Neoplasia in the rat induced by N-hydroxyphenacetin, a metabolite of phenacetin.

N-hydroxyphenacetin, a phenacetin metabolite, was fed to rats as a 0.05-0.5% dietary supplement. After 9 months, tumours of the liver were found in 36 of 64 animals. One animal also developed a renal tumour. No tumours were found in control animals. The findings implicate phenacetin as a carcinogen and suggest that N-hydroxyphenacetin may be the metabolite responsible.     

Adult hyperinsulinemic hypoglycemia not caused by an insulinoma: a report of two cases

Nesidioblastosis is rare in adults and accounts for 0.5–5% of cases of organic hyperinsulinemia. The diagnosis of nesidioblastosis should be considered when peroperative imaging modalities fail to localize a lesion in patients with hyperinsulinism. Two female patients, aged 55 and 16 years, with hyperinsulinemic hypoglycemia are reported. Somatostatin receptor scintigraphy showed slight focal activity in both patients. The first patient underwent a Whipple procedure and became diabetic. The second patient underwent a distal hemi-pancreatectomy and suffered from recurrent hypoglycemic episodes 3 months after surgery, for which she is presently being treated with octreotide. Histological examination of the resected pancreata revealed focally increased islet tissue and a number of slightly hypertrophic beta cells. Such histological abnormalities have been related to functional changes of β-cells. In infantile nesidioblastosis, a proportion of cases has been associated with mutations in one of several genes. Whether such mutations, leading to hyperinsulinism, also play a role in adult nesidioblastosis is presently unknown. Received: 5 July 1999 / Accepted: 19 January 2000     

A recombinant vaccinia virus expressing hepatitis B virus middle surface protein Restricted expression of HBV antigens in human diploid cells

Summary Several vaccinia virus recombinants inducing the synthesis of the middle surface (M) protein of hepatitis B virus (HBV) were constructed. One of them, denoted vl37, was examined in some detail. The virus replicated nearly to the same extent in various cell lines, viz. human embryo diploid fibroblast LEP and MRC-5 cells, rabbit embryo fibroblast REF cells, TK^– rat RAT-2 cells, and green monkey CV-1 cells. However, the production of M protein was found considerably lower in the human LEP and MRC-5 than in the other cells examined. In addition, the kinetics of M formation were different in these two cell systems, LEP cells lagging significantly behind CV-1 cells. The low-level production of M protein in LEP cells was not increased by repeated vl37 passages in LEP cells, nor by a passage in a laboratory worker accidentally infected with the vl37 virus, nor by shortening the leader sequence preceding the translation initiation codon. The greater part of the M antigen was found to be cell associated, more so in the cells of human than monkey origin. From the major HBV S antigen (HBsAg) isolated from the plasma of chronically infected subjects, the antigen released by cell destruction differed by binding to polymerized human albumin. This property was utilized in ELISA to detect anti-preS2 antibody. Rabbits inoculated intradermally with the vl37 virus developed antibodies reactive in this assay as well as with a synthetic peptide corresponding in the amino acids 14–34 of the NH₂terminus of the HBsAg preS2 region.     

Connective tissue responses to some heavy metals. II. Lead: histology and ultrastructure.

Lead loaded ion exchange resin beads implanted into the loose connective tissue of the rat pinna induced local lesions which differed widely from those of the control (sodium loaded) beads (Ellender & Ham 1987). These lesions were characterized by changes in the granulation tissue and the approximating connective tissue. Granulation tissue contained mononuclear phagocytes in various guises, and some cells with intranuclear inclusion bodies. The matrix of the granulation tissue contained collagen fibrils having a wide range of diameters suggestive of altered collagen biosynthesis. Foci of collagen mineralization occurred in zones of combined trauma and lead impregnation. Once mineralized they became enveloped by giant cells and epithelioid cells. Lead in damaged tissues is thought to modify the protective mechanism of calcification inhibition and the biosynthesis of the matrix.     

Proteomics reveals a global phenotypic shift of NK cells in HCV patients treated with direct-acting antivirals

Chronic hepatitis C virus (HCV) infections compromise natural killer (NK)-cell immunity. Direct-acting antivirals (DAA) effectively eliminate HCV, but the long-term effects on NK cells in cured patients are debated. We conducted a proteomic study on CD56⁺ NK cells of chronic HCV-infected patients before and 1 year after DAA therapy. Donor-variation was observed in NK-cell proteomes of HCV-infected patients, with 46 dysregulated proteins restored after DAA therapy. However, 30% of the CD56⁺ NK-cell proteome remained altered 1 year post-therapy, indicating a phenotypic shift with low donor-variation. NK cells from virus-negative cured patients exhibited global regulation of RNA-processing and pathways related to “stimuli response”, “chemokine signaling”, and “cytotoxicity regulation”. Proteomics identified downregulation of vesicle transport components (CD107a, COPI/II complexes) and altered receptor expression profiles, indicating an inhibited NK-cell phenotype. Yet, activated NK cells from HCV patients before and after therapy effectively upregulated IFN-γ and recruited CD107a. Conversely, reduced surface expression levels of Tim-3 and 2B4 were observed before and after therapy. In conclusion, this study reveals long-term effects on the CD56⁺ NK-cell compartment in convalescent HCV patients 1 year after therapy, with limited abundance of vesicle transport complexes and surface receptors, associated with a responsive NK-cell phenotype.     

Evolving standards in patient and caregiver support

It has become increasingly clear that family members and others have enormous potential to contribute positively to the care of the patient suffering from Alzheimer disease (AD). Various methods such as respite services and day care as well as counseling and support groups have been shown to reduce caregiver stress and burnout. Moreover, there are many areas in which the informed, trained caregiver can contribute positively to, and even lead, the interdisciplinary ongoing care of AD patients. For example, the caregiver can help with memory aids, behavioral interventions, the maintenance of exercise and nutrition, healthcare proxies and housing arrangements, decisions about intensity of treatment, and the timely implementation of palliative care approaches. Caregivers skilled in such matters will increase the quality of life of the AD patient and reduce their dependency. Many support services and educational activities are known to help caregivers and their patients, yet their availability is variable, and it is unclear whose responsibility it is to organize and finance them.     

Stereoselective synthesis of (±)-epibatidine analog: (±)-2β-(2-chloro-5-pyridinyl)-8-azabicyclo[3.2.1]octane

Stereoselective synthesis of (+/-)-epibatidine analog 2, which contains the 8-azabicyclo[3.2.1]octane ring system, was achieved by using palladium-catalyzed Heck-type coupling reaction from 3.