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Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα’s role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex., Salter et al. show that biallelic variants in PI4KA—which encodes the enzymatic core of the PI4KIIIα-TTC7-FAM126 complex—cause a clinically diverse disorder comprising neurological, intestinal and immunological abnormalities.

Interstrand DNA cross-links (ICLs) block both replication and transcription, and are commonly repaired by the Fanconi anemia (FA) pathway. However, FA-independent repair mechanisms of ICLs remain poorly understood. Here we report a previously uncharacterized protein, SAN1, as a 5′ exonuclease that acts independently of the FA pathway in response to ICLs. Deletion of SAN1 in HeLa cells and mouse embryonic fibroblasts causes sensitivity to ICLs, which is prevented by re-expression of wild type but not nuclease-dead SAN1. SAN1 deletion causes DNA damage and radial chromosome formation following treatment with Mitomycin C, phenocopying defects in the FA pathway. However, SAN1 deletion is not epistatic with FANCD2, a core FA pathway component. Unexpectedly, SAN1 binds to Senataxin (SETX), an RNA/DNA helicase that resolves R-loops. SAN1-SETX binding is increased by ICLs, and is required to prevent cross-link sensitivity. We propose that SAN1 functions with SETX in a pathway necessary for resistance to ICLs., When DNA interstrand cross-links damage occurs, it causes disruption of replication and transcription. Here the authors identify FAM120B/SAN1, a 5′ exonuclease involved in the repair process of Interstrand Crosslinks independently of the Fanconi Anemia pathway.

Mutations that alter signaling through the mammalian target of rapamycin complex 1 (mTORC1), a well established regulator of neuronal protein synthesis, have been linked to autism and cognitive dysfunction. Although previous studies have established a role for mTORC1 as necessary for enduring changes in postsynaptic function, here we demonstrate that dendritic mTORC1 activation in rat hippocampal neurons also drives a retrograde signaling mechanism promoting enhanced neurotransmitter release from apposed presynaptic terminals. This novel mode of synaptic regulation conferred by dendritic mTORC1 is locally implemented, requires downstream synthesis of brain-derived neurotrophic factor as a retrograde messenger, and is engaged in an activity-dependent fashion to support homeostatictrans-synaptic control of presynaptic function. Our findings thus reveal that mTORC1-dependent translation in dendrites subserves a unique mode of synaptic regulation, highlighting an alternative regulatory pathway that could contribute to the social and cognitive dysfunction that accompanies dysregulated mTORC1 signaling.

Frozen section is a reliable technique in gynecologic pathology and is widely used to guide intraoperative management in patients presenting with ovarian masses. However, there are limited data regarding the diagnostic accuracy of frozen section in specific subtypes of ovarian neoplasia. Our impression that primary clear cell carcinoma (CCC) causes disproportionate diagnostic difficulty led us to review the intraoperative and final histopathologic reports from a consecutive series of 44 CCC that were subject to frozen-section assessment and to compare the results with a similar number of primary serous and endometrioid carcinomas. The original intraoperative slides from those CCC with discordant diagnoses were also reviewed. Review of the diagnostic reports showed that CCC was less frequently specifically identified than serous or endometrioid carcinomas on frozen section (44% cases compared with 55% and 65%, respectively), although the differences were not statistically significant. Difficulties in distinguishing primary ovarian carcinoma from tumors metastatic to the ovary occurred in a minority of cases of all histologic subtypes, but was slightly more frequent in CCC. Two CCC were misdiagnosed as borderline epithelial tumors and 1 case as a dysgerminoma. Review of the frozen-section slides from the CCC with discrepant intraoperative diagnoses showed features suggestive or indicative of the correct diagnosis in 7 (39%) of 18 cases.

Several techniques of laparoscopic hysterectomies have been described, but loss of carbon dioxide (CO(2)) pneumoperitoneum is still a problem when the vagina is incised and the specimen has been removed. Our technique allows maintenance of CO(2) pneumoperitoneum by inserting a silicone tube into the vagina. The McCartney tube is open at its vaginal (proximal) end and a cap covers the outer distal end. The total hysterectomy specimen, adnexa, and, if necessary, lymph nodes can be easily removed through the tube.

he specific preoperative diagnosis of a pelvic mass can be challenging despite the excellent anatomic detail provided by sonographic imaging of the female pelvis. There is a wide spectrum of possible differential diagnoses of a complex pelvic mass, including benign ovarian cysts, ovarian carcinoma, hydrosalpinx, tubo-ovarian abscess, gastrointestinal conditions (e.g., inflammatory bowel disease, mucocele, and abscess), peritoneal causes (e.g., pseudocyst, malignancy, and tuberculous peritonitis), lymphoma, and mesothelioma. This report describes a case of tuberculous peritonitis in a young woman with a large pelvic mass and sonographic features mimicking those of an ovarian cystadenoma.

To compare total laparoscopic hysterectomy (TLH) with open hysterectomy in the management of endometrial carcinoma.Retrospective chart review (Canadian Task Force classification II-3).Gynecologic cancer center.All women with endometrial carcinoma managed between January 1, 1993, and June 30, 1999.Of 403 patients reviewed, in 161 (40%) the surgical intention was laparoscopic management, in 230 (57%) the intention was open management, and in 12 (3%) it was vaginal hysterectomy. Total laparoscopic hysterectomy was successfully completed in 153 (95%) of the laparoscopic group.Mean weight of women in the laparoscopic group (80.1 kg) was greater than that in the open group (73.3 kg, p = 0.002), and included 27 patients weighing over 100 kg (maximum individual weight 170 kg). Mean operating times were 138 minutes for laparoscopy and 121 minutes for the open procedure (p = 0.002). Complications differed, with significantly more occurring in the open group (43%, 100) than in the laparoscopic group (17%, 27, p0.00001). Mean postoperative hospital stay was significantly shorter for the laparoscopic group (4.3 days) than for the open group (8.5 days, p = 0.0001). Conclusion. TLH combined with laparoscopic surgical staging has many advantages over the open approach, especially in obese women.

Objectives. The aim of this study was to assess the technique of en bloc resection of ovarian cancer with concomitant rectosigmoid colectomy, in relation to perioperative complication rates, and its impact on survival following the procedure. Methods. A retrospective review was performed of the case notes of 129 consecutive procedures performed between 1989 and 2000 in a regional cancer center. Results. Overall, 48.8% of patients suffered a major or minor complication. Complications relating to bowel anastomosis occurred in 2.4%. Perioperative mortality was 3.1%. Median survival for the group as a whole was 30.6 months. Patients who were optimally debulked had a significantly longer median survival time. Conclusion. En bloc resection of ovarian cancer with concomitant rectosigmoid colectomy allows a high rate of optimal debulking with acceptable morbidity, mortality, and survival.

Niveoscincus ocellatus is an important species in historical analyses of the evolution of viviparity because it is the species upon which the type II chorioallantoic placenta was based. Here we describe the net nutrient uptake across the placenta of N. ocellatus for comparison with other species of skinks with complex placentae. N. ocellatus is highly placentotrophic, with neonates being 1.68-times larger in dry matter than the fresh eggs. There is an increase of nitrogen from 6.3 +/- 0.2 mg to 9.2 +/- 0.6 mg, and ash from 3.8 +/- 0.3 mg to 6.7 +/- 0.6 mg. The increase in ash is made up by a more than two-fold increase in the amounts of calcium, potassium and sodium. There is no significant difference in lipids in the neonates compared to fresh eggs, so considerable lipid must have crossed the placenta to provide energy for embryonic development. N. ocellatus is significantly more placentotrophic than Niveoscincus metallicus, which also has a complex chorioallantoic placenta. Discovery of substantial placentotrophy in this genus confirms that two lineages of Australian lygosomine skinks (represented by the genera Pseudemoia and Niveoscincus) have evolved this pattern of embryonic nutrition and supports the hypothesis that the evolution of reptilian placentotrophy involves specialisations in addition to structural modifications of the chorioallantoic placenta.

Lipid analysis was performed on freshly ovulated eggs (n = 5) of the oviparous lizard Bassiana duperreyi. The fresh weight of the whole egg contents was 132.0 +/- 4.3 mg (mean +/- SE) of which lipid constituted 21.9 +/- 1.1% (w/w). Triacylglycerol formed an exceptionally high proportion (85.4 +/-0.5%, w/w) of the total lipid, whereas phospholipid, free cholesterol, cholesteryl ester, and free fatty acid, respectively, contributed 11.2 +/- 0.3, 1.4 +/- 0.1, 1.3 +/- 0.1, and 0.6 +/- 0.1% of the total lipid mass. Linoleic and alpha-linolenic acids were the major polyunsaturates of the triacylglycerol fraction, respectively, forming 16.3 +/- 0.1 and 8.3 +/- 0.1% (w/w) of the fatty acids. Linoleic acid was the major fatty acid (29.0 +/- 0.1%) of the total phospholipid, which also contained substantial amounts of arachidonic (6.4 +/- 0.1%) and eicosapentaenoic (3.0 +/- 0.1%) acids, but a relatively low proportion (1.6 +/- 0.1%) of docosahexaenoic acid. Phosphatidylcholine formed the major phospholipid class (73.8 +/- 2.3%) w/w of total phospholipid) and was enriched in linoleic acid, whereas phosphatidylethanolamine, which formed 20.4 +/- 1.9%(w/w) of total phospholipid, contained higher proportions of arachidonic and docosahexaenoic acids.

Hysterectomy performed totally by laparoscopy has few advocates because separating the cervix from the vagina is difficult. This technical difficulty can be overcome by placing a wide-bore plastic tube in the vagina to expose the cervico-vaginal junction and stretch the vaginal fornices. The stretched vagina falls away from the cervix as diathermy cuts over the tube rim. The tube guides the incision, and the plastic protects any adjacent structures. The most convenient external diameter is between 4-5 cm. Made from smooth, electrically-inert plastic, the tube's opposite distal end has a valve that maintains the pneumoperitoneum. We have used it in 73 cases, and the only associated complication has been one vault pelvic hematoma.

To compare Total Laparoscopic Hysterectomy (TLH) and Total Abdominal Hysterectomy (TAH) with regard to surgical safety.Between October 2005 and June 2010, 760 patients with apparent early stage endometrial cancer were enroled in a multicentre, randomised clinical trial (LACE) comparing outcomes following TLH or TAH. The main study end points for this analysis were surgical adverse events (AE), hospital length of stay, conversion from laparoscopy to laparotomy, including 753 patients who completed at least 6 weeks of follow-up. Postoperative AEs were graded according to Common Toxicity Criteria (V3), and those immediately life-threatening, requiring inpatient hospitalisation or prolonged hospitalisation, or resulting in persistent or significant disability/incapacity were regarded as serious AEs.The incidence of intra-operative AEs was comparable in either group. The incidence of post-operative AE CTC grade 3+ (18.6% in TAH, 12.9% in TLH, p 0.03) and serious AE (14.3% in TAH, 8.2% in TLH, p 0.007) was significantly higher in the TAH group compared to the TLH group. Mean operating time was 132 and 107 min, and median length of hospital stay was 2 and 5 days in the TLH and TAH group, respectively (p0.0001). The decline of haemoglobin from baseline to day 1 postoperatively was 2g/L less in the TLH group (p 0.006).Compared to TAH, TLH is associated with a significantly decreased risk of major surgical AEs. A laparoscopic surgical approach to early stage endometrial cancer is safe.

p f ( t t a v t m m o r d t c t t n r l p q A67-YEAR-OLD woman was admitted to the hospital with a left hemispheric hemorrhagic insult. Previously, the atient had been treated with low-dose aspirin for a transient schemic attack and had moderate obesity (with an estimated eight of 90 kg and an estimated height of 1.70 m) but was therwise healthy and independent. Because of a lack of neuologic improvement and difficulties weaning from ventilation weeks after the insult, a decision was made to perform a edside percutaneous dilatational tracheostomy using a comercial kit set (CIAGLIA Blue Rhino; Cook Incorporated, loomington) in the intensive care unit. The procedure was erformed under bronchoscopic guidance. After puncture of the rachea and subsequent aspiration of air into a saline-filled yringe, a guidewire was placed, and the position was conrmed by bronchoscopy. The dilatational sequence was neventful, and the tracheostomy tube was placed. After a entilation check, the absence of CO2 return was noted by apnography. Bronchoscopy showed that the tracheostomy ube had passed through both the anterior and the left posteroateral tracheal wall. The tracheostomy tube was withdrawn, nd an endotracheal tube with a 7.0-mm internal diameter was eplaced beyond the lesion under bronchoscopic guidance. Efective ventilation was confirmed by CO2 return waveform with cceptable value. During the entire procedure, no significant decrease in oxyen saturation or major hemodynamic instability was noted; owever, extensive subcutaneous emphysema in the neck and pper chest was found. The chest x-ray revealed a left-sided neumothorax, which was treated by inserting a chest tube. hereafter, the patient was transferred rapidly to the operating oom for repair of the tracheal tear. The planned operative pproach was through an anterior cervical incision with the eck fully extended. It was believed this would provide good xposure to the site of injury and allow for an open tracheosomy to be performed at the end of the case. The surgeons were repared to perform a partial sternal split if necessary. Before he start of the surgery, a 2nd chest tube was inserted because f the posterior malposition of the 1st tube. Bronchoscopy was erformed through the endotracheal tube so that a bronchial lesion ould be excluded. Thereafter, a 7F Arndt bronchial blocker Arndt Endobronchial Blocker Set; Cook Incorporated, Bloomingon, IN) was advanced successfully through the single-lumen .0-internal diameter endotracheal tube into the right main ronchus under bronchoscopic guidance using the guidewire

We report 2 unusual gynaecological manifestations of Donovanosis in young tribal aborigines. The first patient presented for medical attention after haemorrhaging from a large pedunculated lesion arising from the left labium minus and majus. This lesion was subsequently confirmed as pseudo-elephantiasis resulting from long-standing Donovanosis of the vulva. The second patient, with initial findings consistent with a diagnosis of advanced cervical malignancy, was referred to the oncology service of a tertiary referral centre. Because of her age and race a differential diagnosis of Donovanosis was considered and subsequently confirmed on special staining (Warthin-Starry) of biopsy specimens. No evidence of malignancy was found in these specimens.

To determine whether there is a difference in disease severity between familial and sporadic primary open-angle glaucoma (POAG).A cross-sectional study design compared the distribution of Glaucoma Inheritance Study in Tasmania (GIST) severity scores of patients with genealogically confirmed familial POAG and those with sporadic POAG. The GIST severity scores provide a combined weighting of glaucoma severity based on findings from visual field defects and optic disc analysis, with and without intraocular pressure. A Poisson regression analysis, t test, and chi(2) tests were performed.One thousand twelve (59.5%) of 1700 subjects had familial glaucoma. The mean +/- SD age at examination was greater in the sporadic POAG group compared with the familial group (72.6 +/- 10.3 years vs 70.6 +/- 12.6 years; P = .001). The family group was significantly younger at diagnosis than the sporadic group (mean +/- SD, 61.4 +/- 13.0 years vs 64.0 +/- 12.6 years; P.001). The GIST severity scores were significantly skewed toward greater disease severity in the familial group compared with the sporadic group (P.001).Identifying individuals at risk of severe POAG will be more successful if screening programs are developed with appropriate weighting toward those with a positive family history of the disease.

Frozen section is often requested in the intraoperative assessment of patients, presenting with ovarian masses, to provide guidance for appropriate surgical management. To assess the accuracy of frozen section and identify causes of diagnostic error, we reviewed 914 consecutive ovarian frozen sections performed over a 5-year period in 2 laboratories; one of which provides a general surgical pathology service and, the other, a specialist gynecologic pathology service. Cases, in which there were significant diagnostic discrepancies between the intraoperative and the final histological diagnoses, were reviewed. The series included 552 benign lesions (60.4%), 96 borderline (atypical proliferating) epithelial tumors (10.5%), and 266 malignancies (29.1%). The overall accuracy of frozen section diagnosis was 95.3%. There were 43 cases with diagnostic discrepancy; 20 (3.8% cases) of which were reported in the specialist laboratory and 23 (5.9% cases) in the general laboratory. Underdiagnosis of tumor type accounted for 32 of 43 discrepant cases and was most frequent in borderline mucinous tumors. The most common cause of overdiagnosis was the misinterpretation of serous cystadenofibroma as borderline serous tumor. Slide review of the 41 assessable cases indicated that sampling error, pathologist misinterpretation, and suboptimal slide preparations contributed to misdiagnoses in 17, 23, and 9 tumors, respectively (in 9 cases, 2 factors were contributory), whereas no specific error was identified in the remaining case. Technical factors and pathologist misinterpretation were more common in the general pathology laboratory. This study confirms that ovarian frozen section is a generally reliable technique, but there are problematic areas, particularly involving the assessment of borderline tumors.

Frozen section is widely used in the intra-operative assessment of patients with ovarian tumors. The diagnosis of malignancy is usually straightforward but in some cases it may be difficult to distinguish whether tumors are of ovarian origin or represent matastases from other sites. Recently, Seidman and colleagues presented a simple algorithm based on tumor size and unilateral versus bilateral involvement to aid in intra-operative assessment of ovarian mucinous neoplasms. In this study we have reviewed the accuracy of frozen section in distinguishing primary ovarian malignancies from tumors metastatic to the ovaries encountered in two hospitals over a 5-year period. The algorithm was also applied to our cases retrospectively irrespective of histological type. Nine hundred fourteen ovarian frozen sections were performed in the study period including 266 cases with a final diagnosis of malignancy. Thirty-seven malignancies (13.9%) were of metastatic origin (exclusing one lymphoma), 21 of which (58.8%) were correctly identified on frozen section. In 5 additional cases metastatic origin was included in the differential diagnosis while a primary ovarian tumor was favored un 11 cases (29.7%). Application of the algorithm to the metastatic tumors led to correct classification in 26/33 (78.8%) assessable cases. Conversely, 195/228 primary ovarian malignancies were correctly identified intra-operatively but the possibility of extra-ovarian malignancy was considered or not excluded in 33 cases (14.5%). Application of the algorithm to the latter problematic primary ovarian tumors overall was not helpful in distinguishing primary or metastatic origin. However if only low-grade primary adenocarcinomas were considered then 10/12 assessable cases were correctly assigned. In conclusion frozen section is only moderately successful in distinguishing primary ovarian malignancies fron tumors metastatic to the ovaries. The simple algorithm proposed by Seidman and colleagues for assessment of ovarian mucinous tumors is helpful and can be applied to low-grade adenocarcinomas of other histological types.

Full-length cDNA for a mouse gene A2-macroglobulin induced by pregnancy (A2mp) was cloned from mesometrial decidua at Gestation Day 10. The 4622-base pair cDNA encodes a protein of 1473 AA with70% sequence identity and all typical domains of other A2M-family members in humans and rodents, despite unique absence of hepatic expression. The bait region is most distinct and has the greatest sequence similarity with rat acute-phase A2m. Northern blotting, reverse transcription and real-time-PCR, and in situ hybridization studies using C57Bl/6 mice revealed uterine induction of A2mp during decidualization and strong, midgestational association with modifying spiral arteries. Ovaries, testes, lactating mammary glands, heart, and kidney were the only additional organs with A2mp expression that was localized to granulosa and cumulus cells in secondary follicles; primary seminiferous epithelium, including Sertoli cells, mammary alveolar, and ductal epithelium; cardiac endothelium; and renal collecting tubules, respectively. Infusion of native human A2M into pregnant alymphoid or interferon-gamma gene-ablated mice overcame blocks to pregnancy-induced spiral artery modification in these strains. Activated human A2M was also effective, suggesting mechanisms independent of proteinase inhibition. Identification of cytokines, growth factors, or other molecules bound to A2MP should provide new insights into decidualization, spiral artery modification, and cardiovascular adaptation to pregnancy.

The difficult transtemporal ultrasound window is a relatively frequent occurrence. The authors assessed if the thickness of the temporal bone squama as measured in the "bone window" of the head computerized tomography (CT) scan can predict the transtemporal acoustic window.The authors retrospectively reviewed the head CTs on their bone window setting of patients in which nonimaging transcranial Dopplers (TCDs) had been performed. The thickness of the temporal squama in its thinnest portion was measured. The temporal TCD windows were graded in three classes: class 1 as good, class 2 when only a partial study is possible, and class 3 as an impossible ultrasonic window. In a case-control design, for every patient with any class 2 and 3 TCD temporal window, a patient with a class 1 window was randomly included from the same time period.Fifty-five temporal bones (56%) were class 1, 17 (17%) were class 2, and 27 (27%) were class 3. Bone thicknesses (in mm, mean +/- SD) were greater in those with poorer windows: class 1 = 2.67 +/- 0.70, class 2 = 4.06 +/- 0.56, and class 3 = 5.04 +/- 1.06, Por = .0001 by Cusick's nonparametric test of trend. Temporal squama thickness ofor = 5 mm portends 86% sensitivity, 90% specificity, 70% positive predictive value, and a positive likelihood ratio of 8.6 for a class 3 transtemporal ultrasound window.Measurement of temporal bone thickness on the bone window setting of the head CT scan may be useful in identifying patients who are poor candidates for transcranial ultrasound.

Laparoscopic pelvic lymphadenectomy for gynecological malignancy involves mobilizing and exteriorizing the lymph nodes. We removed the nodes by passing a 4- to 5-cm-diameter tube through the vagina to the abdomen following the hysterectomy. The nodes were passed through the tube rather than pulled through the abdominal ports. The tube is easy to insert and is a valuable conduit for exteriorizing tissue during laparoscopic pelvic surgery for gynecological cancer.

Study Objective To evaluate feasibility and morbidity of a total laparoscopic radical hysterectomy (TLRH). Design Retrospective chart review (Canadian Task Force classification II-3). Setting Gynecologic cancer center. Patients Fifty-five women with cervical (39), endometrial (8), vaginal (2), or recurrent colon cancer (1), or severe pelvic endometriosis (5) followed for 3 years. Intervention TLRH in 55 women, converted to laparotomy in 3 (5.5%). Measurements and Main Results Feasibility, safety, patterns of recurrence, and survival were assessed. Estimated blood loss was 200 ml (range 50–2000 ml), median total operating time was 210 minutes, and median hospital stay was 5 days. Intraoperative complications were three vascular injuries and one obturator nerve palsy, all of which occurred in the first half of the series. Early postoperative morbidity included deep vein thrombosis, pulmonary embolism, bladder infection and dysfunction, and vaginal fistula. These events occurred less frequently in the second half of the series. Late postoperative morbidity consisted of lymphedema, pelvic abscess and lymphocyst formation, pelvic cellulitis, hyperesthesia of the leg, and small bowel obstruction. The only fatality was a patient who developed a pulmonary embolus on postoperative day 3. Median follow-up was 36.5 months. Of 39 women with cervical cancer, 34 were alive and disease free at their last visit. No case of port site metastasis occurred during follow-up. Conclusion TLRH carries acceptably low morbidity that can be reduced with experience with the technique.

Objective . The impact of laparoscopic surgery on the patterns of recurrence and on prognosis in patients with endometrial cancer remains unclear. The objective of the current study was to evaluate the effect of the laparoscopic approach on patterns of recurrence, disease-free (DFS), and overall survival (OS) in patients with endometrial cancer. Methods . A retrospective review of patients presenting with stages 1–4 endometrial cancer who had a hysterectomy, bilateral salpingo-oophorectomy with or without surgical staging was performed. Patients either had a total laparoscopic hysterectomy (TLH) or a total abdominal hysterectomy (TAH). Patterns of recurrence, DFS and OS were the study endpoints. Results . The surgical intent was TLH in 226 patients (44.3%) and TAH in 284 patients (55.7%). TLH was converted to laparotomy in 11 patients. Patients for TLH were younger, heavier, and had a higher ASA score and were more likely to present with early-stage, well-differentiated tumors and were less likely to have undergone lymphadenectomy. Median follow-up was 29.4 months. DFS and OS were adversely and independently affected by increasing age, higher stage, higher grade, and by deeper myometrial invasion, whereas the intention to treat (TLH vs. TAH) did not influence DFS or OS. Patterns of recurrence were similar in both groups and no port-site metastasis was noted in the TLH group. Conclusions . The incidence of port-site metastasis in early-stage endometrial cancer treated by TLH is low. Laparoscopic management does not seem to worsen the prognosis of patients with endometrial cancer.

BACKGROUND Isoforms of the adhesion molecule CD44 are involved in carcinogenesis and the metastatic cascade of tumor cells by increasing the affinity of malignant cells to their extracellular matrix. Preliminary data with respect to the prognostic value of the CD44 isoforms CD44v3 and CD44v6 in patients with vulvar carcinoma showed promising results. The current multicenter study aimed to determine the prognostic value of CD44v3 and CD44v6 in patients with surgically staged vulvar carcinoma. METHODS Expression of CD44v3 and CD44v6 in vulvar carcinoma tissue was assessed by immunohistochemistry. Immunohistochemic staining was performed according to established protocols. Results were correlated to clinical data. RESULTS A positive CD44v3 and CD44v6 staining was detected in 33.3% (33 out of 99) and 39.4% (39 out of 99) of the tumor samples, respectively. Overexpression of CD44v6 was associated with an impaired prognosis with respect to disease-free survival (P = 0.01) and overall survival (P = 0.04). Multivariate analysis showed that CD44v6 provided prognostic information with respect to disease-free survival (P = 0.001) and overall survival (P = 0.005) independently of the two established prognosticators, tumor stage and groin lymph node involvement. Overexpression of CD44v3 had no impact on patient survival. CONCLUSIONS The current multicenter study, involving a large series of patients with surgically staged vulvar carcinoma, allowed for multivariate survival analysis and showed that CD44v6 confers prognostic information in addition to that provided by the established clinicopathologic parameters of tumor stage and lymph node status. Cancer 2002;94:125–30. © 2002 American Cancer Society.

To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP).Cross-sectional genetic study.Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania.Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing.From the eight pedigrees, 29 Gln368STOP mutation-carrying individuals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 +/- 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 +/- 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 individuals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these individuals the mean age at diagnosis was higher (62.3 +/- 13.7 years, P0.01), and the mean peak IOP was lower (25.4 +/- 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at age 40 years and 82% at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more individuals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy.The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.

The Eugongylus species group of Australian lygosomine skinks provides an unparalleled opportunity to study the evolution of placentotrophy. Viviparity and placentotrophy have evolved in two lineages, currently recognised as the genera Pseudemoia and Niveoscincus. The genus Niveoscincus is important because it is the only lineage of squamates in which variation in placental morphology and in the pattern of embryonic nutrition is known. Niveoscincus coventryi has the least complex placental morphology among species currently assigned to the genus. We quantified the net uptake of nutrients across the placenta of N. coventryi for comparison with other species in the genus and with other viviparous and oviparous lizards. The pattern of embryonic nutrition of N. coventryi is similar to other viviparous lizards with simple placentae in that there is no net uptake of dry matter during development but there is a net uptake of water, calcium, potassium, and sodium. There is no net uptake of lipid, nitrogen (an index of protein), or magnesium. We conclude that N. coventryi is predominantly lecithotrophic. Further, if N. coventryi is the sister taxon to Tasmanian Niveoscincus, then the distribution of patterns of embryonic nutrition among members of this clade suggests that the evolution of placentotrophy occurred during radiation of this lineage in Tasmania. J. Exp. Zool. 290:291–298, 2001. © 2001 Wiley-Liss, Inc.

The contents of eggs and neonates of the Australian skinks, Lampropholis guichenoti and L. delicata, are described and compared to allow interpretation of nutrient utilisation by the developing embryo. Even though the females are the same size, L. guichenoti lay smaller clutches of larger eggs (egg contents=41.6+/-1.2 mg dry mass) than L. delicata (26.6+/-2.8 mg). The energy density is the same for eggs (30.5+/-0.9 J/g ash-free dry mass for L. guichenoti and 29.9+/-1.1 J/mg for L. delicata) and neonates (22.5+/-1.3 J/mg for L. guichenoti and 23.5+/-0.4 J/mg for L. delicata) between species. The amount of nitrogen (protein) in neonates is only slightly lower than that in eggs, whereas there is a large and significant decline in total lipids. Thus, like some other skinks, protein is a source of metabolic energy during embryogenesis, although not as important as lipid. Triacylglycerol is the major lipid component of the eggs (80% of total lipid), with phospholipid forming only approximately 10% of the total lipid. The fatty acid profile of the phospholipid is distinguished by a high proportion of arachidonic acid (8%), a significant proportion of eicosapentaenoic acid (2-4%) and a relatively low proportion of docosahexaenoic acid (2-3%) compared to chickens. Eggs of both species have remarkably low concentrations of free cholesterol compared to other amniote eggs (0.7% for L. guichenoti and 1.3% for L. delicata). The loss of lipid during embryonic development is almost entirely due to the selective utilisation of yolk triacylglycerol, presumably for energy. By contrast, the amount of phospholipid recovered from the neonates was the same as that originally in the eggs. Moreover, significantly more total cholesterol was present in the neonates than in the eggs, suggesting that biosynthesis of additional cholesterol occurred during development. The phospholipids of the neonates contain higher proportions of arachidonic (11-12%) and docosahexaenoic (8%) acids than the phospholipids of the eggs. Eicosapentaenoic acid is less prevalent in phospholipids in neonates than in eggs. Neonates of both species contain significantly more calcium than the fresh egg contents (L. guichenoti, eggs 0.303+/-0.051 mg, neonates 0.641+/-0.047 mg; L. delicata, eggs 0.187+/-0.013 mg, neonates 0.435+/-0.033 mg), presumably as a result of resorption of calcium from the eggshell. Interestingly, there is also significantly more sodium in neonates than in the contents of fresh eggs (L. guichenoti, eggs 0.094+/-0.010 mg, neonates 0.184+/-0.011 mg; L. delicata, eggs 0.084+/-0.011 mg, neonates 0.151+/-0.010 mg). There is no significant difference in the content of potassium and magnesium in eggs and neonates of either species. Although the fresh eggs of L. delicata have a significantly higher sodium concentration than L. guichenoti, there is no difference in the concentrations of calcium, magnesium, potassium or sodium in the neonates of the two species.

Eulamprus tympanum is a high-altitude viviparous lizard that was probably used to help define a Type I chorioallantoic placenta. In this article, we (1) describe the net transport of nutrients across the placenta of E. tympanum, and (2) compare placental uptake in E. tympanum with a previous study of Eulamprus quoyii, which occurs in warmer environments, to assess the potential importance of thermal regime on placentotrophy. Freshly ovulated eggs are 387.3+/-19.7 mg. There is a significant net uptake of water and a net loss of dry matter during development, so the dry neonate is only 84% the size of the dry egg. There is no significant change in the total ash or nitrogen in eggs during embryonic development, with the entire loss of dry matter being lipid. Almost the entire loss of lipid occurs in the triacylglycerol fraction, with no net change in phospholipids. A net increase in total cholesterol suggests that cholesterol is synthesised by the developing embryo. The lipid profile of eggs of E. tympanum reflects that of other species with simple placentae in having a relatively high proportion of triacylglycerol and little cholesterol. The fatty acid composition of eggs reflects that expected in the diet of E. tympanum. There is a preservation and some synthesis of arachidonic (20:4n-6) and docosahexaenoic (22:6n-3) acids in the phospholipid fraction during embryonic development. Despite there being no net uptake of ash, there is a net increase in calcium, potassium, sodium, and magnesium in the neonate compared with the egg. We conclude that E. tympanum, like E. quoyii, is predominantly lecithotrophic with little, if any, uptake of organic molecules but with significant uptake of some inorganic ions and water. In addition, there is no difference in placentotrophy correlated with differences in the environments inhabited by each species.

A brief review of the causal and treatment literature relating to volatile substance dependency suggests the interaction between individual and system requires careful attention and understanding. A model is tentatively and provisionally adumbrated to help clarify the main factors involved from a dynamic biopsychosocial perspective. Ego boundary disturbances emerge from and reciprocally influence behaviour and social interactions. These disturbances can be avoided temporarily, although inevitably deepened in the long-term, by substance dependence. Two case examples, selected because they differ in many respects, including relative treatment effectiveness, illustrate this integrative perspective. The discussion focuses on explaining the differing outcomes in terms of the extent to which the inner-outer boundary is open to modification and how far it can be successfully negotiated and clarified. A major factor in differentiating between inside and outside is thought to be causal perceptions or "attributions." Successful differentiation tends to facilitate change, as opposed to reinforcing maladaptive homeostasis. Key issues for therapists overlap with addictions treatment in general, including emotional blocks or barriers in patients, difficulty engaging systems in a strategic manner, and countertransference problems. It is argued that these difficulties in therapy might respond to integrative psychotherapeutic responses, provided the differences in perspective are sufficiently understood.

A substantial proportion of cases of glaucoma have a genetic basis. Mutations causing glaucoma have been identified in the chromosome 1 open-angle glaucoma gene (GLC1A), which encodes a 57-kd protein known as myocilin. The normal role of this protein and the mechanism by which mutations cause glaucoma are not known.We screened 716 patients with primary open-angle glaucoma and 596 control subjects for sequence changes in the GLC1A gene.We identified 16 sequence variations that met the criteria for a probable disease-causing mutation because they altered the predicted amino acid sequence and they were found in one or more patients with glaucoma, in less than 1 percent of the control subjects. These 16 mutations were found in 33 patients (4.6 percent). Six of the mutations were found in more than 1 subject (total, 99). Clinical features associated with these six mutations included an age at diagnosis ranging from 8 to 77 years and maximal recorded intraocular pressures ranging from 12 to 77 mm Hg.A variety of mutations in the GLC1A gene are associated with glaucoma. The spectrum of disease can range from juvenile glaucoma to typical late-onset primary open-angle glaucoma.

The 'GIST' score was developed to facilitate linkage analysis of adult-onset primary open angle glaucoma (POAG) pedigrees in the Glaucoma Inheritance Study of Tasmania (GIST). Previous genetic linkage studies on juvenile open angle glaucoma pedigrees have relied upon an analysis of definitely affected individuals using the 'single best diagnosis' convention. Studies of adult-onset POAG have been complicated by limited numbers of unequivocally affected members identified even in very large pedigrees due to the later onset of the disease. Many members of the pedigree may have equivocal clinical features or are too young to show signs of the disease. The 'GIST score' is a numeric value between zero and one where zero is clinical certainty of absence of the disease and one is the definitive diagnosis of POAG. The score is developed by assigning relative weighting to key clinical features which results in a 'pedigee probability' of the diagnosis being present or absent in a member of a pedigree. Ranking of borderline and unaffected glaucoma subjects allows the laboratory more flexibility in the use of the members of the pedigree for linkage analysis. The score is not intended to have clinical usefulness in management of glaucoma.

An empirical study of a British clinical population is reported, in which the influence of relationships on confidence in maintaining change across a number of addictive behaviors was investigated. The hypothesis was that the perceived quality of relationships would be correlated with a client's confidence in sustaining abstinence or change. It was also thought that qualitative data would help clarify some of the underlying processes mediating such a link if it were established. The results largely supported the predictions, although relationship difficulties were significantly more common in gamblers and alcoholics compared with smokers and overeaters. The discussion develops the view that the notion of emotional disclosure and system theory's emphasis on circular causality are particularly useful concepts in making sense of the data.

The association of Turner's syndrome and endometrial carcinoma has been previously established but has never been described in conjunction with a uterine papillary serous carcinoma (UPSC). This histological variant is usually found in considerably older women and has no clear relationship to the prior use of estrogen replacement therapy. Despite presenting with stage IV disease, treated by surgery and medroxyprogesterone only, this patient has had an 8-year disease-free remission, suggesting that radical debulking of an endocrine-responsive tumor may be of considerable benefit to some women with this unfavorable histological subtype of endometrial carcinoma.

Objective To evaluate the feasibility, safety and advantages of laparoscopic hysterectomy. Design Retrospective review. Setting St. John of God Hospital, Perth, Australia. Subjects Fifty-four women scheduled to undergo laparoscopic hysterectomy for a variety of benign gynaecological conditions. Main outcome measures Failure to complete the operation laparoscopically, time taken in theatre, incidence of febrile morbidity, incidence of major complications, duration of post-operative stay in hospital, interval from operation to full activity and return to work. Results Laparoscopic hysterectomy was attempted in 54 women. A total of 53 operations were completed laparoscopically with one conversion to laparotomy because of haemorrhage. Major complications occurred in two women, both of whom required further surgery. There were four cases of febrile morbidity. The average duration of post-operative stay was four days (range 2–9), with return to normal activity in two and a half weeks and to work in three weeks. Conclusions Laparoscopic hysterectomy can be successfully achieved in most women selected for the procedure. Serious complications are inherent to some of the techniques used, but these can be overcome by modifications. Proper training and supervision in laparoscopic surgery is essential during the learning phase of the technique. There are considerable advantages to eligible women in terms of a rapid return to normal activities and work.

Estrogen-inducible pS2 mRNA was previously detected in human cancer cell lines the growth of which was sensitive to estrogen. In the present study, the expression of the pS2 gene was analyzed in 111 gynecological carcinomas. The pS2 message was detected in greatest abundance in 6 primary carcinomas of the ovary (6 of 29), 4 of these being mucinous cystadenocarcinomas. A secondary carcinoma of the ovary, and another of the omentum (1 of 4), also contained detectable levels of pS2 mRNA. Weak pS2 mRNA signals were occasionally observed in endometrial (2 of 55) and cervical carcinomas (2 of 33) as well. There was a poor correlation between estrogen receptor and pS2 mRNA in ovarian carcinomas.

Objective: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the myocilin mutation Thr377Met. Method and Design: Cross-sectional genetic study. Four unrelated pedigrees carrying the Thr377Met mutation were ascertained from more than 2000 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania and from families with glaucoma referred to the study from throughout Australia. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Thr377Met mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. Results: From the 4 pedigrees carrying the Thr377Met mutation, 23 individuals with either ocular hypertension (OHT) or POAG were found, with a mean±SD age at diagnosis of 41.2±11.5 years, and a mean peak intraocular pressure of 31.7±9.9 mm Hg. A further 9 mutation carriers older than 18 years were studied who as yet showed no signs of OHT or POAG (6 of these 9 were younger than 30 years). A single individual with POAG was identified who did not carry the Thr377Met mutation. For Thr377Met carriers, age-related penetrance for OHT or POAG was 88% at age 30 years. A positive family history of POAG was present for 3 of the 4 index cases. Thirteen (57%) of the 23 Thr377Met carriers with OHT or POAG had undergone glaucoma drainage surgery. Although the glaucoma in these families appears to be pressure dependent, 2 individuals showed optic disc cupping before detected elevation in intraocular pressure. One family was of British origin, with a different background haplotype from the other 3 families from Greece or Macedonia, who shared a common haplotype. Conclusions: The GLC1A Thr377Met mutation is associated with POAG that, in the pedigrees studied, had a younger age at onset and higher peak intraocular pressure than in pedigrees with the more common Gln368STOP mutation. In addition, patients with glaucoma with the Thr377Met mutation were more likely to have undergone glaucoma drainage surgery.

In a series of 173 consecutive patients with endometrial cancer treated by a fixed protocol 62 tumors (36%) appear "estrogen independent," i.e. there is no history of estrogen ingestion and no recognized risk factors such as obesity or diabetes mellitus. A high proportion of these tumors are of advanced stage and grade. Prognosis is poorer and mortality higher than for "estrogen-dependent" tumors. Twenty-two tumors were truly occult (no spontaneous vaginal bleeding). Factors which identify this high-risk group are described and the reasons for delay in diagnosis discussed. Spread by intraperitoneal dissemination is considered a major factor in the poorer prognosis. Cytology of peritoneal washings is a useful diagnostic and prognostic aid. An estrogen provocation test is suggested as a means of earlier recognition which could reduce mortality in this group.

In contrast to skin surface or sebum lipid, cattle epidermis was found to contain a lower proportion of wax ester and unesterified fatty acid and a high proportion of triglyceride. The epidermal triglycerides differed significantly in their fatty acid composition from those of the skin surface and sebum. In particular they contained extremely low levels of linoleic acid. It is concluded that the skin surface triglycerides and most likely the other major lipid fractions of the bovine skin surface are derived mainly from sebum.

The various surgical treatments of CIN, VAIN, and VIN have been discussed. The necessity for careful pretreatment, histological diagnosis and colposcopic mapping of the various conditions has been stressed. The relative risks of malignant progression of the various conditions have been discussed along with the various modes and methods of surgical therapy. The facts emerging are that traditional surgical therapy is giving ground to more modern techniques of ablation, particularly that of carbon dioxide laser photoevaporation therapy. Particularly in treatment of CIN and VIN, laser therapy has begun to show many advantages. Traditional surgical techniques for treatment of intraepithelial neoplasia of the lower genital tract in the female have, in response, become more conservative in their application with an emphasis on preservation and reconstruction. However, in some cases confirmation of early results by long-term follow-up will be necessary. The general tendency of close surveillance and conservative treatment befits the management of non-invasive genital tract intraepithelial neoplasia.

The Glaucoma Inheritance Study in Tasmania (GIST) is a population survey of Australia's island state, Tasmania (population 450,000). Its aim is to find families with autosomal dominant, adult-onset, primary open angle glaucoma (POAG) suitable for genetic linkage analysis. POAG is relatively common, affecting around 3% of the Australian population. By finding the large families with POAG and identifying all the descendants in a captive population, it is possible that there may be overlap of different glaucoma pedigrees. Three of the first thirteen families in the study were composed of overlapping pedigrees. In one GIST family, GTas3, there has been intermarriage with other pedigrees with glaucoma on five occasions. The possibility of multiple genotypes was also reinforced by the inability to determine a single glaucoma phenotype in this family. When finding large families of POAG for linkage analysis, researchers must be aware of the risk of affected individuals inheriting their gene from the alternate parent. Thus, the alternate parents or their families must be examined, especially if the phenotype is atypical for the rest of the family.