Time course and degree of hyperinflation with metronome-paced tachypnea in COPD patients

In COPD patients, tachypnea should increase (dynamic) hyperinflation by shortening expiratory time. We developed a method to evaluate the time course and degree of dynamic hyperinflation during metronome-paced tachypnea. Fourteen patients with stable COPD (FEV(1) 43 +/- 13% predicted) were studied. Inspiratory capacity (IC) was measured breathing through a flow transducer. Subjects paced their respiratory rate (f(R)) at 20/min, 30/min and 40/min for 60-second periods in response to audible tones generated by a computer. IC measurements were obtained at baseline and after 30 and 60 seconds at each f(R). End-tidal carbon dioxide was monitored and f(R) was allowed to return to baseline between periods of tachypnea. Tachypnea produced reductions in IC of 200 +/- 240 ml, 380 +/- 330 ml and 540 +/- 300 ml after 30 seconds at 20/min, 30/min and 40/min, respectively. IC reduction at 60 seconds was similar to 30 seconds for each f(R). In patients with moderate-to-severe COPD, the dynamic hyperinflation induced by metronome-paced tachypnea was shown to occur rapidly and be complete by 30 seconds for a given f(R). Controlled increments in f(R) produced stepwise increases in dynamic hyperinflation. This standardized method could be a useful and easier method of assessing dynamic hyperinflation in COPD patients before and after therapeutic interventions.     

Time dependency of uterine effects of naringenin type phytoestrogens in vivo

Phytoestrogens exhibit significant estrogen agonistic/antagonistic properties in animals and humans. Naturally occurring flavonoids with a naringenin backbone like 8-prenylnaringenin (8-PN) and 6-(1,1-dimethylallyl)naringenin (6-DMAN) are considered to be some of the most potent phytochemicals activating nuclear receptors. 8-PN is a more potent estrogenic substance while 6-DMAN appears to have a higher antiandrogenic potency, however these are less well characterized compared to other phytoestrogens such as genistein. The aim of this study was to assess the estrogenic properties of 8-PN and 6-DMAN in an ovariectomized in vivo rat model. 8-PN and 6-DMAN were applied at concentrations of 15mg/kgBW. We assessed the uterotrophic response after 7h, 24h and 72h of treatment. In contrast to 8-PN, 6-DMAN did not alter uterine wet weight or the level of expression of proliferation markers at any time point. In contrast to the uterotrophic response, 6-DMAN stimulated uterine mRNA expression of estrogen responsive genes carrying an estrogen response element (ERE) in the ovariectomized rats, but to a lesser extent than E2 and 8-PN. In all treatment regimens, the mRNA expression of estrogen receptors alpha and beta mRNA was measured. In summary, we assessed the time dependent uterine responses and estrogenic activities of 6-DMAN and 8-PN. In contrast to 8-PN which mimicked the E2 induced responses on uterine wet weight and gene expression, 6-DMAN has no uterotrophic effect and only regulated the mRNA expression of genes carrying an ERE. Therefore, 6-DMAN is an exciting candidate molecule for future investigations and potentially a natural occurring selective estrogen receptor modulator.     

Etomidate reduces glutamate uptake in rat cultured glial cells: involvement of PKA

Background and purpose:

Glutamate is the main excitatory neurotransmitter in the vertebrate CNS. Removal of the transmitter from the synaptic cleft by glial and neuronal glutamate transporters (GLTs) has an important function in terminating glutamatergic neurotransmission and neurological disorders. Five distinct excitatory amino-acid transporters have been characterized, among which the glial transporters excitatory amino-acid transporter 1 (EAAT1) (glutamate aspartate transporter) and EAAT2 (GLT1) are most important for the removal of extracellular glutamate. The purpose of this study was to describe the effect of the commonly used anaesthetic etomidate on glutamate uptake in cultures of glial cells.

Experimental approach:

The activity of the transporters was determined electrophysiologically using the whole cell configuration of the patch-clamp recording technique.

Key results:

Glutamate uptake was suppressed by etomidate (3–100 μM) in a time- and concentration-dependent manner with a half-maximum effect occurring at 2.4±0.6 μM. Maximum inhibition was approximately 50% with respect to the control. Etomidate led to a significant decrease of V_max whereas the K_m of the transporter was unaffected. In all cases, suppression of glutamate uptake was reversible within a few minutes upon washout. Furthermore, both GF 109203X, a nonselective inhibitor of PKs, and H89, a selective blocker of PKA, completely abolished the inhibitory effect of etomidate.

Conclusion and implications:

Inhibition of glutamate uptake by etomidate at clinically relevant concentrations may affect glutamatergic neurotransmission by increasing the glutamate concentration in the synaptic cleft and may compromise patients suffering from acute or chronic neurological disorders such as CNS trauma or epilepsy.     

The Prognostic Importance of Bronchoalveolar Lavage Fluid CXCL9 During Minimal Acute Rejection on the Risk of Chronic Lung Allograft Dysfunction

The clinical significance and treatment strategies for minimal acute rejection (grade A1), the most common form of acute rejection (AR), remain controversial. In this retrospective single‐center cohort study of 441 lung transplant recipients, we formally evaluate the association between minimal AR and chronic lung allograft dysfunction (CLAD) and test a novel hypothesis using bronchoalveolar lavage (BAL) CXCL9 concentration during minimal AR as a biomarker of subsequent CLAD development. In univariable and multivariable models adjusted for all histopathologic injury patterns, minimal AR was not associated with CLAD development. However, minimal AR with elevated BAL CXCL9 concentrations markedly increased CLAD risk in a dose–response manner. Minimal AR with CXCL9 concentrations greater than the 25th, 50th, and 75th percentile had adjusted hazard ratios (HRs) for CLAD of 1.1 (95% confidence interval [CI] 0.8–1.6), 1.6 (95% CI 1.1–2.3), and 2.2 (95% CI 1.4–3.4), respectively. Thus we demonstrate the utility of BAL CXCL9 measurement as a prognostic biomarker that allows discrimination of recipients at increased risk of CLAD development after minimal AR. BAL CXCL9 measurement during transbronchial biopsies may provide clinically useful prognostic data and guide treatment decisions for this common form of AR, as a possible strategy to minimize CLAD development.     

Immunosuppressive and cytotoxic therapy: pharmacology, toxicities, and monitoring

Treatment strategies for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are evolving. Cyclophosphamide (CYC) plus corticosteroids (CSs) is the mainstay of therapy for generalized, multisystemic AAV. Historically, the combination of CYC plus CS was used for a minimum of 12 months, but concern about late toxicities associated with CYC has led to novel treatment approaches. Currently, short-course (3 to 6 months) induction treatment with CYC plus CS, followed by maintenance therapy with less toxic agents (eg, methotrexate, azathioprine, mycophenolate mofetil) is recommended. Further, methotrexate combined with CS may be adequate for limited, non-life-threatening AAV. Recent studies suggest that rituximab may be useful for induction therapy or for CYC-refractory AAV. This article reviews the key agents used to treat AAV, with a focus on pharmacology, toxicities, and monitoring.     

Usual interstitial pneumonia

Usual interstitial pneumonia (UIP) is a distinct histological lesion observed in idiopathic pulmonary fibrosis (IPF) but can be found in other etiologies. The diagnosis of UIP can be established by surgical lung biopsy or by high-resolution thin-section computed tomographic (CT) scans (provided the radiographic features are classical). Historically, patients labeled as "IPF" encompassed a group of disorders, including UIP as well as other idiopathic interstitial pneumonias that differ from UIP in prognosis and responsiveness to therapy. Current recommendations from international consensus statements restrict the term IPF to patients with idiopathic UIP. The inciting cause(s) and pathogenesis of UIP have not been elucidated, but alveolar epithelial cell injury and dysregulation or altered phenotypic expression of fibroblasts are key elements. Inflammatory cells may play minor roles in initiating or propagating the fibrotic process. The prognosis of UIP is poor. Mean survival following diagnosis approximates 3 years. Current therapies are of unproven value. Corticosteroids or immunosuppressive agents have been most often used, but data affirming benefit are lacking. Lung transplantation is a viable option for patients failing medical therapy. This review discusses diagnostic criteria for UIP (both histopathological and radiographic), natural history and clinical course, and therapeutic approaches (both current and future).     

Jackhammer esophagus: high‐resolution manometry and therapeutic approach using peroral endoscopic myotomy (POEM)

We present the first report on peroral endoscopic myotomy (POEM) in the treatment of jackhammer esophagus. A 34‐year‐old female patient was newly diagnosed with a jackhammer esophagus. After failure of medical treatment, the patient underwent POEM procedure for myotomy of the spastic segment. Postoperatively, a mild emphysema and pneumothorax occurred that required drainage and antibiotic therapy until full recovery. Discharge was possible after 5 days. Six months later, she presented with recurrent but mild pain due to a remnant spastic segment proximal to the myotomy. Endoscopic balloon dilation was performed twice within 6 weeks with full symptomatic relief of pain and mild symptoms of dysphagia.