Although RNA interference (RNAi) has become a ubiquitous laboratory tool since its discovery 12 years ago, in vivo delivery to selected cell types remains a major technical challenge. Here, we report the use of lentiviral vectors for long-term in vivo delivery of RNAi selectively to resident alveolar macrophages (AMs), key immune effector cells in the lung. We demonstrate the therapeutic potential of this approach by RNAi-based downregulation of p65 (RelA), a component of the pro-inflammatory transcriptional regulator, nuclear factor κB (NF-κB) and a key participant in lung disease pathogenesis. In vivo RNAi delivery results in decreased induction of NF-κB and downstream neutrophilic chemokines in transduced AMs as well as attenuated lung neutrophilia following stimulation with lipopolysaccharide (LPS). Through concurrent delivery of a novel lentiviral reporter vector (lenti-NF-κB-luc-GFP) we track in vivo expression of NF-κB target genes in real time, a critical step towards extending RNAi-based therapy to longstanding lung diseases. Application of this system reveals that resident AMs persist in the airspaces of mice following the resolution of LPS-induced inflammation, thus allowing these localized cells to be used as effective vehicles for prolonged RNAi delivery in disease settings.

Pulmonary arterial hypertension (PAH) is a progressive disease marked by the irreversible pulmonary vascular changes of vasoconstriction, thrombosis, and proliferation of smooth muscle and endothelial cells. The untreated clinical course is characterized by progressive dyspnea and a median survival of less than 3 years. Many of these patients are of child-bearing age; however, pregnancy leads to physiologic changes that are particularly poorly tolerated in PAH, conferring a 30%-56% mortality. We present a case of PAH that spontaneously resolved after termination of pregnancy and recurred during each of two subsequent pregnancies. To our knowledge, this case is unique, because no cases of spontaneous resolution of idiopathic PAH have been reported in adults, nor have there been any reports of pulmonary hypertension that is isolated to the gestational period.Keywords: pulmonary arterial hypertension, pregnancy, gestation, pulmonary vascular disease, resolution. The World Health Organization (WHO) classifies pulmonary hypertension (PH) into five groups that are based on mechanisms of disease; group I PH is defined as pulmonary arterial hypertension (PAH). 1 PAH, characterized by vasoconstriction, thrombosis, and proliferation of smooth muscle and endothelial cells, 2 is defined as a mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, a mean pulmonary capillary wedge pressure or left ventricular enddiastolic pressure of <15 mmHg, and a pulmonary vascular resistance of 3 Wood units. Among the entities included in group I PH (PAH) is idiopathic pulmonary arterial hypertension (IPAH); a rare disorder with an untreated clinical course generally characterized by progressive worsening of symptoms and cardiopulmonary hemodynamics and a median survival of less than 3 years. 3 With currently available therapies, prostaglandin analogs, endothelinreceptor antagonists, phosphodiesterase inhibitors, and soluble guanylyl cyclase agonists, symptoms, hemodynamic characteristics, and survival have been improved in patients with IPAH. However, mortality is still as high as 30% over a 3-year period. [4][5][6] Outcomes of patients who develop PAH during pregnancy are particularly poor, with an estimated maternal mortality of 30%-56%. 7 To date, there have been no reported cases of spontaneous resolution of PAH in adults, nor have there been reports of PAH isolated to the gestational period. We present a unique case of PAH that was diagnosed during pregnancy, resolved after termination of pregnancy, and recurred during two subsequent pregnancies. CASE DESCRIPTIONThe patient, a 20-year-old woman who was 17 weeks pregnant (gravida 3, para 1011), presented to the emergency department (ED) unresponsive, febrile, hypotensive, and hypoglycemic. Initial echocardiographic examination in the ED revealed a severely dilated right ventricle (RV) with moderately depressed systolic function; initial laboratory data suggested adrenal insufficiency. The patient was admitted to the medical intensive care unit (MICU); with administration ...

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Purpose The purpose of this paper is to describe family intervention (FI) with four families in which the service user is under the care of forensic mental health services. There is a focus on identifying how systemic practice is used or adapted in working with families who have a family member who has presented risk and caused harm. Design/methodology/approach Four case studies are used to provide a basis for the exploration of commonalities in practice between the cases and the utility of FI within forensic services, which have the dual purpose of promoting mental health recovery and reducing offending/risk behaviour. Findings Family work can be a key healing tool in the recovery journey of forensic service users and their families. An integrated systemic and psycho-educational FI approach was found to be appropriate in the cases described. Issues particular to forensic services are identified; these include the role of safety planning; the function of talking about the history of trauma in the family including the impact of offending behaviour; mediating difficult relationships between family members and professionals; and overcoming barriers to having difficult and emotive conversations. Research limitations/implications The absence of outcome assessments limits the findings to observational data and self-reported experiences from the authors. Practical implications FI can be safely and effectively used within forensic settings, facilitated by practitioners competent in working with trauma and complexity, as an integrated component of the therapeutic treatment. Originality/value There are recognised barriers to the provision of FI within forensic settings, with limited research regarding the application of such therapies with forensic patients and their families. This paper adds to the small pool of knowledge regarding useful applications of FI in such settings.