Citations

BACKGROUND: The mechanism between ventilator-induced lung injury (VILI) and multiple organ injury is unclear. The aim of our study was to investigate the mechanisms of VILI-induced distal organ injury. METHODS: VILI was induced in rat lungs with high tidal volume (V T ) ventilation of 40 mL/kg for 6 h. Rats with low V T ventilation of 6 mL/kg served as controls. Inflammatory and apoptotic indices in lung and distal organs were assessed. RESULTS: VILI increased lung weight, airway pressure, inflammation, and apoptotic pathologic changes without hemodynamic changes. The white blood cell count and the levels of H 2 O 2 , interleukin-1β (IL-1β), tumor necrosis factor alpha, and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid were higher in the VILI group compared with the control group. H 2 O 2 , IL-1β, and tumor necrosis factor alpha in blood from the left ventricle were up-regulated. H 2 O 2 , IL-1β, tumor necrosis factor alpha, macrophage inflammatory protein-2, c-Jun N-terminal kinase, p38, nuclear factor kappa B, and caspase-3 in lung, heart, liver, and kidney tissues in the VILI group were up-regulated. Furthermore, the apoptotic score for the kidneys was higher than those for other distal organs in the VILI group. CONCLUSIONS: High V T ventilation induces VILI and is associated with inflammation and apoptosis in distal organs. Up-regulation of reactive oxygen species and cytokines in VILI is associated with systemic inflammatory responses. Kidney tissue appears to be more vulnerable than heart and liver tissues following VILI.

Key Points Weekly oral proteasome inhibitor ixazomib appears generally well tolerated with manageable toxicity, limited grade 1/2 neuropathy. Data show that more than 25% of 30 evaluable relapsed/refractory myeloma patients who received the MTD had clinically meaningful responses.

AbstractBackgroundThe aim of the study was to assess which aspects of an enhanced recovery programme are associated with better outcomes following laparoscopic colorectal surgery.MethodsA database of laparoscopic colorectal procedures performed in 2011 was reviewed. Elements of the enhanced recovery programme and compliance were evaluated for short-term (30-day) outcomes. Individual elements included gabapentin, celecoxib, intrathecal analgesia, diet, postoperative fluids, and paracetamol/non-steroidal anti-inflammatory drug pain management.ResultsFive hundred and forty-one consecutive procedures were included. Compliance with the enhanced recovery programme elements ranged from 82·4 to 99·3 per cent. Median length of hospital stay was 3 (i.q.r. 2–5) days, with 25·9 per cent of patients discharged within 48 h. Patients without complications had a median length of stay of 3 (i.q.r. 2–4) days if compliant and 3 (3–5) days if not (P < 0·001). Low oral opiate intake (oral morphine equivalent of less than 30 mg) (odds ratio (OR) 1·97, 95 per cent confidence interval 1·29 to 3·03; P = 0·002), full compliance (OR 2·36, 1·42 to 3·90; P < 0·001) and high surgeon volume (more than 100 cases per year) (OR 1·50, 1·19 to 1·89; P < 0·001) were associated with discharge within 48 h. Compliance with the elements of oral intake and fluid management in the first 48 h was associated with a reduced rate of complications (8·1 versus 19·6 per cent; P = 0·001). Median oral opiate intake was 37·5 (i.q.r. 0–105) mg in 48 h, with 26·2 per cent of patients receiving no opiates.ConclusionCompliance with an enhanced recovery pathway was associated with less opiate use, fewer complications and a shorter hospital stay.

BACKGROUNDWith the advent of limits to resident duty hours and the size of teaching services, many academic institutions have introduced nonteaching services, often triaging perceived better teaching cases to the resident services.OBJECTIVETo compare resident versus faculty perceptions of ideal cases for teaching services and compare these perceptions with actual triage decisions made by faculty who assigned patients to either teaching or nonteaching services.DESIGNResidents and hospitalist faculty were surveyed about their perceptions of ideal and actual teaching admissions, first with qualitative, open‐ended questions and then with quantitative, specific questions generated from responses to the first survey. Characteristics of patients admitted to teaching and nonteaching services were analyzed retrospectively and compared with resident and faculty perceptions.RESULTSResidents and faculty agreed that rare cases, patients with unique physical findings, and a variety of pathology were ideal for teaching services and that social admissions, benefactors, and patients with chronic or functional pain were not. Residents believed that traditional (“bread and butter”) medicine cases were under‐represented on the teaching services. Although residents perceived that they received a disproportionate number of older patients, outside transfers, patients with chronic pain, and patients with cancer, the only statistically significant difference was in patient age, with the teaching service actually receiving younger patients (66.7 vs 69.3 years; P = 0.008).CONCLUSIONSResidents and faculty have similar views about ideal teaching cases, but a triage system based on perceived educational merit creates the possibility of resident misperceptions about their case mix, even if patients are distributed relatively equitably. Journal of Hospital Medicine 2014;9:508–514. © 2014 Society of Hospital Medicine

Common variable immunodeficiency (CVID) is associated with an increased risk of gastric cancer. The aim of the study was to determine the morphological features of CVID-associated gastric adenocarcinoma (CAGA) and of the background gastritis. The population of gastric cancer patients with CVID of Mayo Clinic in the period 2000-2010 was studied; 6 cases of CVID (2 males, 4 females, average age 47 years, age range 26-71 years) were found in 5793 patients with gastric cancer in the study period. Each patient underwent gastric resection for which histology slides were reviewed. Chronic gastritis variables, CVID-related findings, and features of the adenocarcinoma were recorded. CAGA was of intestinal type, with high number of intratumoral lymphocytes (ITLs). Cancer was diagnosed in younger patients than in the overall population of gastric cancer. Severe atrophic metaplastic pangastritis with extensive dysplasia was present in the background in 4 cases, with features of lymphocytic gastritis in 2 cases. Features of CVID (plasma cells paucity in 4 of 6 cases, lymphoid nodules prominent in four cases) could be detected. In summary, gastric adenocarcinoma at young age with ITLs, accompanied by atrophic metaplastic pangastritis, should alert the pathologist of the possibility of CAGA. It follows that, in presence of those characteristics, the search of CVID-associated abnormalities should be undertaken in the nonneoplastic tissues.

Abstract Classic hyperacute rejection is dependent on the activation of the terminal components of complement. Recently, xenoantibodies with limited abilities to activate the classical pathway of complement in vitro have been implicated in the acute vascular rejection of xenografts. It is unclear how these Abs affect their pathogenic activities in vivo. In this study, we demonstrate the ability of an anti-Gal-α1,3Gal (Gal) IgG1, with modest complement-activating abilities in vitro, to induce xenograft rejection. This rejection was dependent on the activation of complement, on FcγR-mediated interactions, and on the presence of NK cells. Inhibition of any one of these factors resulted in the abrogation of IgG1-mediated rejection. In contrast, an anti-Gal IgG3 mAb induced classic, hyperacute rejection that was solely dependent on complement activation. Our observations implicate two types of IgG-mediated rejection; one that is dependent on complement activation, and a second that is uniquely dependent on complement, FcγR, and NK cells.

Background Current evaluation of suspected allergic contact dermatitis to lanolin includes patch testing to lanolin alcohol (30% in petrolatum). Using this method, the prevalence of lanolin allergy is low (1.8%–2.5%). Objective The objective of this study was to determine whether patch testing to a single lanolin derivative results in underdiagnosis compared with patch testing to 12 lanolin derivatives. Methods Patients were prospectively patch tested to (1) lanolin alcohol (30% in petrolatum) in our standard allergen series; (2) Amerchol L101 (50% in petrolatum) in our cosmetic series; and (3) 10 lanolin derivatives (using concentrations and vehicles recommended in the literature) in a supplemental series. Results Of 286 patients, the overall prevalence of positive reactions to lanolin in at least 1 of the 3 patch test series was 6.29% (95% confidence interval [CI], 3.48%-9.11%) (n = 18). The prevalence rates of lanolin allergy using the standard, cosmetic, and supplemental series were 1.05% (95% CI, 0%–2.23%), 3.85% (95% CI, 1.62%–6.07%), and 3.85% (95% CI, 1.62%–6.07%), respectively. Amerchol L101 was associated with increased reaction rates compared with the standard (odds ratio, 3.81; P = 0.007) and supplemental (odds ratio, 8.85; P < 0.001) series, whereas reaction rates were similar for the standard and supplemental series ( P = 0.78). Conclusions Amerchol L101 and patients’ own products should be added to a standard patch testing allergen series to adequately identify lanolin allergy.

ABSTRACT Pneumocystis pneumonia (PcP) is a significant cause of morbidity and mortality in immunocompromised patients. In humans, PcP is caused by the opportunistic fungal species Pneumocystis jirovecii . Progress in Pneumocystis research has been hampered by a lack of viable in vitro culture methods, which limits laboratory access to human-derived organisms for drug testing. Consequently, most basic drug discovery research for P. jirovecii is performed using related surrogate organisms such as Pneumocystis carinii , which is derived from immunosuppressed rodents. While these studies provide useful insights, important questions arise about interspecies variations and the relative utility of identified anti- Pneumocystis agents against human P. jirovecii . Our recent work has identified the histone acetyltransferase (HAT) Rtt109 in P. carinii (i.e., PcRtt109) as a potential therapeutic target for PcP, since Rtt109 HATs are widely conserved in fungi but are absent in humans. To further address the potential utility of this target in human disease, we now demonstrate the presence of a functional Rtt109 orthologue in the clinically relevant fungal pathogen P. jirovecii (i.e., PjRtt109). In a fashion similar to that of Pcrtt109 , Pjrtt109 restores H3K56 acetylation and genotoxic resistance in rtt109 -null yeast. Recombinant PjRtt109 is an active HAT in vitro , with activity comparable to that of PcRtt109 and yeast Rtt109. PjRtt109 HAT activity is also enhanced by the histone chaperone Asf1 in vitro . PjRtt109 and PcRtt109 showed similar low micromolar sensitivities to two reported small-molecule HAT inhibitors in vitro . Together, these results demonstrate that PjRtt109 is a functional Rtt109 HAT, and they support the development of anti- Pneumocystis agents directed at Rtt109-catalyzed histone acetylation as a novel therapeutic target for human PcP.

Background The study aims to compare methods of determining headache directionality (imploding, exploding, and/or ocular headaches) in women with migraine, investigate the concordance between physician assignment and patient self‐assignment of pain directionality, and evaluate whether patients assigned their headaches to the same direction when queried using different methods. Directionality of migraine headache pain (imploding, exploding, or ocular) may reflect differences in the underlying pathogenesis of individual migraine attacks among and within individuals. Emerging evidence suggests that directionality of pain in migraine sufferers may predict response to onabotulinumtoxin A . The best method of determining headache directionality in migraine sufferers has not been systematically explored. Methods We conducted a prospective cross‐sectional survey study of 198 female patients with migraine presenting to a W omen's H ealth C linic. Patients determined the directionality (imploding, exploding, and/or ocular) of their own migraine pain by choosing among 3 pictures graphically representing directionality and also by responding to a written question regarding directionality. Clinicians then classified directionality of migraine pain using structured interviews. Concordance between clinician assignment of directionality and patient self‐assignment was determined with K appa coefficients. Results Subjects were females between the ages of 18 and 77 years (mean 48 years). According to patient selection of representative pictures, 62 (31.6%) had imploding headaches with or without ocular pain, 36 (18.4%) had exploding headaches with or without ocular pain, 78 (39.8%) had ocular pain only, and 20 (10.2%) had imploding and exploding headaches with or without ocular pain. Two subjects did not respond. According to patient responses to a written question, 80 (41.0%) had imploding headaches with or without ocular pain, 53 (27.2%) had exploding headaches with or without ocular pain, 46 (23.6%) had ocular pain only, and 16 (8.2%) had imploding and exploding headaches with or without ocular pain. Three subjects did not respond. For physician assignment, 69 (34.9%) subjects had imploding headaches with or without ocular pain, 89 (45%) had exploding headaches with or without ocular pain, 14 (7.1%) had ocular pain only, and 26 (13.1%) had imploding and exploding headaches with or without ocular pain. The concordance ( K appa coefficient) between physician assignment of headache directionality with patient response to the written question was 0.33 (weak agreement), between physician assignment and patient assignment via selection of representative pictures was 0.35 (weak agreement), and between patient assignment via written question and via selection of representative pictures was 0.35 (weak agreement). Conclusions The assignment of headache directionality varied substantially depending upon the method of determination. The concordance between clinician assignment, patient‐self assignment via answering a written question, and patient self‐assignment via choosing a representative picture was weak. Improved methods of determining pain directionality are needed.