Erythropoietin in pregnancies complicated by severe anemia of renal failure. Recombinant human erythropoietin has been approved for treatment of the anemia of renal failure since 1989, yet data regarding the safety and efficacy of this drug in pregnancy are limited. We used recombinant human erythropoietin to treat the anemia of renal disease in three pregnant women. Nadir hematocrit values before initiation of erythropoietin were 19-23%. Erythropoietin, 50-160 U/kg/week subcutaneously, was begun at 14-26 weeks' gestation. Initially, the rise in hematocrit averaged 0.6-2% each week, with peak values of 26.7-32%. Iron supplementation was given simultaneously. Maternal and neonatal outcomes were favorable despite the development of preeclampsia or worsening renal function requiring early delivery. In this small series, erythropoietin begun during the second trimester in a dose of about 100 U/kg/week, in conjunction with orally administered iron, appeared to be effective in treating the anemia of renal failure during pregnancy. Additional experience is needed to evaluate the safety of this medication during pregnancy.


Acute uric acid nephropathy in pregnancy. Although uric acid clearance increases during gestation, uric acid nephropathy is a rare cause of acute renal failure in the pregnant woman. A 38-year-old woman experienced acute renal failure due to acute uric acid nephropathy at 30 weeks' gestation. The diagnosis was based on extreme hyperuricemia and an elevated uric acid-creatinine ratio. Treatment with forced diuresis, urine alkalinization, and mannitol infusion resulted in a prompt and complete recovery of renal function. The woman ultimately gave birth to a healthy child. Acute uric acid nephropathy during pregnancy responds to conventional medical therapy.


Post-miscarriage thyroid dysfunction.

Post-miscarriage thyroid dysfunction. Thyroid dysfunction is a common postpartum event affecting as many as 16.7% of women. The purpose of this paper was to report the first known case of post-miscarriage thyroid dysfunction. A 32-year-old woman with a 9-year history of infertility underwent in vitro fertilization. After two spontaneous miscarriages, she delivered a full-term healthy child. Spontaneous menses did not return following delivery, and hormonal evaluation revealed severe postpartum thyroid disease associated with hyperprolactinemia. Retrospective analysis of frozen sera revealed thyroid dysfunction and hyperprolactinemia after the first miscarriage, even though the gestation lasted only 47 days. The present case of thyroid dysfunction following a first-trimester miscarriage raises issues concerning the immunology of pregnancy and thyroid dysfunction after pregnancy. The incidence of post-miscarriage thyroid dysfunction and severe postpartum thyroid disease resulting in amenorrhea requires further study.


Successful pregnancy outcome in a patient with congenital biliary atresia. Congenital biliary atresia is one of the most common congenital anomalies of the biliary tree. Without surgical correction, two-thirds of all cases of extrahepatic biliary atresia are fatal within 18 months. Historically, the preferred surgical procedure to correct this anomaly has been the Kasai procedure. Surgical treatment of congenital biliary atresia is associated with substantial perioperative morbidity and mortality, as well as long-term sequelae. Portal hypertension and hypersplenism can complicate the course of up to 50% of patients who survive for more than 2 years. Not surprisingly, few of these patients reach adulthood. We report the case of a woman with congenital biliary atresia surgically corrected with the Kasai operation who subsequently reached adulthood and became pregnant. Despite a prenatal course complicated by portal hypertension, bleeding esophageal varices, and hypersplenism, the woman delivered a healthy infant at 36.5 weeks' gestation.


Axillary vein thrombosis during pregnancy: a case report. A 32-year-old multiparous woman had progressive swelling of the right arm at 32 weeks' gestation, accompanied by cyanosis and a preserved radial pulse. Phlebography demonstrated a 5-cm thrombus in the axillary vein. No known etiologic factors were found. Intravenous heparin administration resulted in rapid resolution of the clinical findings. Subcutaneous heparin 10,000 U/day was administered for secondary prophylaxis until cesarean at 39 weeks, during which a full dose was administered without complications. Axillary vein thrombosis during pregnancy may be diagnosed by either phlebography or duplex scanning, and preferably should be treated by heparin. Thrombolytic therapy is justified mainly for life-threatening complications such as pulmonary embolism.


Fetal stroke associated with elevated maternal anticardiolipin antibodies. Middle cerebral artery infarction explains some cases of congenital hemiparesis with or without neonatal stroke. The etiology of the stroke is often obscure. We describe two infants with imaging evidence of middle cerebral artery infarction whose mothers had elevated anticardiolipin antibody levels after delivery. We speculate that these antibodies may have been responsible for intrauterine thromboembolic stroke.


Acute iron intoxication in pregnancy: case report and review of the literature. Limited reports exist regarding acute iron intoxication during pregnancy. The maternal and fetal effects of accidental or deliberate ingestion of large amounts of iron may be catastrophic. A case report of acute iron intoxication, management strategies, and a review of the literature are presented. The cornerstones of effective therapy are aggressive management with emesis induction or gastric lavage, bicarbonate instillation, vigorous intravenous hydration, and chelation therapy with deferoxamine.


An unusual complication in a gravida with factor IX deficiency: case report with review of the literature. Factor IX deficiency (hemophilia B, Christmas disease) is an X-linked recessive coagulation disorder. It occurs in one out of every 25,000-30,000 male births and requires even rarer genetic circumstances for phenotypic expression in females. We report the occurrence of a large, late-trimester subchorionic hematoma in a gravida with factor IX deficiency and with laboratory evidence of consumptive coagulopathy during treatment. The patient was managed conservatively and had a successful outcome at term. The only four reported cases of antepartum management of factor IX deficiency in the English literature are reviewed.


Antepartum diagnosis of placenta previa percreta by magnetic resonance imaging. Placenta previa percreta is a rare but highly morbid condition usually diagnosed intraoperatively. Placental manipulation results in severe bleeding. Magnetic resonance imaging (MRI) might allow antepartum diagnosis of this condition. A multiparous woman with five previous abdominal deliveries had complete placenta previa diagnosed at 16 weeks' gestation. Bleeding ensured at 29 weeks and she was managed with bed rest. Before planned abdominal delivery, MRI was performed and placenta percreta was diagnosed, which allowed her physician to avoid placental manipulation. Hysterectomy was accomplished with an estimated blood loss of only 2000 mL. Antepartum diagnosis of placenta previa percreta by MRI altered the usual diagnostic and surgical approach, diminishing blood loss and morbidity.


Transvaginal color Doppler sonography in the prenatal diagnosis of placenta accreta. In a case of placenta accreta diagnosed antepartum, the sonographic findings included absence of the normal retroplacental clear space and presence of multiple dilated blood vessels beneath the placenta. Transvaginal color Doppler sonography was particularly useful in identifying these features.


Delivery through the maternal bladder during trial of labor. The safety of trial of labor after cesarean has been documented by numerous studies. Large series have demonstrated that in a properly chosen setting, 75% of women can achieve vaginal delivery without undue risk to the mother or fetus. In a small percentage of cases, trial of labor deviates from the expected outcome. Two infants were delivered through the maternal bladder, one after uterine dehiscence and the other after vaginal rupture at trial of labor. Standard and unique complications are reported with trial of labor. Because these complications occur infrequently, they should not discourage an attempt at vaginal delivery after cesarean.


Abdominal rescue after failed cephalic replacement. Since the introduction of cephalic replacement for shoulder dystocia, the management of failures has not been addressed. The purpose of this report is to describe abdominal hysterotomy as an alternative approach to the resolution of shoulder dystocia. A 21-year-old woman, gravida 1, experienced severe shoulder dystocia following partial delivery of a 4320-g infant. Classical maneuvers as well as cephalic replacement were unsuccessful before and after general anesthesia. A low transverse hysterotomy permitted manual rotation of the anterior shoulder to the oblique diameter and further descent of the posterior shoulder. Delivery of the posterior arm was then completed without difficulty. Persistent failed cephalic replacement, especially after general anesthesia, can be successfully resolved with a hysterotomy using a low transverse uterine incision.


First-trimester diagnosed cervico-isthmic pregnancy resulting in term delivery. A 30-year-old multiparous woman at 5.5 weeks' gestation was diagnosed by ultrasound to have a cervical pregnancy. She refused termination because of religious beliefs. After expectant management until 38 weeks' gestation, she delivered a viable infant by cesarean, followed by immediate hysterectomy. Pathologic examination verified cervico-isthmic implantation as well as placenta percreta.


Methotrexate pneumonitis in nonsurgical treatment of ectopic pregnancy. We describe a case of pneumonitis following local administration of methotrexate for nonsurgical termination of an ectopic pregnancy. The signs and symptoms were similar to those seen with systemic use of the drug for other ailments. We believe that methotrexate represents a relatively effective alternative to surgery in patients with early unruptured tubal pregnancy, but suggest that it be used with caution in view of possible systemic toxicity.


Umbilical artery aneurysm: prenatal diagnosis and management. An umbilical artery aneurysm is an extremely rare lesion. The purpose of this report is to describe the prenatal sonographic characteristics of such a lesion and potential obstetric complications. A 26-year-old woman, gravida 2, para 1, at 30 weeks' gestation was referred for an ultrasound examination because of "an abnormality of the umbilical cord." An ellipsoid cystic lesion was noted in a single umbilical artery. Doppler and color flow Doppler examinations demonstrated nonpulsatile and turbulent blood flow within the lesion, consistent with a diagnosis of umbilical artery aneurysm. The aneurysm increased in size over time with a progressive decrease in amniotic fluid volume. Despite reassuring bi-weekly antenatal testing and planned delivery by 36 weeks' gestation, the fetus died in utero, probably because of acute umbilical venous compression by the aneurysm. Autopsy confirmed the presence of a large calcified aneurysm of a single umbilical artery. Dissection of the aneurysm demonstrated anatomical patency of the entire artery. The umbilical vein was histologically normal, as were sections of the artery. Although extremely rare, an umbilical artery aneurysm is a potentially lethal anomaly. We recommend delivery as soon as fetal lung maturity is assured when this diagnosis is made prenatally.


Fetal ascitic fluid: a new source of lymphocytes for rapid chromosomal analysis. The cells found in ascites can be processed like amniotic fluid for fetal karyotyping. We have characterized these cells and used them for a rapid cytogenetic result. Three patients presented with massive fetal ascites detected by sonography. Samples of ascitic fluid were obtained at fetal paracentesis. Cells from the fluid were cultured using standard methods for fetal blood, and were compared with fetal blood lymphocytes and amniocytes. The length of time in culture, chromosome morphology, and mitotic index of ascitic fluid cells were equivalent to those of fetal blood. In the third case, we performed immunophenotyping on the ascitic fluid cells. Ascitic fluid contains lymphocytes that permit rapid chromosomal analysis within 96 hours.


The perinatal management of severe laryngeal stenosis. Conditions that completely occlude the fetal larynx are rare. We describe the perinatal course of an infant with severe congenital subglottic stenosis, for whom the prenatal recognition of airway occlusion led to enhanced neonatal management. Serial ultrasound examinations from 23-37 weeks' gestation led to the diagnosis of upper airway obstruction in the fetus of a 29-year-old woman. Significant findings included fetal ascites, echogenic enlarged lungs, and a dilated fluid-filled trachea. The infant was delivered in a level III hospital with a neonatologist and anesthesiologist in attendance. The cord was not clamped until a tracheostomy was secured. Upper-airway obstruction can be diagnosed prenatally by the presence of secondary manifestations. Infant survival may depend on foreknowledge of the pathology and prompt, directed efforts at bypassing the airway obstruction.


Hysteroscopic resection of fibroid with thermal injury to sigmoid. Hysteroscopy is being used increasingly, especially as a means of performing uterine surgery. Uterine perforation is the most frequent complication of hysteroscopy. A 31-year-old woman sustained uterine perforation with a resectoscope during hysteroscopic resection of a pedunculated myoma. The perforation was identified laparoscopically, but laparotomy was necessary to assess the pelvic viscera fully. Perforation of the sigmoid was discovered and the defect was repaired primarily. Laparoscopy may be insufficient to evaluate fully the possible sequelae of uterine perforation. Penetrating thermal injury to the colon can be managed successfully with primary repair.


Ureteroscopy: a new asset in the management of postoperative ureterovaginal fistulas. Iatrogenic ureteral injury, an uncommon entity, is primarily caused by complications of gynecologic surgery. This report describes a case of ureterovaginal fistula discovered 13 days after a vaginal hysterectomy. Ureteroscopy was performed, with passage of an indwelling ureteral stent for 6 weeks. The patient immediately became continent of urine and the fistula healed, thus avoiding the need for further surgery.


Enterobius vermicularis salpingitis: a distant episode from precipitating appendicitis. Chronic pelvic inflammatory disease is a common gynecologic diagnosis in women with chronic pelvic pain. When standard antimicrobial therapy does not improve the clinical status, uncommon diagnoses such as Enterobius vermicularis should be considered. In this case, E vermicularis presented as acute and chronic salpingitis in a patient who had had E vermicularis-related appendicitis 5 years earlier.


Percutaneous catheter drainage of tubo-ovarian abscesses. We present the successful treatment of tubo-ovarian abscesses in three young patients by continuous percutaneous drainage, inserted under the guidance of real-time ultrasonography using only local anesthesia. Each patient had been diagnosed laparoscopically as suffering from acute pelvic inflammatory disease, but had formed abscesses despite extensive broad-spectrum antibiotic therapy. One case involved a complication of the ovum pick-up procedure; the woman had tubo-ovarian abscesses with infected hematomas. Because the abscesses were localized anteriorly in the lower abdomen and did not reach the pouch of Douglas, they could not be drained through a posterior colpotomy. Ultrasound guidance allowed us to drain all the areas of the multioculated abscesses. We suggest that percutaneous abscess drainage be the initial treatment of choice for tubo-ovarian abscesses before laparotomy is considered.


Serous carcinoma of the peritoneum after oophorectomy. Prophylactic oophorectomy in premenopausal women has been recommended to prevent ovarian cancer. However, serous carcinoma of the peritoneum, which is indistinguishable from ovarian carcinoma, can occur after oophorectomy. Two cases are reported of serous carcinoma of the peritoneum after oophorectomy. Presentation, management, and outcome are similar to those for ovarian carcinoma. More data are needed to quantify the risk of carcinoma after oophorectomy. Such knowledge may change the risk-benefit calculations of recommending prophylactic oophorectomy to premenopausal women at a certain age, and must be discussed with the patient who is considering prophylactic oophorectomy with or without other planned surgery.


Giant ovarian leiomyoma associated with ascites and polymyositis. Primary ovarian leiomyoma is rare. Most cases are asymptomatic; this benign neoplasm is usually found incidentally on routine pelvic examination, at surgery, or at autopsy. We present what we believe to be the first case of ovarian leiomyoma associated with ascites and polymyositis, both of which resolved after oophorectomy. This case emphasizes the important fact that preoperative evaluation may be inaccurate. Excision of a pelvic mass with histologic evaluation remains the only reliable way to establish a diagnosis.


Meigs syndrome with elevated serum CA 125. Elevation of serum CA 125 levels is associated with malignant serous ovarian carcinomas and has been described in one patient with Meigs syndrome. We present two additional cases of Meigs syndrome with significant elevations in serum CA 125 and report the results of immunohistochemical staining for CA 125. CA 125 expression was localized to the omentum and peritoneal surfaces rather than the fibroma. We suggest that expression of CA 125 and accumulation of ascites in these two patients may have resulted from some common peritoneal process.


Intestinal invasion by a dysgerminoma in a patient with Swyer syndrome. An unusual case is presented of advanced dysgerminoma in a patient with Swyer syndrome, 46,XY pure gonadal dysgenesis. Unexpected regional invasion necessitated bowel resection, total abdominal hysterectomy, and bilateral salpingogonadectomy for a complete en bloc excision of the primary tumor mass and the dysgenetic gonads. This report illustrates the possible need for extensive operative resection in patients with Swyer syndrome.


Pseudomyxoma peritoneii: treatment with the argon beam coagulator. The argon beam coagulator facilitates tumor debulking of peritoneal carcinomatosis. A patient with pseudomyxoma peritoneii originating from the left ovary with multiple peritoneal and omental implants was treated with the argon beam coagulator, enabling ablation of all gross disease.


Accumulation of cis-diamminedichloroplatinum (II) and its analogues in sensitive and resistant human ovarian carcinoma cells. Human ovarian carcinoma cell line (NOS2), established from a patient with serous cystadenocarcinoma of the ovary, has been exposed to a stepwise increase in cis-diamminedichloroplatinum (II) (CDDP) concentration to produce a CDDP-resistant cell line NOS2CR) as an experimental model for resistance to CDDP. NOS2CR cells showed a 7-fold resistance to CDDP and a lesser degree of cross-resistance to diammine (1,1-cyclobutanedicarboxylato)-platinum (II) (CBDCA) and (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato) platinum (II) (DWA2114R). In the absence of CDDP, cross-resistance to DWA2114R was reduced to the original level by 2 months, although 83% resistance to CDDP remained up to 6 months. To investigate CDDP-resistant mechanisms, alterations in the intracellular accumulation of CDDP and analogues were assayed by atomic absorption. In both NOS2 and NOS2CR cells, accumulation of CDDP increased linearly with time and was concentration-dependent. NOS2CR cells demonstrated 71, 52 and 12% reduction in accumulation of CDDP, CBDCA, and DWA2114R, respectively. These reductions did not seem to be due to P-glycoprotein, because expression of multidrug-resistant 1 gene was not detected in either NOS2 or NOS2CR cells. These studies indicate that the mechanisms of resistance to CDDP and analogues in NOS2CR cells are related in the main to reduced intracellular accumulation of drugs. DWA2114R might be helpful to treat CDDP-resistant and recurrent tumors which were treated by CDDP.


Pain killing with calcitonin nasal spray in patients with malignant tumors. The physiological role of calcitonin is the preservation of osseal integrity by reducing the osteoclast activity. On the other hand, this 32 amino acid peptide acts as an analgetic drug in cancer caused by osteolytic metastases. In previous studies using injection form the pain killing activity was observed in 65% of the patients. As medical assistance is required for this treatment form, it was decided to compare the pain reducing activity of nasal spray with the ampule form. It was found that 300 MRC units of nasal spray equalled 100 MRC units injection. The pain killing activity was observed in 53.8% of the patients. The reduction in quantity of other analgetics used daily was 48.5%. The average decrease of the pain duration (in h) was 42.5%. The pain intensity measured by visual analogue scale dropped to 2.13 from 3.00. The results are similar to the analgetic effect observed in the injection form. Taking this into consideration, calcitonin nasal spray is highly recommended instead of ampules.


Mitomycin C and 5-fluorouracil salvage chemotherapy in platinum-resistant ovarian carcinoma. Twenty-four patients with progressing or recurrent ovarian carcinoma, all pretreated with cisplatin, were evaluated for response and toxicity to mitomycin C (MMC) and 5-fluorouracil (5-FU) chemotherapy. Eligible patients had histologically proven intra-abdominal disease (67% clinically measurable; 33% nonmeasurable), and 67% of them had progressed on prior platinum-based chemotherapy. WHO response criteria were adopted in patients with measurable disease while those with nonmeasurable lesions were considered as responding in case of nonevident disease and CA-125 values less than 35 U/dl for at least 6 months. All patients received at least 2 treatment courses (median 6, range 2-10), and 5 patients (21%) could be considered as responding: 4/8 (50%) with nonmeasurable and 1/16 (6%) with measurable disease. The overall median survival was 12 months, range 7-30+ (median follow-up: 29.5 months, range 28-30). Progression-free survival was significantly different in responders (15 months) versus nonresponders (3 months) (p = 0.0001). Toxicity was mainly represented by myelosuppression (grade I 29%; II 8% and III 4%). MMC and 5-FU did not show significant activity against large tumor burden, while a relatively good activity was detected in patients with minimal disease. The limited toxicity and possible schedule modifications have to be taken into account for further investigation on selected patients.


Development and validation of prognostic models in metastatic breast cancer: a GOCS study. The significance of several prognostic factors and the magnitude of their influence on response rate and survival were assessed by means of uni- and multivariate analyses in 362 patients with stage IV (UICC) breast carcinoma receiving combination chemotherapy as first systemic treatment over an 8-year period. Univariate analyses identified performance status and prior adjuvant radiotherapy as predictors of objective regression (OR), whereas the performance status, prior chemotherapy and radiotherapy (adjuvants), white blood cells count, SGOT and SGPT levels, and metastatic pattern were significantly correlated to survival. In multivariate analyses favorable characteristics associated to OR were prior adjuvant radiotherapy, no prior chemotherapy and postmenopausal status. Regarding survival, the performance status and visceral involvement were selected by the Cox model. The predictive accuracy of the logistic and the proportional hazards models was retrospectively tested in the training sample, and prospectively in a new population of 126 patients also receiving combined chemotherapy as first treatment for metastatic breast cancer. A certain overfitting to data in the training sample was observed with the regression model for response. However, the discriminative ability of the Cox model for survival was clearly confirmed.


Immunohistochemical detection of estrogen receptors on paraffin sections of normal, hyperplatic and carcinomatous endometrium. The present study is the first dealing with the demonstration of estrogen receptors (ER) in up to 8-year-old paraffin blocks of endometrial curettage samples routinely fixed in 10% formalin. The Mab ER-ICA was used in a modified peroxidase-antiperoxidase method after pretreatment of paraffin sections with pronase. Eleven cases with proliferative, 11 cases with secretory endometrium, 20 cases with adenocystic, 21 with adenomatous hyperplasia and 27 endometrial adenocarcinomas were tested. The two main parameters, namely the percentage of ER-positive cells and the intensity of the immunostaining, were higher in the proliferative phase followed in a declining sequence by adenocystic hyperplasia, adenomatous hyperplasia, adenocarcinomas and the secretory phase of endometrium. Interestingly, the intensity of the immunostaining showed a positive relationship to the percentage of ER-positive cells (r = 0.93, p less than 0.001). It seems that the immunohistochemical demonstration of ER in paraffin sections of uterine specimens is an easy and reliable method for the mapping of the heterogeneous expression of ER and their comparative study with the well preserved histopathological features even in old archival paraffin-embedded material.


Pattern of growth factor, proto-oncogene and carcinoembryonic antigen gene expression in human colorectal carcinoma cell lines. The aim of the present study was to examine whether the expression of growth factor genes, proto-oncogenes and carcinoembryonic antigen (CEA) gene in human colorectal cancer cell lines was related to their clinicobiological behavior. A significant variability among cell lines was detected for both insulin-like growth factor II and transforming growth factor beta gene message. Detectable levels of c-myc, Her-2, c-myb, K-ras and EGF receptor mRNA were found in most cell lines, whereas only 1/11 and 2/11 cell lines were positive for N-myc and c-sis message, respectively. N-myc expression was limited to a cell line originated from a tumor with neuroendocrine features, while high levels of K-ras message were found only in a cell line derived from a radioresistant tumor. CEA mRNA levels correlated well with the concentration of antigen in each cell line. On the basis of these results, our findings demonstrated that human colorectal cancer cell lines show heterogeneous expression of growth factor and CEA genes and proto-oncogenes; however, with the exception of K-ras, N-myc and CEA, other correlations between gene expression and the clinicobiological characteristics of these cell lines could not be demonstrated.


Effects of a preoperative therapy with interleukin-2 on surgery-induced lymphocytopenia in cancer patients. It is known that major surgery may determine immunosuppression. This side effect might have a prognostic significance particularly in cancer patients, in whom the decrease in host defenses during the postoperative period could promote the proliferation of possible micrometastases. Since antitumor immune response is an IL-2-dependent phenomenon, a study was started to evaluate the effects of a preoperative injection of IL-2 on surgery-induced immune changes in cancer patients. The study included 12 colon cancer patients, treated subcutaneously with IL-2 at a dose of 9 x 10(6) IU/m2 twice daily for 3 consecutive days before surgery. Patients underwent surgery within 36 h from IL-2 interruption. The results were compared to those found in a control group of 18 colon cancer patients. Mean number of lymphocytes, T lymphocytes and NK cells significantly decreased after surgery in control patients; on the contrary, no postoperative decrease in immune cells was seen in IL-2 group. No anesthesiologic or surgical complication was seen in patients pretreated with IL-2 before surgery. This preliminary study would suggest that a preoperative therapy with IL-2 is an effective and well tolerated medical approach to neutralize surgery-induced immunosuppression in cancer patients.


Intratumoral heterogeneity in DNA ploidy of bladder carcinomas. In order to investigate whether DNA ploidy in a single area of a tumor could be representative of the entire tumor, flow-cytometric DNA analysis was performed for multiple samples (an average of 7 samples) obtained from the same tumor in 9 cases of transitional cell carcinoma of the urinary bladder. The incidence of DNA aneuploidy was 88.9% (8 out of 9 cases) and, furthermore, in 7 of these, intratumoral regional heterogeneity in DNA ploidy was evident. With high frequency, bladder carcinoma consisted of heterogeneous cell populations with different ploidy. There were 2 cases in which the tumor consisted of mixed subpopulations of diploid and aneuploid clones which were located in different parts of the same tumor. In such cases, an aneuploid line could not have been detected in a single specimen from the tumors.


Studies of actinomycin D induced B23-translocation in P388D1 cells implanted in DBA/2 mice. Nucleophosmin/B23 is a nucleolar phosphoprotein which redistributes from nucleoli to nucleoplasm (B23-translocation) when cells are exposed to certain anticancer drugs, particularly intercalators. The B23-translocation assay has been demonstrated in cell culture to correlate with drug effects and to detect drug-resistant cells. We now report the effect of actinomycin D on B23-translocation in P388D1 cells implanted in DBA/2 mice. B23-translocation was observed in cells after actinomycin D treatment in a dosage- and time-dependent manner. Translocation could be observed within 30 min after drug treatment. Complete B23-translocation with at least 1-day duration was achieved by a single injection of 0.25 mg/kg. Reduced dosages produced partial B23-translocation with shorter durations. These results indicate that B23-translocation may be useful in monitoring drug effects in animals.


Cytotoxicity of mitomycin C and carboquone combined with hyperthermia against hypoxic tumor cells in vitro. Enhancement of the cytotoxicity of mitomycin C (MMC) and carboquone (CQ) by hypoxia at elevated temperature was examined using the SDI test of mouse Sarcoma 180 and Ehrlich cells and clonogenic assay of HeLa cells. When Sarcoma 180 and Ehrlich cells were incubated at 43 degrees C for 2-10 h, the hyperthermic effect was enhanced by hypoxia. The succinate dehydrogenase activity of the cells was reduced by hyperthermia to a greater extent in the presence of hypoxia (O2:5%) than under conditions of aeration (O2:20%). When the cells were exposed to various concentrations of MMC and CQ, under hypoxia, activity of the drugs was enhanced compared to the findings under conditions of aeration. The enhancement was prominent in case of drugs and hyperthermia combined. Clonogenicity of hypoxic HeLa cells was also reduced to a greater extent with this combination than in case of aerated cells. We tentatively speculate that hyperthermo-chemotherapy using MMC and CQ has a potential to attack selectively hypoxic cells present in a solid tumor.


Etoposide microcrystals suspended in oil: a new dosage form to peritoneal carcinomatosis in mice. Etoposide microcrystals suspended in oil (ETOP-OIL) were examined for their therapeutic effects on peritoneal carcinomatosis in mice. Two days after intraperitoneal inoculation with 10(5) P388 leukemia cells/mouse to CDF1 male mice, etoposide at 10-80 mg/kg was administered intraperitoneally in bolus in the form of ETOP-OIL or in the aqueous solution form. In every dose, the survival curve of the mice given ETOP-OIL was statistically significantly improved in spite of its small lethal toxicity, as compared with those given the identical dose of etoposide aqueous solution.


Chemopreventive action of selenium on methylcholanthrene-induced carcinogenesis in the uterine cervix of mouse. The placement of cotton thread impregnated with beeswax containing methylcholanthrene (MCA, approximately 600 micrograms) inside the canal of the uterine cervix of virgin, adult mice results in the emergence of precancerous and cancerous lesions in the cervical epithelium. Employing this experimental carcinogenesis model system, the present study evaluates the chemopreventive action of selenium on the incidences of precancerous and cancerous lesions in the cervical epithelium. When selenium was administered through drinking water at the dose level of 1 ppm for 1 week before and 12 weeks following carcinogen thread insertion, the cervical carcinoma incidence, as compared to that in control mice (72%), was 37%. This decline in the incidence of carcinoma was significant (p less than 0.05). The incidences of hyperplasia and dysplasia show a decreasing trend with selenium treatment in MCA-thread-inserted animals.


Effects of switching from a high-fat diet to a low-fat diet on tumor proliferation and cell kinetics of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats. We investigated the stimulatory effect of a high-fat diet on tumorigenesis, tumor proliferation and cell kinetics of 7,12-dimethylbenz(a)anthracene-induced mammary carcinomas in Sprague-Dawley rats, and sought to determine whether switching the animals from a high-fat diet to a low-fat diet would suppress tumor proliferation and cell kinetics. The high-fat diet significantly stimulated tumorigenesis, tumor proliferation and cell kinetics. After the animals were switched from the high-fat diet to the low-fat diet, however, tumor growth decreased, the BrdUrd labeling indices of tumors significantly decreased, and the potential doubling times of tumors significantly increased. Therefore, switching from a high-fat diet to a low-fat diet may improve the prognosis of breast cancer.


Induction of neoplasms in Egyptian toads Bufo regularis by oil of chenopodium. Feeding the Egyptian toad Bufo regularis with oil of the chenopodium plant induced hepatocellular carcinomas in 23% of the animals, and metastases of the primary liver tumors appeared in the kidneys of 6 toads. The earliest evidence of tumors appeared after 3 months of treatment. The average latent period of tumor induction was 3.6 +/- 0.4 months. It is speculated that oil of chenopodium may be one of the constituents of Chenopodium ambrosoides which is responsible for tumor induction in the toads B. regularis.


Preferential looking--clinical lessons.

Preferential looking--clinical lessons. Preferential looking-based tests of acuity have been available for over a decade. The authors discuss their use in clinical practice, particularly in three groups in whom acuity could not be quantified by traditional means: normal infants, and young children who are either mentally retarded, or who have visual disorders. Preferential looking (PL) testing has increased our understanding of the natural history of visual pathway disorders and has revealed certain patterns of acuity development. Early acuity development may be normal, delayed, or stationary, while in later infancy and childhood the following abnormal patterns have been identified: asymptotic, parallel, catch-up, or regressing. While this information has introduced a degree of complexity hitherto unknown which, if misunderstood, can lead to test misinterpretation, it offers the clinician invaluable information to improve patient care, and may also offer clues to the fundamental mechanisms of visual development.


Update of sporadic microphthalmos and coloboma. Non-inherited anomalies. The majority of patients with microphthalmos and colobomas have genetic disorders. This is a survey of non-inherited, sporadic microphthalmos. Such cases may occur in the Goldenhar, CHARGE and VATER associations; it may also be due to teratological agents, for instance maternal ingestion of drugs, maternal infection, fever or irradiation. In these cases it is possible that neural crest cell development is abnormal. Some drugs, for instance retinoic acid are regulators of Hox genes which control an ordered sequence of differentiation; coloboma or microphthalmos may appear if deregulation occurs. Large choristomas of the anterior segment of the eye may be associated with microphthalmos or anophthalmos. Encephaloceles or orbital tumours may deform the growing eye and are another cause of non-inherited microphthalmos.


[The detection and characteristics of substances with fibroblast growth factor properties in the cells of loach embryos]. The substances extracted and partially purified from embryos of the loach (Misgurnus fossilis L.) at the late blastula stage are shown to possess properties characteristic of the fibroblast growth factor (FGF): 1) they bind with Heparin-Sepharose; 2) induce DNA synthesis in mouse NIH-3T3 and Swiss-3T3 fibroblast cell lines and in the primary culture of human embryonic fibroblasts; 3) have an apparent molecular weight of 15-16 kDa (according to SDS-electrophoresis); and 4) show positive reaction with antibodies against bovine basic FGF.


Autosomal dominant congenital miosis with megalocornea. A family with AD congenital miosis is presented. The ocular symptoms were: megalocornea, iris translucency, microcoria with poor pupillary dilatation and goniodysgenesis with anterior insertion of the iris. This observation confirms that in congenital miosis abnormal development of the whole anterior eye segment may occur. The patients have an increased risk to develop glaucoma. If retinoscopy is impossible due to pin-point pupils, ultrasonic biometry to determine the axial length is recommended. An optical iridectomy could improve visual performance at low illumination; the complaints of photophobia, which are related to the iris translucency, persist.


[The structural changes in chromatin at different levels of its organization during aging]. The data about changes in the molecular organization of the cell nucleus during aging are reviewed. Changes in DNA primary and secondary structure include deletions of some sequences, changes in base methylation pattern and the increasing number of DNA breaks. Conditions underlying poor reproducibility of the results obtained in corresponding experiments are discussed. Changes observed in the nucleosomal and supranucleosomal chromatin structure reflect either its increasing compactization or the loss the nucleosomal structure during aging. The data about the increased DNA superhelicity and topoisomerase activity in aging organisms contradict the accepted views about age-related decrease in chromatin activity. It is suggested that the gene activity in aging organisms is specifically altered rather than generally decreased. The data are presented about the ways of preventing or reverting the age-related changes in chromatin structure.


Peters' anomaly and combination with other malformations (series of 16 patients). A series of 15 patients with Peters' anomaly observed from 1987-1991 and a patient showing Wolf-Hirschhorn syndrome were studied retrospectively. Combined ocular anomalies were: microphthalmos (9x), myopia (4x), aniridia (2x), cataract (2x). Five of the patients had combined general anomalies: mental retardation, deafness, cardiac malformation (ASD II), and luxatio coxae. In two of them chromosomal anomalies were found: 4p minus syndrome, mosaic trisomy 9. After comparison of these data with those known from the literature the author confirms that Peters' anomaly is a morphologic finding rather than a distinct entity. Treatment depends on individual histopathologic findings and on the psychophysical development of the child.


[The development of the thoracic duct lymphangions in the prenatal period of human ontogeny]. This paper concerns structural and functional organization of the human lymphatic system during the prenatal period. For the first time the data is presented on the development of thoracic duct based on the concept of lymphangion as a structural and functional unit of a lymphatic vessel. The formation of the duct is considered in connection with structural changes of its wall and variants of duct roots fusion. The following stages are distinguished in the development of the thoracic duct: valval segment stage, protolymphangion, and lymphangion.


Peters' anomaly. The spectrum of associated ocular and systemic malformations. The cases of Peters' anomaly seen over the past decade, at Hospital Ste-Justine in Montreal, are reviewed. Associated ocular anomalies were observed in 50% of cases while 60% of patients presented with associated systemic defects. It is clear, from these patients and those reported in the literature, that Peters' anomaly can be an isolated condition, or part of distinct syndromes: the Krause-Kivlin syndrome or the Peters'-plus syndrome. The authors emphasize the importance for the ophthalmologist to recognize these possibilities if proper management is to be provided.


[The effect of carbohydrate metabolic changes during pregnancy on the capacity of liver mitochondria in rat progeny to oxidize the lipid intermediate]. Respiration rate, respiration control and ADP of liver mitochondria were studies in one-, ten-, and twenty-day-old rats born of females who had received subcutaneous insulin injections (0.25 U/100 g body weight) on days 5-7, 11-13 and 19-21 of pregnancy or glucose (1 g/100 g body weight, in the morning before feeding). Caprylate, an intermediate of the lipid metabolism, was used as the substrate for oxidation. In the control, caprylate oxidation in one-day old rats occurred at a low rate without providing for synthesis of ATP from ADP and phosphate. Insulin administration and alimentary hyperglycemia in females on days 5-7 of pregnancy had no significant effect on respiration rate of liver mitochondria in progeny of all ages tested. Administration of the above preparations on days 11-13 and 19-21 of pregnancy improved caprylate oxidation in mitochondria of the newborn rats. In other series the difference between experiments and the control was insignificant. Metabolic changes in the newborns are shown to be related to hyperinsulinemia in pregnant females.


Mapping the eye diseases.

Mapping the eye diseases. In this review the authors first give an overview of the general strategies of mapping which differ whether the biochemical (molecular) defect of the disease is known or not. The main problems besides mapping are concerned for the first category with the correlation between mutation and phenotype and for the second, with heterogeneity, genetic vs phenotypic. Finally, tables are displayed of eye diseases or diseases with eye involvement (metabolic or not) which have been currently mapped, as well as candidate genes actually or putatively involved in visual transduction.


Horner's law. The first step in the history of the understanding of X-linked disorders. Earlier reports on colour blindness are descriptions which almost always mention the familial occurrence. Horner's publications (1876), however, gave the first scientific analysis of the hereditary transmission of Daltonism. Since this genealogic study was published only in a local bulletin of the City of Zurich it seemed necessary to give a translation of the most important part of the article. 'Horner's law' says that colour-blind fathers have colour-normal daughters; and these colour-normal daughters are the mothers of colour-blind sons. In his first pedigree Horner demonstrates that colour-blindness is transmitted from the grandfather to the grandson. A second pedigree, however, shows the possibility that the transmission is also possible via female carriers through more than one generation. The similarity with the inheritance of haemophilia, published by Lossen (Heidelberg), was mentioned by Horner. In the further progress of genetic research the chromosomes were visualized, at first in tumour-cells 1881, in cells of human tissue. The final point in this development was the description of sex chromosomes, which made the interpretation of Horner's law possible by Wilson (1911), i.e., the localization of the pathologic gene of Daltonism on the X-chromosome.


Retinal angioma and juvenile sex-linked retinoschisis. A 13-year-old boy presented with juvenile X-linked retinoschisis and in the right fundus a typical retinal angioma situated at the temporal site of the macula. A maternal uncle and a maternal grand uncle were known to be also affected by juvenile retinoschisis. Family history was negative for retinal angiomatosis. Extensive internal, neurologic and radiologic examinations did not reveal associated neurologic or visceral involvement in the affected child. The association of a retinal angioma and juvenile X-linked retinoschisis is most probably fortuitous.


A practical approach to albino diagnosis. VEP misrouting across the age span. In addition to the genetic heterogeneity in albinism, widespread clinical heterogeneity frequently impedes albino detection and differential diagnosis. Further, several auxiliary ocular and/or cutaneous manifestations of this inherited error of pigmentary metabolism are neither pre-requisite nor specific to the albino condition. However, one feature that is specific to albinism regardless of genotype or phenotype is a unique pattern of abnormal visual pathway organization. With an appropriate test paradigm, the albino visual pathway can be revealed by the non-invasive recording of the visual evoked potential (VEP) distribution across the occiput which shows contralateral hemispheric asymmetry following full field monocular stimulation. As described in this report, the VEP albino misrouting detection test has been refined to yield extraordinarily high sensitivity and selectivity across the age span from the neonate to the elderly. As the VEP profile undergoes maturational changes, these changes have been taken into account in the development of an albino age-range VEP test recipe which includes the pattern onset paradigm for older albinos and a luminance flash paradigm for the albino infant. The age appropriate optic pathway misrouting test provides reliable albino detection and definitive differential diagnosis. Further, as the albino VEP signature of contralateral asymmetry is also age specific, the VEP misrouting test can be extended to the objective assessment of visual pathway maturation.


Aspects of albinism.

Aspects of albinism. Genetic, clinical and electrophysiological aspects of albinism are described. Emphasis is placed on electrophysiological features which help to distinguish albinism from other clinical conditions, and on stimulating and recording factors which can affect the clarity of VEP results.


Vision in the "good" eye of children treated for unilateral congenital cataract. The authors examined linear acuity and contrast sensitivity in the "good" (fellow) eye of children treated for unilateral congenital cataract to determine (1) whether there were subtle deficits like those described for the good eye of patients with strabismic amblyopia and (2) whether any deficits were related to the degree to which the good eye had been patched. The authors tested patients treated for unilateral congenital cataract who had a well-documented history of patching. The good eye was physically normal with minimal refractive error. The measures were linear acuity at far (n = 15) and contrast sensitivity (n = 9). Compared with age-matched control subjects, the good eyes of patients had subtle deficits in linear acuity and in contrast sensitivity at high spatial frequencies. These deficits occurred even in eyes that had received minimal patching, and their severity was not related systematically to the duration of patching, which varied widely across the group. The visual sensitivity of the good eye of children treated for unilateral congenital cataract is, on average, slightly reduced, even in cases of minimal patching. Consequently, any deficits discovered after aggressive patching may not have been caused by occlusion amblyopia.


Surgical treatment of subluxated lenses in children. Surgical removal of subluxated lenses had traditionally been discouraged because of concerns about poor surgical results and unacceptably high complication rates. The authors reviewed the surgical results of 29 eyes in 15 consecutive patients who were operated on for subluxated lenses. Best-corrected visual acuity improved in all 29 eyes and was limited only by amblyopia. There were no significant complications in follow-up ranging from 5 months to 12 years. Modern surgical techniques using vitrectomy instruments allow the vitreous to be handled more effectively and have led to improved results and lower complication rates. Surgery for subluxated lenses can be done effectively and safely when indicated.


Head nodding is compensatory in spasmus nutans. Spasmus nutans is defined as asymmetric nystagmus with associated head nodding in childhood. It is not clear whether head nodding is a compensatory mechanism to control the nystagmus or an involuntary movement of pathologic origin. The authors analyzed the relation between head and eye movements by simultaneous eye and head movement recordings of 35 patients with spasmus nutans. In 21 of these patients, the fine, fast, dissociated nystagmus changed during head nodding to larger and slower symmetric eye movements with both eyes oscillating at the same amplitude in phase and 180 degrees out of phase to the head movements, corresponding to a normal compensatory vestibulo-ocular reflex. These findings indicate that head nodding is compensatory in spasmus nutans.


Tendon laxity in superior oblique palsy. Some congenital superior oblique palsies are known to be due to anomalous or lax superior oblique tendons. This prospective study of 24 patients with a diagnosis of superior oblique palsy was performed to determine the prevalence and significance of anatomic tendon anomaly or laxity as diagnosed by traction testing of the superior oblique tendon. Traction testing was performed on 24 consecutive superior oblique palsy patients to determine the relative laxity of the tendons. All 14 patients who were believed to have congenital palsy by history and clinical examination were found to have lax tendons. No patient with acquired unilateral palsy showed similar tendon laxity. These findings have significant implications regarding the diagnosis and possible cause of congenital superior oblique palsy as well as implications for surgical management.


Ophthalmologic assessment of young patients with Alport syndrome. Alport syndrome is an X-linked disease affecting basement membrane collagen. It is characterized by nephritis associated with high-tone sensorineural hearing impairment and ophthalmic signs. Although ocular changes have been described in adults, few data exist regarding the incidence of abnormal ocular features in adolescence and childhood. Fifteen male and five female patients with Alport syndrome underwent ophthalmologic, audiologic, and nephrologic assessments. All patients studied had hematuria and a positive family history of Alport syndrome. Thirteen patients had a renal biopsy that showed characteristic electron microscopic changes of the disease. Eleven patients had high-tone sensorineural impairment. Electrophysiologic investigations performed included electroretinography, visual-evoked potentials, and electro-oculography. Two patients had early signs of anterior lenticonus, three had flecks in the retina, and two patients also had posterior subcapsular cataracts. None of the patients had significant electrophysiologic abnormalities. These findings indicate that ocular changes are uncommon and subtle in young patients with Alport syndrome, and suggest that the signs increase in frequency and severity with age.


Contrast and glare sensitivity. Association with the type and severity of the cataract. Contrast and glare sensitivity tests are now being used as adjuncts to visual acuity in the assessment of visual function. Limited data are available on the associations of the former tests with cataract type and severity. The aim of the study is to assess these associations using standardized techniques. Contrast sensitivity tests (using the Pelli-Robson chart) and glare sensitivity tests (using the Vistech MCT 8000) were done on 128 patients with cataracts and no other ocular disease and on 29 control volunteers. The cataracts were graded using the Lens Opacities Classification System II (LOCS II). Data from the left eyes were analyzed using logistic regression models. Contrast sensitivity loss was associated with cataract severity for cortical (P less than 0.0001) and posterior subcapsular (P = 0.0001) cataracts and with decreased visual acuity (P = 0.0001). Night and day glare sensitivity were each associated only with increased severity of posterior subcapsular cataracts (P less than or equal to 0.003) and with decreased visual acuity (P less than 0.001). Additional analyses showed that contrast and glare sensitivity were similar in eyes with no cataracts and early cataracts. These results suggest that the Pelli-Robson Chart and the Vistech MCT 8000 are good techniques for evaluating visual function in moderate to advanced cataracts. However, for early cataracts, other techniques need to be explored to assess visual function loss.


Quantitative analysis of wound healing after cylindrical and spherical excimer laser ablations. Superficial corneal ablation using the 193 nm excimer laser for the correction of myopia and astigmatism produces histologic changes in the corneal profile that can be quantitatively analyzed. Using the excimer laser, spherical and cylindrical corneal ablations were performed on rabbit eyes at depths of 2, 4, 6, and 8 diopters. After 12 weeks, the corneas were examined histologically using a dichlorotriazinyl aminofluorescein stain for collagen, and the results were quantified using a digital video image analysis system. Epithelial thickness and thickness of new collagen were positively correlated with the depth of ablation after spherical ablations. With astigmatic ablations, epithelial thickness and new collagen production were correlated with ablation depth in one axis only. These results suggest that during cylindrical corneal ablations with the excimer laser, radially asymmetrical stromal ablations produce quantitatively asymmetrical wound healing.


Risk analysis in the development of pterygia. No detailed analysis of risk factors in the development of pterygia has been previously performed. In this report, the authors identify and quantify these risk factors. In a case-control study, 278 patients treated in a Brisbane hospital for primary pterygium between 1973 and 1978 were compared with a similar number of people without pterygium who were matched for age, race, and sex, using information from a standard questionnaire completed during a personal interview. Risk of pterygium was increased among patients who, in their third decade of life, worked outdoors in an environment with high surface reflectance of ultraviolet light compared with those who worked indoors. The elevation of risk was raised several hundred-fold among those subjects who worked mainly on sand compared with those who worked indoors when results were adjusted for associated risk factors. When risk was measured among subjects who worked in an environment that was mainly concrete, risk was increased almost 20-fold. Those subjects who spent their first 5 years of life at latitudes less than 30 degrees had almost 40 times the risk of pterygium than those living at latitudes greater than 40 degrees; spending the majority of times outdoors in these earliest years was associated with a 20-fold increase in risk of developing pterygium. There was a strong protective element in the wearing of regular glasses, sunglasses, or a hat. There is a strong suggestion of a causal relationship between ultraviolet light exposure and the development of pterygia during the early years of life and the cumulative exposure over the next 2 to 3 decades in occupations in which there is a high component of reflected ultraviolet light.


Oral acyclovir for herpes zoster ophthalmicus. Reports on the natural history of herpes zoster ophthalmicus stress its high morbidity related to vicious scars on eyelids, ocular complications, and post-herpetic neuralgia. Early treatment with oral acyclovir is effective, but the optimal duration of treatment has not been defined. The authors performed a bicentric, prospective, randomized, double-masked study of 86 patients with acute herpes zoster ophthalmicus, within 72 hours of skin eruption, who received oral acyclovir (800 mg 5 times daily), either for 7 days (plus 7 days oral placebo) or for 14 days. All patients concomitantly received ophthalmic 3% acyclovir ointment; follow-up was at least 6 months. Statistical analyses of subjective symptoms, skin lesions, and ocular complications showed no significant differences between the groups, suggesting that a 7-day course of treatment was sufficient. Drug tolerance was good. Pooled data from both groups corroborated earlier reports that prompt treatment with oral acyclovir reduces the severity of the skin eruption, the incidence and severity of late ocular manifestations, and the intensity of postherpetic neuralgia. At 6 months, late ocular inflammatory complications were seen in 29.1% of our 86 patients, versus 50% to 71% of untreated patients described by others. Only 13% of our patients experienced post-herpetic neuralgia, which in no case required the use of analgesics. The authors believe it is not useful to prolong treatment with 800 mg of oral acyclovir 5 times daily for more than 7 days in herpes zoster ophthalmicus. This study confirms the efficacy of oral acyclovir not only against skin lesions and ocular complications, but also against postherpetic neuralgia in herpes zoster ophthalmicus.


Panstromal Schnyder's corneal dystrophy. Ultrastructural and histochemical studies. A large cohort comprising four kindreds of patients with Schnyder's dystrophy has been identified in central Massachusetts. All patients were Swede-Finn with ancestry from the southwest Finnish coast on the Bay of Bothnia. Of 60 members of this cohort examined by one of the authors (JSW), 18 had evidence of Schnyder's dystrophy. One female with Schnyder's dystrophy from each of three kindreds underwent penetrating keratoplasty for decreased visual acuity. We examined 4 corneal buttons from these unrelated women, aged 47, 63, and 72 years. The fluorescent probe filipin revealed that the majority of the lipid deposits were rich in unesterified cholesterol. Electron microscopy demonstrated abnormal accumulation of lipid and dissolved cholesterol in the epithelium, Bowman's layer, and throughout the stroma. Examination of the kindreds reflected the variable expression of crystals, which were present only in two patients, the 47-year-old and 63-year-old women. Ultrastructural and histochemical studies showed the panstromal localization of lipid in Schnyder's corneal dystrophy in three patients with Schnyder's dystrophy who underwent penetrating keratoplasty.


Ocular surface alteration after long-term treatment with an antiglaucomatous drug. This study was undertaken to see whether long-term locally applied ocular medications produced any alterations in the ocular surface, and, in particular, whether it caused damage to the mucus layer of the tear film. The authors studied the ocular surface of 40 control subjects (group 1), 21 patients (group 2) chronically treated with a commercial preparation of 0.5% timolol maleate, and 20 previously untreated glaucomatous patients (group 3) in need of treatment with the same drug. Parameters studied were Schirmer's test, lacrimal meniscus height, break-up time, fluorescein and rose Bengal stains, conjunctival impression cytology, mucus staining, and the ferning test. Patients in groups 2 and 3 showed a significant decrease (P less than 0.001) in the number of normal Schirmer's and break-up time tests. All had positive vital stains. Results showed a significant decrease (P less than 0.001) in goblet-cell density, mucus granules, and reticular sheets, and an increase (P less than 0.001) in pathologic crystallization patterns. These results demonstrate that chronic application of a commercial preparation of timolol maleate damaged the ocular surface, especially the mucus layer of the tear film.


Contact transscleral Nd:YAG laser cyclophotocoagulation. Midterm results. Early reports of both contact and noncontact transscleral Nd:YAG laser cyclophotocoagulation have been encouraging; however, recent evidence indicates a significant incidence of hypotony, visual loss, and phthisis with the noncontact technique with more than 6 months of follow-up. The authors sought to determine the intermediate term effects of contact transscleral Nd:YAG laser cyclophotocoagulation (CYC). The authors followed 116 eyes of 114 patients for a minimum of 1 year after treatment of advanced glaucoma with CYC. The mean preoperative intraocular pressure (IOP) of 35.0 +/- 1.0 mmHg decreased to 18.6 +/- 1.1 mmHg (P less than 0.0001) during the average follow-up of 19.0 +/- 0.6 months (range, 12 to 36 months). Intraocular pressure control of 3 to 25 mmHg was achieved in 72%, 3 to 22 mmHg in 65%, and 3 to 19 mmHg in 56% of eyes. Retreatment was required in 31 of the 116 eyes (27%). Intraocular pressure decreased to less than 3 mmHg in 9 eyes and to 0 mmHg in 6 of these 9 eyes. Nineteen eyes, all with initial visual acuity of counting fingers or worse, progressed to no light perception; 17 of 36 eyes (47%) with visual acuity of 20/200 or better lost 2 or more Snellen lines. Midterm results of CYC continue to be encouraging but are tempered by a nearly 10% incidence of hypotony or phthisis and the progression of visual loss.


Effects of jogging exercise on patients with the pigmentary dispersion syndrome and pigmentary glaucoma. Exercise-induced anterior chamber pigment dispersion with intraocular pressure (IOP) elevation has been reported in patients with the pigmentary dispersion syndrome. Marked pigment dispersion with or without elevation of IOP could predispose these patients to visual field loss. The authors designed this study to evaluate the effects of jogging exercise on anterior chamber pigment and IOP in a group of patients with the pigmentary dispersion syndrome or pigmentary glaucoma. Fourteen subjects with the pigmentary dispersion syndrome, 10 subjects with pigmentary glaucoma, and 10 control subjects underwent a 45-minute protocol of jogging exercise. Anterior chamber pigment was graded and IOP was measured before and up to 3 hours after completion of the exercise protocol. Eyes of experimental subjects were significantly more likely to develop exercise-induced pigment dispersion than were eyes of control subjects. In experimental subjects, eyes treated with pilocarpine at the time of the study were significantly less likely to develop exercise-induced pigment dispersion than eyes not treated with pilocarpine. In two experimental subjects, pre-exercise treatment with pilocarpine appeared to inhibit exercise-induced pigment dispersion. The authors do not believe that all patients with the pigmentary dispersion syndrome or pigmentary glaucoma need to avoid exercise. However, for patients with these disorders who regularly engage in jogging or more strenuous or more jarring types of exercise, they suggest an evaluation before and after the type of exercise in question. If marked exercise-induced pigment dispersion occurs, pilocarpine therapy may be an alternative to avoidance of the exercise.


Changes in reversal of cupping in experimental glaucoma. Longitudinal study. The authors prospectively and longitudinally studied changes in optic disc topography during spontaneous reduction of intraocular pressure (IOP) in five monkeys with experimental glaucoma, using a computerized image analyzing system (Topcon IMAGEnet). Glaucomatous optic neuropathy was produced in one eye of each animal by repeated argon laser photocoagulation of the trabecular meshwork. The duration of follow-up was 12 months. After laser treatment, IOP fluctuated and tended to increase. Spontaneous reduction in IOP was frequently observed during follow-up. Changes in optic disc parameters (vertical and horizontal cup-to-disc ratios, rim area/disc area, cup volume/disc area) that accompanied a given magnitude of spontaneous reduction in IOP at the early stage of glaucoma (first 4 months of follow-up) were compared with those at the later stage of glaucoma (last 4 months of follow-up). All optic disc parameters improved significantly during IOP reduction at each stage of glaucoma. Although there was no significant difference between the two stages in the magnitude of IOP reduction, the extent of improvement in each disc parameter was significantly less in the later stage than in the early stage. In both stages, reversal of cupping occurred symmetrically in the vertical and horizontal dimensions. Expansion of the cup occurred symmetrically in the early stage, but this was predominantly vertical in the later stage. These results suggest that the extent of cupping reversal after IOP reduction may decrease with progressive glaucomatous damage in primate glaucoma.


Neuroretinal rim area measurements by configuration and by pallor in ocular hypertension and glaucoma. The purpose of this study is to examine the differences between measurements of neuroretinal rim area of the optic disc defined by configuration and by pallor. One hundred seventy-one patients were studied (59 with glaucoma, 96 ocular hypertensive patients, and 16 controls). The magnification-corrected neuroretinal rim area was measured from black-and-white stereoscopic paper prints. The central area of pallor was measured using computer-assisted image analysis techniques. The percentage of central area of pallor was converted into mm2, and an estimate of neuroretinal rim area defined by color was calculated. The correlation between the measurements of neuroretinal rim area by configuration and by pallor was statistically highly significant (r = 0.89, P less than 0.0001). No consistent differences between measurements were found in different diagnostic groups, or in different stages or types of glaucomatous optic disc abnormality. The correlation of changes of both measurements during a 9-year follow-up period also was statistically significant (r = 0.68, P less than 0.001). In clinical routine measurements of the neuroretinal rim area, using both configuration and pallor definition does not seem to add to the information.


Epibulbar molluscum contagiosum in acquired immune deficiency syndrome. Case report and review of the literature. While molluscum contagiosum of the eyelid skin is commonly complicated by conjunctivitis, primary involvement of the conjunctiva or cornea by molluscum lesions is exceedingly rare. The authors studied a 34-year-old man with acquired immune deficiency syndrome (AIDS) in whom multiple molluscum lesions of the lids and a single nodule of the limbus developed. The nodular lesion was excised from the limbus and processed for histologic examination by light microscopy. Pertinent literature concerning epibulbar molluscum contagiosum was reviewed. Histopathology of the excised lesion showed molluscum bodies within the acanthotic, hyperkeratotic conjunctival epithelium with surrounding chronic, nongranulomatous inflammation. Only 10 previous cases of conjunctival or corneal primary lesions have been reported, half of which showed associated cutaneous involvement. Lesions tended to be single, noninflamed, dome-shaped, and umbilicated, often with a yellowish central core. Patients were otherwise well and ranged in age from 3 to 55 years. Simple excision was effective in eradicating the lesions. Primary epibulbar molluscum contagiosum is rare. Although cutaneous molluscum is common in AIDS, this report is the first to document conjunctival molluscum in a patient with AIDS.


Treatment of ocular adnexal Kaposi's sarcoma in acquired immune deficiency syndrome. To determine the most effective, safe, and cost-efficient treatment for ocular adnexal Kaposi's sarcoma in the acquired immune deficiency syndrome. Eighty-two patients with ocular adnexal Kaposi's sarcoma related to the acquired immune deficiency syndrome were examined, and 25 were selected to participate in a 3-year study that treated the ocular lesions based on stage of development and location. Of 14 patients with bulbar conjunctival Kaposi's sarcoma treated with surgical excision, 2 stage III lesions recurred during a follow-up that ranged from 8 to 31 months; no stage I or stage II lesion recurred. Of 7 patients with eyelid Kaposi's sarcoma treated with cryotherapy, 2 stage III lesions recurred during a follow-up that ranged from 9 to 24 months; no stage I or stage II lesion recurred. Four patients with stage III Kaposi's sarcoma of the bulbar conjunctiva were treated with fluorescein angiography-based surgical excision. None of these lesions recurred during a follow-up that ranged from 4 to 8 months. A treatment regimen for ocular adnexal Kaposi's sarcoma related to the acquired immune deficiency syndrome based on tumor stage and location, using cryotherapy and surgical excision with or without fluorescein angiography, is effective, safe, and cost-efficient.


Repair of telecanthus by anterior fixation of cantilevered miniplates. The accepted surgical method for telecanthus repair is transnasal wiring. This procedure requires a stable posterior lacrimal crest on the affected side and surgical manipulation of the wires as they exit the contralateral side. A method for repairing telecanthus that obviates these prerequisites is presented. Indications for use of this technique and comparison to transnasal wiring is discussed. A Y-shaped titanium rigid orbital plating system ("miniplate") was used to surgically correct traumatic telecanthus in five patients, two in the acute setting and three in late reconstruction. The miniplate was cantilevered from the lateral aspect of the nose and directed posteriorly into the orbit. This provided a stable fixation point for the medial canthal tendon. Marked resolution of the telecanthus was noted in four patients. No post-operative complications have been encountered to date. Miniplate fixation was used successfully to repair unilateral traumatic telecanthus. Miniplate fixation of the medial canthal tendon should be considered in unilateral cases of traumatic telecanthus and in cases where poor bony support for transnasal wires is evident.


Tricompartment model of the lacrimal pump mechanism. The role of the lacrimal sac in the lacrimal pump mechanism is controversial. Movements of the lateral wall of the lacrimal sac with blinking were videotaped through an endoscope in eight patients after dacryocystorhinostomy. In addition, movements of an air bubble at the opening of the nasolacrimal duct with blinking were studied in three patients with an incompetent valve of Hasner. The superior half of the lateral wall of the lacrimal sac moved laterally with lid closure and medially with lid opening. The inferior half of the lateral wall of the lacrimal sac moved medially with lid closure and laterally with lid opening. In patients with an incompetent valve of Hasner, the air bubble at the opening of the nasolacrimal duct bulged into the nose with lid closure and retracted into the nasolacrimal duct with lid opening. A tricompartment model of the lacrimal pump is presented that incorporates these findings. With lid closure, the orbicularis muscle contracts, compressing the canaliculi and pulling the superior half of the lateral wall of the lacrimal sac laterally. This creates a lower pressure in the superior sac, allowing tears to be propelled from the canaliculi into the sac. At the same time, the inferior half of the lateral sac wall moves medially, creating a positive pressure in the inferior sac and nasolacrimal duct, thus forcing tears down the duct into the nose. With lid opening, the orbicularis muscle relaxes, allowing the canaliculi to open and the superior half of the lateral sac wall to move medially. The resulting negative intracanalicular pressure allows tears to flow from the lacrimal lake into the canaliculi, and the higher pressure in the superior sac closes the valve of Rosenmueller and forces tears from the superior to inferior sac and proximal nasolacrimal duct. At the same time, the inferior half of the lateral sac wall moves laterally, resulting in a negative pressure in the inferior sac and nasolacrimal duct.


Diagnosis of cavernous sinus arteriovenous fistula by measurement of ocular pulse amplitude. The ocular pulse amplitude (OPA), the difference between the maximum and minimum intraocular pressure (IOP) during the cardiac cycle, has been reported to be elevated in the eye ipsilateral to a cavernous sinus arteriovenous fistula. The OPA was measured with a pneumotonometer in three groups of patients. Patients in group 1 had no orbital disease (n = 50), patients in group 2 had either unilateral or asymmetric orbital disease (n = 30), and patients in group 3 had angiographically proven cavernous sinus arteriovenous fistulas (n = 15). Patients in group 3 had a higher OPA than patients in either group 1 (P less than 0.001) or group 2 (P less than 0.001). The difference in OPA between an individual's eyes (delta OPA) also was higher in patients with cavernous sinus arteriovenous fistulas than in patients without fistulas (P less than 0.0001). A delta OPA of more than 1.6 mmHg was 100% sensitive and 93% specific in identifying patients with cavernous sinus arteriovenous fistulas. There was no difference in delta OPA between direct and dural cavernous sinus arteriovenous fistulas. Successful transvascular embolization of the cavernous sinus arteriovenous fistula normalized the delta OPA by reducing the OPA on the affected side.


Retinal manifestations of ocular lymphoma (reticulum cell sarcoma). Diagnosis and treatment of ocular large cell lymphoma may lessen visual loss and prolong life. Although reports in the literature have described retinal infiltrates in eyes with large cell lymphoma, they have focused on the more prominent vitreous and subretinal pigment epithelial findings. Eyes with retinal infiltrates and hemorrhagic retinal necrosis are usually believed to harbor a microbial infection. The authors describe 5 patients, aged 57 to 85 years, with ocular lymphoma in whom the most prominent initial findings were in the retina. Patients presented with findings suggestive of an infectious retinal necrosis. When the initial therapy failed, investigators performed a vitreous biopsy. Two patients had a concomitant retinal biopsy. Radiation therapy was given to four patients. All five patients had vitreous cells. Three patients had prominent perivascular exudate. Four patients had grayish-white retinal infiltrates, and three patients had associated retinal hemorrhage. Three patients had subretinal small white spots. An edematous thickened retina developed in three patients, and hemorrhagic retinal necrosis developed in three patients. The initial diagnosis was believed to be acute retinal necrosis (ARN) in three patients, toxoplasmosis in one patient, and frosted branch angiitis in one patient. Vitreous biopsy was positive in two patients but negative in three patients. In two of these three patients, the diagnosis was established by retinal biopsy. Ocular lymphoma should be considered in the differential diagnosis of retinal vasculitis or necrotizing retinitis in a middle-aged or older patient. Retinal biopsy may be helpful in establishing the diagnosis.


Transforming growth factor-beta 2 for the treatment of full-thickness macular holes. A prospective randomized study. Full-thickness macular holes generally cause a significant reduction in visual acuity, due in part to a rim of surrounding neurosensory retinal detachment and retinal thickening. Recent studies have suggested that flattening of this narrow rim of neurosensory detachment can result in improved visual acuity. However, the ability to flatten the neurosensory detachment is limited using current surgical techniques. Transforming growth factor-beta 2 (TGF-beta 2) is a recently discovered potent stimulator of wound healing. The authors, therefore, performed a prospective randomized study of 60 patients to determine if the local application of TGF-beta 2 to the edge of the macular hole can reproducibly induce flattening of the surrounding neurosensory detachment. The results of a study designed to determine the effect of a pars plana vitrectomy, fluid-gas exchange, and intravitreal instillation of TGF-beta 2 in eyes with a full-thickness macular hole and reduced visual acuity are reported. After treatment, visual acuity improved 2 lines or more in 5 of 11 eyes treated with 70 ng, in 4 of 12 eyes treated with 330 ng, and in 10 of 11 eyes treated with 1330 ng of TGF-beta 2. In some eyes, hyaluronic acid was added. In these cases, visual acuity improved 2 lines or more in 0 of 9 eyes treated with 70 ng TGF-beta 2, in 2 of 8 eyes treated with 330 ng, and in 4 of 9 eyes treated with 1330 ng. Logistic regression analysis demonstrated a statistically significant beneficial effect of TGF-beta 2 on visual improvement (P = 0.003).


A survey of intraocular silicone oil use in the United States. This survey was conducted to determine the pattern of usage of intravitreal silicone oil in the United States. A questionnaire was sent to 542 members of the Retina and Vitreous Societies in December 1990, and again 6 weeks later in an attempt to improve the response rate. Two hundred eighty-seven questionnaires (53%) were returned. Ninety-eight percent of the respondents perform vitreous surgery, and 61% of them use silicone oil. This survey determined the degree of participation in Food and Drug Administration (FDA)- and institutional review board-approved protocols and the most common indications for use of silicone oil. Ninety-six percent of the respondents indicated that the use of silicone oil represented an acceptable standard of care. Silicone oil is widely used in the United States despite its lack of FDA approval.


How to start a direct patient care team. Many American hospitals are embracing the philosophies of continuous quality improvement (CQI) or total quality management (TQM). To date, case studies in the literature have largely dealt with administrative processes. However, CQI can also improve direct patient care (clinical) processes using direct patient care teams. The establishment of such teams has been an elusive task at many organizations, largely because of the traditional paradigm of the appropriate relationship between provider and patient. However, similarities between direct patient care teams and other cross-functional teams far exceed differences. Using case studies from two teams (HIV and chest pain) at HCA West Paces Ferry Hospital and Southeastern Health Services, this article suggests ways facilitators can help providers examine, redesign, and improve direct patient care processes.


Advancing the epidemiology of injury and methods of quality control: ACEs as an outcomes-based system for quality improvement. Accelerated-compensation events (ACEs) are classes of avoidable medical injuries. Originally, these classes were used in tort reform to speed payment for avoidable injuries. However, ACEs also have potential as tools to monitor and improve the quality of health care. ACEs are developed by physicians, based on medical decision making. Rather than simply identify an adverse outcome, they link that outcome to clinical processes. Therefore, ACEs can help identify the critical elements of care that would result in desirable outcomes. Also, ACEs are discerning: they identify only events of which the vast majority are preventable. In one project, ACEs have been developed for obstetrics/gynecology, general surgery, and orthopedic surgery, using a three-phase process of sifting data and honing definitions. Future plans include improving these ACEs, statistically evaluating them, and testing them for utility in quality monitoring and improvement.


[Childhood accidents].

[Childhood accidents]. A survey of accidents in a period of one year in County Vas, Hungary was performed. The injury of children in the age-group of 0-14 was found in case 5841 i.e. in 22.5% of the total number of the injured. The incidence was 101/1000 head of puerile population. The rate of accidents appeared to be low in early childhood while it showed a significant increase in the school age. The home accidents accounted for the most of the accidents especially in the early childhood. Over the age of 7 the school and sport/playground accidents exceeded. The roads were involved as a high risk factor for each of the age groups. The high (21.5%) rate of fractures indicates severity of the injuries although the number of the most severe injuries remained low. The accident conditions of County Vas are at an advantage compared with international data meanwhile the high rate of accidents in the school age group calls for prevention and educational work.


[Experience with surgical treatment of osteosarcoma]. The authors treated 79 patients with osteosarcoma by surgery and chemotherapy 1975 through 1991. The appearance, localization and differential diagnosis are discussed. Attention is called to the doctor's delay. The effective pre- and postoperative chemotherapy decreased the incidence of the lung metastases and increased the survival rate (71% 3 years overall survival and 41% 5 years survival) and made the limb-sparing surgery possible. The development of the reconstructive surgical technique and new designs of tumor endoprostheses enabled us to perform limb-sparing surgery in more than one third of the cases at the same survival chance. The limb-sparing means a decisive change in the quality of the rehabilitation of the osteosarcoma patients.


[Why is the Doppler pressure gradient higher than the one measured by catheter?]. Hemodynamic assessment of aorto-iliac occlusive disease is necessary for successful arterial reconstruction of the legs. Various methods have been proposed and the "pull-through" intra-arterial pressure measurement method is accepted as the best standard. The pressure readings, however, seemed to depend on the intraluminal position of the catheter. To explain these observations and make a comparison between the Doppler method and the "pull-through" method, we have studied center-line velocity changes at the stenosis throat by Doppler ultrasound, and axial and lateral pressure gradients using pressure transducers, mounted 10 mm and 40 mm downstream of short (4 mm) and long (40 mm) axisymmetric sharp-edged model stenoses having cross sectional reduced areas of 64%, 84%, 91%, and 96%. Axial manometric pressures measured 10 mm after the throat of 84% stenosis were more than twice as high as the lateral pressures. There was no significant difference between axial and lateral pressures measured 40 mm downstream from throat. This pressure distribution has important clinical relevance. Mean and peak pressure gradients for both the Doppler method and manometric measurements were compared. Measurements with Doppler method and manometric measurements, indicated that mean pressure gradients (r = 0.98; SEE = +/- -2.4 mmHg) correlate better than peak pressure gradients (r = 0.90; SEE = +/- 16.5 mmHg). Doppler gradients were higher than manometer gradients. Overestimation was 13% for mean pressure gradients, and ranging from 10% to 150% for peak pressure gradients. Explanation for the difference between mean Doppler and catheter gradient may be the pressure recovery occurring in the relaminarized poststenotic regions.


[SPECT follow-up of cerebral blood circulation after stroke]. rCBF SPECT investigations with 99mTc-HMPAO were performed in 22 completed ischemic stroke patients on average 2.5, 16.8 and 38.0 days after stroke onset. As control group, 12 neurologically healthy volunteers were examined with the same method. The overall sensitivity of the rCBF SPECT method in the detection of cerebral blood flow abnormalities was 91%, with a specificity of 83% and an accuracy of 88%. The rCBF study was highly effective, particularly in the acute phase of the disease. Regional increased tracer uptake or a false normal 99mTc-HMPAO distribution due to the developing hyperemia mostly complicated the rCBF image interpretations in the subacute period. In the chronic phase, the spatial resolution of the SPECT system limited the detection of the continuously retracted stroke lesions.


[Rhabdomyolysis in a medical student induced by body-building exercise (rhabdomyolysis following acute muscular exertion)]. A medical student sportsman had been admitted to the hospital because of weakness and painful swelling of the muscle as well as dark urine appearing after carrying out an excessive body-building performance. On the basis of indirect evidences pigmenturia "per exclusionem" was a manifestation of urinary myoglobin excretion. The development of an "acute exertional rhabdomyolysis" was confirmed by the increased serum enzyme levels and myoglobinuria. The outcome of the illness was fortunate, as acute renal failure could be avoided. On the basis of survey of the literature it can be stated, that this presumably frequently occurring, but rarely recognized disease may have importance from clinical, sporting medicine and pathophysiological point of view.


[Migraine according to the International Headache Society]. The classification of headache and facial pain established by the International Headache Society (IHS) in 1988 is a useful tool for general practitioners, specialists and scientists. This classification provides a detailed description of the diagnostic criteria for the different forms of migraine headache, ranging from common migraine with or without an aura to less frequent or atypical forms such as migraine without headache or periodic syndromes of childhood.


Migraine--disease or syndrome?

Migraine--disease or syndrome? Migraine is a common condition with, usually, stereotyped symptomatology, suggesting that it is a specific disease entity (a morbus sui generis). However, occasionally a migraine sufferer will exhibit atypical manifestations of the condition; also, some specific diseases such as systemic lupus erythematosus and arteriovenous malformations, may exactly mimic the symptoms of migraine. These latter considerations raise the possibility that migraine is a syndrome rather than a disease. The recent delineation of the trigeminovascular system allows a conception of migraine as being neither disease nor syndrome, but rather a constitutional predisposition of the neurovascular system to react excessively to internal or external stimuli by a pattern of hyperactivity of the brain and of the trigeminovascular apparatus. Activation of the trigeminovascular system, whether by neural impulses from the brain or humoral factors in the circulation, results in vascular headaches, while associated activity in the brain may produce such typically migrainous symptomatology as prodrome and aura, and nonspecific symptoms such as nausea, vomiting and dizziness. In this model specific diseases may gain access to the trigeminovascular apparatus, detonating it to produce vascular headaches and neurological symptomatology which may more or less exactly mimic migraine.


Migraine and heredity.

Migraine and heredity. Since the time of Liveing and Gowers in the nineteenth century, migraine has been thought to be inherited, although family history has been widely studied, nearly all the reports are not scientifically based and studies on twins have never shown 100% concordance in monozygotic (MZ) pairs, indicating that migraine cannot be inherited by a single gene. Furthermore, the criteria for a polygenic trait are not fulfilled by migraine patients. The only two syndromes with a strong genetic basis of inheritance are familial hemiplegic migraine and migraine occurring in Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes (MELAS). It is the predisposition to headache that is likely to be inherited; this is supported by the induction of migraine-like headaches with either m-chlorophenyl-piperazine (m-CPP) or nitroglycerin in normal subjects with a positive family history for migraine.


[Electrophysiologic investigations in migraine]. This article is a critical review of standard electroencephalography (EEG), brain mapping, evoked potential, and electromyography (EMG) studies carried out in various forms of migraine during and between attacks. With the exception of contingent negative variation, the exteroceptive silent period of the temporalis muscle, and possibly fast activity in response to visual stimuli, which are useful for the differential diagnosis of functional headache, the main value of electrophysiologic studies is to provide insight into the pathophysiology of the disease. Results of the different methods consistently indicate that the brain of migraine patients is characterized by hypersensitivity to some forms of stimuli between attacks and by, often focal, hypoactivity during attacks.


[Platelets and migraine].

[Platelets and migraine]. Platelet function studies in migraine patients have evidenced a number of anomalies (hyperreactivity and serotonin metabolism disorders) that have been suggested as causative factors in migraine attacks. However, a review of the literature shows that these disorders are inconsistent and are probably consequences rather than causes of the headache, although they may contribute to the pathophysiology of the attack. From a broader perspective, the demonstration of platelet dysfunction in migraine raises questions as to the source of these disorders (secondary to plasma factors or due to platelet anomalies) and their significance (do they have any link with transient ischemic attacks or central serotonin neurotransmission dysfunction?).


Cerebral blood flow in migraine with aura. Pathognomonic changes in regional cerebral blood flow (rCBF) have gradually been described during the last decade. They support spreading cortical depression as the mechanism underlying the migraine aura but are not the direct cause of pain since they are absent in migraine without aura and are present in migraine aura without pain. Dilatation of intra- and extracranial arteries, on the other hand, takes place in both forms of migraine and seem closely associated to the pain. Dilatation and perivascular nociceptor sensitization may, very likely, be caused by neuropeptides and monoamines released from perivascular nerves and/or mast cells.


[Cerebral blood flow in migraine without aura]. For several years, cerebral blood flow (CBF) studies have been fueling the controversy surrounding the pathophysiology of migraine headache. The earliest studies focused mainly on migraine with aura (MA+) and provided evidence in support of the classical hemodynamic theory: a decrease in blood flow during the aura is followed by reactive vasodilation during the headache phase. Studies in migraine without aura (MA-), although less numerous, consistently demonstrated an increase in CBF during the attack. Olesen et al., gave rise to a heated debate by suggesting that hemodynamic manifestations are different in MA+ and MA-; in their view, CBF remains unchanged in MA-, whereas MA+ is associated with a wave of posterior blood flow deficiency which slowly spreads forwards in a manner reminiscent of experimental spreading depression; they interpret this hemodynamic pattern as evidence that the attack is mainly caused by a neural mechanism rather than a vascular spasm. This concept of MA- with no hemodynamic changes suggests that the pathophysiology of MA- may be completely different from that of MA+. However, most studies using stationary detectors or single photon emission computerized tomography (SPECT) with Xenon 133 or HMPAO as the tracer have demonstrated increased CBF during migraine attacks. The increase was not correlated with the side of the pain suggesting that vasodilatation is not the only cause of the pain. Current data do not seem to support the view that MA- and MA+ are different pathophysiologic entities; whether the mechanism of the attack is neural or vascular cannot be determined on the basis of CBF data.(ABSTRACT TRUNCATED AT 250 WORDS)


Spreading depression and migraine.

Spreading depression and migraine. Cortical spreading depression (CSD) is a slowly-moving suppression of electrical activity that travels across the cortex at a rate of 2-5 min-1. CSD is transient, and accompanied by a severe disruption of ion homeostasis, depolarization of nerve cells and enhanced energy metabolism. The slow march of migraine prodromes has many features in common with CSD. On this background it has been suggested that CSD is a mechanism of migraine. Recently, the notion has gained renewed credibility with the demonstration of unique abnormalities of brain blood flow, energy metabolism and magnetoencephalography during migraine attacks which have been replicated point-by-point in the animal model during CSD. Simultaneously, a series of experiments have indicated that CSD is closely linked to activity of the N-methyl-D-aspartate (NMDA)-subtype of the glutamate-receptor. It is suggested, that N-methyl-D-aspartate-antagonism could be the next bid of a rational migraine therapy.


[Neuro-imaging studies in migraine].

[Neuro-imaging studies in migraine]. Neuroimaging studies in migraine patients are useful for three important reasons. 1) Brain imaging techniques and primarily CT-scan should be used in every patient with atypical or complicated migraine to rule out a vascular malformation or brain tumor; 2) angiography, which was extensively used in the 1960's and 1970's, discloses a number of arterial anomalies including spasm or occlusion, of unclear pathogenic significance; 3) T2-weighted magnetic resonance images in migraine often show increased signals generated by the white matter; this finding is as yet poorly understood but is undoubtedly related to factors very different from those seen in elderly patients or patients with vascular risk factors.


[Positron emission tomography and migraine]. Positron emission tomography (PET) is a brain imaging technique that allows in vivo studies of numerous physiological parameters. There have been few PET studies in migraine patients. Cerebral blood flow changes with no variations in brain oxygen consumption have been reported in patients with prolonged neurologic manifestations during migraine attacks. Parenteral administration of reserpine during migraine headache has been followed by a fall in the overall cerebral uptake of glucose. The small sample sizes and a number of methodologic problems complicate the interpretation of these results. Recent technical advances and the development of new PET tracers can be expected to provide further insight into the pathophysiology of migraine. Today cerebral cortex 5 HT2 serotonin receptors can be studied in migraine patients with PET.


NMR spectroscopic and magnetoencephalographic studies in migraine with aura: support for the spreading depression hypothesis. The authors propose that patients who suffer from migraine with aura have a susceptibility to spontaneous neuronal discharges and subsequent spreading depression. This is based upon a state of central neuronal excitability involving the excitatory neurotransmitter glutamate, in combination with supersensitivity of the N-méthyl-D-aspartate (NMDA) receptor. This hypersusceptibility is supported by increased turnover of high-energy phosphates, low intracellular Mg2+ and large amplitude depolarizing waves on magnetoencephalography (MEG).


[Methodology of clinical trials in migraine: a rating system]. Several problems confront trials of drugs for migraine: no clinical or biological markers for objective diagnosis are available, severity of the attack cannot be readily evaluated, the placebo effect is significant, and both compliance with therapy and patient follow-up may be difficult to ensure. No statistical method is capable of solving these problems and it is the clinicians' role to minimize them by consistent efforts at establishing good communication with their patients during the trial. Because of these significant intrinsic difficulties, trials of drugs for migraine require especially stringent data collection and analysis protocols in order to minimize the risk of errors which exist in any drug trial. The protocol used have not always been satisfactory with this respect. A rating system for helping non-specialists to evaluate the reliability of migraine drug trials is proposed.


Migraine triggers: practice and theory.

Migraine triggers: practice and theory. The basis of our belief in migraine triggering factors is questioned. To avoid creating migraine-mythology, it is proposed that a trigger for migraine must also cause headache in non-migrainous subjects. This headache-migraine parallelism is examined and if correct, casts doubt on migraine precipitation by cheese, chocolate or allergy. A further weakness of "dietary migraine" is pointed out because the quantity of the trigger consumed, or the time interval between ingestion and the onset of attacks, are rarely mentioned, let alone studied. A difficulty in assessing migraine precipitants is that two factors may act in unison, e.g. stress and not eating. Further an external factor may provoke an attack only if the migraine "milieu intériur" is set appropriately, for example the hormonal state in a woman's menstrual cycle. The value of studying migraine precipitants is two-fold: (1) it provides a means of counselling patients to avoid or reduce these factors, thereby diminishing frequency and severity of attacks; (2) a comprehensive migraine pathogenetic theory must incorporate how and where precipitants act. It is concluded that analysis of triggering mechanisms lends support to the concept that migraine is a primary neurological disturbance with secondary vascular manifestations.