[Münchausen syndrome with forgery on biologic results. A case report]. / Pseudoleucémie par falsification d'examens biologiques: genèse d'un syndrome de Münchausen.

Münchausen syndrome is a disorder defined by the following: acute factitious symptoms leading to inappropriate investigation and therapy, a restless journey from hospital to hospital and autobiographical falsification. We report here a 20-year-old woman who presented at our hospital consultation of internal medicine with laboratory-test results suggesting the diagnosis of leukemia. A new complete blood cells count and a medullogram by sternal puncture did not show any abnormality. Comparative examination of laboratory-test sheets lead to the diagnosis of Münchausen syndrome as some results had been falsified. With unlimited access to information through internet and word or image processing softwares, laboratory results have become easy to falsify nowadays, particularly for patients with Münchausen syndrome, who may then be quite difficult to diagnose accurately in the context of medical consultation.

The protein ICP0 of herpes simplex virus type 1 is targeted to nucleoli of infected cells. Brief report.

This study describes the nucleolar localization of the viral protein ICP0 of herpes simplex virus type 1. We show that the RING finger domain of ICP0 is essential for ICP0 to localize in nucleoli of transfected and 4 hour-infected cells. ICP0 forms particular intranucleolar domains that do not correspond to any known nucleolar domains. This distribution was confirmed by immunoblots performed on fractionated infected cells. Quantitative RT-PCR experiments indicated that ICP0 did not increase the transcription from the RNA polymerase I (Pol I) promoter in transfected cells, an effect opposite to that observed on viral and cellular Pol II promoters. Nucleoli are thus, after PML bodies and centromeres, a novel nuclear structure targeted by ICP0.

[Surveillance and prognosis of "Ta" superficial tumors of the bladder. Homogeneous series of 138 cases followed for 1 to 18 years]. / Surveillance et pronostic des tumeurs superficielles "Ta" de vessie. Une série homogène de 138 cas suivis de 1 à 18 ans.

OBJECTIVE: To identify prognostic factors (risk of recurrence and risk of progression) and define the rules for the surveillance of stage Ta superficial bladder cancers, based on the follow-up of a homogeneous patient series. MATERIAL AND METHOD: 138 Ta bladder cancers were recruited from 1975 to 1995 and regularly followed by the same urologist. The follow-up was 1 to 18 years with a mean of 66 months and a median of 60 months. RESULTS: 30% of patients developed no recurrence (mean follow-up: 52 months). 70% developed one or several recurrences (mean follow-up: 80 months): 46% of Ta recurrences without progression and 24% of T > or = 1, with 10% of T > 1 recurrencesed. 13/138 patients died from bladder cancer, including 11 patients in less than 10 years. The risk of recurrence and the risk of progression were significantly correlated with: the macroscopic appearance of the cancer: size, number and extent of implantations, sessile or pedunculated nature, its site: slightly more serious on the fixed part of the organ, its clinical course assessed over the first 12 months: in patients without recurrence at 12 months: the risk of recurrence decreased from 70% to 35% the risk of deterioration decreased from 24% to 10%. However, this risk persisted in the long term: after more than 5 years without recurrence, 2 patients developed fatal recurrences, 11 and 15 years after the initial treatment. CONCLUSION: Although superficial, Ta bladder cancers are serious cancers. The risk of recurrence and progression justify close surveillance in the year following diagnosis. Subsequently, the frequency of follow-up can be adapted to the specific course of each case, but, regardless of these modalities, long-term (indefinite?) surveillance is recommended.

[Surveillance and prognosis of "T1" superficial tumors of the bladder. Homogeneous series of 88 cases followed for 1 to 22 years]. / Surveillance et pronostic des tumeurs superficielles "T1" de vessie. Une série homogène de 88 cas suivis de 1 à 22 ans.

OBJECTIVE: Define the prognostic factors (risk of recurrence and risk of progression) and the rules for surveillance of stage T1 papillary bladder tumours based on the clinical course of a homogeneous patient series. MATERIAL AND METHOD: 88 T1 bladder tumours recruited from 1975 to 1995 and regularly followed by the same urologist. The follow-up ranged from 1 to 22 years with a mean of 52 months and a median of 48 months. RESULTS: 26% patients relapsed (mean follow-up: 71 months) 74% developed one or more recurrences (mean follow-up: 48 months) with recurrences staged > T1 in 35% of cases. 29/88 patients died from invasive bladder cancer, 14 before 3 years, 19 before 5 years, 28 before 10 years. The risk of recurrence and progression was statistically significantly related to the macroscopic appearance of the tumour; size, number and extent of implantations; its rate of progression assessed by the frequency of recurrence. In patients with no recurrence at 12 months, the risk of recurrence decreased from 74% to 50% and the risk of progression decreased from 35% to 20%. In this cohort, neither histological grading of the initial tumour, nor the degree of invasion of the submucosal lamina propria appeared to modify the prognosis. CONCLUSION: Stage T1 papillary bladder tumours, generally considered to be a superficial tumours regardless of their histological grade, have a serious prognosis and warrant close endoscopic surveillance during the year following the diagnosis. The subsequent frequency of follow-up can then be adapted to the specific mode of progression of each case, but, regardless of this mode of progression, the authors recommend long-term (life-long?) surveillance.

Enhancer and long-term expression functions of herpes simplex virus type 1 latency-associated promoter are both located in the same region.

During herpes simplex virus type 1 (HSV-1) latent infection in vivo, the latency-associated promoter (LAP) is the only promoter to remain highly active long term. In a previous attempt to characterize LAP activity in vitro and in a mouse model, we showed that a 1.5-kb fragment called the long-term expression element (LTE), located immediately downstream from the transcriptional start site of LAP, was able to (i) increase gene expression in an orientation-independent manner, regardless of the cell type or the promoter used in vitro (enhancer activity) and (ii) keep LAP active during latency in vivo (long-term expression activity) (H. Berthomme, J. Lokensgard, L. Yang, T. Margolis, and L. T. Feldman, J. Virol. 74:3613-3622, 2000). To determine if these two functions could be separated genetically, we conducted a mutational analysis on the LTE and analyzed the effect on the LAP-LTE properties in both transient expression in cell culture and mouse dorsal root ganglia lytic and latent infection. In this report, we show that the first half of the LTE sequence, corresponding to the region previously described as LAP2 or exon1, encodes the enhancer function. This same region is also required to keep the LAP active during latency. These results exclude the intron region as containing any significant enhancer activity or any ability to keep the LAP active during latency. The results also show that these two functions have not been separated, leaving open the possibility that there is no long-term expression function per se but that the enhancer itself may function to keep the LAP active during latency by raising the level of expression to a detectable one. Further mutational analysis will be required to determine if these two potential functions continue to cosegregate.

Severe hereditary spherocytosis and distal renal tubular acidosis associated with the total absence of band 3.

Absence of band 3, associated with the mutation Coimbra (V488M) in the homozygous state, caused severe hereditary spherocytosis in a young child. Although prenatal testing was made available to the parents, it was declined. Because the fetus stopped moving near term, an emergency cesarean section was performed and a severely anemic, hydropic female baby was delivered. She was resuscitated and initially kept alive with respiratory assistance and hypertransfusion therapy. Cord blood smears revealed erythroblastosis, poikilocytosis, and red cells with stalk-like elongations. Band 3 and protein 4.2 were absent; spectrin, ankyrin, and glycophorin A were significantly reduced. Renal tubular acidosis was detected by the age of 3 months. Nephrocalcinosis appeared soon thereafter. After 3 years of follow-up the child is doing reasonably well on a regimen that includes regular blood transfusions and daily bicarbonate supplements. The long-term prognosis remains uncertain given the potential for hematologic and renal complications. (Blood. 2000;96:1602-1604)

Early hominid stone tool production and technical skill 2.34 Myr ago in West Turkana, Kenya.

Well-documented Pliocene archaeological sites are exceptional. At present they are known only in East Africa, in the Hadar and Shungura formations of Ethiopia and in the Nachukui formation of Kenya. Intensive archeological survey and a series of test excavations conducted in the Nachukui formation since 1987 have led to the discovery of more than 25 archaeological sites whose ages range from 2.34 to 0.7 million years before present (Myr), and to the extensive excavation of two 2.34-Myr sites, Lokalalei 1 in 1991 and Lokalalei 2C in 1997. Lokalalei 2C yielded nearly 3,000 archaeological finds from a context of such good preservation that it was possible to reconstitute more than 60 sets of complementary matching stone artefacts. These refits, predating the Koobi Fora refits by 500 Kyr, are the oldest ever studied. Here we describe a technological analysis of the core reduction sequences, based on these refits, which allows unprecedented accuracy in the understanding of flake production processes. We can thus demonstrate greater cognitive capacity and motor skill than previously assumed for early hominids, and highlight the diversity of Pliocene technical behaviour.

MR and CT findings in a case of hibernoma of the thigh extending into the pelvis.

Review of the literature shows no report of hibernoma of the thigh extending into the pelvis. Herein we report a case of hibernoma which appeared on CT and MR as a well-defined pelvic mass with contrast enhancement extending through the obturator foramen into the thigh. Fat was demonstrated by CT, whereas MR, using multiplanar sections, better analyzes the extension of the mass. This case demonstrates that hibernoma as liposarcoma can extend through the obturator foramen. However, no definite diagnosis could be made by CT or MR and the tumor must be considered as a "potential" malignant liposarcoma.

Modulation of clinical expression and band 3 deficiency in hereditary spherocytosis.

We present two novel alleles of the anion-exchanger 1 (AE1) gene, allele Coimbra and allele Mondego. Allele Coimbra (V488M, GTG --> ATG) affects a conserved position in the putative second ectoplasmic loop of erythrocyte band 3. In 15 simple heterozygotes, it yielded a mild form of hereditary spherocytosis (HS) with band 3 deficiency (-20% +/- 2%) and a reduced number of 4,4'-diisothiocyano-1,2-diphenylethane-2,2'-disulfonate (H2DIDS) binding sites (-35%). However, two additional heterozygotes presented with an aggravated HS and a more pronounced reduction of band 3 (-40%) and of H2DIDS binding sites (-48%). They carried, in trans to allele Coimbra, allele Mondego, defined by two mutations: E40K, GAG --> AAG, the known mutation Montefiore, and P147S, CCT --> TCT, a novel mutation, both located in the cytoplasmic domain of band 3. Allele Mondego itself resulted in no clinical or hematologic HS signs in the simple heterozygous state. Yet it yielded a slight decrease in band 3 (-6% to -12%) and in the number of H2DIDS binding sites (-19%). Thus, the more pronounced decrease in band 3 in the two compound heterozygotes derived from the additive effects of two unequally expressed AE1 alleles, resulting in a more severe clinical picture.

Hereditary spherocytosis with band 3 deficiency. Association with a nonsense mutation of the band 3 gene (allele Lyon), and aggravation by a low-expression allele occurring in trans (allele Genas).

We describe an 18-year-old with moderate hereditary spherocytosis. The condition was associated with a 35% decrease in band 3. The underlying mutation was Arg to stop at codon 150 (CGA-->TGA) and was designated R150X, which defined allele Lyon of the EPB3 gene. The inheritance pattern was dominant. However, the mother, who also carried the allele Lyon, had a milder clinical presentation and only a 16% decrease of band 3. We suggested that the father had transmitted a modifying mutation that remained silent in the heterozygous state. Nucleotide sequencing after single strand conformation polymorphism analysis of the band 3 cDNA and promoter region revealed a G-->A substitution at position 89 from the cap site in the 5'-untranslated region, designated 89G-->A, which defined allele Genas. A ribonuclease protection assay showed that (1) the allele Genas (father) resulted in a 33% decrease in the amount of band 3 mRNA, (2) the reduction caused by the allele Lyon (mother) was 42%, and (3) the compound heterozygous state for both alleles (proband) resulted in a 58% decrease. These results suggest that some mildly deleterious alleles of the EPB3 gene are compensated for by the normal allele in the heterozygous state. They are shown through the aggravation of the clinical picture, based on more obvious molecular alterations when they occur in trans to an allele causing a manifest reduction of band 3 membrane protein concentration.

The cisternae decorating the red blood cell membrane in congenital dyserythropoietic anemia (type II) originate from the endoplasmic reticulum.

We studied 20 individuals from 17 unrelated families with congenital dyserythropoietic anemia (type II; CDAII). The clinical phenotype was mild to moderate. The inheritance pattern was invariably recessive. Coomassie blue stained gels after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) show that band 3 was thinner and migrated slightly faster than usual. In addition, staining showed two unknown minor bands (in the patients), but not in normal controls, the obligate carrier parents, or in patients with other anemic syndromes. These minor proteins were studied using partial digestion, amino acid sequencing, Western blotting, immunofluorescence, and immunogold electron microscopy. They were identified as the glucose-regulated protein GRP78 and calreticulin that are resident proteins of the endoplasmic reticulum (ER). Using specific antibody, we showed that protein disulfide isomerase (PDI), a third major protein of the ER, was also present on the SDS-PAGE of red blood cell (RBC) ghosts. Immunofluorescence colocalized PDI with the dense discontinuous ring decorating the RBC membrane. Immunogold electron microscopy showed that PDI was localized in the lumen of the cisternae, confirming that these originate from the smooth ER. From a practical point of view, screening the above minor proteins in RBC membranes appears to be a straightforward and reliable diagnostic test for CDAII.

Band 3 Chur: a variant associated with band 3-deficient hereditary spherocytosis and substitution in a highly conserved position of transmembrane segment 11.

We studied a large Swiss family with dominantly inherited hereditary spherocytosis and band 3 (anion exchanger 1, AE1) deficiency. Band 3 cDNA was analysed by single-strand conformation polymorphism analysis and nucleotide sequencing. A new point mutation was found: G771D (GGC-->GAC). This change was present in all eight investigated patients but absent in four healthy members of the family. It is located at a highly conserved position in the middle of transmembrane segment 11, introducing a negative charge in a stretch of 16 apolar or neutral residues. None of the six amino-acid substitutions already known in this region as being associated with band 3 deficiency were recorded. To rule out any major transcriptional or post-transcriptional defect, we evaluated the amount of band 3 mRNA by RNase mapping using a band 3-protein 4.1 chimaeric probe. Similar mRNA amounts were present in patients and controls. Our results strengthen the view that some amino-acids, that are well conserved throughout the AE family, may be crucial for the insertion and/or the stabilization of band 3 within the lipid bilayer. At the present time, most of the mutations altering such residues are located in the C-terminal region of band 3.

Hepatic lesions of vascular origin in multicentric Castleman's disease, plasma cell type: report of one case with peliosis hepatis and another with perisinusoidal fibrosis and nodular regenerative hyperplasia.

We report two cases of multicentric Castleman's disease, plasma cell type, associated with three different liver lesions. Peliosis hepatis was observed in one case and perisinusoidal fibrosis with nodular regenerative hyperplasia in the other. These observations give some evidence that Castleman's disease, per se, may be involved in these three presumably interrelated liver vascular lesions. These changes, already described in monoclonal lymphoproliferations such as myeloma and Waldenström's disease, may also be recorded in a disease characterized by a strong polyclonal plasma cell hyperplasia.

A deletional frameshift mutation in protein 4.2 gene (allele 4.2 Lisboa) associated with hereditary hemolytic anemia.

We studied a 26-year-old Portuguese patient with recessively transmitted hereditary hemolytic anemia. Protein 4.2 was absent from red cell ghosts by Western blotting. Although the 4.2 mRNA was not detected in Northern blots, it was shown to be present by a procedure based on nested reverse transcription-polymerase chain reaction (RT-PCR). Partial nucleotide sequencing disclosed a one-nucleotide deletion at nt 264 (or 265): AAG GTG-->AAG TG, in codon 88 (or 89) belonging to exon 2. This change, defining allele 4.2 Lisboa, placed in frame the nonsense triplet that normally overlaps codons 136 and 137 (GTG ACC). This mutation, which abolishes an EcoNI site, was also found in the gene of the proband (homozygous state), her parents, and her brother (heterozygous state). Apart from anemia, the patient was free of clinical manifestations. Platelet membranes were also investigated using Western blots. Antibodies to red cell protein 4.2 showed a doublet (72 and 70 kD) both in the controls and the patient. This finding raises an interesting question concerning the relationship between this doublet and erythroid protein 4.2.

Frequency of inhibitor-resistant TEM beta-lactamases in Escherichia coli isolates from urinary tract infections in France.

Over a six-month period in 1993, 2972 non-duplicated isolates of Escherichia coli causing urinary tract infections were collected in a French teaching hospital (n = 785) and in three private laboratories (n = 2187). The resistance rate to amoxycillin-clavulanate combination (MIC > 16 mg/l) was 25.0% in the hospital isolates and 10.0% in the community isolates. Respectively, 27.5% and 45.0% of hospital and community isolates resistant to amoxycillin-clavulanate exhibited an unusual beta-lactam resistance pattern, suggesting inhibitor-resistant TEM (IRT) beta-lactamase production. These isolates were highly resistant to amoxycillin-clavulanate (MIC90 > 1024 mg/L), but were susceptible to cephalosporins (MIC < 32 mg/L). Enzyme extracts of these IRT-producing strains focused at pI 5.2 (n = 100) or 5.4 (n = 53). DNA-DNA hybridization confirmed that the beta-lactamases involved in this resistance mechanism were TEM-1 derived and contained variations in the altered positions described in IRT enzymes. This study shows a total frequency of 4.9% of IRT-producing isolates among E. coli isolated from urine specimens.

An unusual epithelial pleomorphic giant cell tumour of the pancreas with osteoclast-type cells.

A case of giant cell tumour of the pancreas with a mixture of pleomorphic giant cells and osteoclast-like cells is described. This association is rare and its histogenesis has been debated. The presence of a small differentiated adenocarcinomatous area at the periphery of the tumour indicates an epithelial origin. Moreover, some pleomorphic cells were positive for keratin (KL1). The osteoclast-like cells strongly expressed CD68 (a marker of histiomonocytic lineage) and did not show proliferative activity. They probably correspond to an unusual reaction of the stroma. Their clinical importance in this type of tumour remains unknown.

Evidence that red blood cell protein p55 may participate in the skeleton-membrane linkage that involves protein 4.1 and glycophorin C.

Human erythrocyte p55 is a peripheral membrane protein that contains three distinct domains in its primary structure: an N-terminal domain, an SH3 motif, and a C-terminal guanylate kinase domain. We used naturally mutated red blood cells (RBCs) with primary genetic defects resulting in the absence of protein 4.1 (4.1[-] hereditary elliptocytosis) or glycophorin C (Leach elliptocytosis). The absence of either protein was associated with the absence of p55. On a stoichiometric basis, the reduction in glycophorin C (about 80%) was concomitant to the lack of p55 in RBCs devoid of protein 4.1. Similarly, the reduction of protein 4.1 (about 20%) was equivalent to the absence of p55 in RBCs devoid of glycophorin C. These correlations suggest that p55 is associated, in precise proportions, with the protein 4.1-glycophorin-C complex, linking the skeleton and the membrane. The protein 4.1-glycophorin-C cross-bridge is known to be critically important for the stability and mechanical properties of human RBC plasma membrane. Because isoforms of protein 4.1, glycophorin C, and p55 exist in many tissues, these results provide evidence of a linkage between the skeleton and the membrane that may have implications in many nonerythroid cells.