DGCR8 deficiency impairs macrophage growth and unleashes the interferon response to mycobacteria.

The mycobacterial cell wall glycolipid trehalose-6,6-dimycolate (TDM) activates macrophages through the C-type lectin receptor MINCLE. Regulation of innate immune cells relies on miRNAs, which may be exploited by mycobacteria to survive and replicate in macrophages. Here, we have used macrophages deficient in the microprocessor component DGCR8 to investigate the impact of miRNA on the response to TDM. Deletion of DGCR8 in bone marrow progenitors reduced macrophage yield, but did not block macrophage differentiation. DGCR8-deficient macrophages showed reduced constitutive and TDM-inducible miRNA expression. RNAseq analysis revealed that they accumulated primary miRNA transcripts and displayed a modest type I IFN signature at baseline. Stimulation with TDM in the absence of DGCR8 induced overshooting expression of IFNß and IFN-induced genes, which was blocked by antibodies to type I IFN. In contrast, signaling and transcriptional responses to recombinant IFNß were unaltered. Infection with live Mycobacterium bovis Bacille Calmette-Guerin replicated the enhanced IFN response. Together, our results reveal an essential role for DGCR8 in curbing IFNß expression macrophage reprogramming by mycobacteria.

Feasibility of cardiopulmonary exercise testing and training using a robotics-assisted tilt table in dependent-ambulatory stroke patients.

BACKGROUND: We evaluated the feasibility of an augmented robotics-assisted tilt table (RATT) for incremental cardiopulmonary exercise testing (CPET) and exercise training in dependent-ambulatory stroke patients. METHODS: Stroke patients (Functional Ambulation Category ≤ 3) underwent familiarization, an incremental exercise test (IET) and a constant load test (CLT) on separate days. A RATT equipped with force sensors in the thigh cuffs, a work rate estimation algorithm and real-time visual feedback to guide the exercise work rate was used. Feasibility assessment considered technical feasibility, patient tolerability, and cardiopulmonary responsiveness. RESULTS: Eight patients (4 female) aged 58.3 ± 9.2 years (mean ± SD) were recruited and all completed the study. For IETs, peak oxygen uptake (V'O2peak), peak heart rate (HRpeak) and peak work rate (WRpeak) were 11.9 ± 4.0 ml/kg/min (45 % of predicted V'O2max), 117 ± 32 beats/min (72 % of predicted HRmax) and 22.5 ± 13.0 W, respectively. Peak ratings of perceived exertion (RPE) were on the range "hard" to "very hard". All 8 patients reached their limit of functional capacity in terms of either their cardiopulmonary or neuromuscular performance. A ventilatory threshold (VT) was identified in 7 patients and a respiratory compensation point (RCP) in 6 patients: mean V'O2 at VT and RCP was 8.9 and 10.7 ml/kg/min, respectively, which represent 75 % (VT) and 85 % (RCP) of mean V'O2peak. Incremental CPET provided sufficient information to satisfy the responsiveness criteria and identification of key outcomes in all 8 patients. For CLTs, mean steady-state V'O2 was 6.9 ml/kg/min (49 % of V'O2 reserve), mean HR was 90 beats/min (56 % of HRmax), RPEs were > 2, and all patients maintained the active work rate for 10 min: these values meet recommended intensity levels for bouts of training. CONCLUSIONS: The augmented RATT is deemed feasible for incremental cardiopulmonary exercise testing and exercise training in dependent-ambulatory stroke patients: the approach was found to be technically implementable, acceptable to the patients, and it showed substantial cardiopulmonary responsiveness. This work has clinical implications for patients with severe disability who otherwise are not able to be tested.

Chronic osteomyelitis: results obtained by an integrated team approach to management.

BACKGROUND: The pathology of chronic osteomyelitis suggests that thorough debridement of bone and soft tissue, with closure of dead space, supported by appropriate antibiotics would be the optimal therapeutic strategy. METHODS: In 1993, we formed a multidisciplinary Bone Infection Team (orthopaedic surgeon, infectious diseases specialist, plastic surgeon, and nurse practitioner) to apply those principles to the treatment of chronic osteomyelitis. We present the outcomes of such therapy in 82 patients treated by the Team in the first seven years. All patients underwent surgical debridement with other procedures including bone distraction, muscle flap implantation and bone grafts as necessary to foster restoration of bone and soft-tissue integrity. Antibiotic choice was based on sensitivity data, with a short course of intravenous antibiotics and a prolonged course of oral antibiotics being the usual therapy. RESULTS: During the first seven years, we treated 82 patients for chronic osteomyelitis. Most patients required multiple surgical procedures (mean = 2.2), with 10 patients requiring five or more operations. Staphylococcus aureus was the single most common pathogen, although the majority (57%) of the infections were polymicrobial. Intravenous antibiotics were administered for a median of 16 days; 16 patients received intravenous antibiotics only during the immediate perioperative period. Oral antibiotics were administered for a median of 59 days. The infection was cured in all but one patient in our clinic; the remaining patient had definitive surgical repair at another clinic and is now infection free. In 77/82 patients, the limb afflicted with chronic osteomyelitis was salvaged. Because of extensive damage to bones and surrounding soft tissues, amputation was necessary in five patients. Five patients required internal fixation 12 or more months after the infection was controlled for nonunion; all such procedures were successful. No patient whose infection remained inactive for six or more months after surgical debridement has reactivated the infection during a median follow-up of 56 months (range: 23-89 months). CONCLUSIONS: Management of chronic osteomyelitis requires thorough debridement of infected bone and soft tissues coupled with rigid stabilization with external fixators, elimination of dead space, often requiring soft-tissue flap coverage, and staged bone reconstruction. When such a surgical approach is accompanied by appropriate antibiotics based on the sensitivity of the microbes isolated from the infected site, the infected focus is eliminated and bone length and integrity are restored.

Palliative approaches to the patient with breast cancer.

Despite an increasing trend towards early diagnosis of breast cancer,patients still present with locally advanced disease. Also, in some patients chemotherapy will fail, and local and regional recurrence will occur. This article outlines options for palliative care for such patients.

Hemangiomas of the nasal tip.

The treatment of nasal hemangiomas is controversial. Results of nonsurgical treatment methods have been disappointing. In a series of 42 patients with nasal hemangioma, 22 patients underwent early excision. The open rhinoplasty approach proved safe and effective and yielded satisfactory long-term results. The article discusses protocols for evaluation and guidelines for treatment.