From neurons to the neuro-glio-vascular unit: Seizures and brain homeostasis in networks.

While seizures are undoubtedly neuronal events, an ensemble of auxiliary brain cells profoundly shapes synaptic transmission in health and disease conditions. Endothelial-astrocyte-pericyte assemblies at the blood-brain barrier (BBB) and neuroglia within the neuro-glio-vascular unit (NGVU) finely tune brain parenchymal homeostasis, safeguarding the ionic and molecular compositions of the interstitial fluid. BBB permeability with neuroinflammation and the resulting loss of brain homeostatic control are unifying mechanisms sustaining aberrant neuronal discharges, with temporal specificities linked to acute (head trauma, stroke, infections) and pre-existent (genetic) or chronic ( dysplasia, tumors, neurodegenerative disorders) pathological conditions. Within this research template, one hypothesis is that the topography of BBB damage and neuroinflammation could associate with symptoms, e.g., limbic structures for seizures or pre-frontal for psychiatric episodes. Another uncharted matter is whether seizure activity, without tissue lesions or sclerosis, is sufficient to promote stable cellular-level maladaptations in networks. Contingent to localization and duration, BBB damage and inflammation forecast pathological trajectories, and the concept of an epileptic NGVU could enable time-sensitive biomarkers to predict disease progression. The coherence between electrographic, imaging and molecular NGVU biomarkers could be established from the epileptogenic to the propagating zones. This paradigm shift could lead to new diagnostic and therapeutic modalities germane to specific epilepsies or when seizure activity represents a comorbidity.

PDGFRß(+) cells in human and experimental neuro-vascular dysplasia and seizures.

INTRODUCTION: Neuro-vascular rearrangement occurs in brain disorders, including epilepsy. Platelet-derived growth factor receptor beta (PDGFRß) is used as a marker of perivascular pericytes. Whether PDGFRß(+) cell reorganization occurs in regions of neuro-vascular dysplasia associated with seizures is unknown. METHODS: We used brain specimens derived from epileptic subjects affected by intractable seizures associated with focal cortical dysplasia (FCD) or temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Tissues from cryptogenic epilepsy, non-sclerotic hippocampi or peritumoral were used for comparison. An in vivo rat model of neuro-vascular dysplasia was obtained by pre-natal exposure to methyl-axozy methanoic acid (MAM). Status epilepticus (SE) was induced in adult MAM rats by intraperitoneal pilocarpine. MAM tissues were also used to establish organotypic hippocampal cultures (OHC) to further assess pericytes positioning at the dysplastic microvasculature. PDGFRß and its colocalization with RECA-1 or CD34 were used to segregate perivascular pericytes. PDGFRß and NG2 or IBA1 colocalization were performed. Rat cortices and hippocampi were used for PDGFRß western blot analysis. RESULTS: Human FCD displayed the highest perivascular PDGFRß immunoreactivity, indicating pericytes, and presence of ramified PDGFRß(+) cells in the parenchyma and proximal to microvessels. Tissues deriving from human cryptogenic epilepsy displayed a similar pattern of immunoreactivity, although to a lesser extent compared to FCD. In TLE-HS, CD34 vascular proliferation was paralleled by increased perivascular PDGFRß(+) pericytes, as compared to non-HS. Parenchymal PDGFRß immunoreactivity co-localized with NG2 but was distinct from IBA1(+) microglia. In MAM rats, we found pericyte-vascular changes in regions characterized by neuronal heterotopias. PDGFRß immunoreactivity was differentially distributed in the heterotopic and adjacent normal CA1 region. The use of MAM OHC revealed microvascular-pericyte dysplasia at the capillary tree lining the dentate gyrus (DG) molecular layer as compared to control OHC. Severe SE induced PDGFRß(+) immunoreactivity mostly in the CA1 region of MAM rats. CONCLUSION: Our descriptive study points to microvascular-pericyte changes in the epileptic pathology. The possible link between PDGFRß(+) cells, neuro-vascular dysplasia and remodeling during seizures is discussed.

Use of a high-risk human papillomavirus DNA test as the primary test in a cervical cancer screening programme: a population-based cohort study.

OBJECTIVE: To present the results of the first 2 years of a human papillomavirus (HPV) test-based screening programme outside the research context. DESIGN: Population-based cohort study. SETTING: A cervical service screening programme in Italy. POPULATION: Women aged 25-64 years invited to screening from April 2009 to April 2011. METHODS: Eligible women were invited to undergo an HPV test: those with a negative HPV test went on to the next screening episode; those with a positive HPV went on to triage with a Pap smear. Women with positive cytology (i.e. positive for atypical squamous cells of undetermined significance or worse, ASC-US+) were referred to colposcopy, whereas those with negative cytology were referred to repeat HPV testing 1 year later. MAIN OUTCOME MEASURES: Participation rate, positivity at HPV and at triage, referral rate to colposcopy, positive predictive value for cervical intraepithelial neoplasia grade 2+ (CIN2+) at colposcopy, and detection rate for CIN2+. RESULTS: Participation increased compared with the previous Pap programme (60.6 versus 43.9%). The HPV positivity rate was 7.0; 39.6% of Pap smears were scored as positive, and therefore 2.8% of the women screened were referred for immediate colposcopy. The compliance of women who scored positive for HPV and negative for Pap for repeat HPV testing at 12 months was 78.6%, and the HPV positivity rate was 56.6%. The overall referral rate to colposcopy was 4.6%. The overall detection rate for CIN2+ was 4.5 versus 1.5% of the Pap programme (25-34 years, 8.2%; 35+ years, 3.6%). CONCLUSIONS: Compared with the traditional Pap test, the HPV programme recorded a higher response to invitation and an increased DR for CIN2+. The most critical aspects were the reading of cytology in women that were positive for HPV and the increased workload at colposcopy.

Vasectomy within the public health services in Campinas, São Paulo, Brazil.

OBJECTIVE: To describe some of the characteristics of men who underwent a vasectomy in the public health network of Campinas, São Paulo, Brazil. METHODS: A descriptive study including 202 men randomly selected from a list of all the men vasectomized between 1998 and 2004 in the public health network. RESULTS: Most of the men were 30 years of age or older when vasectomized, had completed elementary school and had two or more children of both sexes. Most of the men came from the lowest income segment of the population: 47.6% in 1998-1999 and 61.3% in 2003-2004. Although the men knew various contraceptive methods, 51.2% reported that their partners were using combined oral contraceptives at the time of surgery. Most men initially sought information on vasectomy at health-care clinics where care was provided by a multidisciplinary team; most received counselling, however, 47.9% of the men waited more than 4 months for the vasectomy. CONCLUSIONS: The profile of the vasectomized men in this study appears to indicate that the low-income population from Campinas, São Paulo, Brazil has access to vasectomy; however, the waiting time for vasectomy reveals that difficulties exist in obtaining this contraceptive method in the public health service.

Transporters in drug-refractory epilepsy: clinical significance.

Drug resistance remains an unmet challenge in a variety of neurological disorders, but epilepsy is probably the refractory disease that has received most experimental, preclinical, and therapeutic attention. Although resective surgery continues to improve our ability to provide seizure relief, new discoveries have potential as alternative therapeutic approaches to multiple drug resistance. As discussed here, the field is replete with controversies and false starts, in particular as it concerns the existence of genetic predisposition to inadequate pharmacological seizure control.

Combined effects of prenatal inhibition of vasculogenesis and neurogenesis on rat brain development.

Malformations of cortical development (MCD) are one of the most common causes of neurological disabilities including autism and epilepsy. To disrupt cortical formation, methylazoxymethanol (MAM) or thalidomide (THAL) has been used to affect neurogenesis or vasculogenesis. Although previous models of MCD have been useful, these models primarily attack a single aspect of cortical development. We hypothesized that simultaneous prenatal exposure to MAM or THAL will lead to the development of a novel and specific type of brain maldevelopment. Rats were prenatally exposed to MAM and THAL. At early postnatal days, brains displayed abnormal ventricular size and hemispheric asymmetry due to altered brain water homeostasis. The postnatal brain was also characterized by gliosis in regions of focal leakage of the blood brain barrier. These morphological abnormalities gradually disappeared at adult stages. Although the adult MAM-THAL rats showed normal cortical morphology, abnormal hippocampal connectivity and mossy fiber sprouting persisted well into adulthood.

The effect upon the human vaginal histology of the long-term use of the injectable contraceptive Depo-Provera.

The objective of the study was to evaluate the effect of long-term use of the injectable contraceptive depot medroxyprogesterone acetate (DMPA) on human vaginal histology. Twenty premenopausal women currently using DMPA as a contraceptive method for two and three years were compared with 20 regularly menstruating women, who never used Depo-Provera and/or other kind of hormonal contraceptive in the last 6 months prior to the study. Subjects and controls were matched by age (+/-1 year), body mass index (kg/m2) (+/-1.0), number of pregnancies (+/-1), age at first intercourse (+/-1 year), years of sexual activity (+/-1 year), and number of partners during their life (+/-1). Vaginal biopsies were performed in users at 90+/-7 days after the last injection and in nonusers at day 20-25 of the menstrual cycle. In addition, at the day of the biopsy a blood sample was collected to measure estradiol (in all women) and DMPA in users. The level of serum estradiol was significant lower in Depo-Provera users than in controls (p < 0.001). The thickness of the vaginal epithelium was not smaller among DMPA users than among controls, the mean count of Langerhans cells per mm of epithelium were almost identical in both groups, and no significant differences were found on the vaginal maturation indices. In conclusion, the use of Depo-Provera between two and three years did not affect vaginal thinning of the epithelium, Langerhans cell count or maturation index.

Self-administration with UniJect of the once-a-month injectable contraceptive Cyclofem.

The objective of this study was to evaluate women's acceptance of and ability to self-administrate the injectable contraceptive Cyclofem using prefilled UniJect devices. A total of 102 women were invited to participate in the study. Fourteen women (13.7%) refused to participate. Of the remaining 88 women, 32 women (31.4%) consented to participate and were trained using oranges but were still afraid of the procedure and ultimately refused to self-administer the injections. Only 56 women (55%) ultimately self-injected Cyclofem with UniJect. They performed a total of 144 injections, all of them on the ventral side of the thigh. When nurses evaluated women's ability to activate the devices, they found that more than 80% were successful in both the group of women that later self-administered the injections and the group that did not. The evaluation of the self-administered injection technique showed that more than 90% of the women correctly self-administered the contraceptive using UniJect. With respect to the opinion of the women about the self-administration of the contraceptive, more than 50% (32 of 56) of women who self-injected preferred to self-administer the injection and said that they wished to continue with the self-administration, one-third (17) reported that they were afraid, and seven women (12.5%) expressed the opinion that the injection in the thigh was more painful than the administration in the buttocks or arm. In conclusion, our study showed that women can be trained to successfully self-administer the monthly injectable contraceptive Cyclofem and generally respond positively to UniJect.

PIP: Women's capability to self-administer the monthly injectable contraceptive, Cyclofem, through use of prefilled UniJect devices was evaluated in 88 volunteers recruited from three Brazilian health clinics. After training in self-injection in which oranges were used for practice, only 56 of these women (55%) elected to continue with the study. They performed a total of 144 injections on the ventral side of the thigh. When nurses evaluated women's ability to activate the UniJect device, they found more than 80% of women trained in the method and 93% of those who actually performed self-injection used the technique correctly in an angle of 90 degrees. 32 (57.1%) of the 56 women who self-injected indicated they preferred this method and wished to continue to self-inject at home, another 17 (30.4%) reported they liked the method but were afraid to perform it on their own, and seven (12.5%) complained of pain associated with injection in the thigh compared with the buttocks or arm. Self-administration of injectable contraception, a popular method in Latin American countries, has the potential to increase contraceptive coverage as well as reduce costs associated with transportation to a source of contraception. If women are to perform self-injection at home rather than at a clinic, they will require reminders about the dates of reinjection and the importance of aseptic procedures and proper disposal of injecting equipment.

Uniject as a delivery system for the once-a-month injectable contraceptive Cyclofem in Brazil.

This study assessed the administration of Cyclofem using prefilled Uniject devices. A total of 480 injections were administered divided equally between standard syringes and Uniject. The majority of women (82%) reported that they felt anxious prior to receiving the injection with Uniject. After injection, more than 80% expressed no anxiety about the appearance of Uniject or about the technique of injection. A total of 96.3% of the participants reported slight to no pain with Uniject. In comparison to the standard syringe, 5.6% expressed having had more pain with Uniject. Ninety percent of the service providers reported that Uniject was easy to activate and inject and that it was reassuring for users to know that the syringe and needle had never been used previously. Only two service providers demonstrated difficulties in activating the device. No accidental punctures occurred during the manipulation, and incomplete emptying of the Uniject was not observed. In conclusion, Uniject is a good device for the administration of the injectable contraceptive Cyclofem. It is likely to be appropriate for the delivery of other injectable contraceptives after the necessary stability tests have been performed.

The influence of human chorionic gonadotrophin administration upon the next ovarian cycle.

We examined the influence of human chorionic gonadotrophin (HCG), used as an ovulation inducer and/or for supporting the luteal phase, on the next ovarian cycle. Four women received 10,000 IU of HCG at mid-cycle and another four received the same dose plus 1500 IU on the 17th, 19th and 21st days of the cycle. In the menstrual cycle prior to our experiments, venous blood samples were collected and vaginal ultrasound of the ovaries was performed every other day from day 21-28; the same data were also collected on days 1-10 of the experiment cycle. In such a way, control values were obtained. After the administration of HCG, venous blood samples were collected and ultrasound was performed in the same way and on the same days as in the controls. Follicle stimulating hormone (FSH) and luteinizing hormone were determined by radioimmunoassay in all blood samples, and HCG only in samples collected after the experiment. The results showed that only FSH was lower in the late luteal phase after the administration of 10,000 IU of HCG. Follicular diameters were higher during the follicular phase than during the previous cycle only in women who received the low dose of HCG. In addition, one woman presented with detectable HCG in the following ovarian cycle. The use of HCG in the preceding cycle may reduce FSH and develop persistent follicles in the subsequent cycle. We suggest that an ultrasound of the ovaries should be performed before starting a new ovulation induction cycle in a woman who has received HCG in the previous cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Multidisciplinary experience in the selection of patients for tubal sterilization.

Results of the use of a special protocol for evaluation of patients requiring tubal ligation is presented after applied by a multidisciplinary group. The authors conclude that the use of defined parameters of age, parity, marital union duration, number of children alive and the presence of maternal clinical pathology are useful to identify patients with smaller chances of regret after surgery.

PIP: 27% of reproductive-age women in Brazil have chosen surgical sterilization as their contraceptive method. Most of these women who have undergone tubal sterilization opted for cesarean surgery. However, given the young ages of many of these women, many regret having been sterilized. This paper summarizes the experience of a multidisciplinary group in evaluating women who apply for surgical sterilization at the Department of Tocogynecology, Faculdade de Ciencas Medicas, Universidade Estadual de Campinas in Sao Paulo. Detailed descriptions are presented of the medical and social characteristics of cases seen between June 1988 and July 1989. The authors conclude that the use of the defined parameters of age, parity, marital union duration, number of living children, and the presence of maternal clinical pathology are useful in identifying the patients who are least likely to regret undergoing surgical sterilization.

Vertebral histiocytosis.

Thirty-five cases of vertebral histiocytosis are examined for a total of 52 vertebrae affected. The study is conducted on the radiographic picture at the onset and at long-term follow-up in 32 cases (24-223 months, average 45). Diagnosis may be based on radiology only in typical cases, otherwise there may be errors in differential diagnosis with malignant neoplastic lesions. Radiotherapy does not seem to influence the volumetric reconstruction of the vertebral body, which is inversely proportional to age. In those cases submitted to chemotherapy, the morphological results, in the absence of other types of local treatment, are often excellent. Orthesic or surgical treatment must be chosen based on the extent of the lesion and on its ability to progress; CT scan may be useful to this purpose, but initial orientation may be suggested by multiple adjacent lesions or by radiographic images such as osteolysis of the pedicles.

School-related behavior in children with cancer.

Ninety-one children with cancer (thirty-seven with leukemia and fifty-four with solid tumors)--school aged (elementary and middle school), residing in Emilia-Romagna Region (Italy), and receiving treatment at the Department of Pediatrics (III), University of Bologna, from August 1973 to April 1987--took part in a study of school behavior as perceived by the teacher. The research was carried out through a 29-item forced-choice questionnaire based on the questionnaire proposed by Deasy-Spinetta for a similar study in the U.S.A. Results revealed that children with cancer have a school behavior scoring at levels significantly lower than controls. There are more difficulties for children attending middle than elementary school, for children on therapy than off therapy, and for children with leukemia than with solid tumors. In conclusion, the main obstacle to school performance seems to be lower attendance, which is mainly due to treatment and clinic visits and probably in part to an overprotection and an excessive concern on the part of physicians and parents.

[Action of lithium salts on hepatocytes in histiotypic culture]. / Action des sels de lithium sur les hépatocytes en culture histiotypique

Addition of lithium salts to cultures of hepatocytes increases glycogen in these cells. Glycogenolytic action of glucagone or AMPc becomes slow. Toxic action of paraquat is suppressed.