Nonimmune Hydrops Fetalis, Hydramnios, Microcephaly, and Intracranial Meningeal Hemangioendothelioma

Necropsy findings in a male stillborn at 31 weeks gestational age included nonimmune hydrops, hydramnios, and microcephaly secondary to a hemangioendotheliomatous malformation at the tentorium. The vascular lesion was composed by large and small tortuous endothelium-lined vessels and leiomuscular septa. The lesion is thought to be related to the more frequent arteriovenous malformation of the vein of Galen.     

Morphofunctional evidence for the involvement of hypothalamic dopaminergic and GABAergic neurons in the mechanisms of photoperiod-dependent prolactin release in the mink.

This study was designed to examine possible relationships between the photoperiodic regulation of prolactin secretion and the activity of dopaminergic and GABAergic neurons projecting to the external layer of the median eminence. The study was carried out on the mink whose remarkable photosensitivity has been clearly demonstrated. The animals were reared in short (4L:20D) or long (20L:4D) photoperiods. The experiment began in November when day length is short (9.5 h). Dopaminergic and GABAergic neurons were studied using immunocytochemical methods allowing evaluation of the immunoreactivities of tyrosine hydroxylase (TH) and glutamate decarboxylase (GAD), which are respective markers of these neurons. The results were quantified by image analysis. The plasma prolactin level of animals maintained in 4L:20D decreased after 60 days and TH and GAD immunoreactivity were strongly stimulated. After 110 days, the prolactin concentration and TH and GAD immunoreactivity recovered their starting levels. In animals maintained in 20L:4D, the prolactin level was 3 times higher than at the beginning of the photoperiodic treatment but only dopaminergic neurons showed a change, i.e. a decrease in immunoreactivity. At the end of the experiment, prolactin secretion was no longer affected by the stimulatory effect of long-day treatment, and TH immunoreactivity remained low. These results confirm the generally accepted concept that dopaminergic neurons are potent PIF-producing components. GABAergic hypothalamic system appears to be implicated in photoperiodic PRL regulation, but this remains to be clearly demonstrated.     

The effect of hyperbaric oxygen treatment on early regeneration of sensory axons after nerve crush in the rat

Abstract The effect of hyperbaric oxygen treatment (HBO) on sensory axon regeneration was examined in the rat. The sciatic nerve was crushed in both legs. In addition, the distal stump of the sural nerve on one side was made acellular and its blood perfusion was compromised by freezing and thawing. Two experimental groups received hyperbaric exposures (2.5 ATA) to either compressed air (pO2 = 0.5 ATA) or 100% oxygen (pO2 = 2.5 ATA) 90 minutes per day for 6 days. Sensory axon regeneration in the sural nerve was thereafter assessed by the nerve pinch test and immunohistochemical reaction to neurofilament. HBO treatment increased the distances reached by the fastest regenerating sensory axons by about 15% in the distal nerve segments with preserved and with compromised blood perfusion. There was no significant difference between the rats treated with different oxygen tensions. The total number of regenerated axons in the distal sural nerve segments after a simple crush injury was not affected, whereas in the nerve segments with compromised blood perfusion treated by the higher pO2, the axon number was about 30% lower than that in the control group. It is concluded that the beneficial effect of HBO on sensory axon regeneration is not dose-dependent between 0.5 and 2.5 ATA pO2. Although the exposure to 2.5 ATA of pO2 moderately enhanced early regeneration of the fastest sensory axons, it decreased the number of regenerating axons in the injured nerves with compromised blood perfusion of the distal nerve stump.     

Pazopanib Inhibits the Activation of PDGFRβ-Expressing Astrocytes in the Brain Metastatic Microenvironment of Breast Cancer Cells

Brain metastases occur in more than one-third of metastatic breast cancer patients whose tumors overexpress HER2 or are triple negative. Brain colonization of cancer cells occurs in a unique environment, containing microglia, oligodendrocytes, astrocytes, and neurons. Although a neuroinflammatory response has been documented in brain metastasis, its contribution to cancer progression and therapy remains poorly understood. Using an experimental brain metastasis model, we characterized the brain metastatic microenvironment of brain tropic, HER2-transfected MDA-MB-231 human breast carcinoma cells (231-BR-HER2). A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor β (at tyrosine 751; p751-PDGFRβ) was identified around perivascular brain micrometastases. p751-PDGFRβ⁺ astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte-enriched glial cells. Previously, we reported that pazopanib, a multispecific tyrosine kinase inhibitor, prevented the outgrowth of 231-BR-HER2 large brain metastases by 73%. Here, we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment. Pazopanib treatment resulted in 70% (P = 0.023) decrease of the p751-PDGFRβ⁺ astrocyte population, at the lowest dose of 30 mg/kg, twice daily. Collectively, the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib, suggesting its potential to prevent the development of brain micrometastases in breast cancer patients.Breast cancer is the second most common cause of brain metastasis after lung cancer, occurring in 10% to 15% of advanced patients and in approximately 30% of autopsies.^1,2 Risk factors for the development of brain metastases include young patient age, large primary tumors, multiple positive lymph nodes, and hormone receptor negativity.³ In addition, the incidence of brain metastasis appears to be increasing because of the introduction of more sensitive diagnostic methods and improved therapies, the latter particularly in patients with HER2-overexpressing metastatic breast cancer.⁴ The standard of care for brain metastases is palliative, and in most cases chemotherapy is ineffective.^5,6 New drugs that are both brain permeable and prevent specific pathogenic mechanisms of the brain metastasis process have been identified in preclinical experiments but await appropriate clinical trials.^7–11The cancer microenvironment is of crucial importance for a complete understanding of the disease^12–15 because it is the interface between cancer cells and pathophysiology of the patient.¹⁶ The brain represents a unique microenvironment for epithelial cancers that remains to be further investigated. Salient features include the blood-brain barrier that surrounds the vasculature and protects the brain from unwanted substances and leukocyte infiltration, and a rich cellular milieu, including neurons, pericytes, and glial cells. Because the brain is critical for both cognitive and physical function, microenvironmental changes during cancer metastasis may adversely affect the patient. A better understanding of the brain microenvironment during metastasis may contribute to development of more effective therapeutics.Relatively little is known about the microenvironment of brain metastases of breast or other cancers. Most of our information comes from experimental models of brain metastasis in which brain tropic lines are introduced into the circulation of mice via the left cardiac ventricle or carotid artery and then colonize the brain over a several-week period.^17–20 In the 231-BR model system, cancer cells extravasate the circulatory system and bind to the surrounding basement membrane through β1 integrin; in this microenvironment, cancer cells move and proliferate along the outside of the blood vessels.²¹ During the subclinical stage of the brain metastasis process, where injury is subtle but consistent, a continuous neuroinflammatory response involves activation of astrocytes and microglia, identified by expression of glial fibrillary acidic protein (GFAP) and F4/80 or CD11b/CD45, respectively.^21–23 This neuroinflammatory response is also observed in clinical samples from resected human brain metastases in which reactive astrocytes and microglia both surround and infiltrate the metastatic lesion, validating experimental observations.²² In coculture experiments, glial cells increased the number of colonies formed in soft agar by 231-BR cells by fivefold,²² and astrocytes also increased cancer cell proliferation and up-regulated the expression of survival genes,^24,25 suggesting mechanistic contributions of microenvironmental cells to brain metastasis.Consistent with what has been reported for other organs, platelet-derived growth factor (PDGF)-B is also a key protective factor in noncancerous brain damage,^26,27 contributing to blood-brain barrier stability, angiogenesis, and vascular remodeling through the activation of PDGF receptor β (PDGFRβ)-expressing brain pericytes and neuroglial progenitor cells.^28,29 During cancer progression PDGFRβ expression has long been associated with tumor-associated stromagenic and angiogenic activities.³⁰ However, its role during brain metastasis development is unknown.In this article, we characterize the neuroinflammatory microenvironment of a breast cancer experimental brain metastasis model system (231-BR cells transfected with HER2; 231-BR-HER2) and identify a novel subpopulation of metastasis-activated astrocytes that express an active (phosphorylated) form of PDGFRβ (p-PDGFRβ). The existence of this novel subset of astrocytes was confirmed in resected specimens of human brain metastasis from five patients with HER-2–overexpressing breast cancer, two patients with lung cancer, and one patient with colorectal cancer. Importantly, we demonstrate that primary cultured human astrocytes expressed (activated) p-PDGFRβ in response to tumor-derived soluble factors. We previously reported that pazopanib, an inhibitor of vascular endothelial growth factor receptors, PDGFRs, c-kit,³¹ and B-Raf^19,32 prevented brain metastasis formation in the 231-BR-HER2 model by 73%, targeting B-Raf activation in the tumor cells.¹⁹ Herein, we show that pazopanib also inhibited the activation of p-PDGFRβ–expressing astrocytes in the experimental brain metastasis model and in tumor-activated astrocytes in vitro. Our results indicate that brain-permeable drugs can target both tumor cells and the neuroinflammatory microenvironment in the brain metastatic process.     

Precipitating factors of heart failure decompensation,short-term morbidity and mortality in patients attended in primary care

Objective To evaluate the precipitating factors for heart failure decompensation in primary care and associations with short-term prognosis. Design Prospective cohort study with a 30-d follow-up from an index consultation. Regression models to determine independent factors associated with hospitalisation or death.Setting Primary care in ten European countries. Patients Patients with diagnosis of heart failure attended in primary care for a heart failure decompensation (increase of dyspnoea, unexplained weight gain or peripheral oedema).Main outcome measures Potential precipitating factors for decompensation of heart failure and their association with the event of hospitalisation or mortality 30 d after a decompensation.Results Of 692 patients 54% were women, mean age 81 (standard deviation [SD] 8.9) years; mean left ventricular ejection fraction (LVEF) 55% (SD 12%). Most frequently identified heart failure precipitation factors were respiratory infections in 194 patients (28%), non-compliance of dietary recommendations in 184 (27%) and non-compliance with pharmacological treatment in 157 (23%). The two strongest precipitating factors to predict 30 d hospitalisation or death were respiratory infections (odds ratio [OR] 2.8, 95% confidence interval [CI] (2.4–3.4)) and atrial fibrillation (AF) > 110 beats/min (OR 2.2, CI 1.5–3.2). Multivariate analysis confirmed the association between the following variables and hospitalisation/death: In relation to precipitating factors: respiratory infection (OR 1.19, 95% CI 1.14–1.25) and AF with heart rate > 110 beats/min (OR 1.22, 95% CI 1.10–1.35); and regarding patient characteristics: New York Heart Association (NYHA) III or IV (OR 1.22, 95% CI 1.15–1.29); previous hospitalisation (OR 1.15, 95% CI 1.11–1.19); and LVEF < 40% (OR 1.14, 95% CI 1.09–1.19).Conclusions In primary care, respiratory infections and rapid AF are the most important precipitating factors for hospitalisation and death within 30 d following an episode of heart failure decompensation.

Key points

• Hospitalisation due to heart failure decompensation represents the highest share of healthcare costs for this disease.
• So far, no primary care studies have analysed the relationship between precipitating factors and short term prognosis of heart failure decompensation episodes.
• We found that in 692 patients with heart failure decompensation in primary care, the respiratory infection and rapid atrial fibrillation (AF) increased the risk of short-term hospital admission or death.
• Patients with a hospital admission the previous year and a decompensation episode caused by respiratory infection were even more likely to be hospitalized or die within 30 d.

     

Translational research in brain metastasis is identifying molecular pathways that may lead to the development of new therapeutic strategies

Central nervous system (CNS) or brain metastasis is an emerging area of interest in organ-specific metastasis research. Lung and breast cancers are the most common types of primary tumors to develop brain metastases. This disease complication contributes significantly to the morbidity and mortality of both of these common cancers; as such, brain metastasis is designated an unmet medical need by the US Food and Drug Administration (FDA). Recently, an increase in incidence of CNS disease has been noted in the literature for breast cancer, while it has been an ongoing major complication from lung cancer. Progress in treating brain metastases has been hampered by a lack of model systems, a lack of human tissue samples, and the exclusion of brain metastatic patients from many clinical trials. While each of those is significant, the major impediment to effectively treating brain metastatic disease is the blood–brain barrier (BBB). This barrier excludes most chemotherapeutics from the brain and creates a sanctuary site for metastatic tumors. Recent findings on the biology of this disease and translational leads identified by molecular studies are discussed in this article.     

Transvaginal evisceration after hysterectomy: Is vaginal cuff closure associated with a reduced risk?

OBJECTIVE: To evaluate the overall incidence of transvaginal evisceration following hysterectomy and to assess the risk associated with indication, route of surgery, age and vaginal cuff closure technique. MATERIALS AND METHODS: A database was used to identify all patients undergoing hysterectomy from 1995 to 2001 at our institution and all the patients admitted for vaginal evisceration during the same period. Each vaginal evisceration was analyzed for time of onset, trigger event, presenting symptoms, details of prolapsed organs and type of repair surgery. RESULTS: Of the 3593 patients enrolled in the study, 63.5% underwent abdominal hysterectomy, 33.0% vaginal hysterectomy, and 3.5% laparoscopic hysterectomy. Ten patients (0.28%) presented to the emergency room with vaginal evisceration. No statistical differences in evisceration rates were seen according to the route of surgery. No differences were found between the 1440 patients who had closure of the vaginal cuff and the 2153 who had an unclosed cuff closure technique. CONCLUSIONS: Our data suggest that, in young patients, sexual intercourse is to be considered the main trigger event before the complete healing of the vaginal cuff while, in elderly patients, the evisceration is a spontaneous event. Uterine prolapse was not associated with a higher rate and the route of surgery or vaginal cuff closure technique did not influence the dehiscence rate.