 +/- 8.5 follicles and the non-MFD group 3.2 +/- 1.6 follicles. There was no difference in the circulating E2 concentration (pmol/l) per follicle between the two groups (non-MFD cycles, n = 6,345 +/- 28.9; MFD cycles, n = 8, 308 +/- 40.29). However, the immunoreactive inhibin concentration (U/ml) per follicle was lower, P < 0.001, in the MFD group (4.3 +/- 1.6 vs 6.9 +/- 0.5). The maximum and mean follicle diameter were lower, P < 0.01, in the MFD group (maximum follicle size 16.5 +/- 3.9 vs 21.2 +/- 1.5 mm, mean follicle size 11.5 +/- 2 vs 14.9 +/- 2.3). When individual cycles were examined E2 and immunoreactive inhibin secretion rose in parallel in cycles with less than five follicles with a rapid rise occurring when the follicles reached about 12 mm in diameter. In cycles where there was MFD there was a disparity between E2 and immunoreactive inhibin secretion with E2 levels rising 4.3 +/- 1.4 days before immunoreactive inhibin levels. These data suggest that in cycles where there are multiple small follicles, E2 secretion is maintained whereas immunoreactive inhibin secretion is substantially lower. Thus, in view of the disparity between E2 and immunoreactive inhibin secretion evident in the MFD group, measurement of immunoreactive serum inhibin concentration may be a better indicator of granulosa cell maturity. Immunoreactive inhibin secretion may occur only from healthy mature follicles.


Human chorionic gonadotrophin contributes to the bioactivity of Pergonal.

We examined batch variation in the LH-like bioactive content of Pergonal and determined whether hCG contributes to this. Random selection of three batches of Pergonal, consisting of three ampoules in each batch. The LH content in each ampoule was determined by radioimmunoassay (R-LH), immunoradiometric assay (I-LH) and in vitro Leydig cell bioassay (B-LH) using the urinary hMG International Standard 70/45. Human chorionic gonadotrophin was determined by immunoradiometric assay (I-hCG) using the hCG IRP 75/537. The isohormone content of each batch was examined by chromatofocussing over the range pH 4.5-7.0 and the fractions collected were assayed for LH and hCG content. The variability in potency between batches was assessed by single factor analysis of variance. The gonadotrophin content of each batch (IU/ampoule, mean +/- SEM, n = 3 ampoules) was R-LH (40.9 +/- 0.5, 40.8 +/- 0.2, 39.3 +/- 0.7, P > 0.15), I-LH (39.0 +/- 1.5, 28.3 +/- 0.8, 36.9 +/- 3.3, P < 0.001), B-LH (27.3 +/- 0.3, 12.0 +/- 0.9, 19.3 +/- 0.9, P < 0.001) and I-hCG (16.4 +/- 0.7, 11.7 +/- 0.2, 10.5 +/- 0.5, P < 0.001). The chromatofocussing recoveries below pH 5.5 expressed as a percentage of the total amount of analyte eluted from the column and collated for all three batches of Pergonal were (mean % +/- SD, n = 3 batches) R-LH (58.4 +/- 4.0), I-LH (41.3 +/- 7.5), B-LH (81.4 +/- 2.8) and I-hCG (87.8 +/- 3.7). There was significant batch variation in the I-LH, B-LH and I-hCG (P < 0.001) but not the R-LH (P > 0.15) content of Pergonal. More than 80% of the total B-LH recovery chromatofocussed below pH 5.5 and corresponded to the region of highest I-hCG (> 87%) and lowest I-LH (< 42%) recovery. This was highly suggestive of hCG contributing to the LH-like bioactivity of Pergonal.


Non-autonomy of parathyroid hormone secretion in acute primary hyperparathyroidism.

A patient with acute primary hyperparathyroidism treated with mithramycin preoperatively, underwent neck exploration and two enlarged parathyroid glands were excised: one huge adenoma (6g) and another smaller gland. Mithramycin was administered preoperatively to lower life-threatening hypercalcaemia, and parathyroid slices from the huge adenoma removed at surgery were submitted in vitro to various calcium concentrations in the media to determine the influence of calcium on parathyroid adenoma secretory pattern in acute primary hyperparathyroidism. Mithramycin induced a significant decline in calcium levels and significant elevations of calciotrophic hormones (intact PTH, mid-region specific PTH, calcitonin and calcitriol). Significant suppression in PTH output in vitro was achieved by increasing calcium levels in the media. These results exclude autonomous PTH secretion (non-calcium dependent) as a possible aetiology of acute primary hyperparathyroidism. We suggest that a sudden increase in the set-point of the diseased parathyroid cells in the presence of a huge cell mass accounts, in large part, for both the marked hypercalcaemia and elevated PTH levels in this patient.


Thyroid abscess complicating subacute thyroiditis: a consequence of steroid therapy?

A patient with subacute thyroiditis developed a thyroid abscess after drainage of a pilonidal abscess. An infective focus in a patient with subacute thyroiditis on steroids should be treated aggressively with adequate antibiotic cover.


Effect of potassium infusion on renal function in ANF-transgenic mice.

Transgenic mice expressing an ANF fusion gene in the liver were used to study renal function before and during an intravenous KCl load. These animals are characterized by a 10- to 20-fold elevation in plasma ANF concentration, and by a reduction in arterial blood pressure by 20-30 mm Hg, compared to nontransgenic littermates. Before the KCl infusion, renal excretions of fluid, sodium, potassium, and chloride were not different from corresponding values in the nontransgenic sibling mice. Glomerular filtration rates were slightly lower in the transgenic animals. During the KCl infusion, diuresis, saluresis, and kaliuresis were found in both groups. However, salt and water excretion, but not potassium excretion, were significantly greater in the transgenic group. In a separate series, plasma aldosterone concentrations were significantly higher in the transgenic, compared to the nontransgenic mice. These data are interpreted as indicating that antinatriuretic mechanisms, including aldosterone-dependent sodium reabsorption in the cortical collecting tubule, can counteract the effect of ANF to inhibit sodium reabsorption in the medullary duct system, thus allowing maintenance of salt balance. Furthermore, a reduced tubular flow rate at the aldosterone-sensitive site would ensure normal potassium excretion despite the elevated mineralocorticoid level. During KCl infusion, the known increase in tubular delivery of salt and water to the duct would allow full expression of the downstream ANF effect, accounting for the relatively greater diuresis and saluresis in the transgenic mice. We conclude that both renal and adrenal actions of ANF can be rendered ineffective by countervailing mechanisms, suggesting an explanation for the apparent lack of biological activity of endogenously elevated plasma NAF in some disease states.


Definition of a small chromosomal rearrangement on chromosome 11p14 by molecular cytogenetics in situ hybridization.

Chromosomal in situ hybridization allows the detection and the definition of single copy DNA segments of very small size. In a particular case, we demonstrate the inactivity of this molecular cytogenetic technique. In this case, karyotype analysis revealed a chromosome 11p+. In situ hybridization of probes PBGD, D11S29, NCAM, and ETSI located at 11q23-qter shows that the extra chromosomal material on chromosome 11p+ is a duplication of the 11q23-qter region.


Evidence for T lymphocyte reactivity to the 65 kilodalton heat shock protein of mycobacterium in active Crohn's disease.

The role of mycobacterial heat shock proteins (Hsp) of the 65 kilodalton Hsp family as a possible factor governing cell-mediated immune responses, leading to chronic mucosal inflammation, was examined. Purified peripheral blood mononuclear cells (PBMC) from patients with CD and ulcerative colitis (UC), and from healthy and disease controls were stimulated in culture with a highly purified, recombinant 65 kilodalton Hsp (rHsp65) of M. bovis BCG for 5 d. Cultures were then pulsed with 3H-thymidine for 24 h and uptake determined by liquid scintillation. We found that PBMC from patients with active CD exhibited a significant proliferative response to the soluble rHsp65 as compared with normal controls. In contrast, the proliferative responses of PBMC from patients with inactive CD, inactive and active UC, pancreatitis and cecal carcinoma were found to be not different from controls. Purified T cells or non-T cells of PBMC in the absence of antigen-presenting cells from active CD patients exhibited a lack of proliferative responses to the rHsp65 stimulation in culture. The data indicate an aberrant sensitization of T cells to the 65 kilodalton mycobacterial Hsp in a specific type of IBD, and thus may provide an important clue for the etiopathogenesis of Crohn's disease.


A pilot study of steroid withdrawal followed by oral acyclovir in the treatment of chronic type B hepatitis.

Ten patients with chronic type B hepatitis were treated for four weeks with a rapidly tapered dose of oral prednisone (initial dose, 40 mg/d) followed by two weeks of no therapy followed by four weeks of oral acyclovir (600 mg/d). Liver biochemistry, HBsAg, HBeAg, DNA-polymerase and HBV-DNA levels in serum were determined prior to, during and for six months following therapy. The mean age +/- SD of the study population was 33 +/- 15 years (range 18-58). Nine of the patients were male. Four patients were Caucasian and six of Southeast Asian origin. Three patients were homosexual, all HIV antibody negative. The mean ALT level prior to treatment was 89 +/- 62 IU/L (range: 30-214). During the six month post-treatment follow-up period, 5/8 (63%) patients became DNA-P negative and 6/10 (60%) HBV-DNA negative. One responder reverted to DNA-P positive (final response, 50%) and another to HBV-DNA positive (final response, 50%) prior to completion of the study. Patients were more likely to become DNA-P or HBV-DNA negative if they had elevated pre-treatment ALT values and low levels of DNA-P and HBV-DNA. HBeAg became undetectable in 3/10 (30%) individuals, one of whom reverted to positive at the end of the follow-up period (final response, 20%). All patients remained HBsAg positive. Mild fatigue, which occurred in four individuals, was the most common side effect. The results of this study suggest that a controlled clinical trial of oral prednisone/acyclovir is warranted in the treatment of adults with chronic type B hepatitis.


The quality of medical science.

Is the quality of science aimed at understanding and treating disease inferior to more basic investigations of basic biology, or does the different quality of medical science reflect a distinct nature? This duality in the meaning of quality is central to any critique of the quality of medical science. The nature of medical science, which deals with the dysfunction of integrated genetic, epigenetic, environmental, or stochastic phenomenon, is distinct from that of basic science which seeks to describe discrete biological processes. In physical sciences it is generally accepted that there are practical boundaries between disciplines such as quantum physics, thermodynamics, and chemistry even though, in theory, such investigations are related. In meteorology, the development of chaos theory establishes that there are even theoretical limits to the ability to predict large scale processes from their essential, constituent processes. So too, the quality of medical science may be distinct from that of basic biology.


Prospects for academically trained pediatricians in academic medicine.

There is widespread concern about the commitment and ability of physicians to enter careers in academic medicine. We studied MEDLINE citations by 150 academically trained pediatricians to determine whether they remained in academic medicine and to assess the nature of their contribution. We identified 2098 citations by 122 of the 150 individuals which reflected substantive involvement in clinical and basic research. Most individuals published their first papers within three years after residency and thereafter exhibited a stable level of productivity. Individuals who published prior to completing residency were most likely to enter academic medicine and achieve a high level of productivity. These reassuring data suggest that individuals who pursue an academic track may assume the traditional role of the physician scientist, and suggest measures which may be taken to attract more physicians to academics.


Twenty years of randomized clinical trials of manipulative therapy for back pain: a review.

Manipulative therapy has been one of the most intensively studied approaches to back pain management. This paper reviews 20 years of randomized clinical trials of manipulative therapy, and addresses the following issues: for what condition were these patients treated? What was the population studied, and were workers included? Was a specific technique, spinal manipulation, or a more global approach the object of the trial? Finally, were there long-term outcome measures? The 21 randomized clinical trials reviewed here provide some indication that manipulative therapy offers some positive short-term results; it is not clear at this point whether long-term effects of the treatment have been adequately evaluated. Lack of specificity in the description of samples makes it impossible to conclude on the benefit of spinal manipulation for workers. Whether manipulation is solely responsible for the changes mentioned in these studies, independently of the global approach put forth by its practitioners, is also an open question that awaits further study.


Correlation of morphometric analysis of pancreatic islets and diabetes in spontaneously diabetic BB/W rats.

Morphometric analysis of pancreatic islets was performed on BB/W rats, which were divided into moderately diabetic and severely diabetic as well as normoglycemic during four months of observation. In normoglycemic rats, total islet area occupied 1.2% of total pancreatic tissue area with a mean area of 19,000 microns2 per islet. Total pancreatic area was markedly decreased to 22% and 10% in moderately and severely diabetic rats, respectively, compared with that of normoglycemic rats. Mean islet area of moderately and severely diabetic rats decreased to 28% and 25% per islet that of normoglycemic rats, respectively, in which severely diabetic rats showed variable sizes of islets. Concomitant morphometric analysis of renal glomeruli showed decreasing sizes of glomeruli in severely diabetic rats whereas number of glomeruli in renal cortex increased in severely diabetic rats compared with normoglycemic rats. Moderately and severely diabetic states were also studied by I.V. glucose and insulin tolerance tests in regard to plasma glucose and insulin levels compared with normoglycemic rats. During months of observation severely diabetic rats had their total islet area reduced to 10% that of normoglycemic rats as a result of cell mediated immune destruction of islets. And concomitant reduction of glomeruli may be a part of diabetic glomerulopathy. Yet, diabetic rats were normotensive. The degree of water intake, urine volume, urine glucose, urine protein and albumin was also correlated with the degree of diabetes. This study further provides the feasibility of using diabetic BB/W rats for diabetic conditions and their complications.


Prediction of insulin dependent diabetes mellitus in non-obese diabetic mice by the endogeneous tumor necrosis factor-alpha level.

The non-obese diabetic (NOD) mouse is an animal model of human insulin dependent diabetes mellitus (IDDM). In this strain, the serum concentration of tumor necrosis factor-alpha (TNF alpha) after OK432 (a streptococcal preparation) stimulation is much lower than in any other non-diabetic control strain. Female NOD mice which have a higher incidence of diabetes have significantly lower TNF alpha level (6.5 +/- 4 U/ml, mean +/- SEM) than do male NOD mice (21 +/- 5 U/ml) (P < 0.02) which have lower incidence of diabetes. On the basis of these results, we designed a prospective study to evaluate the relationship between the serum TNF alpha concentration and the incidence of diabetes in individual male NOD mice. Mice were studied until 30 weeks of age. During this period four of eight mice with a low TNF alpha level (TNF alpha < or = 1.1 U/ml) became diabetic, whereas none of eighteen mice with a high TNF alpha level (TNF alpha > 1.1 U/ml) developed overt diabetes. These results indicate that by measuring of endogeneous TNF alpha level after stimulation by OK432, one could predict IDDM in male NOD mice.


Insulin, glibenclamide or metformin treatment for non insulin dependent diabetes: heterogenous responses of standard measures of insulin action and insulin secretion before and after differing hypoglycaemic therapy.

Using carefully selected relatively non-obese non insulin dependent diabetic patients, we were not able to show differences in standard measures of insulin production or insulin action between patients treated with a long acting crystalline zinc insulin, with glibenclamide, or with metformin for a six week period. All three drugs were hypoglycaemic, but a fall in basal hepatic glucose output measured by the 3H3 glucose technique was only seen in those patients who had an initial fasting plasma glucose above 12.0 mmol/l, irrespective of treatment.


Influence of blood glucose levels on peripheral lymphocytes in patients with diabetes mellitus.

Abnormalities in lymphocyte subpopulations in patients with type 1 diabetes have been reported previously. To evaluate the effect of blood glucose levels on peripheral lymphocyte concentrations we studied the proportion and phenotypic composition of the T-cell population in 7 patients with type 1 and in 12 patients with type 2 diabetes at hospitalization because of metabolic dysregulation and in a period of restored control. Both the number of CD-4 and CD-8 positive cells increased significantly (p < 0.05), although no change in the CD-4:CD-8 ratio was observed. After restoring metabolic control there was a significant rise in the mean number of total lymphocytes (1760 +/- 759 x 10(6)/ml vs 2385 +/- 889 x 10(6)/ml, p < 0.05). The number of total lymphocytes increased in all patients but one. It is concluded that metabolic control can influence immunological parameters such as numbers of peripheral lymphocytes of various phenotypes.


Growth hormone levels in the basal state and after thyrotropin-releasing hormone stimulation in young type 1 (insulin-dependent) diabetic patients with severe retinopathy.

Sixteen young patients with type 1 diabetes mellitus and rapidly progressive severe retinopathy were examined regarding serum levels of growth hormone before and after the i.v. administration of 200 micrograms thyrotropin-releasing hormone (TRH). Serum IGF I, HbA1c, blood pressure, urinary albumin, and serum creatinine levels were also measured. The control group consisted of type 1 diabetic patients matched for age, duration of diabetes and metabolic control with no or minimal background retinopathy. The results show that basal growth hormone levels were above normal in both groups, and that there was a paradoxical increment in growth hormone levels after TRH stimulation (p < 0.05) in patients with severe retinopathy, but the values did not differ from patients with background retinopathy. IGD I levels were normal in all patients but one, and no differences were seen between the two groups. HbA1c, serum creatine, blood pressure, and urinary albumin levels were similar in the groups but patients with severe retinopathy were treated with more insulin (p < 0.001). Thus, neither abnormal growth hormone levels, nor IGF I, seems to be associated with the development of severe retinopathy in young type 1 diabetic patients.


Delayed replication of human umbilical vein endothelial cells in high glucose is corrected by L-tyrosine.

Human umbilical vein endothelial cells (HUVEC) cultured in high glucose exhibit delayed replication and colchicine-resistant microtubules. Tubulin dysfunction and stabilization, brought about by acetylation of the NH2-terminal residues, loss of the C-terminal tyrosine and binding of microtubular-associated proteins (MAPs) may be involved in the above phenomenon. The effects of L-tyrosine on HUVEC replication in high glucose were tested and the hypothesis that non-enzymatic glycosylation might impair tubulin depolymerization was also checked by growing the cells in the presence of L-glucose, which binds to intracellular proteins but remains metabolically inactive. After 18 days in culture, the number (mean +/- SEM, n = 7) of HUVEC grown in 28.0 mmol/l D-glucose (435.7 +/- 59.1 x 10(3)) was lower than in 5.6 mmol/l D-glucose (818.3 +/- 75.2 x 10(3)), p < 0.0001. The addition of L-tyrosine 1.7 mmol/l corrected such growth inhibition (623.3 +/- 81.7 x 10(3)), p < 0.0001 vs. D-glucose 28.0 mmol/l, but the cells recovered were less numerous than in physiological glucose alone (p = 0.016). The addition of L-tyrosine to D-glucose 5.6 mmol/l (731.0 +/- 63.2 x 10(3)) did not modify the cell number significantly. HUVEC in extra L-glucose (687.4 +/- 72.0 x 10(3)) were less numerous than in 5.6 mmol/l D-glucose, p = 0.028, but more than in D-glucose 28 mmol/l, p < 0.0001, and were not modified by the addition of L-tyrosine (729.4 +/- 67.1 x 10(3)). HUVEC grown in physiologic and high glucose exhibited specific immunofluorescence for acetylated tubulin and MAPs.(ABSTRACT TRUNCATED AT 250 WORDS)


A comparison of four methods for assessing in vivo beta-cell function in normal, obese and non-insulin-dependent diabetic man.

Several methods of varying complexity are available for the measurement of in vivo insulin secretion in man. No study has previously compared these in the same subjects to establish which is the most appropriate for routine use. We have, therefore, compared four methods for measuring insulin secretion in man: Hyperglycaemic clamp (Hy), Minimal model (MIN), shortened intravenous glucose tolerance test (IVGTT) and continuous infusion of glucose with model assessment (C.I.G.M.A.). Seventeen subjects with varying degrees of insulin sensitivity were studied. Seven normal (BMI 22.5 +/- 1.5 kg/m2), five obese (BMI 38 +/- 5 kg/m2) and five NIDDM subjects (BMI 27 +/- 3 kg/m2) were investigated, in a randomised fashion, on separate days. First (PSI) and second phase (PSII) rate constants (MIN); incremental insulin secretion 0-10 mins (Hy delta I) and steady state insulin levels from the last 30 minutes (Hy120-150) from the hyperglycaemic clamp; 3 minute insulin concentration and incremental area under insulin secretion curve 0-10 min (IVGTT) and beta-cell function (%) from C.I.G.M.A. were used as indicators of insulin secretion. Each index of insulin secretion could detect an overall difference between the groups. Insulin secretion in normals and obese was similar but significantly increased compared to NIDDM. In normals PSI correlated with C.I.G.M.A. (Rs = 0.92, p < 0.02) and Hy120-150 (Rs = 0.82, p < 0.05). IVGTT0-10 correlated with PSII (Rs = 0.83, p < 0.05), HY delta I (Rs = 0.84, p < 0.05) and IVGTT3 min (Rs = 1.0, p < 0.001). In obese PSII correlated with C.I.G.M.A. (Rs = 0.91, p < 0.05), Hy delta I (Rs = 1.0, p < 0.02) Hy120-150 (Rs = 0.92, p < 0.05) and IVGTT3 min Rs = 1.0, p < 0.02). In addition Hy delta I also correlated with C.I.G.M.A. (Rs = 0.92, p < 0.05) and IVGTT3 min (Rs = 1.0, p < 0.02). In NIDDM Hy delta I correlated with C.I.G.M.A. (Rs = 0.91, p < 0.005). When all subjects from the three groups were combined, significant positive correlations were obtained between each index of insulin secretion. In conclusion we have demonstrated that: (a) C.I.G.M.A., IVGTT, Minimal model and hyperglycaemic clamp can provide similar overall results for, in vivo, beta-cell function in man. (b) Significant positive correlations were obtained between each index of insulin secretion when all subjects were combined. (c) Using the above methodologies insulin secretion in normal and obese appears similar but significantly increased compared to NIDDM subjects.(ABSTRACT TRUNCATED AT 400 WORDS)


Pancreastatin inhibits insulin secretion from isolated rat islets: studies on its mechanism of action.

The peptide pancreastatin is known to inhibit insulin secretion. To study its mechanism of action, we examined the effects of pancreastatin on 45Ca(2+)- and 86Rb(+)-efflux from isolated rat islets. We found that glucose (8.3 mmol/l)-stimulated insulin secretion was totally abolished by pancreastatin (100 nmol/l). It is known that glucose reduces the 86Rb(+)-efflux and increases the 45Ca(2+)-efflux from prelabelled islets, which reflects its action on the K(+)- and Ca(2+)-permeabilities. We found that pancreastatin reduced the glucose-stimulated increase in 45Ca(2+)-efflux without affecting the 86Rb(+)-efflux. This shows that pancreastatin inhibits the action of glucose on Ca(2+)-channels, without influencing the closure of K(+)-channels induced by the sugar. The results indicate that pancreastatin does not inhibit insulin secretion by hyperpolarizing the B-cells, but rather that the peptide inhibits insulin secretion by inhibiting the glucose-stimulated B-cell Ca(2+)-uptake that evolves by depolarization.


Reduced platelet thromboxane formation after long-term administration of a dihydropyridine calcium channel blocker: a prospective, double-blind, placebo-controlled study with nitrendipine in borderline hypertensive patients with IDDM-type diabetes mellitus.

Twenty-nine IDDM patients with borderline hypertension were randomly allocated to placebo or nitrendipine treatment. Nitrendipine was given orally at a dosage of 20 mg once daily over 4 weeks. Stimulated platelet thromboxane formation at rest and after standardized, non exhausting exercise was measured by standard methods. In addition, plasma levels of platelet factor 4 and aggregation responses to collagen and ADP were determined. In the treatment group thromboxane formation after stimulation with collagen (0.3 and 1.0 micrograms/ml) and 1 mM arachidonic acid (AA) was reduced in the resting state. Exercise induced change of thromboxane synthesis in response to 1.0 micrograms/ml collagen was significantly lower as compared to placebo (p < 0.05). In parallel, PF4 plasma levels were significantly lowered (p < 0.05). Whole blood aggregation after collagen stimulation (1.0 micrograms/ml) was reduced after 4 weeks of nitrendipine treatment, but ADP (5 microM) induced aggregation was not. These effects of nitrendipine were not seen in platelet rich plasma. In conclusion long-term nitrendipine treatment may inhibit collagen dependent platelet activation in the blood of diabetic patients with borderline hypertension.


Maternal postprandial blood glucose levels influence infant birth weight in diabetic pregnancy.

Relationships between maternal glycaemia and neonatal birth weight were studied prospectively in 14 tightly controlled pregnant women with pre-existing type 1 diabetes mellitus. Maternal glycaemia throughout pregnancy was determined from daily self blood glucose (BG) monitoring with memory meters and fortnightly fructosamine (Fr) and glycated haemoglobin (HbA1) measurements. Mean non-fasting BG and mean HbA1 throughout pregnancy correlated strongly (Spearman rank) with birth weight (0.64 and 0.73 respectively), as did mean second trimester non fasting BG (0.54), HbA1 (0.7) and Fr (0.64) and mean third trimester HbA1 (0.65), whereas mean fasting BG showed no significant correlations with birth weight at any age of pregnancy. The disparity between the strong correlation of non fasting BG with birth weight and the poor correlation of fasting BG suggests that postprandial as opposed to basal glycaemia significantly influences foetal growth and neonatal size.


Significance of 3HOH generation from D-[2-3H]glucose.

The significance of 3HOH generation by cells exposed to D-[2-3H]glucose is reevaluated. It is proposed that such a metabolic variable, rather than being taken as an index of D-glucose phosphorylation, may provide information on the extent of D-glucose 6-phosphate and D-fructose 6-phosphate interconversion in the reaction catalyzed by phosphoglucoisomerase. In order to reach such an information, the total production of 3HOH from D-[2-3H]glucose needs to be corrected for that attributable to either the catabolism of D-[1-3H]fructose 1,6-bisphosphate or the circulation of D-[2-3H]glucose 6-phosphate in the pentose phosphate pathway. A method is introduced which allows for such a correction.


Antipyretic therapy in the febrile child.

General principles of thermoregulation, the pathophysiology of fever, controversies concerning the use of antipyretic therapy, and nonpharmacologic and pharmacologic treatments commonly used for antipyresis in the pediatric population are reviewed. Several arguments can be made for not ameliorating the febrile response. Fever is an important diagnostic and prognostic clinical sign that may have beneficial effects for the host. In addition, body temperatures of < or = 41 degrees C (105.8 degrees F) are relatively harmless. Reasons for treating fever include patient discomfort, the potential for adverse sequelae, the possibility of seizures, and the possibility that fever could affect the pharmacokinetic profiles of drugs. Nonpharmacologic treatment for fever includes environmental measures to enhance dissipation of body heat and sponging. Aspirin and acetaminophen are the agents used most frequently for antipyresis in pediatric patients. However, aspirin use in children with a viral illness has been associated with development of Reye's syndrome. As a result, its use in children has declined in the United States. Acetaminophen is relatively free of adverse effects and is considered first-line pharmacologic antipyresis therapy. Ibuprofen suspension should be considered as second-line antipyretic therapy. Combination therapy with acetaminophen and aspirin may be considered if the patient fails to respond to other nonpharmacologic and pharmacologic therapies; however, combination therapy may result in increased risk of drug toxicity, increased probability of adverse reactions, and increased risk of intoxication. Aspirin, acetaminophen, and ibuprofen are equally effective for antipyresis in pediatric patients. However, because acetaminophen is the safest medication, it is currently the therapy of choice.


Evolution in indications for blood component transfusion.

Indications for blood components are changing but continue to be based on a combination of clinical assessment and laboratory data. In the perioperative setting, some decisions must be made before laboratory data are available. To prevent the inappropriate usage of blood components, prophylactic or expectant treatment should be limited. In red cell transfusion, physiologic indices of oxygen utilization may soon supplement hemoglobin/hematocrit levels in clinical decision making. Less progress has been made in transfusion for hemostasis. Well-designed clinical studies are needed to answer remaining questions; in the interim, nationally accepted guidelines are available to assist clinicians in their decisions.


Donor screening.

The primary goals of donor screening are to protect the recipient and safeguard the donor. These goals are accomplished through a variety of techniques, the most important of which is the donor medical history interview. This article reviews all elements of predonation donor screening, including donor education, the medical history interview, and the confidential unit exclusion procedure. Specific guidelines, including a proposed national uniform donor medical history questionnaire, are provided for all aspects of donor screening.


Safety in transfusion practices. Red cell compatibility testing issues.

Pretransfusion compatibility testing, if performed properly, helps to maximize the effectiveness of transfusion therapy and to minimize the risk of hemolytic transfusion reactions. Each laboratory should select the procedures and protocols that are best suited to meet their patient care and institutional needs. Quality assessment monitoring of the elements of compatibility testing helps to ensure a high level of safety for patients receiving transfusion therapy.


Safety in transfusion practices. Preventing infectious complications.

The benefits of transfusion therapy must always be weighed against the unavoidable chance of an infectious complication. Strategies to minimize the infectious risks inherent in the use of human blood and blood components can be categorized under four general headings: donor selection, testing, appropriate use, and follow-up and reporting of complications. The application of these strategies in the context of their role in the prevention of some of the infectious complications of transfusion therapy is discussed in this article.


Leukocyte-reduced blood components in transfusion medicine. Current indications and prospects for the future.

Transfusion medicine is a rapidly evolving specialty, and efforts are ongoing to improve the safety and quality of blood component therapy. Leukocytes are known to be the cause of numerous adverse effects of transfusion therapy, and their removal from red cells and platelet components may be desirable in a variety of clinical settings. The various complications of transfusion that can be attributed to contaminating leukocytes and the benefits of leukocyte depletion are addressed in this article. Laboratory as well as clinical data are summarized.


Immunosuppressive effects of blood transfusion.

Various in vitro studies, animal models, and retrospective investigations suggest that blood transfusion modulates the immune system. Not all studies, however, support this trend. This article provides a balanced presentation of the issues surrounding the concept of the immunosuppressive effects of blood transfusion.


Special issues in transfusion medicine.

This article reviews four controversial aspects of transfusion practices: the clinical circumstances, survival, and complications of massive transfusion; specific problems related to neonatal transfusion practices and the surgical support of the small child, including the appropriate age for red cells to be transfused, cytomegalovirus transmission, and the reduction in homologous donor exposures; the clinical presentation, incidence, and prevention of transfusion-associated graft-versus-host disease; and the biochemistry, function, genetics, and clinical indication for replacement therapy of antithrombin III.


New testing approaches in transfusion medicine.

A revolution has occurred in the availability of molecular diagnostic technology in the last decade. We are just now beginning to bridge the gap between research and the availability of rapidly licensed clinical assays. Many of these new technologies will be useful in the general practice of transfusion medicine. Some of these techniques may be discarded as impractical. However, many of these methods should prove to be useful in clinical transfusion research and diagnosis.


Limiting homologous blood exposure.

Successful limitation of homologous blood transfusion may necessitate multiple strategies and advance planning. Preoperative and intraoperative autologous blood collection may have to be supplemented with hemostatic pharmacologic agents. The use of cytokines is increasing. More efficient use of directed donors can have an important role in blood use. As these expensive and time-consuming techniques become available, a major challenge will be to determine which patients may benefit from or really need them.


Inactivation of microbial contaminants of blood components.

Despite the low risk of transfusion-transmitted infection currently present in the blood supply, processes to inactivate contaminating viruses and bacteria may improve the safety of transfusion even further. A variety of techniques, using both physical and chemical processes, are being explored. Particularly promising is adaptation of the solvent/detergent technique (already in use for plasma derivatives) to plasma for transfusion. Inactivation of viruses in cellular components may require a combination of techniques, possibly including leukocyte depletion filtration, photoactive compounds, and subsequent washing. Concerns about potential toxicity of the agents employed and retention of component efficacy after treatment and storage remain unresolved, however.


Redefining and expanding quality assurance.

To meet the current standards of excellence necessary for blood establishments, we have learned from industry that a movement toward organization-wide quality assurance/total quality management must be made. Everyone in the organization must accept responsibility for participating in providing the highest quality products and services. Quality must be built into processes and design systems to support these quality processes. Quality assurance has been redefined to include a quality planning function described as the most effective way of designing quality into processes. A formalized quality planning process must be part of quality assurance. Continuous quality improvement has been identified as the strategy every blood establishment must support while striving for error-free processing as the long-term objective. The auditing process has been realigned to support and facilitate this same objective. Implementing organization-wide quality assurance/total quality management is one proven plan for guaranteeing the quality of the 20 million products that are transfused into 4 million patients each year and for moving toward the new order.


Legal issues in transfusion medicine. Is blood banking a medical profession?

In legislation concerning the transfusion of AIDS, the issue of whether blood banking is a profession has become extremely important. The status of blood banking determines how blood center actions will be judged and what liability rules will be applied. The issue was recently hotly argued in the high courts of Colorado and Florida. The courts' decisions impact not only on the outcome of other lawsuits regarding the transfusion of AIDS against blood banks, but also on the way blood bank practices will be made in the future.


Regulatory and legislative issues in transfusion medicine.

The nation's blood supply is safer than ever following the implementation of more restrictive donor screening and additional tests for infectious agents. As a result of the AIDS crisis, however, there is a heightened awareness that blood transfusion is not an entirely benign therapy. As blood banking practices continue to undergo close scrutiny by members of Congress, regulators, and the American public, blood banks and transfusion services are striving to communicate effectively their efforts to ensure the provision of quality blood components and services.


The fourth dimension. Management of the postmodern clinical laboratory.

The clinical laboratory has undergone historic changes over the past decade. The Clinical Laboratory Improvement Amendments of 1988 are the regulatory acknowledgement of the technological revolution that has occurred. Challenged to meet increasingly diverse medical needs while facing cost restraints, managerial leadership will replace technical leadership in the clinical laboratory. Ignored for half a century by most American industries, total quality management has been invoked as the embodiment of systems engineering and group decision making in the postmodern clinical laboratory. The matrix organization, workload recording, and productivity measuring are cost-effective applications of total quality management in the clinical laboratory.


Changes in serum erythropoietin levels during chemotherapy for lung cancer.

Serial serum erythropoietin (EPO) levels were measured in 12 adult lung cancer patients during cancer chemotherapy. In major cases, EPO levels increased significantly after chemotherapy while the hemoglobin (Hb) remained at initial levels. EPO fell gradually or rapidly to initial levels after a peak, although the patients were anemic. The increase of EPO levels was linearly related to the decrease in Hb (y = 17.48x + 1.003). The mechanism of the rapid increase of EPO is not simply explained by anemia, but might be related to new synthesis, corresponding to depressed bone marrow.


Simple method for measuring the antibiotic concentration required to kill adherent bacteria.

A simple method was developed for measuring the antibiotic susceptibility of bacteria adherent to plastic surfaces. Staphylococcus aureus cells adhered to the bottom of a 96-well plastic tissue culture plate were incubated in serially diluted antibiotic solutions. After a 24-hour-incubation the solutions were removed, and fresh medium without antibiotics was added to each well. The viability of the cells was judged by their growth after a further 24-hour-incubation. The antibiotic concentration required to kill adherent bacteria was far higher than that required for planktonic cells, although we used bactericidal drugs; beta-lactam, quinolone, and aminoglycoside antibiotics. The tolerance demonstrated by adherent cells is likely to play a role in the difficulties encountered in the chemotherapy of biofilm infections.


Beta-lactamase expression and cross-resistance to beta-lactam antibiotics in a nosocomial population of Enterobacter.

This study sought to quantitatively describe the spectrum of constitutive and inducible beta-lactamase activity present in a tertiary care center's population of Enterobacter species. beta-Lactamase activity in the absence and presence of 2 recognized beta-lactamase-inducing antibiotics, cefoxitin and imipenem, was measured. The Enterobacter cloacae (n = 35) population was strikingly bimodal, expressing 'all-or-none' cross-resistance to beta-lactams (except imipenem) corresponding to the baseline level of beta-lactamase expression. E. aerogenes (n = 14) displayed a less dichotomous pattern of resistance, and MICs of beta-lactam antibiotics were less strongly related to the magnitude of enzyme activity. We conclude that our nosocomial population of E. cloacae, like strains rendered resistant to beta-lactams in vitro, is largely dependent upon beta-lactamase as a mechanism of this resistance. Furthermore, we document the presence of a large subpopulation of beta-lactam-susceptible isolates possessing inducible beta-lactamase and therefore subject to selection for enzyme derepression.


In vitro activity of amphotericin B, hamycin and their novel water-soluble compounds against pathogenic yeasts.

Twenty-eight pathogenic isolates, 4 each of Candida albicans, C. lusitaniae, C. parapsilosis, Cryptococcus neoformans, Torulopsis glabrata and Trichosporon beigelii were tested for their in vitro sensitivity to amphotericin B (AmB), hamycin (HA) and their novel water-soluble compounds, namely JAI-AmB (oral and injectable; patents pending) and JAI-HA (Jaimycin Inc., Walnut Creek, Calif., USA), using a standard double-dilution broth (1 ml/tube) procedure. The 2 novel compounds, namely JAI-AmB and JAI-HA, contain one twenty-fifth (w/w) of the AmB and HA, respectively. Results showed that the minimal inhibitory concentrations (MICs) of AmB for all species, except C. lusitaniae and Tr. beigelii (3.125-6.25 micrograms/ml), were 0.195-1.56 micrograms/ml. The values of JAI-AmB (oral) for C. albicans, C. parapsilosis, Cr. neoformans and To. glabrata ranged from 0.78 to 25 micrograms/ml. The MICs of JAI-AmB (oral) for the other yeasts were 100 micrograms/ml. All of the yeasts yielded higher MICs (3.125-100 micrograms/ml) against JAI-AmB (injectable) than the JAI-AmB (oral) preparation. Except for C. parapsilosis (MICs 25-100 micrograms/ml), all of the other species showed greater sensitivity to the parent HA (0.195-100 micrograms/ml) than AmB. The values for JAI-HA ranged from 0.195 to 100 micrograms/ml for all isolates, except C. tropicalis (100 micrograms/ml). Based on our in vitro findings, in vivo efficacies of JAI-AmB and JAI-HA should be carried out.


Incidence of beta-lactamase production among out patient clinical isolates in Middle Eastern countries and their antibiotic susceptibilities. Middle Eastern Study Group.

In a multicenter survey in seven Middle Eastern countries, 1,827 clinical isolates from patients with community-acquired infections (outpatients) were examined for both production of beta-lactamase and their susceptibility to commonly prescribed antibiotics. Of these isolates, 63% were gram-negative and 37% were gram-positive organisms. beta-lactamase was produced by 65% of all isolates, representing 61 and 75% of gram-negative and gram-positive organisms, respectively. Using standardized disk susceptibility testing, high rates of resistance were observed among gram-negative and gram-positive organisms, respectively, for penicillin (86 and 75%), ampicillin (67 and 66%) and amoxicillin (58 and 52%). Resistance to tetracycline and co-trimoxazole were also seen, but to a lesser degree. Susceptibility of these organisms towards the cephalosporins cepharadine, cephalexin and cefadroxil ranged from 30 to 70%, which appears to correlate fairly closely with the prevalence of beta-lactamase production. Cefuroxime inhibited about 94 and 79% of gram-positive and gram-negative organisms, respectively, regardless of the production of beta-lactamase. These data are valuable since antibiotic therapy is usually instituted on a best-guess principle against the most likely potential pathogens.


In vitro activity of meropenem and other agents against oral bacteria.

The susceptibility of 106 oral bacteria to meropenem, a new carbapenem antimicrobial, penicillin V, tetracycline and metronidazole was assessed by an agar dilution method. Meropenem was the most effective of the antimicrobials, with all strains tested being inhibited at < or = 1 mg/l. A number of strains were resistant to penicillin V, particularly Bacteroides gracilis, and tetracycline resistance was widespread amongst the streptococci tested. Metronidazole was extremely effective against obligate anaerobes. The results of this study suggest that meropenem has potential for use in the treatment of serious head and neck infections.


Studies on the antibiotic transfer into the bile of canines with different bile duct pressures.

There have been many studies on the transport of antibiotics into the bile; however, these studies have not taken the bile duct pressure into consideration. The bile duct pressure of the patient with acute obstructive cholangitis is high, and after drainage of the bile, the pressure is not always decreased to the normal range. We studied the effects of the bile duct pressure on the antibiotic (flomoxef sodium) transfer into the bile using beagles after creating the model of acute obstructive cholangitis. Our results showed that sufficient bile flow after drainage is important for the antibiotic transport, and, moreover, the bile acid concentration which may be related to the bilirubin concentration is also highly considerable.


Experimental evaluation of preventive and therapeutic potentials of lysozyme.

Therapeutic efficacy and preventive role of egg white lysozyme was evaluated in three types of murine ascitic tumours, namely sarcoma 180, Ehrlich's carcinoma, and Dalton's lymphoma. Lysozyme treatment produced regression of tumour growth and improved the life expectancy of the host. Growth of tumour cells treated in vitro with lysozyme prior to transplantation was also affected. In addition, lysozyme was found to have a preventive effect when administered to normal mice. The antitumour activity, therapeutic and preventive, of lysozyme seems to be due to its action on the tumour cell surface as well as on the host-mediated immune response.


Effect of tetrahydrouridine on metabolism and transport of 1-beta-D-arabinofuranosylcytosine in human cells.

Deamination of cytosine arabinoside (ara-C) by cytidine deaminase is the main mode of inactivation of this drug which can be responsible for ara-C resistance. The present study was undertaken to determine the effect of tetrahydrouridine (THU; a potent inhibitor of cytidine deaminase) on ara-C transport and metabolism in human cells. A rapid transport of ara-C into freshly isolated hepatocytes and an increased intracellular accumulation of the unchanged drug were observed in the presence of 50 micrograms/ml THU. THU inhibited the intracellular deamination of ara-C by 80% and slowed elimination of the compound extracellularly. The intracellular ara-C concentrations achieved after incubation with 1 micrograms/ml ara-C plus 50 micrograms/ml THU are similar to those attained with ara-C (10 micrograms/ml) alone. Treatment of leukemic K562 cells with the combination of THU (50 micrograms/ml) and ara-C (1 micrograms/ml) led to an augmentation of intracellular ara-C triphosphate formation up to twofold.


Two cases of disseminated toxocariasis in compromised hosts successfully treated with mebendazole.

Two cases of disseminated (hepatosplenic, pulmonary and in 1 case also cerebral) toxocariasis in compromised hosts-1 with malignancy (mycosis fungoides) and 1 on chronic corticosteroid treatment due to autoimmune disease--are reported. Besides fungi, also other unusual pathogens (of parasitic origin), especially in cancer, shall be considered.


[A comparison between nasotracheal and orotracheal intubation in treating chronic obstructive pulmonary disease complicated by respiratory failure].

Endotracheal intubation and mechanical ventilation were given to 100 COPD patients complicated by respiratory failure from Dec. 1977 to May 1990. Among them 42 were intubated through mouth. The tubes were kept from 1 to 6 days. In only 8 cases (19.0%) the tubes could be withdrawn according to the criterion, and 25 patients (59.0%) were tracheostomized. Nasotracheal intubation were given to 58 patients. The tubes were kept from 1 to 220 days and could be withdrawn in 39 cases (81.0%), with an incidence higher than that in patients intubated orotracheally (P < 0.01). Tracheostomy mas given to 6 patients intubated nasotracheally (10.3%), being fewer than in patients intubated through mouth (P < 0.01). Although the tubes have been kept for longer time, the duration of hospitalization was not prolonged.


[Perfusion lung scan in unexplained pulmonary hypertension].

Thirty-two patients were diagnosed as unexplained pulmonary hypertension by clinical history, physical examination, hemodynamics, pulmonary angiography and perfusion lung scanning. The findings of pulmonary scans in twenty patients (62.5%) showed patchy heterogeneous perfusion defects, which suggested chronic silent pulmonary thromboembolism (CSPT) and in twelve cases (37.5%) demonstrated normal or equally diffuse radionuclide scattering due to primary pulmonary hypertension (PPH). This result corresponded with the pathological data in some of the relevant references. Pulmonary perfusion scan is a noninvasive, safe and simple procedure for determining whether CSPT or PPH is the causative factor in patients with unexplained pulmonary hypertension.


[Nosocomial pneumonia: a report of 372 cases].

Three hundred seventy-two cases of hospital-acquired pneumonia occurring during a 4-year period were reviewed. It was found that the annual incidence of the pneumonia was 1.44% which ranked first in the incidence of nosocomial infections at this institution. Most of the patients had suffered from primary severe underlying diseases with immunosuppression of different degrees. A variety of factors such as antibiotic and steroid therapy, operation, intensive care, endotracheal intubation, tracheostomy, chemotherapy and radiotherapy predisposed to the acquisition of this pneumonia. Most frequent etiologic agents for hospital-acquired pneumonia were Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. The overall mortality rate was 25.3%. However, deaths associated with Pseudomonas aeruginosa and Staphylococcus aureus are particularly high, with rates of 70.6% and 66.7% respectively. The incidence, mortality, pathogenesis, diagnosis, treatment and prevention of the disorder were discussed briefly.


[Correlation among electrocardiogram, important risk factors of coronary artery diseases and coronary lesion in patients with chest pain].

Clinical and angiographic data from 103 patients with chest pain were evaluated to determine their correlation with ST-T abnormality in resting electrocardiogram. Univariate analysis suggested that male sex, hypertension, old myocardial infarction, severe coronary lesion, multiple vessel lesion and left ventricular wall motion abnormality significantly increase the likelihood of ST-T abnormality. Multivariate analysis suggested that male sex, hypertension and left ventricular wall motion abnormality were significant independent predictors of abnormal ST-T. It is essential to improve the electrocardiographic accuracy of diagnosing CAD so as to help clinical doctors in preventing and treating this disease.


[Tumor necrosis factor and interleukin 6 in hepatitis C virus infection].

Tumor necrosis factor (TNF) was determined with ELISA in 72 patients with hepatitis C and hepatitis B virus infections. Interleukin 6 (IL-6) was determined at the same time. TNF and IL-6 were significantly increased in patients with hepatitis C virus infections when compared with normal subjects and hepatitis B patients. There was a significant positive correlation between TNF and IL-6. It is suggested that increased TNF and IL-6 may play an important role in pathogenesis of hepatitis C virus infection.


[Detection of anti-dsDNA-F(AB')2 antibody and evaluation of its clinical significance].

Purified anti-dsDNA antibody was obtained from the serum of patients with systemic lupus erythematosus by affinity-column chromatography. Anti-dsDNA-F(ab')2 fragment (idiotype) was prepared from digested anti-dsDNA antibody with pepsin. We have developed a sensitive and specific method for detection anti-dsDNA-F(ab')2 antibody. Our result revealed that low titer of anti-dsDNA was observed in patients with active stage of systemic lupus erythematosus.


[Effects of various recombinant human hematopoietic growth factors on proliferation of blast cells in acute myeloid leukemia in vitro].

In vitro proliferative response of the blast cells from 21 AML patients to hematopoietic growth factors (IL-3, GM-CSF, G-CSF and MCSF) was investigated. Proliferation of AML cells in the majority of cases was induced or promoted by one or more CSFs, among which the stimulation of IL-3 was the most effective. Spontaneous proliferation of the blast cells was also observed in half of the cases and could be inhibited as well as promoted by some CSFs. It is suggested that in vitro proliferation of AML cells varies from patient to patient and that CSF plays important roles in leukemogenesis.


[Associations between plasma insulin and high blood pressure].

We studied the relationship between plasma insulin level and hypertension in 510 cases with normal glucose tolerance and impaired glucose tolerance. In nonobese group (BMI < 25kg/m2), plasma insulin was higher in those with hypertension than those with normal blood pressure (P < 0.0001). There was no correlation between diastole blood pressure and plasma insulin; multiple regression analysis showed that fasting plasma insulin was significantly associated with systolic blood pressure after controlling age, BMI and plasma glucose level (beta = 0.27, P = 0.0078). The result suggested that age, BMI and plasma insulin level were independent risk factors of hypertension. In obese group (BMI > 25kg/m2), blood pressure was significantly associated with age and BMI, there was no association between blood pressure and plasma insulin level.


[Long-term effects of intracerebral implantation of adrenal medulla in the treatment of parkinsonism].

24 patients with parkinsonism received intracerebral autotransplantation of adrenal. Follow-up for 1-4 years showed that the long-term effectiveness was 70.8%, and the substantial effectiveness 41.7%. The patients with no improvement or deterioration after some improvement comprised 20.8%. The operative mortality rate was 8.3%. Possible factors influencing the effectiveness were analysed, and how to improve the survival rate of the implanted chromaffin cells was also discussed.


[Congenital absence of vein valves of the lower extremities].

Sixteen patients with congenital absence of venous valves in the deep veins of 18 lower limbs are reported. The disease limbs characterized by venous hypertension is frequently seen in teen-agers. Venographically, no valve is to be found in the deep venous system. Conservative treatment may be tried in those without pigmentation and ulcer formation in the goiter area. However, valvular reconstructive operation of the deep veins is the effective method of treatment.


[Transaxillary approach first rib resection for thoracic outlet syndrome].

From 1981 to 1991, 26 patients with thoracic outlet syndrome were treated by transaxillary first rib resection. Investigation of its indications, modes and results showed that this is one of the ideal methods of treatment for thoracic outlet syndrome.


[Successful replantation of circularly severed palm and multiply severed fingers. A case report].

Replantation of a circularly severed palm, partially severed middle finger and completely severed ring and small fingers was done successfully in one patient. Two palmar arteries, 5 digital arteries, 3 dorsal palmar veins, 9 dorsal digital veins were anastomosed. Vein transplantation was carried out to repair the ulnar digital artery defect of the middle finger. Severe swelling after arterial thrombosis was noted on the 7th day and was eliminated by the use of urokinase. All the replanted parts survived with good functional results. Precise anastomosis, prevention and treatment of thrombosis, early exercises were essential to the survival of fingers and functional recovery of hand.


[Cavernomas of the central nervous system].

18 cases of pathological cavernoma of the central nervous system were reported. The took 11.25 per cent of verified vascular malformations in our department in the same period. 15 cases located intracranially, and 3 cases were within the vertebral canal. Repeated small amount hemorrhages in the lesions were the major cause of the clinical symptoms of these patients. MRI was the most reliable method for making a correct diagnosis of cavernomas before operation. Cavernomas usually had clear border and surrounded with gliotic tissues, so that extirpation of tumor with microsurgical technique was the best choice.


[A study on origin of the hyperplastic synovial lining cells in rheumatoid arthritis].

The one of striking microscopic feature is synovium hyperplasia in rheumatoid arthritis. The origin of the hyperplastic synovial lining cells in RA remains unsettled. Two marked monoclonal antibodies and two marked antisera are used to run the immunohistochemical study. Our finding revealed that synovial lining cells bear marks for blood monocytes. It is suggested that the increased synovial lining cells population appear to derive from bone marrow. Besides, the results of immunoelectron microscopy showed that synovial lining cells of type A and type C express HLA-DR antigen. HLA positive dendritic cells are distinctly more frequently seen in RA synovium than in that of osteoarthritis.


[Effect of glutamine and glutamine-dipeptide enriched amino acid solution on rat small bowel mucosa regeneration].

To mine the effects of glutamine and it's dipeptide enriched nutrition solution on the gastro-intestinal structure and protein metabolism, 40 male Wistar rats were studied for 8 days. The rats were randomly divided into four groups: sham operation group, standard amino acid solution group, glutamine enriched group and glutamine dipeptide enriched group. Observation parameters were: weight change; serum AA profile analysis; computerized morphometric analysis of mucosa thickness and villus height; total nitrogen balance; and liver, kidney functional results. The data were managed by multiple sample comparison methods (ANOVA of Statview 512 software) on Macintosh PC. Significant level was put on P < 0.05. The results showed that significant differences of body weight, serum glutamine level, nitrogen balance, intestinal mucosa thickness and villus height were found between the control and study groups. No significant difference in liver and kidney function was found. Gln-Ala dipeptide had same effects as free glutamine did.


[A clinical investigation of rHuIFN alpha-1 in the treatment of herpes simplex virus keratitis].

A double blind clinical investigation on the treatment of 100 cases of HSV keratitis with rHuIFN alpha-1 and acyclovir instillations was carried out in 8 institutions in Beijing and elsewhere. Both eyedrops proved about equally effective with cure rates of 88.1% and 82.9% respectively. Until recently, 128 cumulative cases of various types of HSV keratitis treated with rHuIFN alpha-1 demonstrated a cure rate of 82.0%, indicating that topical rHuIFN alpha-1 was an effective nonspecific remedy for HSV keratitis.


[Treatment of severe Mooren's ulcer with cyclosporin A eyedrops].

16 patients (21 eyes) with severe progressive Mooren's ulcer unresponsive to medical or surgical therapy were treated with 0.5% cyclosporin A (CsA) eyedrops. 15 eyes showed remarkable amelioration within 12 days, and 11 eyes completely healed without side effects in an average 1.3 months. The total effective rate was 83.3%, with no recurrence in a follow-up of 12-19 months. Whole-blood levels of CsA were determined by high pressure liquid chromatography to average 28.95 ng/ml in 7 random patients. Autoimmunity was believed to be an important factor in the pathogenesis of Mooren's ulcer, and the efficacy of topical CsA was attributable to the local depression of ocular immunopathological reactions.


[A preliminary report of epikeratophakia for the treatment of myopia].

Since 1987, 9 cases of high myopia were treated by epikeratophakia with concave corneal lenses shaped by a rapid method on a self-made cryolathe. After the surgery, all patients showed reduced degrees of myopia and astigmatism, with marked improvement in uncorrected visual acuity. The corrected visual acuity was the same as preoperative in 3 cases and improved in 6 cases. No serious complications occurred.


[Evaluation of penetrating keratoplasty for the treatment of keratoconus].

22 cases (26 eyes) of keratoconus were performed penetrating keratoplasty and followed up 0.5-5 years. The disease was effectively controlled. The rate of graft transparency was 100%, and the immune rejection rate was 7.7%. Corrected vision was 0.4 or better in 23 cases after the operation. The authors regard keratoplasty the best choice for treatment of keratoconus.


[An immunohistochemical study of Langerhan's cells (LC), T-cells and the HLA antigen in human cornea].

The distribution of Langerhan's cells (LC), T-cell subsets, and HLA system in 12 normal and 7 morbid corneas, including 4 of suppurative corneal ulcer and 3 of uveogenic endophthalmitis, were investigated with monoclonal antibodies. The results revealed that a small amount of LC and T-cell subsets were present in the limbal region of normal corneas, while large numbers of LC and OKT4+ were observed in the corneas of suppurative ulcer. HLA-ABC antigens were expressed on the epithelial cells and keratocytes of the normal corneas, while the HLA-DR antigens were expressed on the surface of LC at the limbus.


[Recovery of corneal sensitivity following keratoplasty and corneal diseases].

Corneal sensitivity (CS) was tested in 201 eyes with clear plastic grafts and in 193 eyes with corneal diseases, using the Cochet-Bonnet Aesthesiometer. After keratoplasty, the CS returned to normal in 40.0% and 50.0% of the eyes with non-HSK in 5-6 years and 7-22 years respectively, while only 17.2% of the eyes with HSK showed normal CS in 7-22 years postoperative. The corneas of HSK patients were markedly hypoesthetic all over, whereas in non-HSK patients, the corneal hypoesthesia involved only the morbid area. The examination of CS is useful in the diagnosis of corneal diseases and evaluation of nerve regeneration after keratoplasty.


[The clinical significance of following up the differential light threshold in glaucoma].

The correlation of the differential light threshold changes in the Bjerrum area to the glaucomatous visual field defects that followed was studied prospectively by the Humphrey Field Analyzer. Of 42 early glaucomatous eyes without field defects, 24 developed reproducible glaucomatous field defects in 2.5 years of follow-up. The agreement in location between the field defects and the meridian of highest light threshold elevation was remarkable (87.0%), and a mean 5 dB decline in local light sensitivity predicted ensuing field defect development. Thus, the discovery of glaucomatous field defects with automated Humphrey perimetry could be 1-2 years earlier than with Goldmann perimetry.


[The exfoliation or pseudo-exfoliation syndrome].

The exfoliation or pseudo-exfoliation syndrome (PE) is very rare in China. The clinical and histopathologic features in 13 patients were that the loss of pigment at the pupillary ruff and dense pigmentation on the trabecular meshwork were early signs easily overlooked, and the dandruff-like particles at the pupillary margin and greyish white ring at the anterior periphery of the lens were typical findings. Histopathologic study demonstrated that the PAS-positive amorphous material under light microscopy were fibrils in structure and accumulated at various sites in the anterior segment of the eye.


[Clinical applications of MRI in ophthalmology].

Magnetic resonance imaging (MRI) of the normal eyeball and orbital tissues is introduced, along with the MRI manifestations in 39 patients comprising 6 cases of intraocular and 29 cases of intraorbital disorders, and 4 cases of vascular diseases. The advantages and limitations of MRI in ophthalmology are discussed. It appears that MRI is more sensitive than ultrasonic B-scan or CT.


[Family investigation and clinical genetic analysis of a large pedigree with congenital stationary night blindness].

A large pedigree of congenital stationary night blindness (CSNB) was investigated by both the family method and the family history method, and the diagnosis was confirmed by dark adaptation and full-field electroretinogram tests. There were 57 affected members of 7 successive generations in the pedigree which showed typical autosomal dominant inheritance with a complete gene penetrance. Based on this study and other sources, the genetic aspect and the clinical manifestations of CSNB, especially the characteristics of dark adaptation and electroretinogram, were discussed.


[The effect of dosage on oral fluorescein angiography of the fundus].

105 patients were orally given fluorescein of different dosage and concentration for fundus angiography. The results indicated that the dosage of 30mg/kg at 2% concentration produced more distinct angiograms.


[A clinical study of vertical saccadic eye movements].

The authors studied the vertical saccadic movements of 12 patients with vertical paretic strabismus (< 6 degrees) by Scott's method, comparing the saccade of the paretic muscle with that of its antagonist. The results showed that the former was reduced in amplitude by 15%-50%, averaging 31.5%, and improved to 0%-25%, averaging 8.1%, after operations. The authors proposed that a difference of saccadic amplitude over 15% between a muscle and its antagonist indicated presence of muscle paresis. Besides, the methods of assessing saccadic movements were discussed.


[An experimental study of gentamycin delivery into cornea and aqueous humor from the collagen corneal shield].

Collagen corneal shields immersed in 13.33 mg/ml gentamycin solution for 5 minutes were placed in rabbit eyes and the gentamycin concentrations in the cornea and aqueous humor were determined with radioimmunoassay. The results were compared with those achieved by soft contact lens, subconjunctival injection, and frequent instillations. It was found that (1) 1 and 3 hours after application, the collagen corneal shield produced significantly higher concentration of gentamycin in the aqueous than did the other methods, and in the cornea than did the contact lens or instillations; and (2) 6 hours after application, the antibiotic level in the cornea dropped lower than that by subconjunctival injection, but still 15-30 times higher than the bactericidal concentration.