Disturbances of diurnal phase markers, behavior, and clock genes in a rat model of depression; modulatory effects of agomelatine treatment.

Major depressive disorder (MDD) is a growing problem worldwide. Though, the etiology remains unresolved, circadian rhythm disturbances are frequently observed in MDD and thus is speculated to play a key role herein. The present study focuses on circadian rhythm disturbances in the chronic mild stress (CMS) animal model of depression and examined whether the atypical antidepressant, agomelatine, which is mediating its action via melatonergic and serotonergic receptors, is capable of resynchronizing the perturbed rhythm. Melatonin is often used as a marker of the circadian phase, but the functional and behavioral output is dictated on a cellular level by the molecular clock, driven by the clock genes. We applied in situ hybridization histochemistry to measure the expression levels of the core clock genes, period (Per) 1 and 2 and bone and muscle ARNT-like protein 1 (Bmal1), in multiple brain regions believed to be implicated in depression. Agomelatine showed an antidepressant-like effect in the sucrose consumption test and an anxiolytic-like profile in the elevated zero maze. We found that CMS increased nighttime melatonin release in rats and that agomelatine attenuated this effect. Stress was shown to have a time and region-specific effect on clock gene expression in the brain. Treatment with agomelatine failed to normalize clock gene expression, and the observed modifying effect on gene expression did not associate with the antidepressant-like effect. This suggests that the antidepressant actions of agomelatine are mainly independent of circadian rhythm synchronization and, in this regard, not superior to traditional antidepressants tested in our model.

Disturbed diurnal rhythm of three classical phase markers in the chronic mild stress rat model of depression.

Disturbances of circadian rhythms have been suggested to be a causal factor in the development of major depressive disorder. However, the mechanisms underlying the association between circadian rhythm abnormalities and mood disorders are still unknown. In the current study the association between diurnal pattern of key phase markers (melatonin, corticosterone, and core body temperature) and anhedonic-like behavior was investigated using the highly validated rat chronic mild stress (CMS) model of depression. Phase marker measurements were done after 3.5 weeks of CMS in 48 control rats and 48 anhedonic-like rats at 6 time points within 24h. The results showed that anhedonic-like behavior associates with changes in all three phase markers: an increased dark phase melatonin secretion, an additional peak in corticosterone level in the beginning of the light phase, and hypothermia in the dark phase. The result adds to the validity of the CMS model in general and in particular to be adequate as a model for studying the chronobiology of depressive disorder.

Long term follow-up of superficial invasive bladder carcinoma with or without concomitant epithelial atypia--recurrence and progression.

OBJECTIVE: To examine the significance of concomitant epithelial atypia on late recurrence and progression by long-term follow-up of superficial invasive bladder tumours (stage T1). MATERIAL AND METHODS: Seventy consecutive, unselected patients with newly diagnosed transurethral resection (TURB)-treated stage T1 bladder tumour, and at least 1 year progression-free survival. Preselected site biopsies (PSB) were obtained prospectively to evaluate the significance of concomitant urothelial atypia. Followed for up to 17.6 years. RESULTS: The cumulative probability of recurrence (overall) was 85%, and for new stage T1 tumour 70% after 10 years. Forty per cent of those who survived 5 years without recurrence, were readmitted with often invasive recurrence later. Positive PSB significantly (p < 0.0001) predicted new T1 tumour. Progression (T2+ or metastases) occurred in 27 cases (39%) after the first year. The cumulative probability was 60% (15 years), with a mean progression-free interval of 64 months. Positive PSB, size >3 cm and early recurrence were significant predictive factors in multivariate analysis. CONCLUSION: T1-tumours are at high risk for late invasive recurrence and progression, especially if associated with urothelial atypia elsewhere in the bladder.

Long-term follow-up of noninvasive bladder tumours (stage Ta): recurrence and progression.

OBJECTIVE: To evaluate long-term recurrence-free and progression-free survival of noninvasive bladder tumours (stage Ta), and the significance of simple risk factors, including concomitant epithelial dysplasia. PATIENTS AND METHODS: The study included 217 patients with primary noninvasive bladder tumour (stage Ta) who were followed routinely for up to 20 years. Voided urine cytology (VUC) and preselected site biopsies (PSB) were obtained prospectively to evaluate the significance of concomitant epithelial dysplasia. RESULTS: The mean follow-up was 84 months (maximum 238). Of all tumours, 39% did not relapse, a further 20% recurred infrequently (less than once a year) and 41% recurred frequently, amongst which the most frequent were multiple and early recurrent tumours; 42 (19%) tumours progressed to stage T1+ and 23 (11%) progressed further (stage T2+ or metastases). No grade 1 tumours became invasive. Positive VUC or PSB, a short recurrence-free period or multiplicity, and size > 3 cm were significant predictive factors. The treatment and surveillance of epithelium-confined bladder tumours are discussed. CONCLUSION: Concomitant dysplasia and early recurrence are associated with considerable risk of progression in the long-term follow-up in a group of otherwise low-risk superficial bladder tumours (stage Ta).

Long-term survival of patients with bladder tumours: the significance of risk factors.

OBJECTIVE: To evaluate the significance of known risk factors, accessible by simple endoscopic and histological/cytological examination, on the clinical course and long-term survival of patients with superficial urinary bladder tumours. PATIENTS AND METHODS: The study included 584 consecutive unselected patients, primarily admitted between 1976 and 1984 for newly diagnosed bladder tumour, which was superficial (Ta, T1, Tis) in 362. The patients were followed routinely in a control programme; causes of death were obtained by autopsy (44%), from hospital files (33%) or from death certificates (8%), the remaining patients being alive at the end of the study, up to 20 years after initial diagnosis. Known risk factors, e.g. tumour size, histological grade, multiplicity and positive urine cytology, and dysplasia as assessed by random or pre-selected site biopsies, were evaluated as predetermining factors for new occurrences and survival. RESULTS: Invasion of the lamina propria was the most significant prognostic factor detected in the multivariate analysis. While 14% of patients with Ta tumours had died from cancer after 15 years, 63% of the T1 tumours were eventually fatal, reaching the mortality of those with T2 disease. Other independent significant factors were tumour size and, to a lesser extent, histological grade. Multiplicity and concomitant epithelial changes, as assayed by voided urine cytology and pre-selected site biopsies, were relevant prognostic factors for Ta but not for T1 tumours. CONCLUSION: In the therapy and surveillance of superficial urinary bladder tumours, the presence of lamina propria invasion is very important.

Prognostic significance of DNA content in bladder cancer based on flow cytometric analysis of 249 transitional cell carcinomas.

The prognostic significance of DNA index (DI), S-phase fraction, and heterogeneity determined by flow cytometric DNA analysis was assessed in a prospective study of 249 newly diagnosed transitional cell carcinomas of the bladder. The median observation time was 4.8 years. A total of 456 subpopulations were detected. The S-phases could be estimated in 299 subpopulations. A DI > 1.25 or an S-phase above 9.7% were strongly correlated to invasiveness. One hundred and ten patients were treated with transurethral resection (TUR). Relapse-free survival could not be predicted by the DNA-derived parameters. Univariate analysis of survival showed prognostic significance of diploidy (0.98 < DI < or = 1.02, P = 0.02), hypotetraploidy (1.50 < DI < or = 1.96, P = 0.002), and S-phase size (P = 0.008). Multivariate analysis pointed to the T-classification (RR = 1.64) and hypotetraploidy (RR = 1.57) as prognostic parameters for survival of TUR-treated patients. One hundred and thirty-nine patients received radiotherapy (RT). A significantly better response was found for tumors with a subpopulation with a hypertetraploid DNA content (DI > 2.04, P = 0.05), and a significantly worse response for subpopulations with a maximum S-phase > 24.5% (P = 0.04). T-classification and histological grade had no predictive value. A logistic regression analysis indicated an estimated probability of response to RT of 77% for tumors with a DI > 2.04 and an S-phase < 24.5%, whereas tumors with a DI < 2.04 and an S-phase > 24.5% had only a 28% probability of response. The poor response to RT, predicted by an S-phase > 24.5%, translated into a poor survival, whereas the better treatment response found for patients with a DI > 2.04 did not result in a longer survival. Multivariate analysis pointed to S-phase (RR = 1.70), T-classification (RR = 1.60), and grade (RR = 0.65) as independent prognostic parameters for survival of RT-treated patients.

[3-year experiences with surgical treatment of epilepsy at the Hvidovre hospital]. / Tre års erfaringer med epilepsikirurgi på Hvidovre Hospital.

The results of a retrospective survey of 48 patients submitted to neurosurgery for medically intractable epilepsy are presented. Twenty-eight patients were treated with selective amygdalohippocampectomy, one with temporal lobe resection, 12 with anterior callosotomy and seven with a total callosotomy. Of the amygdalohippocampectomized patients and the one with temporal lobe resection (n = 29), 52% were seizure free, 17% experienced rare seizures, 7% had a worthwhile improvement while 24% observed no worthwhile improvement (follow-up time 6 to 36 months). Of the callosotomized patients, 11% were free from generalized seizures, 69% had a significant seizure reduction and 18% experienced no worthwhile improvement. The observed neurological complications were: one patient had hemianopia, one had superior quadrant anopia, four developed unilateral anosmia and one complete anosmia. The callosotomized patients, with two exceptions, were all mentally and physically handicapped. In the callosotomy group, two patients died, one from a intracerebral hematoma three months after the operation and another patient seven months postoperatively from unknown causes.

Diagnostic value of an abnormal smear in non-pregnant women. Evaluation of positive smear from the surface of the portio obtained by the cottonswab method or by the dry wooden Ayre spatula and the relevance of positive smear from the endocervix and/or from the surface of the portio.

During a 3-4 year period, 324 women with a positive smear were registered consecutively and prospectively and divided into two groups according to the design of the investigation. In one group the smear was taken with an Ayre spatula and in the other group with a cotton swab. The purpose of this investigation has been to make a comparison between the endocervical smear and the smear taken from the surface of the portio and at the same time between the samples taken with a dry wooden Ayre spatula and with a cotton swab. No differences were found. The cytological findings have been registered and correlated both with the histological findings by colposcopically directed punch-biopsies and endocervical curettings and with the final histological diagnosis obtained by punch-biopsy, conization or hysterectomy.

Urothelial atypia and survival rate of 500 unselected patients with primary transitional-cell tumour of the urinary bladder.

In a consecutive series of 500 unselected patients with primary urinary bladder tumours the influence of urothelial atypia on the 5 years survival-rate was examined. All tumours were transitional-cell tumours categorized according to the T-classification. Mucosal biopsies from 7 pre-selected sites were taken at the initial cystoscopy in 391 patients (78%) to identify urothelial atypia. The over-all cumulative 5 years survival-rate was 48%. Submucosal and muscle invasion had major influence on survival, whereas tumour grade was less important. Patients with urothelial atypia fared significantly worse than those with normal bladder mucosa (5 years survival 42% versus 62%). This difference in survival-rate became apparent first after two years of observation. Grade II atypia in the bladder mucosa and grade III (carcinoma in situ) had equal significance assessed by the survival-rates.

Efficacy and safety of two different dose levels of ganciclovir for the treatment of cytomegalovirus chorioretinitis in AIDS patients.

The effect of different dosages of ganciclovir on proved cytomegalovirus chorioretinitis was tested in a randomized trial on 11 homosexual men with AIDS. The effect of 5 mg/kg/day was as good as 10 mg/kg/day. The lower dosage had less toxicity.

Vigabatrin: no microvacuoles in a human brain.

Vigabatrin (gamma-vinyl-GABA) has been shown to be an effective antiepileptic drug. However, clinical investigations have been hampered by the finding of intramyelin edema (microvacuoles) in rats and dogs. In an autopsy study of a 38-year-old woman with astrocytoma, treated with vigabatrin 80 mg/kg body weight per day for over 6 months and 125 mg/kg body weight per day for the last 2 months as add-on therapy because of drug-resistant epilepsy, we did not find any microvacuoles in the brain. So far microvacuoles have never been observed in primates, warranting continued investigations of this promising antiepileptic drug.

Urothelial atypia concomitant with primary bladder tumour. Incidence in a consecutive series of 500 unselected patients.

A consecutive series of 500 primary bladder tumours from a single clinic is presented, with distribution of the tumours according to T category and histologic type and grade. Mucosal biopsies were obtained from pre-selected sites at initial cystoscopy or initial transurethral resection of the tumour in 396 cases. In 54% of the patients with grade III tumour there was concomitant urothelial atypia, either carcinoma in situ (urothelial atypia grade III, 30%) or urothelial atypia grade II (24%). In 30% of the patients with invasive grade II bladder tumour and in 14% of those with noninvasive grade II tumour there was concomitant urothelial atypia, mostly grade II. Since concomitant urothelial atypia predicts new tumour growth after successful transurethral surgery or radiotherapy, mucosal biopsies should be performed at preselected sites during initial cystoscopy or transurethral tumour resection in order to identify high-risk patients.

Endoscann cell sampling for cytological assessment of endometrial pathology.

Cytological samples of the endometrium obtained by Endoscann were compared with histological preparations from conventional curettage of the uterine cavity (D & C) in 275 women. Indications of D & C were irregular menstrual bleeding, postmenopausal bleeding, or suspected ovarian or cervical neoplasia in women of 50 years or more. The women were consecutively enrolled in the study and had an average age of 60.2 years (range 50-87). The cytological investigation detected all 16 cases of endometrial cancer but none of 6 cases of atypical hyperplasia. Insertion of the Endoscann cell sampler was easily performed in 87% of the patients in whom cervical dilatation was unnecessary. The cytological technique had 11 cases of insufficient material (4%). By D & C, sufficient material for histological evaluation could not be obtained in 32 cases (12%). The predictive value of a positive test with respect to endometrial carcinoma was 0.38, the corresponding sensitivity was 1.00, and the specificity 0.90. A positive cytology should lead to immediate further investigation.

Urothelial dysplasia concomitant with bladder tumours: a determinant for future new occurrences in patients treated by full-course radiotherapy.

Concomitant urothelial dysplasia has been shown to predict new tumour occurrences after successful transurethral surgery of primary invasive bladder tumours. Of 114 patients with invasive bladder tumours treated by radiotherapy alone, 32 patients had complete primary tumour response and mucosal biopsies taken at preselected sites during initial cystoscopy. 10 of these patients had concomitant carcinoma-in-situ; in 7 new invasive tumours occurred 9-24 months after completion of radiotherapy. 4 of 9 patients with concomitant dysplasia grade-II also showed new invasive tumour growth. No new tumours developed in 13 patients without concomitant urothelial dysplasia who were followed for 9-75 months. Thus, the presence of concomitant carcinoma-in-situ in patients treated by radiotherapy predicts new invasive tumour growth, whereas its absence favours a very good prognosis. Patients with carcinoma-in-situ concomitant with invasive bladder tumours are not suitable for full-course radiotherapy as the only treatment.

Urothelial dysplasia concomitant with bladder tumours as a determinant factor for future new occurrences.

Of 53 patients with primary bladder tumours of categories T1 or T2 about 50% had concomitant urothelial dysplasia, either carcinoma-insitu or less dedifferentiated dysplasia graded as grade II. In a follow-up study of these patients treated with transurethral resection alone, it was found that new occurrences had developed in 87% of patients with concomitant urothelial dysplasia, compared with 26% of those without dysplasia. Most new occurrences developed within 6 months of initial tumour resection. A new invasive tumour developed in all patients with concomitant carcinoma-in-situ, emphasising the serious prognostic significance of that entity. Thus, urothelial dysplasia concomitant with a bladder tumour is an important determinant factor for future new occurrences.

Prognostic factors in local surgical treatment of invasive bladder cancer, with special reference to the presence of urothelial dysplasia.

Thirty-three patients with bladder cancer of categories pT1 or pT2 were treated by transurethral resection alone. At the initial diagnosis random preselected site mucosal biopsies were obtained to demonstrate the presence or absence of concomitant urothelial dysplasia. A statistically significant (P less than 0.01) relationship was found between the presence or absence of concomitant urothelial dysplasia and the development of new occurrence or the absence of recurrence at cystoscopic follow-up. Four of six patients with concomitant carcinoma in situ developed invasive bladder cancer within 6 months demonstrating the serious prognostic significance of this entity. Thus, the presence or absence of concomitant urothelial dysplasia at the initial diagnosis of invasive bladder cancer seems to be an important prognostic factor for future new occurrences.

Brain CT-scanning and neurological examination in small cell bronchogenic carcinoma.

A brain CT-scan and a neurological examination were performed on forty-nine consecutive patients with small cell bronchogenic carcinoma before the start of chemotherapy and every three months thereafter. Contrast-enhancement was used in 90% of the CT-scans. Ninety percent of the neurologic examinations were performed by the same neurologist. No prophylactic cranial irradiation was given, and cranial irradiation was withheld if a CT-scan indicated metastases, unless the patient was symptomatic. Thirty-five patients are evaluable including 34 with a brain autopsy. CNS-metastases were found in 18 patients. Two of them had not been examined within three months of autopsy and are excluded from the calculations of diagnostic accuracy. Of the remaining 16 patients 10 had a correct diagnosis of cerebral metastases made by CT-scan, while the neurologist made 11 correct diagnoses of CNS-metastases. Seventeen patients did not have CNS-metastases including one patient alive and free of disease. Fifteen and 11 were judged to be free of metastases by the CT-scan and the neurologist, respectively. Two patients with negative autopsies had positive CT-scans turning negative at subsequent examinations. Two had positive CT-scans which became negative and at autopsy CNS-metastases were located at different sites from those initially indicated by CT. The positive predictive value of CT-scan was 71%, while the negative predictive value was 71%. In conclusion, routine CT-scan and neurological examination are equally sensitive but have low yields when there is no clinical suspicion of CNS-metastases. The predictive value of CT-scanning could possibly be higher with the newer generations of equipment.

Superficial eosinophilic squamous epithelial cells in vaginal smears from postmenopausal women.

19 500 vaginal smears from women aged 20-90 years were examined from August 1976 to November 1979. 3 000 were from women more than 55 years of age. 146 of these had smears with an increased proportion of superficial eosinophilic squamous epithelial cells (SESEC). The smears were divided into four groups, A-D with 0-25%, 25-50%, 50-75% and 75-100% of SESEC of the examined squamous epithelial cells. 39% of the 146 with increased proportions of SESEC were either undergoing treatment with estrogenic hormones, or else the possibility of estrogenic influence could not be ruled out. In group D the possibility of an estrogenic influence was more pronounced, here found to be 67%. In 32% of the 146 cases we believe that these cells were possibly the result of changed anatomical conditions in the cervix/vagina. Such an explanation seems most frequently probable in groups A and B. In 5% of the 146 cases the cells appeared changed, as can be seen in trichomoniasis. In 21% the discovery of the cells could not be explained. Finally, no explanation could be found for 5% in group D.