Randomized Trial of Basiliximab Induction versus Steroid Therapy in Pediatric Liver Allograft Recipients Under Tacrolimus Immunosuppression

Avoidance of corticosteroids could be beneficial after pediatric liver transplantation (LTx). To test this hypothesis, we performed a randomized prospective study to compare immunosuppression with tacrolimus (TAC) and steroids versus TAC and basiliximab (BAS) after pediatric LTx. Seventy-two patients were recruited, 36 receiving TAC and steroids and 36 TAC and BAS. The primary endpoint was the occurrence of the first rejection episode. Secondary endpoints were the cumulative incidence and severity of rejection, patient and graft survival, and incidence of adverse events. Overall 1-year patient and graft survival rates were 91.4% and 85.5% in the steroid group, and 88.6% and 80% in the BAS group (p = NS). Patients free from rejection were 87.7% in the BAS group and 67.7% in the steroid group (p = 0.036). The use of BAS was associated with a 63.6% reduction in incidence of acute rejection episodes. Overall incidence of infection was 72.3% in the steroid group and 50% in the BAS group (p = 0.035). We conclude that the combination of TAC with BAS is an alternative to TAC and steroid immunosuppression in pediatric LTx, which allows for a significant reduction in the incidence of acute rejection and infectious complications.     

C-fos expression in the rat nucleus basalis upon excitotoxic lesion with quisqualic acid: a study in adult and aged animals

Summary. A unilateral quisqualic acid lesion was placed in the nucleus basalis magnocellularis of 3- and 24-month-old rats, and the animals were sacrificed at different times post-surgery. The morphology and the number of the cholinergic neurons of the nucleus basalis were analyzed by means of immunohistochemistry for cholineacetyltransferase, in order to evaluate the size and severity of the lesion. Immunohistochemistry for the immediate early gene c-fos was also performed in order to clarify its role in the process of neurodegeneration following the excitotoxin injection. The DNA laddering and TUNEL techniques were used to define the type of cell death involved. At short times (4 hr) the lesion induced alterations in the morphology of cholinergic neurons of the nucleus basalis. Subsequently, a significant decrease in the number of neurons was found in comparison to the contralateral unlesioned side. In the older animals the loss of cholineacetyltransferase immunoreactivity had an earlier onset (4 hr) than in the young (24 hr). C-fos expression was induced by the lesion and not by saline injection in the nucleus basalis and in neighbouring areas of the brain as early as 4 hr after surgery. The c-fos protein was no longer present by 24 hr. Furthermore, the c-fos gene product was consistently absent from the nuclei of cholinergic cells. The aged animals exhibited a slower and smaller increase in c-fos as measured by counting the labelled nuclei in the injected area. Analysis of DNA fragmentation did not provide any evidence for apoptosis as the type of cell death involved in the cholinergic degeneration. These results indicate that the c-fos protein might have a protective role in the response to excitotoxic lesions. Furthermore, we have shown that the aged brain displays a reduced ability to produce a c-fos-mediated plastic response to the lesion. Received December 17, 1997; accepted February 17, 1998     

Cholinergic responses in cloned human TE671/RD tumour cells

The cholinergic responses of the human tumour cell line TE671/RD were examined using digital Ca²⁺ imaging fluorescence microscopy and patch-clamp measurements. In response to stimulation of the muscarinic acetylcholine (ACh) receptor (mAChR), the intracellular concentration of Ca²⁺ ([Ca²⁺]_i) rose about two-fold, in parallel with inositol 1,4,5-trisphosphate accumulation, measured by chromatographic techniques. By contrast, there was no increment of [Ca²⁺]_i upon stimulation of the nicotinic ACh receptor (nAChR), nor after caffeine application. Electrophysiological experiments showed that TE671/RD cells lack functional voltage-activated Ca²⁺ channels. The stimulation of the nAChR induced transient whole-cell currents (I _ACh). Little or no current was detected in isotonic extracellular Ca²⁺, with Cs⁺ in the patch pipette. Cell pretreatment with muscarine reduced I _ACh by about 20%, without consistent modifications of current kinetics. Muscarine applied to the extra-patch membrane under the cell-attached configuration had no obvious effect on ACh-evoked unitary events. In conclusion, in human TE671/ RD cells, muscarinic stimulation increases [Ca²⁺]_i, while nicotinic stimulation does not. In addition, the nAChR exhibits peculiar ion permeability properties and is not functionally regulated by the breakdown of phosphoinositides.     

c-Fos protein expression in the rat subfornical organ following osmotic stimulation.

To examine the role of the subfornical organ (SFO) in the osmotic activation of hypothalamic neurons, the responses of the SFO to osmotic stimulation were evaluated by using c-Fos protein immunohistochemistry. Numerous c-Fos-immunoreactive nuclei were found in the SFO of rats injected i.p. with hypertonic saline solution as early as 30 min after stimulation, and the effect lasted up to 3 h. Only a few c-Fos-positive cells were detected in the SFO of rats injected with isotonic saline. However, electrolytic lesions of the SFO did not prevent the osmotic activation of the hypothalamic paraventricular and supraoptic nuclei. These data suggest that the SFO and the hypothalamic magnocellular nuclei are simultaneously but separately activated by osmotic stress.     

Developing network adequacy standards for VA Community Care

ObjectivesTo inform how the VA should develop and implement network adequacy standards, we convened an expert panel to discuss Community Care Network (CCN) adequacy and how VA might implement network adequacy standards for community care.Data Sources/Study settingData were generated from expert panel ratings and from an audio‐recorded expert panel meeting conducted in Arlington, Virginia, in October 2017.Study DesignWe used a modified Delphi panel process involving one round of expert panel ratings provided by nine experts in network adequacy standards. Expert panel members received a list of network adequacy standard measures used in commercial and government market and were provided a rating form listing a total of 11 measures and characteristics to rate.Data Collection MethodsItems on the rating form were individually discussed during an expert panel meeting between the nine expert panel members and VA Office of Community Care leaders. Attendees addressed discordant views and generated revised or new standards accordingly. Recorded audio data were transcribed to facilitate thematic analysis regarding opportunities and challenges with implementing network adequacy standards in VA Community Care.Principal FindingsThe five highest ranked standards were network directories for Veterans, regular reporting of network adequacy data to VA, maximum wait time/distance standards, minimum ratio of providers to enrolled population, and qualitative assessments of network adequacy. During the expert panel discussion with VA Community Care leaders, opportunities and challenges implementing network adequacy standards were highlighted.ConclusionsOur expert panel shed light on priorities for network adequacy to be implemented under CCN contracts, such as developing comprehensive provider directories for Veterans to use when selecting community providers. Remaining questions focus on whether the VA could reasonably develop and implement network adequacy standards given current Congressional restraints on VA reimbursement to community providers.     

Effect of nerve growth factor and GM1 ganglioside on the recovery of cholinergic neurons after a lesion of the nucleus basalis in aging rats

Summary A unilateral ibotenic acid lesion was placed in the nucleus basalis magnocellularis of 3- and 18-month-old rats. In the lesioned aging rats, the number of choline acetyltransferase-immunoreactive neurons of the nucleus basalis magnocellularis was markedly reduced in the ipsilateral side and to a lesser extent in the contralateral side. Twenty-one days after the lesion, the activity of choline acetyltransferase in the ipsilateral cortex was reduced by 40% in both groups of rats and by 24% in the contralateral frontal cortex of the aging rats. Intracerebroventricular administration of nerve growth factor (10 g, twice a week) to aging lesioned rats for 3 weeks after surgery resulted in a complete recovery in the number of choline acetyltransferase-immunoreactive neurons in the nucleus basalis of both sides, and choline acetyltransferase activity in the contralateral cortex, with little effect on the ipsilateral cortex. No potentiation was seen after the concurrent administration of GM1 ganglioside and nerve growth factor. Complete recovery in cortical choline acetyltransferase activity was only observed in the lesioned rats treated with nerve growth factor for 1 week before and 3 weeks after lesioning. Nerve growth factor treatment, both after the lesion, and before and after the lesion, improved the passive avoidance performance disrupted by the lesion. In young lesioned rats daily intraperitoneal administration of GM1 (30 mg/kg) for 21 days after surgery promoted both the recovery of choline acetyltransferase activity and passive avoidance performance. In aging rats GM1, even at a dose twice as large, failed to reverse the biochemical and morphological deficits and behavioral impairment induced by the lesion. Only when GM1 administration was started 3 days before the lesion, were a complete recovery in choline acetyltransferase activity in the contralateral cortex and a partial recovery in the ipsilateral cortex obtained.Our results indicate that nerve growth factor and, to some extent, GM1 facilitate the recovery of the cholinergic neurons after a lesion of the nucleus basalis in aging rats, but their efficacy is reduced. The lower efficacy of GM1 as compared to NGF might be due to the different routes of administration used.     

NGF treatment potentiates c-fos expression in the rat nucleus basalis upon excitotoxic lesion with quisqualic acid

The induction of the c-fos gene in the rat brain by NGF was studied in a model of acute cholinergic hypofunction, i.e., the lesion of the nucleus basalis magnocellularis (NBM) with quisqualic acid. Choline acetyltransferase and Fos immunoreactivity (IR) in the NBM were analyzed at different times after the excitotoxic lesion. NGF treatment induced a potentiation of Fos expression 4 and 24 h after lesion. The possibility is discussed that c-fos induction is one of the early mechanisms of the neuroprotective action of NGF.     

Clinical Management of COPD in a Real-World Setting. A Big Data Analysis

ObjectiveThe aim of this study was to evaluate the quality of diagnosis and treatment of COPD using Big Data methodology on the Savana Manager 2.1 clinical platform.Materials and methodsA total of 59,369 patients with a diagnosis of COPD were included from a population of 1,219,749 adults over 40 years of age.ResultsIn total, 78% were men. Spirometry data were available for only 26,453 (43.5%) subjects. Disease severity was classified in 18,172 patients: 4396 mild, 7100 moderate, and 6676 severe, although only 27%, 34%, and 28%, respectively, presented obstructive spirometry. The clinical management of COPD is mainly the responsibility of the primary care and pulmonology departments, while internal medicine and, to a lesser extent, geriatrics also participate. Drug treatment was based on bronchodilators and inhaled corticosteroids (ICS). A marked decline in the use of long-acting beta-2 agonists (LABA) in monotherapy and a slight reduction in ICS/LABA combinations, associated with a long-acting anticholinergic (LAMA) in 74% of cases, were observed. All-cause in-hospital mortality among the overall population was 5.6% compared to 1% of the general population older than 40 years. In total, 35% were admitted to hospital, with an average stay of 6.6 days and an in-hospital mortality rate in this group of 10.74%.DiscussionThis study identifies the main features of an unselected COPD population and the main errors made in the management of the disease.