Liposomal nystatin in patients with invasive aspergillosis refractory to or intolerant of amphotericin B

We assessed the activity and safety of liposomal nystatin, a broad-spectrum antifungal agent, for invasive aspergillosis in patients refractory to or intolerant of amphotericin B. Thirty-three patients were enrolled, received at least one dose of the study drug, and were evaluable for safety. Twenty-six patients had confirmed probable or definite aspergillosis and were fully eligible. Most patients had a hematological malignancy (53.8%) or hematopoietic stem cell transplantation (23.0%), were neutropenic (61.5%), and were refractory to previous amphotericin B (92.3%). The median duration of previous amphotericin B treatment was 16.5 days (range, 5 to 64 days). Aspergillosis was definite in 3 cases and probable in 23 cases. Liposomal nystatin was initiated at a dose of 4 mg/kg of body weight/day. Twenty-five patients were evaluable for response: a complete response was achieved for one patient, and a partial response was achieved for six. Thus, the overall response rate is 7 of 25 (28%; 95% confidence interval, 12 to 49%). Seventeen (68.0%) of the 25 evaluable patients died during therapy or within 1 month after the end of therapy. The primary cause of death was invasive aspergillosis for nine patients and underlying malignancy for eight patients. The most frequent side effects included chills, shivering, and fever, leading to discontinuation of therapy for two patients. Grade 1 decline in renal function was seen for 10 (30.3%) patients, and hypokalemia was seen for 13 (39.4%). We conclude that liposomal nystatin can be effective for salvage therapy of invasive aspergillosis. Infusion-related adverse events have been observed frequently.     

Cerebrovascular autoregulation in critically ill patients during continuous hemodialysis

Purpose

In chronic renal failure, intermittent hemodialysis decreases cerebral blood flow velocity (CBFV); however, in critically ill patients with acute renal failure, the effect of continuous venovenous hemodialysis (CVVHD) on CBFV and cerebrovascular autoregulation (AR) is unknown. Therefore, a study was undertaken to investigate the potential effect of CVVHD on CBFV and AR in patients with acute renal failure.

Methods

This cohort study investigated 20 patients with acute renal failure who required CVVHD. In these patients, the CBFV and index of AR (Mx) were measured using transcranial Doppler before and during CVVHD.

Results

The median Mx values at baseline were 0.33 [interquartile range (IQR): 0.02-0.55], and during CVVHD, they were 0.20 [0.07-0.40]. The differences in Mx (CVVHD – baseline) was (median [IQR]) ?0.015 [?0.19-0.05], 95% confidence interval (CI) ?0.16 to 0.05. The Mx was > 0.3 in 11/20 patients at baseline measurement. Six of these patients recovered to Mx < 0.3 during CVVHD. The CBFV was (median [IQR]) 47 [36-59] cm·sec^?1 at baseline and 49 [36-66] cm·sec^?1 during CVVHD. The difference of CBFV was 0.0 [?4 - 2.7], 95% CI ?2.5 to 4.2.

Conclusion

Compared with patients with intermittent hemodialysis, CVVHD did not influence CBFV and AR in critically ill patients with acute renal failure, possibly due to lower extracorporeal blood flow, slower change of plasma osmolarity, and a lower fluid extraction rate. In a subgroup of patients with sepsis, the AR was impaired at baseline in more than half of the patients, and this was reversed during CVVHD. The trial was registered at ClinicalTrials.gov ID: NCT01376531.     

Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir

Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as "subtype-C-infected patients") versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P = 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC(50)) change in susceptibility to nelfinavir only. Other mutations increased IC(50) correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% +/- 22% to 22% +/- 15% (P = 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.     

Somatic Care with a Psychotic Disorder. Lower Somatic Health Care Utilization of Patients with a Psychotic Disorder Compared to Other Patient Groups and to Controls Without a Psychiatric Diagnosis

Patients with non-affective psychotic disorders (NAPD) face higher risk of somatic problems and early natural death compared to the general population. Therefore, treatment guidelines for schizophrenia and psychosis stress the importance of monitoring somatic risk factors. This study examined somatic Health Care utilization (HCu) of patients with NAPD compared to non-psychiatric controls and patients with depression, anxiety or bipolar disorders using a large Health Insurance database. Results show lower specialist somatic HCu of patients with NAPD compared to matched controls and also lower percentages for prescribed somatic medication and general practitioner consultations for patients aged ≥60 years and after longer illness duration.     

Neurotoxizität von Allgemeinanästhetika im Kindesalter

Many animal experiments have shown that anesthetics can have a neurotoxic effect on immature brains because they induce apoptosis and influence neurogenesis and synaptogenesis. In animal experiments this has substantial implications for the neurocognitive functions of animals in later life. Whether these results of animal experiments can be transferred to humans is currently the subject of intensive research. In several retrospective studies no clear association between anesthesia in premature babies, newborns or infants and the occurrence of learning disorders or behavioral problems could be found. The prospective studies GAS and PANDA are designed to obtain a deeper insight and if possible to clarify this problem. Because of the high relevance of this topic and in order to achieve more clarity for this problem when dealing with parents, the scientific working group for neuroanesthesia and pediatric anesthesia of the German Society for Anesthesiology and Intensive Care Medicine (DGAI) has formulated a position document on the basis of currently available data.     

Neuroanästhesie

Anesthesiological challenges during craniotomy result from the anatomically related low compensatory capacity of the intracranial space in response to increased volume and the low ischemic tolerance of brain tissue. The anesthetic agents used should therefore not increase the intracranial volume and improve the ischemic tolerance. An acute life-threatening increase of intracranial pressure can be temporarily treated by hyperventilation until measures, such as osmotherapy and infusion of intravenous anesthetics become effective. During an operation the homeostatic parameters including blood volume, blood pressure, partial pressure of carbon dioxide and oxygen in blood, plasma glucose concentration and core body temperature have to be closely monitored and kept normal (6 Ns). Optimal implementation of anesthesia necessitates a detailed knowledge of the surgical approach and potential complications. Postoperatively, patients should be extubated as soon as possible to closely monitor cognitive function so that potential deterioration can be detected.     

Resolving voltage-dependent structural changes of a membrane photoreceptor by surface-enhanced IR difference spectroscopy

Membrane proteins are molecular machines that transport ions, solutes, or information across the cell membrane. Electrophysiological techniques have unraveled many functional aspects of ion channels but suffer from the lack of structural sensitivity. Here, we present spectroelectrochemical data on vibrational changes of membrane proteins derived from a single monolayer. For the seven-helical transmembrane protein sensory rhodopsin II, structural changes of the protein backbone and the retinal cofactor as well as single ion transfer events are resolved by surface-enhanced IR difference absorption spectroscopy (SEIDAS). Angular changes of bonds versus the membrane normal have been determined because SEIDAS monitors only those vibrations whose dipole moment are oriented perpendicular to the solid surface. The application of negative membrane potentials (ΔV = −0.3 V) leads to the selective halt of the light-induced proton transfer at the stage of D75, the counter ion of the retinal Schiff base. It is inferred that the voltage raises the energy barrier of this particular proton-transfer reaction, rendering the energy deposited in the retinal by light excitation insufficient for charge transfer to occur. The other structural rearrangements that accompany light-induced activity of the membrane protein, are essentially unaffected by the transmembrane electric field. Our results demonstrate that SEIDAS is a generic approach to study processes that depend on the membrane potential, like those in voltage-gated ion channels and transporters, to elucidate the mechanism of ion transfer with unprecedented spatial sensitivity and temporal resolution.     

Identification and modulation of a naturally processed T cell epitope from the diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65)

T cell recognition of autoantigens is critical to progressive immune-mediated destruction of islet cells, which leads to autoimmune diabetes. We identified a naturally presented autoantigen from the human islet antigen glutamic acid decarboxylase, 65-kDa isoform (GAD65), by using a combination of chromatography and mass spectrometry of peptides bound by the type I diabetes (insulin-dependent diabetes mellitus, IDDM)-associated HLA-DR4 molecule. Peptides encompassing this epitope-stimulated GAD65-specific T cells from diabetic patients and a DR4-positive individual at high risk for developing IDDM. T cell responses were antagonized by altered peptide ligands containing single amino acid modifications. This direct identification and manipulation of GAD65 epitope recognition provides an approach toward dissection of the complex CD4(+) T cell response in IDDM.