Relationships between weight loss and circulating cytokines in patients with Alzheimer's disease

106 consecutive patients with Alzheimer's disease living in the community were examined in a memory clinic from a neurological department. They were screened for weight loss over the last 2 years. Age, duration of the disease, behavioral disorders, mini mental status examination, body mass index were recorded. Tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), interleukin 6 (IL-6) and interleukin 2 (IL-2) blood levels were measured. Weight loss was reported in 42.5% of the patients. TNFalpha levels were significantly higher in these patients (18.8 versus 15.8 pg/mL; p=0.04) than in patients without weight loss. Weight loss was also associated with a lower MMSE score (16.9 versus 19.3; p=0.03), current pacing (20% versus 1.6%; p=0.002), and hallucinations (20.0% versus 3.3%; p=0.008). The levels of the other cytokines did not differ between the patients with and without weight loss. Our findings suggest an association between high levels of circulating TNFalpha and unexplained weight loss in Alzheimer's disease.     

Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes?

It is currently accepted that adult tissues may develop and maintain their own stem cell pools. Because of their higher safety profile, adult stem cells may represent an ideal candidate cell source to be used for liver cell therapies. We therefore evaluated the differentiation potential of mesenchymal-like cells isolated from adult human livers. Mesenchymal-like cells were isolated from enzymatically digested adult human liver and expanded in vitro. Cell characterization was performed using flow cytometry, RT-PCR, and immunofluorescence, whereas the differentiation potential was evaluated both in vitro after incubation with specific media and in vivo after intrasplenic transplantation of uPA(+/+)-SCID and SCID mice. Adult-derived human liver mesenchymal-like cells expressed both hepatic and mesenchymal markers among which albumin, CYP3A4, vimentin, and alpha-smooth muscle actin. In vitro differentiation studies demonstrated that these mesenchymal-like cells are preferentially determined to differentiate into hepatocyte-like cells. Ten weeks following intrasplenic transplantation into uPA(+/+)-SCID mice, recipient livers showed the presence of human hepatocytic cell nodules positive for human albumin, prealbumin, and alpha-fetoprotein. In SCID transplanted liver mice, human hepatocyte-like cells were mostly found near vascular structures 56 days posttransplantation. In conclusion, the ability of isolated adult-derived liver mesenchymal stem-like cells to proliferate and differentiate into hepatocyte-like cells both in vitro and in vivo leads to propose them as an attractive expandable cell source for stem cell therapy in human liver diseases.     

Familial cases of glomerulonephritis complicating Crohn's disease

A part from nephrolithiasis, renal involvement is rare in the course of Crohn's disease, particularly glomerulonephritis. On the other hand, while onset of Crohn's disease is strongly influenced by environmental and genetic factors, little is known regarding influence of these factors on extra intestinal manifestations. We report a familial case of glomerulonephritis that occurred in a 38-year old woman and her mother, 59 years old with a 7-year and a 37 year history of stenosing ileocolonic disease, respectively. Both of them developed peripheral oedema with nephrotic syndrome during the course of their Crohn's disease while they had no intestinal symptoms and were not receiving any maintenance therapy. Renal function was conserved in the former while the latter developed renal failure and had already small size kidneys on abdominal sonography. Thus, renal biopsy had been performed only in the former patient and had showed membranous glomerulonephritis. Investigations showed no other underlying disease than Crohn's disease. Through this report we emphasis possible genetic influence on extra intestinal manifestations, particularly glomerulonephritis, in Crohn's disease patients.     

Impact of systematic evaluation of pain and agitation in an intensive care unit

OBJECTIVE: To measure the impact of implementation of the systematic evaluation of pain and agitation by nurses using the Behavioral Pain Scale (BPS), the Numerical Rating Scale (NRS) for pain, and the Richmond Agitation Sedation Scale (RASS) associated with medical staff education in analgesia and sedation management in intensive care unit (ICU) patients. DESIGN: Two-phase, prospective, controlled study. SETTING: Twelve-bed medical-surgical ICU in a university hospital. PATIENTS: Consecutive patients staying >24 hrs in ICU. INTERVENTIONS: BPS, NRS, and RASS were measured twice daily, at rest, by independent observers during 21 wks (control group) and after 4 wks of training, by nurses during 29 wks (intervention group). In the intervention group, the treating physician was alerted in case of pain defined by BPS>5 or NRS>3 or in case of agitation defined by RASS>1. MEASUREMENTS AND MAIN RESULTS: A total of 230 patients were included (control group, n=100; intervention group, n=130). Baseline characteristics were not significantly different. The incidence of pain and agitation decreased significantly in the intervention group: 63% vs. 42% (p=.002) and 29% vs. 12% (p=.002), respectively. Rate of severe pain and agitation events defined by NRS>6 and RASS>2, respectively, also decreased significantly. There were significantly more therapeutic changes in the intervention group in the way of an escalation but also in the way of a de-escalation for analgesic and psychoactive drugs. Compared with the control group, there was a marked decrease in the duration of mechanical ventilation (120 [interquartile range 48-312] vs. 65 (24-192) hrs, p=.01) and nosocomial infections rate (17% vs. 8%, p<.05) in the intervention group. There was no significant difference in median length of stay (9 [4, 15] vs. 7 [4, 13] days) and mortality in ICU (12 vs. 15%). CONCLUSIONS: Systematic evaluation of pain and agitation, and analgesics and sedatives need was associated with a decrease in incidence of pain and agitation, duration of mechanical ventilation and nosocomial infections.     

Retinoic acid metabolism and signaling pathways in the adult and developing mouse testis

As a first step in investigating the role of retinoic acid (RA) in mouse testis, we analyzed the distribution pattern of the enzymes involved in vitamin A storage (lecithin:retinol acyltransferase), RA synthesis (beta-carotene 15,15'-monoxygenase and retinaldehyde dehydrogenases) and RA degradation (cytochrome P450 hydroxylases) as well as those of all isotypes of receptors transducing the RA signal [RA receptors (RARs) and rexinoid receptors (RXRs)]. Our data indicate that in adult testis 1) cytochrome P450 hydroxylase enzymes may generate in peritubular myoid cells a catabolic barrier that prevents circulating RA and RA synthesized by Leydig cells to enter the seminiferous epithelium; 2) the compartmentalization of RA synthesis within this epithelium may modulate, through paracrine mechanisms, the coupling between spermatogonia proliferation and spermatogenesis; 3) retinyl esters synthesized in round spermatids by lecithin:retinol acyltransferase may be transferred and stored in Sertoli cells, in the form of adipose differentiation-related protein-coated lipid droplets. We also show that RARalpha and RXRbeta are confined to Sertoli cells, whereas RARgamma is expressed in spermatogonia and RARbeta, RXRalpha, and RXRgamma are colocalized in step 7-8 spermatids. Correlating these expression patterns with the pathological phenotypes generated in response to RAR and RXR mutations and to postnatal vitamin A deficiency suggests that spermiation requires RXRbeta/RARalpha heterodimers in Sertoli cells, whereas spermatogonia proliferation involves, independently of RXR, two distinct RAR-mediated signaling pathways in both Sertoli cells and spermatogonia. Our data also suggest that the involvement of RA in testis development starts when primary spermatogonia first appear.     

Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency

BACKGROUND & AIMS: Donor cell engraftment with expression of enzyme activity is the goal of liver cell transplantation for inborn errors of liver metabolism with a view to achieving sustained metabolic control. METHODS: Sequential hepatic cell transplantations using male and female cells were performed in a 3.5-year-old girl with argininosuccinate lyase deficiency over a period of 5 months. Beside clinical, psychomotor, and metabolic follow-up, engraftment was analyzed in repeated liver biopsies (2.5, 5, 8, and 12 months after first infusion) by fluorescence in situ hybridization for the Y-chromosome and by measurement of tissue enzyme activity. RESULTS: Metabolic control was achieved together with psychomotor catch-up, changing the clinical phenotype from a severe neonatal one to a moderate late-onset type. The child was no longer hospitalized and was able to attend normal school. Sustained engraftment of male donor liver cells was shown in repeated biopsies, reaching 19% at 8 months and 12.5% at the 12-month follow-up. XXYY tetraploid donor cells were mainly detected during the infusion period (2.5- and 5-month biopsies), whereas in the follow-up 8-month and 1-year biopsies, diploid donor cell subpopulations had become dominant. Moreover, argininosuccinate lyase activity, originally absent, became measurable in 2 different biopsy samples at 8 months, reaching 3% of control activity, indicating in situ metabolic effect and supporting the clinical evolution to a moderate form of the disease. CONCLUSIONS: Liver cell transplantation can achieve donor cell engraftment in humans in a significant proportion, leading to sustained metabolic and clinical control with psychomotor catch-up.     

A PET imaging study of 5-HT(1A) receptors in cat brain after acute and chronic fluoxetine treatment

Immuno-electron microscopic and beta-microprobe studies have demonstrated that the internalization of serotonin 5-HT(1A) autoreceptors, after acute treatment with the selective 5-HT(1A) receptor agonist 8-OH-DPAT or with the specific serotonin reuptake inhibitor (SSRI) fluoxetine, is associated with a marked decrease in the in vivo binding of [(18)F]MPPF in the nucleus raphe dorsalis (NRD) of rat. To determine whether this event might be amenable to brain imaging, the present [(18)F]MPPF positron emission tomographic (PET) study was carried out in anesthetized cats given or not a single dose (5 mg/kg, i.v.) or chronically treated with fluoxetine (5 mg/kg, s.c. for 21 days). Compared to control, [(18)F]MPPF binding potential was considerably (and visibly) decreased in the cat NRD after acute fluoxetine treatment, while it remained unchanged in other brain regions. Unexpectedly, after chronic fluoxetine treatment, [(18)F]MPPF binding potential was not affected in any brain region. In parallel immuno-electron microscopic experiments carried out in rat, the density of 5-HT(1A) autoreceptors on the plasma membrane of NRD dendrites was comparable to control after chronic fluoxetine treatment. If the decrease in [(18)F]MPPF binding at the onset of SSRI treatment was detectable by PET imaging, it could potentially serve as a biological index of efficacy.