Increased oxidative stress, inflammation, and glutamate: Potential preventive and therapeutic targets for hearing disorders.

Hearing disorders constitute one of the major health concerns in the USA. Decades of basic and clinical studies have identified numerous ototoxic agents and investigated their modes of action on the inner ear, utilizing tissue culture as well as animal and human models. Current preventive and therapeutic approaches are considered unsatisfactory. Therefore, additional modalities should be developed. Many studies suggest that increased levels of oxidative stress, chronic inflammation, and glutamate play an important role in the initiation and progression of damage to the inner ear leading to hearing impairments. To prevent these cellular deficits, antioxidants, anti-inflammatory agents, and antagonists of glutamate receptor have been used individually or in combination with limited success. It is essential, therefore, to simultaneously enhance the levels of antioxidant enzymes by activating the Nrf2 (a nuclear transcriptional factor) pathway, dietary and endogenous antioxidant compounds, and B12-vitamins in order to reduce the levels of oxidative stress, chronic inflammation, and glutamate at the same time. This review presents evidence to show that increased levels of these cellular metabolites, biochemical or factors are involved in the pathogenesis of cochlea leading to hearing impairments. It presents scientific rationale for the use of a mixture of micronutrients that may decrease the levels of oxidative damage, chronic inflammation, and glutamate at the same time. The benefits for using oral administration of proposed micronutrient mixture in humans are presented. Animal and limited human studies indirectly suggest that orally administered micronutrients can accumulate in the inner ear. Therefore, this route of administration may be useful in prevention, and in combination with standard care, in improved management of hearing problems following exposure to well-recognized and studied ototoxic agents, such as noise, cisplatin, aminoglycoside antibiotics, and advanced age.

Prognosis for future childbearing after midcavity instrumental deliveries in primigravidas.

The frequency of subsequent childbearing and the method of subsequent delivery among 149 primigravidas who required instrumental delivery for midcavity arrest of the fetal head in the second stage of labor and 1258 primigravidas who delivered spontaneously were compared. The frequency of subsequent childbearing was similar in the two groups, but operative delivery for cephalopelvic disproportion (CPD) in a second pregnancy was six times greater in the instrumentally delivered group (11.2 versus 2%; P less than .005). Nevertheless, more than 75% of instrumentally delivered primigravidas who delivered heavier infants in their second pregnancy did so spontaneously. It is concluded that relative CPD is not a common factor necessitating midcavity deliveries, even if cases in which peridural anesthesia is used and deliveries for fetal bradycardia are excluded from consideration. This probably accounts for the fact that over 97% of instrumentally delivered infants suffered no birth trauma or birth asphyxia.

Treatment of urinary incontinence after radical hysterectomy.

The results of therapy of eight previously untreated women without urinary fistulas who had been severely incontinent for three to eight years after radical hysterectomy are presented and the principles of management discussed. Radiologic and urodynamic studies are required to assess the bladder pressure response to filling, proximal urethral pressures, bladder neck closure at rest, and mobility of the bladder neck, to determine the mechanism responsible for the urine loss and to select appropriate therapy. Augmentation of proximal urethral pressures by medical or surgical means is required if the bladder neck is open at rest. All such patients improved dramatically on ephedrine, but tachyphylaxis developed in cases of total sphincter failure. Retropubic urethropexy did not relieve the incontinence in these cases, whereas a sling operation restored complete continence. If an incremental bladder pressure response to filling is present, operations to increase bladder outlet resistance are contraindicated. Treatment with anticholinergic medications was unsuccessful in these cases.

Sling operation for total incontinence following radical vulvectomy.

A case of total incontinence that developed after radical vulvectomy and subtotal urethrectomy is presented. Complete relief of the incontinence was obtained after an Aldridge sling operation. The rationale for selecting this operation is discussed.

Discriminatory hCG zone: its use in the sonographic evaluation for ectopic pregnancy.

The most reliable ultrasonographic criteria for diagnosing ectopic pregnancy are based on the appearance of the uterus in the presence of a positive urine pregnancy test. The absence of an intrauterine sac signifies ectopic pregnancy, whereas its presence indicates intrauterine gestation. These criteria cannot be applied when serum pregnancy tests are used unless the serum human chorionic gonadotropin (hCG) level at which the sac of an intrauterine pregnancy becomes visible on ultrasound is known, because these tests are far more sensitive and identify pregnancy at an earlier stage than does sonar. In this study, the hCG level that distinguishes patients with intrauterine pregnancies in whom a gestational sac can be seen from those in whom it cannot be seen was determined and designated the discriminatory hCG zone. This zone lies between 6000 and 65000 mIU/ml. The absence of an intrauterine sac in conjunction with hCG values above this level signifies ectopic pregnancy; however, the absence of an intrauterine sac has no diagnostic significance when associated with hCG values below the discriminatory zone. An intrauterine sac associated with hCG levels above the discriminatory zone reliably indicates an intrauterine pregnancy, but at hCG values below the zone, it is suggestive of an abnormal pregnancy-either a missed abortion or an ectopic gestation.

A method of screening for ectopic pregnancy and its indications.

The possibility of distinguishing between normal intrauterine and ectopic pregnancies by determining the lower limit of the rate of human chorionic gonadotropin (hCG) increased in early pregnancy was investigated. This can be expressed as the slope of the log hCG-time curve or as the percent increase in hCG over a given sampling interval. For practical purposes, the rate is most easily determined from 2 samples drawn 48 hours apart. The differences between the 2 hCG values obtained is expressed as a percentage of the initial value, and should be 66% or greater for this sampling interval. Approximately 15% of normal intrauterine pregnancies screened in this way will appear abnormal, and the diagnosis in 13% of ectopic pregnancies will be delayed beyond 48 hours.

Determinants of survival of surgically staged patients with endometrial carcinoma histologically confined to the uterus: implications for therapy.

OBJECTIVE: To determine the factors that influence the survival of patients with endometrial carcinoma histologically confined to the uterus. METHODS: Retrospective analysis was conducted of 262 surgically staged cases using multiple regression (Cox proportional hazards model). RESULTS: After excluding patients with clear-cell and serous tumors, which were adverse prognostic factors unrelated to any other variables, we found that survival was adversely affected by increasing stage, tumor grade and depth of myometrial invasion, cervical stromal and vascular space invasion by tumor, and increasing age. Tumor grade, myometrial invasion, and cervical involvement by tumor exerted their effects on survival as dichotomous rather than as ordinal variables. The greatest effect on survival was obtained by dichotomizing grade as grade 3 versus grade 1 or 2, myometrial invasion as invasion of more versus less than the inner third of the myometrium, and cervical spread as the presence versus absence of stromal invasion. The joint effect of the tumor-related prognostic factors was best expressed by constructing three risk groups consisting of patients with zero or one, two, and three or four risk factors. These risk groups were associated with 5-year survival rates of 97, 66, and 17%, respectively. After adjustment for risk factors, pelvic radiation did not affect survival significantly, although there was a trend toward improved survival of subjects with two risk factors who received pelvic radiation (70 versus 50% survival at 5 years). CONCLUSIONS: The number of tumor-related risk factors present is the best predictor of survival of patients with endometrial carcinoma confined to the uterus, and may provide the optimal basis for individualization of treatment.

Prognostic factors in surgical stage III and IV carcinoma of the endometrium.

OBJECTIVE: To identify prognostic factors in surgical stage III and IV endometrial carcinoma. METHODS: We performed a retrospective analysis of 58 cases of stage III and IV endometrial cancer using the Cox proportional hazards model. RESULTS: Extrapelvic peritoneal metastases and positive peritoneal cytology greatly affected survival. If either of these factors was present, the 2-year survival rate was only 25%, whereas if they were absent, it was 82%. All patients with extrapelvic metastases died of their disease despite systemic therapy, as did ten of 13 patients with positive peritoneal cytology. Although postoperative therapy in these patients varied, it had no obvious effect on survival or on the site of recurrence. In the absence of abdominal disease or positive peritoneal cytology, survival was not influenced significantly by the presence or absence of lymph node metastases. The difference in survival between women with aortic and pelvic lymph node metastases (24% at 5 years) was not significant, but the power to detect this difference was low (35%). Stage affected survival significantly (P < .05), but a two-category variable, indexing patients as having either positive peritoneal cytology or abdominal disease, provided a much better fit and a more parsimonious model for the data. CONCLUSION: Five-year survival rates exceeding 70% can be achieved in endometrial carcinoma even if extrauterine disease is present, provided that peritoneal cytology is negative and abdominal metastases are absent.

Histologic variants of cervical involvement by endometrial carcinoma.

Examination of histologic material from 54 patients with endometrial carcinoma, in whom the pretreatment fractional curettage showed adenocarcinoma in the endocervical specimen, demonstrated 4 main patterns. These were designated as tumor separate from endocervical tissue (13 patients), true stage II (23 patients), tumor in stroma (12 patients), and tumor only (6 patients). Patients with tumor separate from endocervical tissue had a better survival rate (expressed as survival to first recurrence) than did patients in the other 3 groups, and this difference was statistically significant. No statistically significant difference between the survival of patients in the true stage II, tumor in stroma, and tumor only groups could be demonstrated. It is therefore suggested that the treatment protocol used for these 3 groups of patients be similar. Among the true stage II groups, only 3 patients had superficial endocervical involvement, whereas 15 had stromal involvement without surface tumor. Therefore, spread to the cervix in endometrial carcinoma appears to be more frequent by tissue spaces or lymphatic channels than by contiguous surface extension.

New criteria for the diagnosis of gestational trophoblastic disease.

The purpose of the study was to test the hypothesis of whether the combined use of ultrasound and human chorionic gonadotropin (hCG) determinations could increase the diagnostic accuracy of sonography in the diagnosis of hydatidiform mole. The criteria used were the absence of fetal heart movement by ultrasound when the hCG level was above 82,350 mIU/mL and the presence of an hCG level in excess of 2 SD above the mean for the biometrically derived gestational age for suspected partial moles. The threshold of 82,350 mIU/mL was derived by probit analysis of the hCG serum levels of a population of normal intrauterine pregnancies prospectively examined to determine the level of hCG at which fetal heart activity would be visible by sonography. The diagnostic accuracy of these criteria was compared with the preoperative sonographic examination in 36 hydatidiform moles. When sonography was used alone, 15 of 36 cases (41.6%) did not have a definitive diagnosis on the first examination. The combination of hCG and ultrasound would have correctly identified 32 of the 36 cases (88.8%). This improvement was statistically significant (P less than .005).

Ultrasound assessment of the postmature pregnancy.

The use of ultrasound to identify the fetus at risk for postmaturity among postterm pregnancies was evaluated. The ultrasound findings in 85 postterm pregnancies were reviewed. No grade 0 or grade 1 placentas were observed and grade 2 and 3 placentas were found with similar frequency. The incidence of advanced postmaturity was 12.9%. Advanced postmaturity was found with grade 2 and 3 placentas. Oligohydramnios was very common (81.8%) among pregnancies resulting in postmaturity. The neonatal ponderal index was higher with grade 2 placentas than with grade 3 placentas. The presence of immature placentas (grade 0 or 1) is rare after 42 weeks of gestation. Placental grading cannot be used to predict postmaturity.

Value of culdocentesis in the diagnosis of ectopic pregnancy.

The diagnostic value of culdocentesis was examined in all patients admitted with hemoperitoneum during a three-year period. There was a total of 158 women with positive culdocentesis, of whom 132 (83.5%) had tubal ectopic pregnancies and 26 had other diagnoses. Of the 132 patients with ectopic gestations, the majority (62%) had unruptured tubes. A nondiagnostic culdocentesis should not be used either to raise or to lower the clinician's suspicion of ectopic pregnancy as 16% of patients with an ectopic pregnancy had a nondiagnostic culdocentesis, of which one-quarter were ruptured and three-quarters had hemoperitoneum diagnosed at the time of surgery. A positive culdocentesis along with a positive serum human chorionic assay was associated with an ectopic pregnancy in 99.2% of cases. This procedure should not be limited to the evaluation of patients with classic peritoneal signs, as 45% of the authors' patients with a positive culdocentesis did not have such findings.

Diagnosis of ectopic pregnancy: value of the discriminatory human chorionic gonadotropin zone.

A prospective study was conducted to test the hypothesis that the absence of an intrauterine gestational sac when the serum level of human chorionic gonadotropin (hCG) is above 6500 mIU/mL is indicative of ectopic pregnancy. A total of 383 patients who were clinically suspected to have ectopic pregnancies had pelvic ultrasound examinations with serum hCG determinations on the day of the scan. There were 217 (57%) intrauterine gestations, 104 (27%) ectopic pregnancies, and 62 (16%) spontaneous abortions. Forty-one percent of patients had an hCG level above 6500 mIU/mL. The absence of an intrauterine gestational sac at an hCG concentration above this level had a sensitivity of 100%, a specificity of 96%, a positive predictive value of 86%, a negative predictive value of 100%, and was 98% efficient, based on a 19.4% prevalence of ectopic pregnancies among this group.

Further observations on serial human chorionic gonadotropin patterns in ectopic pregnancies and spontaneous abortions.

The half-life of hCG was measured retrospectively in paired blood samples from 108 pregnancies with falling hCG levels. hCG levels fell significantly more slowly in women who had an ectopic pregnancy (41 cases) than in women who had spontaneous abortions (67 cases). When the hCG half-life was greater than or equal to 7 days, 86% of cases had ectopic pregnancies, a third of which had ruptured. By contrast, when the hCG half-life was less than 1.4 days, only 7.6% (2/26) of cases had an ectopic pregnancy (both of which were unruptured), and villi were identified in only 10% of curettage specimens from (presumed) cases of spontaneous abortion. When the half-life of hCG was between 1.4 and 6.9 days, 34% of the cases had ectopic pregnancies, 14% of which had ruptured: chorionic villi were recovered from 76% of the women who had a curettage, and failure to detect villi was more than 80% predictive of an ectopic pregnancy.

Further observations on the doubling time of human chorionic gonadotropin in early asymptomatic pregnancies.

The doubling time (DT) of human chorionic gonadotropin (hCG) in serum was investigated retrospectively using serial serum hCG values that had been obtained from asymptomatic pregnant women with a prior history of infertility. The DT of hCG did not increase significantly as pregnancy advanced during the period in gestation when the serum hCG concentration was less than 10,000 mIU/mL (International Reference Preparation). Serum hCG concentrations increased subnormally in 2 of 60 women with normal intrauterine pregnancies, 5 of 8 women with asymptomatic ectopic pregnancies (EPs), and in 2 of 8 asymptomatic women who subsequently aborted their pregnancies. Neither the sensitivity nor the specificity of serial hCG testing for EP was enhanced by adopting different test criteria at different serum hCG concentrations.

Receiver operating characteristic (ROC) curve analysis of the relative efficacy of single and serial chorionic gonadotropin determinations in the early diagnosis of ectopic pregnancy.

A study was undertaken of 36 patients with viable intrauterine pregnancies who presented in the first trimester with abdominal pain and/or vaginal bleeding, and of 15 patients with ectopic pregnancies, all of whom had at least two human chorionic gonadotropin (hCG) determinations in the same gestation. The mean and lower 25%, 20%, 15%, 5%, and 1% limits of the rate of hCG increase in serum and of the serum hCG at different periods of gestation were determined for intrauterine pregnancy with the use of linear regression analysis, and each was used as a basis for identifying ectopic gestation. It was found that for any given false-positive rate, subnormal rates of hCG increase were more sensitive in identifying ectopic gestations than single "low for date" hCG values. It is suggested that the explanation for this may be that hCG production in many patients with ectopic pregnancies is normal until symptoms develop and falls thereafter as the functional trophoblastic mass is reduced by the shearing off the trophoblast from the tubal wall, which takes place with the development of the pregnancy and of symptoms.

The discriminatory human chorionic gonadotropin zone for endovaginal sonography: a prospective, randomized study.

OBJECTIVE: To determine the probability of detecting the gestational sac of a normal intrauterine pregnancy by vaginal ultrasound at different gestational ages and serum hCG concentrations. DESIGN: Prospective, randomized study. SETTING: Pregnant human volunteers in a university-based clinical research environment. PATIENTS: Women with viable pregnancies who conceived spontaneously or after ovulation induction. INTERVENTIONS: Vaginal ultrasound and serum hCG determinations were performed between 20 and 30 days after conception. The timing of the tests was determined randomly. MAIN OUTCOME MEASURE: Detection of gestational sac. RESULTS: The probability of detecting a gestational sac increased significantly with both gestational age and serum hCG concentration, but the regression on gestational age fitted the data much better than the regression on loge (hCG). The probability of detecting a sac was similar in multiple and singleton pregnancies of the same gestational age but, for a given hCG concentration, the probability of detecting a sac was lower for multiple than for singleton pregnancies because multiple gestations were associated with higher serum hCG concentrations than singleton pregnancies of the same gestational age. CONCLUSION: If it is known, gestational age rather than the serum hCG concentration should be used to determine whether the gestational sac of an intrauterine pregnancy should be detectable by vaginal ultrasound. Failure to image a gestational sac > or = 24 days after conception is presumptive evidence of an ectopic pregnancy. Reliance on serum hCG rather than gestational age may lead to an erroneous diagnosis of ectopic pregnancy in women with multiple pregnancies.

A prospective, randomized study of the chorionic gonadotropin-time relationship in early gestation: clinical implications.

OBJECTIVE: To investigate the hCG-time relationship in early pregnancy. DESIGN: Prospective, randomized study. SETTING: Pregnant human volunteers in a university-based clinical research environment. PATIENTS: Normal pregnant women with viable singleton pregnancies, conceived spontaneously or after ovulation induction. INTERVENTIONS: Vaginal ultrasound was performed, and blood samples were obtained for hormone parameters between 20 and 30 days after conception. The timing of the tests was determined by random assignment using sealed envelopes. MAIN OUTCOME MEASURE: Serum hCG. RESULTS: The log hCG-time relationship was linear, both during the first 20 days and between 20 and 30 days after conception. The inclusion of a quadratic term in either regression was not statistically significant. The slopes of the two regression lines were also not statistically different. CONCLUSION: For practical purposes, the hCG-time relationship in early pregnancy can be treated as log-linear, but short sampling intervals should be used if doubling times are to be calculated from paired samples.

The operative laparoscopy debate: technology assessment or statistical Jezebel?

Laparoscopic surgery has been severely criticized recently because few controlled studies have been performed to show that specific operations are better when carried out endoscopically rather than by using an open technique. Critics have also claimed that only randomized clinical trials can show these procedures to be effective, and they have not been carried out because surgical and medical therapy are held to different standards. These criticisms are examined and discussed in this paper, and many of the arguments are shown to be invalid. Although bias is an undeniable concern in retrospective studies, the scope of randomized clinical trials is limited by the inability to randomize or blind treatment, and their validity is restricted by the failure to select patients randomly for study. Therefore, whatever the limitations of retrospective studies, there is frequently no option but to adopt a research strategy other than a randomized trial, and some possibilities are discussed.

The influence of nipple stimulation at term on the duration of pregnancy.

The influence of nipple stimulation (NS) at term on the duration of pregnancy was investigated among low-risk gravidas in a randomized prospective study. A significant inverse relationship was found between the duration of pregnancy and both gestational age at recruitment and cervical (Bishop) score, although the influence of cervical score was quantitatively small. Nipple stimulation did not influence either the duration of pregnancy or the probability of having a cesarean section or an instrumental delivery. Patient compliance was, however, poor, which may in part account for these findings, as there was an inverse trend between the daily average duration of NS and the duration of pregnancy.