Tamara Tajsic

Smooth muscle cell hypertrophy, proliferation, migration and apoptosis in pulmonary hypertension.

Pulmonary hypertension is a multifactorial disease characterized by sustained elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP). Central to the pathobiology of this disease is the process of vascular remodelling. This process involves structural and functional changes to the normal architecture of the walls of pulmonary arteries (PAs) that lead to increased muscularization of the muscular PAs, muscularization of the peripheral, previously nonmuscular, arteries of the respiratory acinus, formation of neointima, and formation of plexiform lesions. Underlying or contributing to the development of these lesions is hypertrophy, proliferation, migration, and resistance to apoptosis of medial cells and this article is concerned with the cellular and molecular mechanisms of these processes. In the first part of the article we focus on the concept of smooth muscle cell phenotype and the difficulties surrounding the identification and characterization of the cell/cells involved in the remodelling of the vessel media and we review the general mechanisms of cell hypertrophy, proliferation, migration and apoptosis. Then, in the larger part of the article, we review the factors identified thus far to be involved in PH intiation and/or progression and review and discuss their effects on pulmonary artery smooth muscle cells (PASMCs) the predominant cells in the tunica media of PAs.

Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension.

RATIONALE Mutations in bone morphogenetic protein receptor type II (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (PAH). However, disease penetrance is only 20-30%, suggesting a requirement for additional triggers. Inflammation is emerging as a key disease-related factor in PAH, but to date there is no clear mechanism linking BMPR-II deficiency and inflammation. OBJECTIVES To establish a direct link between BMPR-II deficiency, a consequentially heightened inflammatory response, and development of PAH. METHODS We used pulmonary artery smooth muscle cells from Bmpr2(+/-) mice and patients with BMPR2 mutations and compared them with wild-type controls. For the in vivo model, we used mice heterozygous for a null allele in Bmpr2 (Bmpr2(+/-)) and wild-type littermates. MEASUREMENTS AND MAIN RESULTS Acute exposure to LPS increased lung and circulating IL-6 and KC (IL-8 analog) levels in Bmpr2(+/-) mice to a greater extent than in wild-type controls. Similarly, pulmonary artery smooth muscle cells from Bmpr2(+/-) mice and patients with BMPR2 mutations produced higher levels of IL-6 and KC/IL-8 after lipopolysaccharide stimulation compared with controls. BMPR-II deficiency in mouse and human pulmonary artery smooth muscle cells was associated with increased phospho-STAT3 and loss of extracellular superoxide dismutase. Chronic lipopolysaccharide administration caused pulmonary hypertension in Bmpr2(+/-) mice but not in wild-type littermates. Coadministration of tempol, a superoxide dismutase mimetic, ameliorated the exaggerated inflammatory response and prevented development of PAH. CONCLUSIONS This study demonstrates that BMPR-II deficiency promotes an exaggerated inflammatory response in vitro and in vivo, which can instigate development of pulmonary hypertension.

Transforming Growth Factor-β1 Represses Bone Morphogenetic Protein–Mediated Smad Signaling in Pulmonary Artery Smooth Muscle Cells via Smad3

Previous studies of pulmonary arterial hypertension (PAH) have implicated excessive transforming growth factor (TGF)-β1 signaling and reduced bone morphogenetic protein (BMP) signaling in the disease pathogenesis. Reduced BMP signaling in pulmonary artery smooth muscle cells (PASMCs) from patients with heritable PAH is a consequence of germline mutations in the BMP type II receptor (BMPR-II). We sought to establish whether the TGF-β1 and BMP4 pathways interact in PASMCs, and if this is altered in cells with BMPR-II mutations. Control PASMCs or from patients with PAH harboring BMPR-II mutations were treated with BMP4, TGF-β1, or cotreated with both ligands. Signaling was assessed by examination of Smad phosphorylation, luciferase reporters, and the transcription of BMP4 or TGF-β1-responsive genes. TGF-β1 attenuated BMP4-mediated inhibitors of differentiation 1/2 induction and abolished the response in BMPR-II mutant PASMCs, whereas BMP4 did not alter TGF-β1-mediated transcription. Activin-like kinase 5 inhibition blocked this effect, whereas cycloheximide or pharmacological inhibitors of TGF-β-activated kinase 1, extracellular signal-regulated kinase 1/2, or p38 mitogen-activated protein kinase were ineffective. BMP4 and TGF-β1 cotreatment did not alter the activation or nuclear translocation of their respective Smad signaling proteins. Small interfering RNA for Smad3, but not Smad2, Smad6, or Smad7, reversed the inhibition by TGF-β1. In addition, TGF-β-activated kinase 1 inhibition blocked Smad3 phosphorylation, implying that C-terminal Smad3 phosphorylation is not required for the inhibition of BMP4 signaling by TGF-β1. TGF-β1 reduces BMP4 signaling in PASMCs, a response that is exacerbated on the background of reduced BMP responsiveness due to BMPR-II mutations. These data provide a rationale for therapeutic inhibition of TGF-β1 signaling in PAH.

Pulmonary hypertension: advances in pathogenesis and treatment

Pulmonary hypertension is an orphan disease that until recently has received limited attention within the wider medical community. This has changed distinctly in the last 10 years with the advent of new classes of therapy and a renewed interest in mechanisms of pathogenesis. This review utilized information gathered from recent conferences, and a review of the literature was conducted using MedLine and Pubmed. Accepted mechanisms of pathogenesis and currently available treatments are presented. We will discuss interesting new concepts in pathogenesis, including the importance of genetic forms of the disease and in particular the transforming growth factor receptor superfamily and the evolving evidence of the contribution of dysregulated immunity. Areas of research may yield therapeutic benefits in the not-too-distant future, including anti-proliferative therapies and stem cell therapy.

Monitoring the Neuroinflammatory Response Following Acute Brain injury

Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are major contributors to morbidity and mortality. Following the initial insult, patients may deteriorate due to secondary brain damage. The underlying molecular and cellular cascades incorporate components of the innate immune system. There are different approaches to assess and monitor cerebral inflammation in the neuro intensive care unit. The aim of this narrative review is to describe techniques to monitor inflammatory activity in patients with TBI and SAH in the acute setting. The analysis of pro- and anti-inflammatory cytokines in compartments of the central nervous system (CNS), including the cerebrospinal fluid and the extracellular fluid, represent the most common approaches to monitor surrogate markers of cerebral inflammatory activity. Each of these compartments has a distinct biology that reflects local processes and the cross-talk between systemic and CNS inflammation. Cytokines have been correlated to outcomes as well as ongoing, secondary injury progression. Alongside the dynamic, focal assay of humoral mediators, imaging, through positron emission tomography, can provide a global in vivo measurement of inflammatory cell activity, which reveals long-lasting processes following the initial injury. Compared to the innate immune system activated acutely after brain injury, the adaptive immune system is likely to play a greater role in the chronic phase as evidenced by T-cell-mediated autoreactivity toward brain-specific proteins. The most difficult aspect of assessing neuroinflammation is to determine whether the processes monitored are harmful or beneficial to the brain as accumulating data indicate a dual role for these inflammatory cascades following injury. In summary, the inflammatory component of the complex injury cascade following brain injury may be monitored using different modalities. Using a multimodal monitoring approach can potentially aid in the development of therapeutics targeting different aspects of the inflammatory cascade and improve the outcome following TBI and SAH.

Ultrasound non-invasive measurement of intracranial pressure in neurointensive care: A prospective observational study

Background The invasive nature of the current methods for monitoring of intracranial pressure (ICP) has prevented their use in many clinical situations. Several attempts have been made to develop methods to monitor ICP non-invasively. The aim of this study is to assess the relationship between ultrasound-based non-invasive ICP (nICP) and invasive ICP measurement in neurocritical care patients. Methods and findings This was a prospective, single-cohort observational study of patients admitted to a tertiary neurocritical care unit. Patients with brain injury requiring invasive ICP monitoring were considered for inclusion. nICP was assessed using optic nerve sheath diameter (ONSD), venous transcranial Doppler (vTCD) of straight sinus systolic flow velocity (FVsv), and methods derived from arterial transcranial Doppler (aTCD) on the middle cerebral artery (MCA): MCA pulsatility index (PIa) and an estimator based on diastolic flow velocity (FVd). A total of 445 ultrasound examinations from 64 patients performed from 1 January to 1 November 2016 were included. The median age of the patients was 53 years (range 37–64). Median Glasgow Coma Scale at admission was 7 (range 3–14), and median Glasgow Outcome Scale was 3 (range 1–5). The mortality rate was 20%. ONSD and FVsv demonstrated the strongest correlation with ICP (R = 0.76 for ONSD versus ICP; R = 0.72 for FVsv versus ICP), whereas PIa and the estimator based on FVd did not correlate with ICP significantly. Combining the 2 strongest nICP predictors (ONSD and FVsv) resulted in an even stronger correlation with ICP (R = 0.80). The ability to detect intracranial hypertension (ICP ≥ 20 mm Hg) was highest for ONSD (area under the curve [AUC] 0.91, 95% CI 0.88–0.95). The combination of ONSD and FVsv methods showed a statistically significant improvement of AUC values compared with the ONSD method alone (0.93, 95% CI 0.90–0.97, p = 0.01). Major limitations are the heterogeneity and small number of patients included in this study, the need for specialised training to perform and interpret the ultrasound tests, and the variability in performance among different ultrasound operators. Conclusions Of the studied ultrasound nICP methods, ONSD is the best estimator of ICP. The novel combination of ONSD ultrasonography and vTCD of the straight sinus is a promising and easily available technique for identifying critically ill patients with intracranial hypertension.

Cellular and Molecular Mechanisms of Pulmonary Vascular Smooth Muscle Cell Proliferation

Pulmonary arterial hypertension is the end result of a complex series of events termed “vascular remodeling,” which includes proliferation of resident smooth muscle cells in the walls of small muscular pulmonary arteries. This process leads to increased thickness of the smooth muscle component of the vessel wall, which then contributes to reduced lumen diameter and increased contractility. Since smooth muscle cell proliferation contributes significantly to the process of vascular remodeling, it is important to appreciate the main factors driving this process in the hypertensive lung. This chapter will review the basic mechanisms of vascular smooth muscle cell proliferation, focusing on work in pulmonary vascular cells.

Isolated oculomotor nerve palsy in patients with mild head injury

Abstract Isolated oculomotor nerve palsy following head injury is uncommon. It can only be diagnosed with confidence if it is known to have developed immediately following trauma and if adequate investigations exclude secondary causes. The recovery is only partial and this has repercussion on patients’ quality of life.

Giant intradiploic epidermoid cyst with intracranial extension

A 47-year-old gentleman presented to our institution with a 24 h history of worsening headache, increasing confusion and drowsiness. He was afebrile and there were no signs of meningism. No focal neurological deficits were present. A palpable scalp lump was found on examination in the left posterior frontal/parietal area. The lump had been present since childhood according to the patient. There was no clear history of head trauma but he had participated in a mosh pit a few days prior to his presentation. A contrast CT scan of the head revealed a large extra-axial lesion that was centred in the posterior part of the left parietal bone and had a significant intractranial component (Fig. 1). An MRI brain showed some areas of T1 hyperintensity within the lesion, suggestive of blood degradation products (Fig. 2).

Dermatitis artefacta of the scalp complicated by skull erosion and intracranial infection.

Dear Editor, Dermatitis artefacta is a condition characterized by skin lesions produced or inflicted by the patient’s own actions without any rational motive for this behavior but to satisfy an internal psychological need [1, 2]. The condition is linked to psychiatric disorders and has a female preponderance [3]. The diagnosis is made by exclusion. Although the lesions are predominantly confined to the skin, life-threatening complications can develop. Here we present a rare case of pathologic skin picking complicated by skull erosion and intracranial infection Fig. 1a. A 78-year-old gentleman with a background of insulin-dependent diabetes mellitus was admitted to a district general hospital following a collapse at home. On examination, he was febrile, disorientated, and had a right hemiparesis. A large oval scalp defect was noted at the vertex. Shortly after admission, he developed generalized tonic clonic seizures. He was started on antiepileptics and was then transferred to our unit for further management. Inspection revealed a 6×7-cm scalp and skull vault defect with sharp margins and a 3×3-cm dural defect. The underlying cortex had herniated through the dural defect (Fig. 1a). Blood tests revealed raised inflammatory markers. MRI imaging confirmed the large skull and dural defect with minor brain herniation (Fig. 1b). It also revealed features of leptoand pachymeningitis and an area of signal change in the left frontal lobe likely to represent cerebritis. Debridement under general anesthesia was undertaken and the patient was empirically started on antibiotics. Samples were taken for histopathology and this showed inflammation of the skin, skull, and dura. Subsequently, reconstruction with scalp transposition flap and split thickness skin graft to primary donor site was performed with good results (Fig. 1c). From collateral history and general practitioner’s letters, it transpired that the patient had several years’ history of pathological scalp picking and had previously been diagnosed as suffering from dermatitis artefacta of the scalp. It is unknown whether any sharp instruments were used at any stage by the patient. This is one of the few reports in the literature of dermatitis artefacta complicated by intracranial infections [4, 5]. AsMartin and Reed have previously postulated [4], the prolonged scalp picking with a superadded low-grade infection presumably led to skull erosion. Ongoing self-mutilation and lowgrade infection resulted in breach of the dura, which then allowed the seeding of pathogens intracranially. * Tamara Tajsic ttajsic@doctors.org.uk