Limited Progression Research Articles

Distinctive features between community-acquired pneumonia (CAP) due to Chlamydophila psittaci and CAP due to Legionella pneumophila admitted to the intensive care unit (ICU)

The spectrum of community-acquired pneumonia (CAP) due to Chlamydophila psittaci ranges from mild, self-limited CAP, to acute respiratory failure. We performed a retrospective study of 13 consecutive patients with CAP due to C. psittaci and 51 patients with legionellosis admitted in one intensive care unit (ICU) (1993-2011). As compared to patients with legionellosis, patients with psittacosis were younger (median age 48 [38-59] vs. 60 [50-71] years, p = 0.007), less frequently smokers (38 vs. 79 %, p < 0.001), with less chronic disease (15 vs. 57 %, p = 0.02), and longer duration of symptoms before admission (median 6 [5-13] vs. 5 [3-7] days, p = 0.038). They presented with lower Simplified Acute Physiology Score II (median 28 [19-38] vs. 39 [28-46], p = 0.04) and less extensive infiltrates on chest X-rays (median 2 [1-3] vs. 3 [3-4] lobes, p = 0.007). Bird exposure was mentioned in 100 % of psittacosis cases, as compared to 5.9 % of legionellosis cases (p < 0.0001). Extrapulmonary manifestations, biological features, and mortality (15.4 vs. 21.6 %, p = 0.62) were similar in both groups. In conclusion, severe psittacosis shares many features with severe legionellosis, including extrapulmonary manifestations, biological features, and outcome. Psittacosis is an important differential diagnosis for legionellosis, especially in cases of bird exposure, younger age, and more limited disease progression over the initial few days.

Inadequate pain relief (IPR) in knee osteoarthritis: what does it look like? a European survey of osteoarthritis real world therapies (SORT)

s / Osteoarthritis and Cartilage 20 (2012) S54–S296 S178 JSN scores, medially or laterally. Progression was compartment specific for the various clusters. Medial progression occurred only in clusters 1, 2 and 4, most dramatically so in cluster 4 (48%). Cluster 3 again only showed lateral progression (61%). Conclusions: We found clear differences between the various clusters. Cluster 1 could be described as amild type of OA,with nodenuded bone and limited OA progression. Cluster 3 and 4weremore severe and erosive types of OA, showing strong increases in area of denudedbonewith increasingOA severity, and a high prevalence of progression. Interestingly, cluster 3 was purely a lateral type of OA, while cluster 4was purelymedial in all respects. The causes that led to differences between the clusters remain speculative. The higher prevalence of reported trauma in cluster 3 and 4, the more aggressive OA types might suggest a difference in OA initiation. Wekept the complexityof themodels lowtoreduce the riskofoverfittingand increase the likelihood that our findings are generalizable to other cohorts. The fact that clusters also differed on data not included in cluster finding (trauma and progression) indicates that the found clusters are meaningful. In conclusion, latent class cluster analysis confirmed the suspected existence of distinct subtypes of knee OA.

Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury

BackgroundTraumatic brain injury initiates biochemical processes that lead to secondary neurodegeneration. Imaging studies suggest that tissue loss may continue for months or years after traumatic brain injury in association with chronic microglial activation. Recently we found that metabotropic glutamate receptor 5 (mGluR5) activation by (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) decreases microglial activation and release of associated pro-inflammatory factors in vitro, which is mediated in part through inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Here we examined whether delayed CHPG administration reduces chronic neuroinflammation and associated neurodegeneration after experimental traumatic brain injury in mice.MethodsOne month after controlled cortical impact traumatic brain injury, C57Bl/6 mice were randomly assigned to treatment with single dose intracerebroventricular CHPG, vehicle or CHPG plus a selective mGluR5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine. Lesion volume, white matter tract integrity and neurological recovery were assessed over the following three months.ResultsTraumatic brain injury resulted in mGluR5 expression in reactive microglia of the cortex and hippocampus at one month post-injury. Delayed CHPG treatment reduced expression of reactive microglia expressing NADPH oxidase subunits; decreased hippocampal neuronal loss; limited lesion progression, as measured by repeated T2-weighted magnetic resonance imaging (at one, two and three months) and white matter loss, as measured by high field ex vivo diffusion tensor imaging at four months; and significantly improved motor and cognitive recovery in comparison to the other treatment groups.ConclusionMarkedly delayed, single dose treatment with CHPG significantly improves functional recovery and limits lesion progression after experimental traumatic brain injury, likely in part through actions at mGluR5 receptors that modulate neuroinflammation.

The default state of the cell: Quiescence or proliferation?

The default state of the cell: Quiescence or proliferation?

Deep Brain Stimulation in Benign Tremulous Parkinsonism

Benign tremulous parkinsonism (BTP) is characterized by prominent resting plus action tremor, mild parkinsonism with limited disability or progression apart from tremor, and a less-robust response to levodopa therapy. This disorder has an uncertain pathophysiologic relationship to idiopathic Parkinson disease. Deep brain stimulation (DBS) should be efficacious for this condition, but there is no previously published experience. To assess the clinical outcomes and surgical complications of patients with BTP who underwent DBS. Retrospective case series. Tertiary care medical center. Twelve men and 3 women with BTP who underwent DBS for levodopa-refractory tremor. Tremor status after DBS, preoperative vs postoperative scores on the Fahn-Tolosa-Marin tremor scale, and the presence of adverse events. Of the 15 patients, 8 underwent unilateral thalamic nucleus ventralis intermedius (VIM), 4 bilateral VIM, and 3 bilateral subthalamic nucleus DBS. At last follow-up at a median of 4 years post-DBS, 7 patients were tremor free, 6 had only trace tremor, and 2 were definitely improved but with residual tremor. The median preoperative Fahn-Tolosa-Marin tremor scale score was 17 (range, 11-21); the tremor scale score at the last videotaped follow-up was 1 (range, 0-6). Median time between the 2 videotapes was 11.5 months (range, 3-14 months). No patients experienced adverse events after the surgical procedure. These findings support the efficacy of DBS, with VIM and STN targets, in medically refractory BTP-related tremor. Further studies are needed to explore the long-term durability of response and to better compare the surgical targets.

Naringin, the major grapefruit flavonoid, specifically affects atherosclerosis development in diet-induced hypercholesterolemia in mice

Naringin (NAR) from grapefruit has exhibited potential protective effects against atherosclerosis development. However, specific mechanisms responsible for such effects are poorly understood. Thus, we aimed to investigate the antiatherogenic effects of NAR in different mouse models of hypercholesterolemia and decipher its molecular targets in the aorta using transcriptomic approach. Two mouse models of hypercholesterolemia, wild-type mice fed a high-fat/high-cholesterol diet and apolipoprotein E-deficient mice fed a semisynthetic diet, were studied. Mice were fed a respective control diets supplemented or not for 18 weeks with 0.02% of NAR, that is, nutritional supplementation. NAR supplementation reduced plaque progression only in wild-type mice fed the high-fat/high-cholesterol diet (−41%). Consistent with this protective effect, NAR reduced plasma non-high-density lipoprotein cholesterol concentrations as well as biomarkers of endothelial dysfunction. Microarray studies performed on aortas demonstrated differentially expressed genes encoding proteins involved in cell adhesion, actin cytoskeleton organization and cell division. Thus, the changes in gene expression induced by NAR could suggest a limited atherosclerosis progression by preventing immune cell adhesion and infiltration in the intima of vascular wall, as well as smooth muscle cell proliferation. Furthermore, this hypothesis was strengthened by in vitro experiments, which showed the ability of naringenin to reduce monocyte adhesion to endothelial cells and smooth muscle cell proliferation. In conclusion, this study revealed the antiatherogenic effect of NAR supplemented at a nutritionally achievable dose, specifically toward diet-induced atherosclerosis, and depicted its multitarget mode of action at the vascular level.

Massive rotator cuff tear treated with a synthetic patch: a case report 16 years after surgery

Massive rotator cuff tears usually cannot be repaired due to tendon atrophy and marked retraction, as well as muscles fatty degeneration. There are several options for surgical treatment: open or arthroscopic debridement with or without subacromial decompression, arthroscopic isolated biceps tenotomy, partial tendon repair, use of synthetic or biologic patches, tendon transfers, hemiarthroplasty, reverse arthroplasty, and arthrodesis. In this article, we will discuss a particular case of massive rotator cuff tear treated with Marlex mesh. The patient was clinically, radiologically, and MRI checked 16 years after the surgical implant. The active function of shoulder had preserved very well, the Constant score was 76. The X-rays showed a limited progression of osteoarthritis without further cranial migration of the humeral head. At MR cartilage preservation was appreciated, the patch being in good position and the teres minor being smaller than average but it was nonetheless present. This case report can highlight the usefulness of patches in patients with irreparable rotator cuff lesion both for the immediate benefit in terms of pain, strength, movement, and in perspective allowing for the preservation of anatomical structures that might avoid the need for a prosthetic implant over the years.

Gastrointestinal Stromal Tumors: Disease and Treatment Update

Gastrointestinal Stromal Tumors: Disease and Treatment Update

Interferons overrule the TNF-induced proliferation of rheumatoid fibroblast-like synoviocytes

ObjectivesTumour necrosis factor α (TNF-α) and interferons (IFNs), which are abundantly present in the rheumatoid synovium, are thought to exert two opposing effects on RA pathology. We studied the opposing...

Treatment of Periocular Infantile Hemangiomas with Propranolol: Case Series of 18 Children

To study the efficacy of propranolol in the treatment of periocular infantile hemangiomas (IHs). Retrospective interventional case series. Eighteen children presenting periocular IH with occlusion of the pupil, anisometropic astigmatism, proliferating eyelid IH, or cosmetically disfiguring periocular IH. All patients received treatment with propranolol started at 0.5 mg/kg/day with an incremental increase by 0.5 mg/kg/day every 4 days, up to a maximum of 2 to 3 mg/kg/day. Complete eye examinations and serial photographs were obtained before, during, and after treatment. Doppler ultrasound and magnetic resonance imaging performed pre- and post-treatment were compared when available. Evolution of the treated IH was evaluated with respect to astigmatism, amblyopia, and size of the lesion. The IH size decreased in 17 of 18 patients. We noted a greater reduction when treatment was administered during the proliferative phase of growth of IHs. At the conclusion of treatment, none of our patients had amblyopia. The mean value of amblyogenic astigmatism (n = 7) decreased from 2.71 diopters (D) pretreatment to 1.03 D post-treatment. On radiology, 8 patients had significant regression of the lesion size of their IH and 1 patient had a limited progression. Propranolol had to be temporarily discontinued in only 1 patient because of symptomatic hypotension. Propranolol seems to be an effective modality of treatment for periocular IH. It seems to be most efficacious when initiated in the proliferative phase of IH but may be beneficial even in the later stage. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Correlation of fundus autofluorescence with photoreceptor morphology and functional changes in eyes with retinitis pigmentosa

To assess and correlate fundus autofluorescence (FAF) characteristics with photoreceptor morphology and functional features in eyes with retinitis pigmentosa (RP). Thirty-four eyes of 17 patients with RP were examined. We compared FAF images obtained by confocal scanning laser ophthalmoscopy with Spectral-domain optical coherence tomography (SD-OCT) and retinal function assessed by microperimetry. Normal FAF surrounded by a ring of increased FAF at the macular area was detected in 32 (94%) eyes. The diameter of the normal FAF was correlated significantly with the preserved area of the photoreceptor inner segment and outer segment (IS/OS) junction on SD-OCT (R=0.939, p<0.001). The area outside the ring was associated with loss of IS/OS junction and external limiting membrane (ELM). The ring of increased FAF demarcated the border between the central retina with preservation of the IS/OS junction and ELM, and the adjacent eccentric retina with loss of these bands. In two eyes of one patient, there was no preservation of normal FAF at the macula and the photoreceptor IS/OS junction was not detected on SD-OCT. The mean retinal sensitivity derived from microperimetry was correlated significantly with the area of normal FAF (R=0.929, p=0.007) and the preserved area of the IS/OS junction (R=0.851, p=0.032). Ten eyes had progressive reduction in size of the normal FAF inside the ring accompanied by decreased area of preserved IS/OS during 3.1 years. FAF appears to reflect the integrity of the photoreceptor layer. It may serve as a secondary outcome measure for novel therapeutic strategies for RP.

Efficacy of tyrosine kinase inhibitor therapy combined with surgical resection in patients with metastatic gastrointestinal stromal tumor

To investigate the clinical effect of surgery following systemic targeted therapy of tyrosine kinase inhibitors (TKIs) in patients with metastatic gastrointestinal stromal tumors (GIST). From June 2007 to December 2009, data of 15 consecutive patients with metastatic GIST treated with imatinib/sunitinib followed by surgery were retrospectively analyzed. Disease responses to TKI treatment was categorized into controlled disease (including partial response and stable disease) (6, 40.0%), limited progression (4, 26.7%), and generalized progression (5, 33.3%), respectively. Surgeries were performed after mean 12 months following TKI therapies. Gross complete resection or optimal debulking with minimal residual disease were managed to performed in 8/10 patients with disease controlled and limited progression, while optimal debulking only achieved in 2/5 patients with generalized progression. Surgical morbidity was 20.0% (3/15). After operation, patients with disease controlled and limited progression had a median progression-free survival of 25.0 months and 2-year overall survival rate of 100%. In contrast, for patients with generalized progression, the median progression- free survival was 3 months (P<0.01), and median overall survival 10.5 months. Patients with metastatic GIST who have controlled disease or limited progression to TKI therapy can benefit from surgical resection. Surgery should be selective in patients with generalized progression since surgery hardly improves survival in these patients.

Lenalidomide induced good clinical response in a patient with multiple relapsed and refractory Hodgkin's lymphoma

BackgroundA 24-year-old female patient was diagnosed with classic Hodgkin's lymphoma in clinical stage II, and combination chemotherapy followed by radiotherapy was initiated. During the following 5 years, the disease progressed despite several standard therapeutic approaches, including autologous and allogeneic stem cell transplantation.MethodsLenalidomide (25 mg daily) treatment was then initiated in a continuous dosing schedule. Positron emission tomography scans were performed before and during lenalidomide treatment. Hematologic and laboratory values, as well as physical condition were also assessed before and during lenalidomide treatment.ResultsFour months after continuous lenalidomide treatment, tumor load was significantly reduced, B symptoms had resolved, and the patient's physical condition had improved, allowing her to resume normal daily-living activities. Evaluations after 15 months of lenalidomide treatment indicated limited disease progression. Nevertheless, the patient was feeling well and maintaining a normal active life. Treatment was well tolerated, allowing the patient to remain on continuous dosing, which has now been maintained for 18 months.ConclusionDaily, long-term lenalidomide treatment provided clinical benefit and was well tolerated in a patient with relapsed, advanced classic Hodgkin's lymphoma.

CEL-2000: A therapeutic vaccine for rheumatoid arthritis arrests disease development and alters serum cytokine/chemokine patterns in the bovine collagen type II induced arthritis in the DBA mouse model

The mouse model of collagen induced arthritis (CIA) effectively mimics human disease and thus is useful for testing and development of rheumatoid arthritis (RA) therapies. We developed a Ligand Epitope Antigen Presentation System (LEAPS) peptide hetero-conjugate vaccine containing an epitope of human collagen type II (CEL-2000) that acted as a therapeutic vaccine in the collagen induced arthritis (CIA) mouse model. LEAPS technology converts a small peptide containing a disease specific epitope into an immunogen by attaching it to an immune or T cell binding peptide (I/TCBL). For CEL-2000, a peptide from human collagen type II (254–273) is attached to the I/TCBL peptide from human β2 microglobulin (J). Treatment with CEL-2000 limited disease (CIA) progression, as demonstrated by reduced Arthritic Index (AI) score, and footpad swelling. Efficacy was confirmed by histopathological microscopic examination of tissues at the end of the study. CEL-2000 limited disease progression as well or better than the etanercept (Enbrel) therapeutic control with significantly better histopathological results than the etanercept treated mice. Most interestingly, CEL-2000 therapy modulated serum cytokine levels with an increase in IL-12p70 and IL-10, which are not seen with etanercept therapy, and reduced IL-17 and TNF-α, also seen with etanercept, among other cytokines studied. CEL-2000 was safe and well tolerated for the mice that received 5 injections given every 2 weeks in a 90 day study supporting its potential usage for long term therapy. These studies demonstrate that fewer treatments with CEL-2000 provide therapy at least as effective as etanercept by specifically modulating the disease producing autoimmune response.

Long-term follow-up after arthroscopic tenotomy for partial rupture of the biceps brachii tendon

To report the long-term clinical outcomes and radiographic results in dogs diagnosed with partial bicipital rupture and treated by arthroscopic tenotomy. The medical records of dogs that had undergone arthroscopic tenotomy were retrospectively reviewed. Inclusion criteria for this study were: performance of an arthroscopic tenotomy between August 1999 and July 2007, availability of arthroscopic records data for review, and ability to obtain follow-up data for more than one year after arthroscopic tenotomy. In all cases, owners were interviewed during follow-up appointments or via telephone to determine perceived outcome after surgery. Forty-seven arthroscopic tenotomies were performed on 40 dogs without any major surgical complications. Long-term follow-up examinations, ranging from 12 months to 48 months (mean 26 months) after the tenotomy, were obtained for 24 dogs (25 shoulders). Clinical outcome was assessed as excellent in 22 shoulders, with each dog showing a full return of limb function. A total of 10 dogs (11 joints) were evaluated radiographically; six joints revealed no progression of pathology, and five joints showed a limited progression of pathology. Arthroscopic tenotomy in the treatment of bicipital partial rupture yields favourable long-term clinical results and a high degree of owner satisfaction. The feasibility of this technique and the long-term clinical and radiographic outcome from our study indicate that this technique can be considered a reliable and safe treatment for partial bicipital rupture.

Cytoreductive Surgery in Patients with Metastatic Gastrointestinal Stromal Tumor Treated with Sunitinib Malate

In patients with metastatic gastrointestinal stromal tumor (GIST) on first-line imatinib (IM) undergoing cytoreductive surgery, response to IM at time of surgery correlates with completeness of resection and progression-free and overall survival (PFS, OS). Impact of surgery in IM-resistant patients on second-line sunitinib (SU) is unknown. Patients on SU undergoing surgery for metastatic GIST at our institution were reviewed. Response to SU at time of surgery was categorized as responsive disease (RD), limited progression (LP) or generalized progression (GP). Fifty patients underwent surgery after a median 6.7 months of SU. Forty patients (80%) had prior surgery at initial presentation of GIST; 16 (32%) underwent prior surgery on IM. At time of surgery on SU, 10 patients (20%) had RD, 22 (44%) had LP, and 18 (36%) had GP. Resections were macroscopically complete in 25 patients (50%); completeness of resection did not correlate with response to SU. Complication rate was 54%; reoperations were required in 16%. Median PFS after surgery and start of SU was 5.8 and 15.6 months, respectively (median follow-up 15.2 months). Corresponding median OS was 16.4 and 26.0 months, respectively. Differences in PFS and OS based on response to SU were not significant. Younger age was prognostic of survival. Surgery is feasible in patients with metastatic GIST on SU, but incomplete resections are frequent and complication rates are high. Relevance of survival rates is difficult to assess given the selection bias. Benefits of surgery should be weighed against symptoms and alternative treatments.

Congenital valvular aortic stenosis: limited progression during childhood

Objective:Congenital valvular aortic stenosis is a common congenital heart malformation. The rate of progression in childhood, however, remains to be established. We assessed the progression of peak aortic velocity before...

Erosive progression is minimal, but erosion healing rare, in patients with rheumatoid arthritis treated with adalimumab. A 1 year investigator-initiated follow-up study using high-resolution computed tomography as the primary outcome measure

Objective:With computed tomography (CT) and radiography, to investigate if repair of bone erosions, defined as regression of erosion scores, occurs during adalimumab treatment of patients with rheumatoid arthritis (RA).Methods:Fifty-two patients...

BMP‐7 protects against progression of cartilage degeneration after impact injury

In vivo studies were used to characterize a model of cartilage injury leading to osteoarthritis progression in the medial femorotibial joint of sheep. In three subsequent studies, bilateral impact injuries were created and one joint received intraarticular injections of 340 microg of rhBMP-7 protein in a collagen particle carrier while the contralateral knee received the vehicle alone. Sheep were allocated to three groups that received intraarticular injections on day 0 (group A), 21 (group B), or 90 (group C) after experimental knee injury. In each group the, joints were evaluated for signs of osteoarthritis progression 90 days after the last treatment using India ink stained area, OARSI histological scoring, cartilage sGAG content, immunostaining for apoptosis (TUNEL), caspase-3, collagen degradation (Col 2 3/4C short collagen epitope), and the endogenous (pro-) form of BMP-7 protein. Knee joints that received rhBMP-7 immediately after injury had small focal lesions at the injury site that did not progress into the surrounding cartilage. Joints that received BMP-7 3 weeks after injury were improved and had limited progression compared to controls, but joints that received the protein 12 weeks after injury had no statistically significant improvement. These studies suggest that BMP-7 may be chondroprotective after traumatic injury in patients if it is administered within 3 to 4 weeks of the index injury. The mechanism of protection after sublethal injury appeared to be an increased survival of chondrocytes that are able to participate in the repair process.

Abstract 1633: RhoA and Rho Kinase Activation in Human Pulmonary Hypertension - Role of 5-HT Signaling

Background- The complex and multifactorial pathogenesis of pulmonary hypertension (PH) involves constriction, remodeling, and in situ thrombosis of pulmonary vessels. Both serotonin (5-HT) and Rho kinase signaling may contribute to these alterations. Here, we investigated possible links between the 5-HT transporter (5-HTT) and RhoA/Rho kinase pathways, as well as their involvement in the progression of human and experimental PH. Methods and Results- Lungs, platelets, and quiescent cultured pulmonary-artery smooth-muscle cells (PA-SMCs) from patients with idiopathic PH (iPH) were characterized by marked elevations in RhoA and Rho kinase activity and by a strong increase in serotonin binding to RhoA, compared to controls. The 5-HTT inhibitor fluoxetine and the type 2 transglutaminase inhibitor monodansylcadaverin prevented 5-HT-induced RhoA serotonylation and RhoA/Rho kinase activation, as well as 5-HT-induced proliferation of PA-SMCs from iPH patients, that was also inhibited by the Rho kinase inhibitor fasudil. Increased Rho kinase activity, RhoA activation, and RhoA serotonylation were also observed in lungs from SM22–5-HTT+ mice, which overexpress 5-HTT in smooth muscle and spontaneously develop PH. Treatment of SM22–5-HTT+ mice with either fasudil or fluoxetine limited both PH progression and RhoA/Rho kinase activation. Conclusions- RhoA and Rho kinase activities are increased in iPH, as a result of transglutaminase-mediated transamidation of RhoA by 5-HT internalized via 5-HTT. Direct involvement of this pathway in 5-HT-mediated PA-SMC proliferation and platelet activation during PH progression identify RhoA/Rho kinase signaling as a promising target for new treatments against PH.