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.

Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome.

OBJECTIVE: To determine whether there is a relationship between the presence of histological signs of inflammation in the extraplacental membranes and umbilical cord and the concentrations of fetal plasma interleukin-6 (IL-6). METHODS: The study examined a cohort of patients who were admitted with preterm labor or preterm premature rupture of the membranes (PROM) and who underwent cordocentesis. Inclusion criteria included fetal plasma available for IL-6 determination, histological examination of the umbilical cord and placenta, and delivery within 48 h of the procedure. This last criterion was used to preserve a meaningful temporal relationship between fetal plasma IL-6 and the results of histological examination of the placenta. Fetal plasma IL-6 was determined by a high sensitivity ELISA. Forty-five patients were available for study: 18 patients had preterm labor with intact membranes and 27 had preterm PROM. RESULTS: The incidence of funisitis was 44.4% (20/45): 27.8% (5/18) in patients with preterm labor and intact membranes and 55.6% (15/27) in patients with preterm PROM. The median values of fetal plasma IL-6 in patients with funisitis, chorioamnionitis without funisitis, and non-inflamed membranes were 51.4, 18.4 and 5.2 pg/ml, respectively. After log transformation of the fetal plasma IL-6 concentration, the means differed significantly from each other (ANOVA, p < 0.02). There was no difference in log fetal plasma IL-6 concentration between patients with funisitis and those with chorioamnionitis without funisitis. The difference in mean concentration of log fetal plasma IL-6 between patients with funisitis or chorionic vasculitis and those without inflammation was highly significant (post-hoc test, p = 0.01 and p < 0.01, respectively). Fetuses with fetal plasma IL-6 > 11 pg/ml had a significantly higher rate of histological signs of inflammation in the extra-placental membranes and umbilical cord than those with fetal plasma IL-6 < 11 pg/ml (funisitis: 55.6% (15/27) vs. 27.8% (5/18), p < 0.05; chorionic vasculitis: 55.6% (15/27) vs. 12.5% (2/16), p < 0.01; chorioamnionitis only: 25.9% (7/27) vs. 16.7% (3/18), p < 0.05; no inflammation: 18.5% (5/27) vs. 55.6% (10/18), p < 0.05, respectively). Fetuses with funisitis had significantly higher rates of clinical and histological chorioamnionitis, and neonatal infectious morbidity (proven + suspected sepsis) than fetuses without funisitis (40% (8/20) vs. 8% (2/25), 90% (18/20) vs. 36% (9/25), and 40% (8/20) vs. 4% (1/25), respectively; p < 0.01 for each). Fetuses with chorionic vasculitis had significantly higher rates of clinical and histological chorioamnionitis as well as neonatal infectious morbidity (proven + suspected sepsis) than fetuses without chorionic vasculitis (100% (17/17) vs. 42.3% (11/26), p < 0.01; 82.4% (14/17) vs. 50.0% (13/26), p = 0.05; and 41.2% (7/17) vs. 7.7% (2/26), p = 0.01). CONCLUSION: Fetal plasma IL-6 concentration is significantly associated with the presence of inflammatory lesions in the extraplacental membranes and umbilical cord. Fetuses with fetal plasma IL-6 > 11 pg/ml had a significantly higher rate of funisitis and/or chorionic vasculitis than fetuses with fetal plasma IL-6 < 11 pg/ml. These findings suggest that funisitis/chorionic vasculitis is the histological manifestation of the fetal inflammatory response syndrome.

Port-site recurrences following laparoscopic operations for gynaecological malignancies.

OBJECTIVE: To determine the frequency of port-site recurrences following laparoscopic surgical treatment of gynaecological malignancies metastatic at the time of surgery. DESIGN: Retrospective review of metastatic primary and recurrent gynaecological malignancies. RESULTS: Twenty-five women were studied. Twenty-four had metastatic disease at the time of laparoscopic surgery, 22 in association with a primary malignancy (cervix: n = 12, ovary: n = 7, endometrium: n = 3), and two in association with recurrent ovarian cancer; all received pelvic or extended field radiation or chemotherapy after surgery. One woman with Stage IIIC ovarian cancer, disease-free at the completion of neoadjuvant chemotherapy following laparotomy by a general surgeon, was included; she developed scalene node metastases 18 months after definitive laparoscopic surgery. Seventy-one 5 mm trocars and fifty 10 mm trocars (total n = 121) were used for surgery; thirty-one 10 mm trocar sites and forty-four 5 mm sites (total n = 75) received post-operative treatment with chemotherapy (n = 49) or radiation (n = 26). Four women (16%) developed recurrences in association with endometrial (n = 2) and cervical (n = 2) cancer at six trocar sites. All recurrences were associated with abdominopelvic and/or distant metastases, and all occurred at untreated 5 mm trocar sites. The difference in recurrence rates between 5 mm and 10 mm trocar sites (chi(2) = 6; P < 0.025), and between treated and untreated trocars (chi(2) = 5; P < 0.05) were both statistically significant (McNemar's test), but the effects of treatment and trocar size on the port-site recurrence rate were confounded. CONCLUSIONS: Port-site recurrences are local manifestations of disseminated disease that result from the enhancement of tumour growth characteristic of healing tissues and can be prevented by appropriate post-operative therapy.

Preliminary prospective observations on the laparoscopic management of endometrial carcinoma using the two-stage approach to aortic lymphadenectomy.

STUDY OBJECTIVE: To determine the value of a two-stage approach to laparoscopic aortic lymphadenectomy (ALN) in women with endometrial cancer. DESIGN: Prospective case series. PATIENTS: Twenty-three consecutive, unselected women with endometrial cancer were managed prospectively according to a previously defined protocol. All had laparoscopic hysterectomy, ten required pelvic and one had an aortic lymphadenectomy (ALN). Pelvic lymph node metastases (PLNM) were present in two (20%) and aortic lymph node metastases in one (10%) patient. Mean age was 60; three women were over 80 years old, and two were 78 years old. Mean weight and body mass index were 192 and 33.5, respectively; two women weighed over 300 pounds and another two weighed over 250 pounds. Mean anesthetic time was 3.2 hours, mean blood loss 469 ccs, and mean drop in hemoglobin 2.5 g/dl. One patient was transfused. Median hospital stay was 2 days. One patient had a questionable ileus post-operatively, and another was hospitalized for 10 days to control her diabetes and blood pressure. CONCLUSIONS: By predicating ALN on the presence of PLNM in endometrial cancer, the number of ALN can be reduced without reducing the number of aortic lymph node metastases detected, and laparoscopic management can be extended to morbidly obese women.

A new technique of primary trocar insertion for laparoscopy.

A new method of primary trocar insertion exploits the anatomy of the anterior abdominal wall at the umbilicus. The point of fusion between the skin, fascia, and peritoneum is identified, and a tiny incision is made precisely over this point, enabling a small clamp to be introduced directly into the peritoneal cavity. After stretching the opening with this clamp, a 5-mm trocar is introduced into the peritoneal cavity over a blunt probe, and the abdomen is insufflated. The opening is stretched further with a Kelly clamp, and a 10-mm trocar is introduced over a blunt probe. The technique was used in 54 consecutive patients, 20 of whom had prior low vertical incisions. Ten women had very dense periumbilical adhesions, placing at least four at extremely high risk of bowel injury from blind entry. There were no injuries, and the technique is so quick and effective that it is now the author's routine method of trocar insertion for laparoscopy.

Laparoscopic management of gynecological malignancies.

The primary surgical management of endometrial and cervical carcinoma requires four operations: simple and radical hysterectomy, and pelvic and aortic lymphadenectomy. All these four operations can now be carried out laparoscopically with significant reduction in morbidity and among the patient population that develops these malignancies, namely, the elderly and the obese. Moreover, as judged by the number of nodes harvested and the proportion of positive nodes, the radicality of laparoscopic lymphadenectomy is equivalent to its 'open' counterpart. Thus, laparoscopic management is feasible in almost every patient who has carcinoma of the endometrium or cervix. Experience with the laparoscopic management of ovarian cancer is more limited. There has been concern that the increased frequency of cyst rupture makes laparoscopic management inappropriate, but cyst rupture per se does not impair survival provided patients are managed appropriately with adjuvant chemotherapy, and all but stage I, grade I ovarian cancer is treated with neoadjuvant chemotherapy. Many patients who have stage II-IV disease can be satisfactorily 'debulked' laparoscopically, and a significant proportion of those who cannot be debulked primarily can be debulked laparoscopically after neoadjuvant chemotherapy. The laparoscopic management of ovarian cancer promises to be the most active area of advance over the next few years.

Laparoscopic anatomy and dissection of the pelvis.

All anatomically important pelvic structures lie embedded in the fatty-fibrous connective tissue of the retroperitoneum from which they can be freed by blunt dissection in the correct tissue planes. By relying on fixed laparoscopic landmarks, the correct surgical planes of dissection can be found, and all vital structures freed and identified by a systematic dissection consisting of a precise sequence of operative steps. Once the retroperitoneal dissection has been completed and all vital structures identified, most gynaecological operations can be carried out safely and without much difficulty laparoscopically. A non-anatomical approach to laparoscopic pelvic surgery may be easier to learn, but it is neither very versatile nor very safe except in the simplest of cases.

Surgical anatomy and dissection techniques for laparoscopic surgery.

All anatomically important pelvic structures lie embedded in the fatty-fibrous connective tissue of the retroperitoneum from which they may be freed by blunt dissection in the correct tissue planes. By relying on fixed laparoscopic landmarks, the correct surgical planes of dissection can be found, and all vital structures freed and identified by a systematic dissection consisting of a precise sequence of operative steps. Once the retroperitoneal dissection has been completed and all vital structures identified, most gynecologic operations can be carried out safely and without much difficulty laparoscopically. A nonanatomical approach to laparoscopic pelvic surgery may be easier to learn, but it is neither very versatile nor very safe except in the simplest of cases.

Extraperitoneal Laparoscopic Hysterectomy for Fibroid Uteri

The feasibility of dividing the uterine arteries laparoscopically using the extraperitoneal technique for laparoscopic hysterectomy to remove large (>e;500 g) fibroid uteri was assessed in a retrospective review. Over 9 months, 24 women underwent extraperitoneal laparoscopic hysterectomy for a fibroid uterus. Additional procedures were performed in five patients: one colposuspension, one pelvic lymphadenectomy, and three pelvic and aortic lymphadenectomies. In 14 cases the uterus weighed 500 g or more (mean 847 g), 5 weighed 0.7 to 1.0 kg, and 3 weighed 1 kg or more. One patient had pelvic and another had pelvic plus aortic lymphadenectomy in addition to hysterectomy. Two (14%) women required transfusion. Twenty-five (89%) of 28 uterine arteries were divided laparoscopically; both arteries in 12 patients, one artery in 1 patient, and neither artery in 1. None of the women in whom both uterine arteries were divided required transfusion, whereas both in whom one or both arteries were divided vaginally did. In most patients undergoing a laparoscopic hysterectomy by the extraperitoneal technique, both uterine arteries can be divided laparoscopically, and the procedure seems to reduce blood loss.

Avoiding the Space of Retzius During the Laparoscopic Burch Procedure

Although the structures apposed by a Burch colposuspension, the lateral vaginal fornix and Cooper's ligament, are approached surgically by opening the space of Retzius, neither actually lies in the space of Retzius but in the paravesical-paravaginal space. Cooper's ligament cannot be exposed adequately if the paravesical space is opened laparoscopically. Five primary Burch colposuspensions were performed without opening the space of Retzius, four with the uterus in place and one after a hysterectomy. Approaching the operation through the paravesical space has several advantages. A fixed anatomic landmark for the paravesical space is the umbilical ligament, and it can be easily identified laparoscopically. The paravesical space can be opened without risk of bladder injury. The urachus does not have to be divided. All the advantages of a transperitoneal approach are retained. Suture placement is greatly facilitated. Preliminary experience suggests that a laparoscopic Burch procedure can be carried out easily, quickly, and safely through the paravesical space, but this requires confirmation.

Laparoscopic pelvic and aortic lymphadenectomy.

A systematic approach to the laparoscopic management of gynaecological malignancies began about 5 years ago more or less simultaneously in a few centres in France and the USA. Mature data and long-term follow-up are not yet available. Despite the absence of comparative studies, evidence is, in this author's opinion, now compelling that pelvic and aortic lymphadenectomy can be carried out just as effectively laparoscopically as via a laparotomy. This conclusion is based on traditional surgical, anatomical and pathological considerations such as the way in which the operation is executed, photodocumentation of the extensiveness of the dissection, the lymph node harvest and the proportion of positive lymph nodes recovered. The benefits of a laparoscopic approach have yet to be demonstrated in comparative studies, but compared with historical controls, the reduction in morbidity is so dramatic as to leave little doubt that patients benefit from laparoscopic treatment in experienced hands.

Possible metaplastic origin of lymph node "metastases" in serous ovarian tumor of low malignant potential (borderline serous tumor).

A patient with a stage III serous ovarian carcinoma of low malignant potential (borderline serous tumor) is described who had extensive involvement of the pelvic and para-aortic lymph nodes by both borderline tumor and endosalpingiosis. Transition from endosalpingiosis to papillary serous borderline tumor was demonstrable in multiple intranodal sites, and in fully developed lesions, areas of metaplastic growth acquired a desmoplastic stroma. This finding suggests that the lymph node "metastases" may have arisen de novo by neoplastic transformation of preexistent metaplastic tubal-type epithelium (endosalpingiosis), and would lend further credence to the metaplastic (rather than metastatic) origin or extraovarian implants in serous ovarian carcinoma of low malignant potential.

Dissecting the pelvic retroperitoneum and identifying the ureters. A laparoscopic technique.

A technique for dissecting the pelvic retroperitoneum and identifying the ureters and uterine arteries is described that makes use of the obliterated hypogastric arteries. The obliterated arteries are readily identified laparoscopically and, as relatively fixed structures, are easily dissected free of the bladder and surrounding areolar tissues. Once freed by blunt dissection, they are traced proximally to where they are joined by the uterine arteries to form the internal iliac arteries. Blunt dissection just proximal and medial to the uterine artery will open the pararectal space, the medial border of which is bounded by the ureter. The uterine arteries are then traced to where they cross the ureters and are freed from them by blunt dissection. The site at which the uterine arteries are divided and the extent to which the extraperitoneal spaces are developed and ureters mobilized off the medial leaf of the broad ligament are tailored to the operation performed.