To evaluate expression of proangiogenic matrix metalloproteinases (MMP) 2 and 9 at distinct intervals after verteporfin photodynamic therapy (PDT) in human choroidal neovascular membranes (CNV) secondary to age‐related macular degeneration (AMD).
Retrospective review of an interventional case series of 49 patients who underwent removal of CNV. Twenty‐six patients were treated with PDT 3 to 383 days prior to surgery. Twenty‐three CNV without previous treatment were used as controls. CNV were stained for CD34, cytokeratin 18, endostatin, MMP‐2 and MMP‐9 by immunohistochemistry.
CNV without previous therapy disclosed MMP‐2, MMP‐9 in RPE–Bruch's membrane, vessels and stroma in different intensities. Three days after PDT, MMP‐9 expression was significantly weaker in stroma (p = 0.0019). Endostatin was significantly reduced in vessels (p<0.001). At longer post‐PDT intervals, a significant increase of MMP‐9 in stroma (p = 0.037) and of endostatin in RPE–Bruch's membrane (p = 0.02), vessels (p = 0.005) and stroma (p<0.001) were disclosed. No significant changes in MMP‐2 expression were detected.
PDT induced an early, temporary decrease in MMP‐9 and endostatin expression. At longer intervals, MMP‐9 increase is possibly associated with the angiogenic process responsible for recurrence after PDT. MMP‐9, however, acts as a double‐edged sword by concomitant induction of endostatin, an endogenous inhibitor of angiogenesis.
To determine the incidence and outcomes of intensive care unit-acquired neuromyopathy and investigate the role of methylprednisolone in survivors of persistent acute lung injury.
Secondary analysis of completed randomized placebo-controlled trial.
25 hospitals in the NHLBI ARDS Network.
Patients and participants
Patients enrolled in the ARDS Network study of methylprednisolone versus placebo for persistent ARDS who survived 60 days or to hospital discharge.
Measurements and Results
One hundred and twenty-eight study patients survived 60 days. Forty-three (34%) of these patients had evidence by chart review of ICU-acquired neuromyopathy, which was associated with prolonged mechanical ventilation, return to mechanical ventilation, and delayed return to home after critical illness. Treatment with methylprednisolone was not significantly associated with an increase in risk of neuromyopathy (OR 1.5, 95% CI 0.7-3.2).
ICU-acquired-neuromyopathy is common among survivors of persistent ARDS and is associated with poorer clinical outcomes. We did not find a significant association between methylprednisolone treatment and neuromyopathy. Limitations of this study preclude definitive conclusions about the causal relationship between corticosteroids and ICU-acquired neuromuscular dysfunction.
Acute lung injury; Acute respiratory distress syndrome; Critical illness; Glucocorticoids/therapeutic use; Paresis; Critical illness Polyneuropathy
Sentinel headache (SH) is a kind of secondary headache and is characterized as sudden, intense, and persistent, preceding spontaneous subarachnoid hemorrhage (SAH) by days or weeks.
Eighty-nine consecutive patients with a diagnosis of spontaneous SAH were evaluated following admission to the Neurosurgical Service at Santa Casa Hospital, Belo Horizonte, between December 2009 and December 2010.
Out of the 89 patients, 64 (71.9%) were women. Mean age was 48.9 years (SD ± 13.4, ranging from 18 to 85 years). Twenty-four patients (27.0%) presented SH, which occurred, in average, 10.6 days (SD ± 13.5) before a SAH. No statistically significant differences were observed between the presence of SH and gender, arterial hypertension and migraine (P > 0.05), Glasgow Comma Scale (GCS) and World Federation of Neurological Surgeons (WFNS) scale at admission.
The prevalence of SH was 27% in this study but no related factors were identified. Therefore, further clarification of this important entity is required so as to facilitate its recognition in emergency services and improve the prognosis of patients with cerebral aneurysms.
Intracranial aneurysm; sentinel headache; subarachnoid hemorrhage
Transfusion of red blood cells (RBC) is recommended in septic shock and the majority of these patients receive RBC transfusion in the intensive care unit (ICU). However, benefit and harm of RBCs have not been established in this group of high-risk patients.
The Transfusion Requirements in Septic Shock (TRISS) trial is a multicenter trial with assessor-blinded outcome assessment, randomising 1,000 patients with septic shock in 30 Scandinavian ICUs to receive transfusion with pre-storage leuko-depleted RBC suspended in saline-adenine-glucose and mannitol (SAGM) at haemoglobin level (Hb) of 7 g/dl or 9 g/dl, stratified by the presence of haematological malignancy and centre. The primary outcome measure is 90-day mortality. Secondary outcome measures are organ failure, ischaemic events, severe adverse reactions (SARs: anaphylactic reaction, acute haemolytic reaction and transfusion-related circulatory overload, and acute lung injury) and mortality at 28 days, 6 months and 1 year.
The sample size will enable us to detect a 9% absolute difference in 90-day mortality assuming a 45% event rate with a type 1 error rate of 5% and power of 80%. An interim analysis will be performed after 500 patients, and the Data Monitoring and Safety Committee will recommend the trial be stopped if a group difference in 90-day mortality with P ≤0.001 is present at this point.
The TRISS trial may bridge the gap between clinical practice and the lack of efficacy and safety data on RBC transfusion in septic shock patients. The effect of restrictive versus liberal RBC transfusion strategy on mortality, organ failure, ischaemic events and SARs will be evaluated.
ClinicalTrials.gov: NCT01485315. Registration date 30 November 2011. First patient was randomised 3 December 2011.
Sepsis; Septic shock; Intensive care medicine; Red blood cell transfusion; Fluid therapy
The wasp stings usually cause local reactions and rarely anaphylaxis. However the multiple wasp stings may cause multisystem involvement. We report a case of acute renal failure (ARF) following multiple wasp stings. A middle aged healthy gentleman presented with pain and swelling of the upper part of the body following multiple wasp stings. After 2 days, he developed progressive decrease in urine output with high colored urine. Physical examination revealed the edematous and tender affected part. On investigating, it was found to have sequential elevations in renal function tests. The markers of muscle injury were grossly elevated and liver enzymes were deranged. These findings suggest multisystem involvement predominantly ARF secondary to rhabdomyolysis. With the initiation of the intense hemodialysis, all the above parameters became normal. Timely intervention of multiple wasp stings causing ARF with multiorgan involvement by hemodialysis not only prevents mortality but also other complications.
Acute renal failure; Multiple wasp stings; Multisystem involvement
Delivery of critical care by intensivists has been recommended by several groups. Our objective was to understand the delivery of critical care physician services in Michigan and the role of intensivists and non-intensivist providers in providing care.
Participants and Setting
ICU directors and nurse managers at 96 sites, representing 115 intensive care units (ICUs) from 72 hospitals in Michigan.
Measurements and Results
The primary outcome measure was the percentage of sites utilizing a closed versus an open model of ICU care. Secondary outcome measures included the percentage of ICUs utilizing a high-intensity service model, hospital size, intensive care unit size, type of clinician providing care and clinical activities performed. Twenty four (25%) sites used a closed model of intensive care, while 72 (75%) had an open model of care. Hospitals with closed ICUs were larger and had larger ICUs than sites with open ICUs (p < 0.05). Hospitalists serving as attending physicians were strongly associated with an open ICU (odds ratio [OR][(95% confidence interval [CI]]=12.2 (2.5, 60.2), as was the absence of intensivists in the group (OR [95% CI]=12.2 (1.4, 105.8)), while ICU and hospital size were not associated. At eighteen sites (20%) all attendings were board certified in Critical Care. Sixty sites had less than 50% board certified attending physicians.
The closed intensivist led model of intensive care delivery is not in widespread use in Michigan. In the absence of intensivists, alternate models of care, including the hospitalist model, are frequently used.
multi-disciplinary care; leadership; teamwork; care standardization
1. Rabbits inoculated intradermally with certain strains of green streptococci have well marked lesions which, after reaching a maximum size in 24 to 48 hours and then beginning to retrogress, show in over 50 per cent of the animals a secondary increase in size and other signs of inflammation about 8 or 9 days after inoculation. 2. This secondary reaction may follow the inoculation of a variety of strains of green-producing streptococci from various sources, of indifferent streptococci, and occasionally of pneumococci. 3. The inoculation of hemolytic streptococci, staphylococci, Micrococcus catarrhalis, or Bacillus coli has not been followed by this secondary reaction. 4. The secondary reaction is not due to increased activity of the injected bacteria since the lesions are usually sterile at the time it occurs and since the secondary reaction occurs after inoculation of killed organisms as well as after that of living ones. 5. A second inoculation of green streptococci into a rabbit within 9 weeks of a first injection is followed by a primary but not by a secondary reaction. This inhibition of the secondary reaction is not specific; for the phenomenon of secondary reaction can be completely inhibited by previous inoculations of the rabbit with any living streptococcus and usually with pneumococci. Killed organisms are less effectual. 6. Preliminary injection with staphylococci, Micrococcus catarrhalis, and Bacillus coli has not prevented the appearance of a secondary reaction in response to subsequent injections of green streptococci. 7. The agent responsible for the secondary reaction has not as yet been determined; its nature is discussed. The phenomenon is possibly a form of allergic reaction.
The essential points of our results are as follows: The saprophytic Bacillus megatherium produced a definite pulmonary lesion which in gross appearance resembled the lesion of lobar pneumonia. The lesion was one of intense leucocytic exudation which, as in some other cases of experimental lobar pneumonia, did not invade the framework of the lung. But the exudate contained no fibrin. There were practically no bacilli, either in the heart's blood or in the lung. The growth of two colonies from one of the cases hardly changes the rule. The lesion did not progress after twenty-four hours; nor did it show a definite increase in extent or intensity with the increase in quantity of the injected cultures. The resolution of the exudate began practically at the end of twenty-four hours and was far advanced on the third day. Although there was considerable leucocytic infiltration there was no phagocytosis apparent twenty-four hours after inoculation. Taking all the facts into consideration one gains the impression that the lesion produced by the saprophytic Bacillus megatherium differs only quantitatively from that produced by an avirulent pneumococcus. The fact stands out prominently that a saprophytic bacterium is capable of producing a pneumonic lesion similar in gross appearance to that of mild lobar pneumonia. It is not improbable that other saprophytes may be capable of producing pneumonic lesions which, in specific instances, may resemble lobular pneumonia.
To determine whether intensive glycemic therapy reduces the risk of erectile dysfunction (ED) in men with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT).
MATERIALS AND METHODS
DCCT randomized 761 males with type 1 diabetes to intensive or conventional glycemic therapy in 28 sites between 1983–1989, of whom 366 had diabetes for 1–5 years and no microvascular complications (primary prevention cohort) and 395 for 1–15 years with non-proliferative retinopathy or microablbuminuria (secondary intervention cohort). Subjects were treated until 1993 and followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. In 2003, we conducted an ancillary study using a validated assessment of ED in 571 men (80% participation rate); 291 in the primary cohort and 280 in the secondary cohort.
Twenty-three percent of participants reported ED. The prevalence was significantly lower in the intensive versus conventional treatment group in the secondary cohort (12.8% versus 30.8%, p=0.001); but not the primary cohort (17% versus 20.3%, p=0.49). The risk of ED in both primary and secondary cohorts was directly associated with mean HbA1c during DCCT and EDIC combined. Age, peripheral neuropathy, and lower urinary tract symptoms were other risk factors.
A period of intensive therapy significantly reduced the prevalence of ED ten years later among those in the secondary intervention cohort, but not the primary prevention cohort; higher HbA1c was significantly associated with risk in both cohorts. These findings provide further support for early implementation of intensive insulin therapy in young men with type 1 diabetes.
Glycemic Control; Diabetes; Erectile Dysfunction; Risk
The disposition of chloroquine (CQ) and the related 4-aminoquinoline, piperaquine (PQ), were compared in Papua New Guinean children with uncomplicated malaria. Twenty-two children were randomized to 3 days of PQ phosphate at 20 mg/kg/day (12 mg of PQ base/kg/day) coformulated with dihydroartemisinin (DHA-PQ), and twenty children were randomized to 3 days of CQ at 10 mg base/kg/day with a single dose of sulfadoxine-pyrimethamine (CQ-SP). After a 42-day intensive sampling protocol, PQ, CQ, and its active metabolite monodesethyl-chloroquine (DECQ) were assayed in plasma by using high-performance liquid chromatography. A two-compartment model with first-order absorption was fitted to the PQ and CQ data. There were no significant differences in age, gender, body weight, or admission parasitemia between the two groups. The PCR-corrected 42-day adequate clinical and parasitological responses were 100% for DHA-PQ and 94% for CQ-SP, but P. falciparum reinfections during follow-up were common (33 and 18%, respectively). For PQ, the median volume of distribution at steady state, allowing for bioavailability (Vss/F), was 431 liters/kg (interquartile range [IQR], 283 to 588 liters/kg), the median clearance (CL/F) was 0.85 liters/h/kg (IQR, 0.67 to 1.06 liters/h/kg), the median distribution half-life (t1/2α) was 0.12 h (IQR, 0.05 to 0.66 h), and the median elimination half-life (t1/2β) was 413 h (IQR, 318 to 516 h). For CQ, the median Vss/F was 154 liters/kg (IQR, 101 to 210 liters/kg), the median CL/F was 0.80 liters/h/kg (IQR, 0.52 to 0.96 liters/h/kg), the median t1/2α was 0.43 h (IQR, 0.05 to 1.82 h), and the median t1/2β was 233 h (IQR, 206 to 298 h). The noncompartmentally derived median DECQ t1/2β was 290 h (IQR, 236 to 368 h). Combined molar concentrations of DECQ and CQ were higher than those of PQ during the elimination phase. Although PQ has a longer t1/2β than CQ, its prompt distribution and lack of active metabolite may limit its posttreatment malaria-suppressive properties.
Twenty patients with non-Hodgkin's lymphoma were treated with a combination of cyclophosphamide (750 mg m(-2), day 1), epidoxorubicin (60 mg m(-2), day 1), vincristine (1.4 mg m(-2), day 1) and prednisone (100 mg m(-2), days 1-5) every 14 days. Shortening of intervals was associated with the prophylactic employment of granulocyte colony-stimulating factor (G-CSF; specifically, filgrastim) administered at a dose of 300 microg subcutaneously from day 6 to day 11. The ratio between actually delivered dose intensity and planned dose intensity was 1.0 in 18 out the 20 patients. Toxicity was acceptable; response rate and survival are in the expected range. The present study demonstrated the feasibility of acceleration of chemotherapy cycles to obtain dose intensification in non-Hodgkin's lymphoma.
The Toxicological Evaluation of Realistic Emission Source Aerosols (TERESA) project assessed primary and secondary particulate by simulating the chemical reactions that a plume from a source might undergo during atmospheric transport and added other atmospheric constituents that might interact with it. Three coal-fired power plants with different coal and different emission controls were used. Male Sprague-Dawley rats were exposed for 6 h to either filtered air or aged aerosol from the power plant. Four exposure scenarios were studied: primary particles (P); primary + secondary (oxidized) particles (PO); primary + secondary (oxidized) particles + SOA (POS); and primary + secondary (oxidized) particles neutralized + SOA (PONS). Exposure concentrations varied by scenario to a maximum concentration of 257.1 ± 10.0 µg/m3. Twenty-four hours after exposure, pulmonary cellular responses were assessed by bronchoalveolar lavage (BAL), complete blood count (CBC), and histopathology. Exposure to the PONS and POS scenarios produced significant increases in BAL total cells and macrophage numbers at two plants. The PONS and P scenarios were associated with significant increases in BAL neutrophils and the presence of occasional neutrophils and increased macrophages in the airways and alveoli of exposed animals. Univariate analyses and random forest analyses showed that increases in total cell count and macrophage cell count were significantly associated with neutralized sulfate and several correlated measurements. Increases in neutrophils in BAL were associated with zinc. There were no significant differences in CBC parameters or blood vessel wall thickness by histopathology. The association between neutrophils increases and zinc raises the possibility that metals play a role in this response.
Bronchoalveolar lavage; inflammation; histology; inhaled particles; power plant emissions; aerosol sources; pollution sources