Bezafibrate down-regulates fibrinogen biosynthesis in human hepatoma HepG2 cells

Cellular distribution of HIV-1 proviral DNA has been studied, by in situ PCR hybridization, in the testes of infected men who died at various stages of the disease. In seropositive asymptomatic subjects, HIV-1 proviral DNA was present in the nuclei of germ cells at all stages of their differentiation. The presence of provirus did not induce germ cell damage, was associated with normal spermatogenesis, and was not accompanied by morphologic signs of immune response. The observed HIV hybridization pattern of germ cells suggests clonal infection. Mechanisms responsible for HIV penetration in testicular germ cells remain to be clarified; however, the possibility of a direct infection of the germ cells by cell-free virus is suggested. In the testes of AIDS-deceased men, histologic features of hypoplasia with arrested spermatogenesis were evident, and few infected spermatogonia and spermatocytes were observed. The whole of these data demonstrates that the testis is a site of early viral localization that fails to elicit an immunological response, and that HIV-seropositive men produce infected spermatozoa that are released in the genital tract.     

Neuroendocrine differentiated carcinoma of the uterine cervix

Cervical neuroendocrine carcinomas (CNC) are rare tumors. The term includes the cervical carcinoid, the small cell (oat-cell) carcinoma and the primitive neuroectodermal tumor (PNET). Between 1979 and 1993 eight CNC out of 788 cervical carcinomas were identified by conventional light microscopy and immunohistochemistry. Three tumors were small cell carcinomas with positive staining for NSE (6/8 tumors) and chromogranin A (2/8). In one case a PNET was diagnosed by identifying rosette like structures and negative immunohistochemistry for neuroendocrine markers. Two patients (including PNET) died of disease 3.1 (1.3 to 4.8) years after diagnosis. The others showed no evidence of disease after a mean follow up to 4.4 years. Three of them got pelvic radiation postoperatively. Four tumors showed foci of squamous cell carcinoma [3] and adenocarcinoma [2]. There is no evidence, that these foci influence the prognosis on CNC. Therefore, it is important to recognize the neuroendocrine component, as this type of carcinoma requires special therapeutic considerations. The authors favour the metaplastic origin of CNC from a multipotent (endocervical) stem cell.     

Cystoscopic staging of carcinoma uterine cervix, revisited

Of the 378 cases of stage 3 carcinoma uterine cervix, only 10 showed vesical invasion, while 19 of 24 cases of stage 4 disease had vesical invasion. Results of this procedure did not alter the management of the disease in any of these cases. From the whole series it was concluded that cysto-urethroscopy is an unnecessary, cost ineffective, invasive procedure which has no role in either diagnosis or in planning the definitive treatment of carcinoma uterine cervix.     

Angiogenesis in squamous cell carcinoma in situ and microinvasive carcinoma of the uterine cervix

OBJECTIVE: To evaluate angiogenesis in squamous cell carcinoma in situ (CIS) and microinvasive squamous cell carcinoma of the uterine cervix and to investigate the relations among angiogenesis, stromal inflammation, and depth of invasion. METHODS: Three groups of women were studied: 22 controls who had undergone hysterectomy for benign conditions; 18 with squamous cell CIS of the cervix who underwent cone biopsy, hysterectomy, or both; and 14 with microinvasive squamous cell carcinoma who underwent conization of the cervix and subsequent surgical management according to depth of invasion. All specimens were stained immunohistochemically for factor VIII-related antigen. Areas below the basement membrane with the highest angiogenic density were selected. The degree of stromal inflammatory reaction was assessed. Statistical analyses included Kruskal-Wallis, analyses of variance and covariance, Scheffe and Bonferroni-Dunn post hoc procedures, and Pearson correlation analysis. P < .05 was considered statistically significant. RESULTS: Microvessel counts per high-power field (x 400) of microinvasive squamous cell carcinoma of the cervix differed significantly from those of controls and squamous cell CIS (median 34.5 per high-power field, range 9-76 versus median 17, range 7-47, and median 19, range 8-39, respectively; P < .005). Microvessel counts per high-power field in squamous cell CIS did not differ significantly from those of controls (P = .91). Among patients with microinvasive squamous cell carcinoma of the cervix, no significant correlation was found between microvessel counts per high-power field and the depth of invasion (r = 0.19, P = .51). Stromal inflammatory reaction (graded 0-3) differed significantly among controls, squamous cell CIS, and microinvasive carcinoma (mean 0.40, 0.83, and 1.64, respectively; P < .005). CONCLUSIONS: Microinvasive squamous cell carcinoma of the uterine cervix is angiogenic, but depth of invasion is not associated with increased angiogenicity. Squamous cell CIS is not angiogenic.     

Organ preservation in locally advanced carcinoma of the uterine cervix

The purpose of this study was to demonstrate the potential usefulness of the combination of gadolinium and dysprosium to enhance the different between normal and necrotic liver tissue. Small regions of acute necrosis were induced by injecting 200-300 microliters of 95% alcohol into the liver of 26 rats. MRI was performed 24 hours after necrosis induction, before and immediately after injection of one or both contrast agents. Using a mixed T1/T2-weighted sequence, the signal intensity of (SI) of the normal liver was reduced by 70%, whereas the necrotic regions had more than a 50% increase in SI after double contrast. The region that was enhanced corresponded largely with the region of necrosis as observed postmortem. The lesion size, when identified, was largely underestimated using either of the agents along, albeit using the common pulse sequences. The double contrast effect of simultaneous administration of gadolinium and dysprosium allows accurate delineation of liver necrosis.     

Squamous cell carcinoma markers in neoplasms of the uterine cervix

In an extremely well-controlled study, Cohen et al. (1998) add to prior knowledge of stress-illness relationships by showing that self-reports of stress occurrence and duration of 1 month or more, rather than estimates of stressor severity, predict susceptibility to experimentally induced colds (i.e., viral replication and cold symptoms). Although ruling out obvious behavioral and personality factors as causes of the association of stressors to colds, they were unable to identify mediational immune factors, a deficit attributable to the difficulty of assessing the multi-layered, dynamic physiological processes within the bidirectional connections of the nervous (stress) and immune systems. The findings provide an interesting complement to data, showing that people use stressor duration in evaluating the illness implications of somatic symptoms (Cameron et al., 1995), and suggest caution with regard to overestimating the prevalence of stress-induced colds in natural settings.     

The long-term course of carcinoma in situ of the uterine cervix

The malignant potential of carcinoma in situ (CIS) of the uterine cervix has been the subject of great controversy. Despite refinements and additions to knowledge in this area, few reports on the long-term course of the disease have appeared in the past decade. Recent developments in diagnostic and therapeutic techniques coupled with changes in the patient population with this disease have prompted renewed interest in conservative management. Results of long-term observation of a group of patients followed initially without ablative therapy are reported. The data indicate that CIS of the uterine cervix is not the inevitably progressive disease that it has been considered to be. Unequivocal invasive cancer develops in only a small percentage of cases and can be controlled, if not cured, by current therapeutic modalities. The intraepithelial lesion, however, tends to persist despite conization, and eventually requires ablative therapy in most cases. Conservative procedures should be regarded as temporizing, at least until their long-term benefits can be recorded.     

Uterosacral space involvement in locally advanced carcinoma of the uterine cervix

PNU-151774E [(S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate] is a structurally novel anticonvulsant having Na+ channel-blocking and glutamate release-inhibiting properties, as well as being a MAOB inhibitor. Its anticonvulsant activity was evaluated in the maximal electroshock (MES) test and in chemically induced seizures (bicuculline, BIC; picrotoxin, PIC; 3-mercaptopropionic acid, 3-MPA; pentylenetetrazole, PTZ; strychnine, STRYC). Behavioral toxicity was evaluated in the rotorod test with measurements of spontaneous locomotor activity and passive avoidance responding. The anti-MES activity of PNU-151774E in both mice and rats, respectively, produced ED50 values of 4.1 mg/kg and 6.9 mg/kg after i.p. administration or 8.0 mg/kg and 11.8 mg/kg after p.o. administration. Oral anti-MES activity in rats peaked between 1 and 2 h after administration and was evident up to 4 h. This activity was related to brain levels of unchanged drug which peaked at 37 mM within 1 h. Oral ED50 values (mg/kg) effective in blocking tonic extension seizures by chemical convulsants in mice were: BIC (26.9), PIC (60.6), 3-MPA (21.5), STRYC (104.1) and PTZ (26.8). This potency was associated with high therapeutic indices relative to: MES (78.2), BIC (23.3), PIC (10.3), 3-MPA (29.1) and STRYC (6.0). No evidence of tolerance to anti-MES activity after repeated dosing was observed. PNU-151774E did not show anti-absence seizure activity as assessed by i.v. infusion of PTZ. PNU-151774E impaired spontaneous activity in rats only at the oral rotorod ED50 dose of 700 mg/kg p.o. PNU-151774E did not impair passive avoidance responding at doses up to 40 times the oral MES ED50 dose in rats. These results indicate that PNU-151774E is an anticonvulsant effective in various seizure models with a wide therapeutic window, and with a low potential to induce tolerance and locomotor or cognitive side effects.     

Morphology of lesions of the uterine cervix and human papillomaviruses

The question of psychophysiological reactivity of borderline hypertensives is still controversial. METHODS: Young males with borderline blood pressure levels and normotensive controls were recruited during a routine examination. Samples of study I comprised 19 subjects, samples of study II 18 subjects. Two stressors were presented (distressing movie, mental arithmetic), each followed by a recovery phase. Systolic and diastolic blood pressure, heart rate, and electrodermal parameters were assessed repeatedly. RESULTS: Borderline hypertensives showed greater reactions to stressors in systolic blood pressure only. Changes in percentage of baseline levels were essentially the same. Recovery after stress did not differ between groups. CONCLUSION: Only moderate support is given to the hypothesis that borderline hypertensives show increased and slowly recovering psychophysiological responses.     

Coexpression of cholesterol sulfate and cytokeratin as tumor markers in well-differentiated squamous cell carcinoma of the human uterine cervix

The expression of cholesterol sulfate (CS) is known to increase during squamous differentiation of keratinocytes and to activate the epsilon, eta, and zeta forms of protein kinase C as a signal transduction molecule for the subsequent expression of transglutaminase-1 (TG-1) and cytokeratins. To gain further insight into the regulation of cellular differentiation and tumorigenesis by CS, we examined the concentration and the potential for synthesis of CS in seven and four surgical specimens from human ovarian and uterine cervical cancer patients, respectively, and eight cell lines established from human uterine cervical cancer patients and compared them for the rate of expression of cytokeratin. CS was present in all of the uterine cervical cancer tissue specimens but only in the mucinous type of cystadenocarcinoma among ovarian cancer tissue specimens, and cytokeratin was highly expressed in the tissues with a high concentration of CS, which were classified as well-differentiated on the basis of morphological examination. Similarly, cells derived from a keratinizing type of well-differentiated cervical carcinoma demonstrated strong potential for synthesis of CS, stained positive with anti-cytokeratin antibody, and exhibited a higher specific activity of TG-1, whereas the cells without CS did not stain positive with anti-cytokeratin antibody and exhibited a lower specific activity of TG-1. These findings indicate that CS is coexpressed with TG-1 and cytokeratin in the well-differentiated types of squamous cell cancers as a tumor marker.     

Small cell carcinoma of the uterine cervix: a clinicopathological review

Small cell carcinoma of the cervix is rare, with an aggressive natural history. We report on a series of 11 patients treated at the Christie Hospital, Manchester and examine their treatment and survival. Eleven patients with small cell carcinoma of the cervix were identified retrospectively from patient case notes. Treatment was individualised and included a variety of combinations of surgery radiotherapy and chemotherapy. Four patients were disease-free between 21 and 108 months (crude disease-free survival 36%). They presented with earlier disease and were older than the average for the group. They were all initially treated with radical radiotherapy. 7 patients died between 7 and 25 months. Despite combination chemotherapy, survival with advanced disease was poor. Published studies are small and fail to provide definitive answers on the best management of small cell carcinoma of the cervix. Drawing on the experience of small cell carcinoma of the lung however, combination therapy with radiotherapy, chemotherapy and possibly surgery requires careful assessment by an oncologist.     

Papillary squamous cell carcinoma of the uterine cervix: diagnostic pitfalls

BACKGROUND: In 1989, a Boeing 737-400 aircraft crashed at Kegworth, near Nottingham, England. The survivors suffered a large number of pelvic and lower limb injuries, and approximately one-third of the passengers died. Subsequent research has suggested that the "brace-for-impact" position that passengers are advised to adopt prior to a crash landing might be modified in order to reduce the incidence of such injuries. The aim of this research was to evaluate biomechanically such a modified crash brace position. HYPOTHESIS: A modified brace position would help to prevent injuries to some passengers in the event of an impact aircraft accident. METHODS: Impact testing on forward-facing seats was performed at the Royal Air Force Institute of Aviation Medicine, Farnborough, England. Aircraft seats, mounted on a sled, were propelled down a track to impact at -16 Gx. A test dummy was used as the experimental model. Four dummy positions were investigated: a) upper torso braced forward and lower legs inclined slightly rearward of the vertical; b) upper torso braced forward and lower legs inclined forward; c) upper torso upright and lower legs inclined slightly rearward of the vertical; and d) upper torso upright and lower legs inclined forward. The impact pulses used were based on Federal Aviation Administration guidelines. Transducers located in the head, spine, and lower limbs of the dummy recorded the forces to which each body segment was exposed during the impact. These forces were compared for each brace position. RESULTS: Impact testing revealed that the risk of a head injury as defined by the head injury criterion was greater in the upright position than in the braced forward position. The risk of injury to the lower limbs was dependent in part on the flailing behavior of the limbs. Flailing did not occur when the dummy was placed in a braced, legs-back position. CONCLUSIONS: A modified brace position would involve passengers sitting with the upper torso inclined forward so that the passenger's head rested against the structure in front, if possible. The legs would be positioned with the feet resting on the floor in a position slightly behind the knee. The position differs from those previously recommended in that the feet are positioned behind the knee. This study suggests that such a position would reduce the potential for head and lower limb injury in some passengers, given that only a single seat type and single size of occupant have been evaluated. Standardization to such a position would improve passenger understanding and compliance. Such a recommendation should not obscure the fact that an occupant seated in a forward-facing aircraft seat, restrained only by a lap belt, is exposed to considerable forces during an impact accident. Such forces are capable of producing injuries in the femur, pelvis, and lumbar spine.     

Small-cell neuroendocrine carcinoma of the uterine cervix associated with micro-invasive squamous cell carcinoma and adenocarcinoma in situ

A case of small-cell neuroendocrine carcinoma of the uterine cervix associated with squamous cell carcinoma and adenocarcinoma in situ is reported. The tumor consisted mainly of uniform small cells with a population of intermediate cells that resembled carcinoid tumor cells. Foci of micro-invasive squamous cell carcinoma and adenocarcinoma in situ were recognized separately, adjacent to the main tumor. Both Grimelius stain and immunostaining of serotonin were positive for small-cell and intermediate-cell carcinoma. Neurosecretory granules were demonstrated by electron microscopy. Microacini with positive mucin staining and microvilli-like structures suggested glandular or exocrine differentiation of the tumor. Three distinctive types of differentiation, neuroendocrine, exocrine and squamous characteristics, were expressed in the tumor.     

Factors regulating SCC antigen expression in squamous cell carcinoma of the uterine cervix

Expression of squamous cell carcinoma (SCC) antigen emerged concurrently with squamous formation of the uterine cervix and increased during the neoplastic transformation of the cervical squamous epithelium. SCC antigen expression differed considerably among the histomorphologic cell types of cervical carcinoma. Large cell nonkeratinizing carcinoma contained high levels of the antigen. In contrast, no appreciable expression of SCC antigen was observed in small cell nonkeratinizing carcinoma. The pattern of SCC antigen expression closely coincided with EGF receptor (EGF-R) expression in cervical squamous neoplasia. This suggests that the expression of SCC and EGF-R in cervical carcinoma is related to the differentiation or dedifferentiation processes of the tumor cells. SCC production by CaSki cervical epidermoid carcinoma cells was stimulated by EGF. It seems likely that an autocrine system, in which EGF serves as the signal, may exist in cervical squamous carcinoma. 17beta-estradiol and L-triiodothyronine were found to upregulate EGF-R expression, proliferative potential and SCC production in the CaSki cervical carcinoma cells.     

Pseudocystic metastases of carcinoma of the uterine cervix mimicking polycystic liver disease

Pseudocystic liver metastases are rare and mainly described in neuroendocrine or ovarian tumors. We report the case of a 46-year-old woman who presented with multiple hepatic metastases mimicking polycystic liver disease. Carcinoma of the uterine cervix had been diagnosed 9 years earlier, and initially treated by radiumtherapy and surgery. Although histological post mortem examination of the pseudocystic liver metastases was not characteristic, they were related to the uterine cervix carcinoma for the following reasons: no other primary tumor was discovered, especially carcinoid or ovarian tumors: immunostains were positive for epithelial cells and negative for the neuroendocrine panel: the cystic cerebellum metastasis had a typical histologic aspect. Uterine cervical carcinoma must thus be included in the list of tumors which may form cystic hepatic metastases.     

Nitric oxide mediated inhibition of contractile activity in the human uterine cervix

Nitric oxide (NO) is an important modulator of contractile activity in various tissues. The aim of the present study was to investigate the possible existence of an NO system within the human uterine cervix and to study the effects of NO on the cervix in early pregnancy. Cervical tissue specimens were obtained from 24 women in connection with first trimester legal abortion. NADPH diaphorase staining was used to identify nitric oxide synthase activity within the cervical tissue. Cylindrical tissue specimens were mounted in organ bath chambers for isometric registration of contractile activity. The presence of a functional NO system in the cervix was investigated by adding either sodium nitroprusside or spermine NONOate, two different NO donors, or 8-bromo cGMP, an analogue of the second messenger cyclic guanosine monophosphate (cGMP), to the organ baths. Positive NADPH diaphorase staining was clearly observed in the walls of blood vessels, in cervical smooth muscle cells, and cells scattered in the connective tissue. The NO donating drugs sodium nitroprusside and spermine NONOate both caused a dose-dependent inhibition of spontaneous contractile activity with significant inhibition at concentrations of 10(-5) and 10(-7) M respectively. Furthermore, the participation of NO in the regulation of cervical contractility was indicated by a significant concentration-dependent inhibition of spontaneous contractions when 8-bromo cGMP (10(-5)-10(-3) M) was added to the organ baths. The study indicates the existence of an NO system within the human uterine cervix and a role of NO in control of cervical function.     

Differential transforming growth factor-beta secretion in adenocarcinoma and squamous cell carcinoma of the uterine cervix

Tumor cells from eight freshly isolated cervical cancers (i.e., four adenocarcinomas and four squamous carcinomas) were analyzed for their production of the immune-inhibitory cytokine transforming growth factor-beta (TGF-beta) in vitro. All fresh adenocarcinomas secreted significant levels of TGF-beta (mean 397, range between 207 and 782 pg/ml/10(5) cells/48 hr). In contrast, no detectable TGF-beta was present in the supernatants from the four fresh squamous carcinoma cultures (P < 0.001). These data suggest that major differences in the secretion of the immunoinhibitory cytokine TGF-beta exist between squamous cell carcinomas and adenocarcinomas of the uterine cervix. Furthermore, these findings suggest that at least some of the differences in the natural biologic behavior, as well as in the response to radiation treatment, between these two histologic types of cervical cancer could be related to differences in secretion of this immune-inhibitory cytokine.     

The management and natural history of severe dysplasia and carcinoma in situ of the uterine cervix

From 1951 to 1972, a total of 631 cases of invasive carcinoma of the cervix were diagnosed in Frederiksberg, Copenhagen, Denmark. Treatment was either by surgery or radiotherapy, a combination of both being rarely used. The crude five-year survival rates were 99 per cent in stage Ia, 79 per cent in stage Ib, 67 per cent in stage IIa, 45 per cent in stage IIb, 23 per cent in stage III, 5 per cent in stage IV and 63 per cent for all stages. The relative survival rates were respectively 100 per cent, 81 per cent, 73 per cent, 48 per cent, 26 per cent, 5 per cent and 66 per cent. Radical hysterectomy were found more effective than radiotherapy in stage Ib carcinoma of the cervix. This difference was not explained by age but other factors possibly playing a role are considered. The combination of surgery and radiotherapy is discussed and only seems indicated for patients with stage Ib carcinoma and lymph node metastases.