B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase

We show that the enzymatic acetylation and deacetylation of a cell surface carbohydrate controls B cell development, signaling, and immunological tolerance. Mice with a mutation in sialate:O-acetyl esterase, an enzyme that specifically removes acetyl moieties from the 9-OH position of α2–6-linked sialic acid, exhibit enhanced B cell receptor (BCR) activation, defects in peripheral B cell development, and spontaneously develop antichromatin autoantibodies and glomerular immune complex deposits. The 9-O-acetylation state of sialic acid regulates the function of CD22, a Siglec that functions in vivo as an inhibitor of BCR signaling. These results describe a novel catalytic regulator of B cell signaling and underscore the crucial role of inhibitory signaling in the maintenance of immunological tolerance in the B lineage.     

Amino acids of coxsackie B5 virus are critical for infection of the murine insulinoma cell line,MIN‐6

It was shown recently that 15 successive passages of a laboratory strain of the Coxsackie B virus 5 in a mouse pancreas (CBV‐5‐MPP) resulted in apparent changes in the virus phenotype, which led to the capacity to induce a diabetes‐like syndrome in mice. For further characterization of islet cell interactions with a passaged virus strain, a murine insulinoma cell line, MIN‐6, was selected as an experimental model. The CBV‐5‐MPP virus strain was not able to replicate in MIN‐6 cells in vitro but required adaptation over a few days for progeny production and the generation of cytopathic effects. In order to determine the genetic characteristics required for virus growth in MIN‐6 cells, the whole genome of the MIN‐6‐adapted virus variant was sequenced, and critical amino acids were identified by comparing the sequence with that of a virus strain passaged repeatedly in the mouse pancreas. The results of site‐directed mutagenesis demonstrated that only one residue, amino acid 94 of VP1, is a major determinant for virus adaptation to MIN‐6 cells. J. Med. Virol. 81:296–304, 2009. © 2008 Wiley‐Liss, Inc.     

Can various antibiotics be combined for treating salpingitis?]

Despite the therapeutic progress, the possible consequences of salpingitis remains serious: they consist essentially of sterility and ectopic pregnancy. Unfortunately, the biological and etiological diagnosis encounter many difficulties: samples difficult to obtain, slowness of the laboratory. On the basis of the fact that infections of the Fallopians often involve several organisms, the clinician could begin active treatment from the outset versus enterobacteria, anaerobes and Chlamydia. In vitro investigation of imipenem-ofloxacin and imipenem-doxycycline associations versus Chlamydia trachomatis have demonstrated that imipenem has no anti-chlamydia activity. The addition of ofloxacin or oxydoxycycline has no antagonistic effect. These experimental findings justify the clinician's use of an association of imipenem/cilastine for the initial treatment of upper genital tract infection.     

Effective treatment of advanced breast cancer with vinorelbine, mitomycin C plus human granulocyte colony-stimulating factor.

A phase II trial was performed to evaluate the efficacy and tolerance of vinorelbine (VNB), mitomycin C (MMC), and recombinant human granulocyte colony-stimulating factor (G-CSF) in advanced breast cancer. Between October 1992 and July 1994, 55 patients entered this trial. Nine patients had locally advanced disease and 46 had distant metastases, including 14 who had received previous palliative chemotherapy with (n = 9) or without anthracyclines (n = 5). Therapy consisted of VNB 40-50 mg m(-2) diluted in 250 ml saline infused over 30 min every 3 weeks, and MMC 15 mg m(-2) administered by intravenous bolus injection every 6 weeks. G-CSF was given at 5 microg kg(-1) day(-1) subcutaneously from days 2 to 7 following each cytotoxic drug administration. Treatment was continued in case of response or stable disease for a total of six courses. The overall response rate was 73% for all 55 patients (95% confidence interval, 59-84%), including 12 (22%) complete response (CR) and 28 (51%) partial response (PR); 13 patients (24%) had stable disease (SD), and only two (4%) progressed. All nine patients with locally advanced disease were rated responsive (two pCR, seven PR) and underwent surgery with curative intent. Eight out of nine remain disease free after a median observation period of 18 months (range, 13.5-28 months). Among the 32 previously untreated patients with metastatic disease, nine (28%) achieved CR, 15 PR (47%), seven SD (22%) and one PD (3%). Second-line chemotherapy with this regimen resulted in 7/14 (50%) objective remissions (one CR, six PR), six had SD and one PD. The median time to progression was 12 months (range, 2-24+ months) in previously untreated patients with disseminated disease, and 6.0 months (range, 2-22 months) in those who had failed prior chemotherapy. After a median follow-up time of 20 months, 24 patients with distant metastases are still alive with disease; median survival has not been reached yet. The dose-limiting toxicity was myelosuppression: six (11%) and ten patients (18%) had World Health Organization grade 3, and eight (14%) and nine patients (16%) had grade 4 leucopenia and granulocytopenia respectively. Severe (WHO grade 3) non-haematological toxicities included nausea/vomiting in 7%, constipation in 9%, peripheral neuropathy in 5%, infectious episodes in 7%, phlebitis due to drug extravasation in 5%, alopecia in 9%, and acute reversible pulmonary toxicity in 11%. Our data suggest that vinorelbine, mitomycin C plus G-CSF has an excellent anti-tumour activity in advanced breast cancer, probably superior to most other available combination chemotherapy regimens. This combination does not seem to present significant cross-resistance with previous CMF or anthracycline regimens. Apart from reversible, acute pulmonary toxicity, a rare adverse reaction that had previously been described for VNB, as well as the combination of natural vinca alkaloids with mitomycin C, and few episodes of grade 3 neurotoxicity (all of which occurred at the initial 50 mg m(-2) VNB dose level), the tolerance of this regimen seems acceptable and justifies further evaluation in front-line and salvage therapy of advanced breast cancer.     

Living-related liver transplantation for Crigler-Najjar syndrome in Saudi Arabia

OBJECTIVE: To analyse the outcome of six children with Crigler-Najjar syndrome type I (CNS-I) and report the first three living-related liver transplants for this syndrome in Saudi Arabia and the Middle East. SETTINGS: To review the medical records of six children suffering from CNS-I, three of whom underwent living-related liver transplantation (LRLT) between 22 November 1998 and January 2001. MAIN RESULTS: Living-related liver transplantation was performed in three children with a pre-transplant unconjugated bilirubin level of 362, 381 and 502 micromol/L, respectively, despite daily phototherapy of >or= 12 h. Two of the transplanted children developed acute hepatocellular rejection, which was successfully treated with methylprednisolone pulse therapy. One tested cytomegalovirus positive (using the PP65 method), but showed no signs of clinical infection and was treated with ganciclovir. One patient had a biliary leak at the cut surface of the graft which was surgically repaired. Post-operative bilirubin levels returned to normal in all three transplanted children and no further phototherapy was required. One patient, who was not transplanted but received phototherapy, developed severe neurological damage prior to the start of our living-related liver transplant programme with a bilirubin level of 450 micromol/L, her sister is still awaiting transplantation. A 14-yr-old child with a bilirubin level of 420 micromol/L is presently undergoing phototherapy whilst awaiting orthotopic liver transplantation because of the lack of a suitable living-related donor. Six siblings of the six children in our series were reported dead by the families. CONCLUSION: Crigler-Najjar syndrome type I is a relatively common disease in Saudi Arabia for which LRLT is a curative treatment when performed at an early age before the development of kernicterus and neurological deficiency. In countries where there is a severe shortage of cadaveric organs, as is the case in Saudi Arabia, LRLT is the optimum treatment modality for this syndrome.     

In-hospital cost of abdominal aortic aneurysm repair in Canada and the United States

BACKGROUND: Global health care costs in Canada and the United States have been examined on a macroeconomic level. However, to our knowledge, comparative costs of specific procedures in the 2 countries have not been closely studied. METHODS: To perform a microeconomic comparison of costs of open abdominal aortic aneurysm (AAA) repair, we examined the costs of treating 1057 consecutive patients from 4 Canadian (n = 552) and 6 US (n = 505) hospitals. Participating hospitals used the same cost accounting system that provided demographic, clinical, and cost data (excluding physician's fees) for each patient. Canadian dollar costs were converted to US dollar costs using purchasing power parities. RESULTS: Compared with patients who underwent AAA repair in the United States, Canadian patients were significantly younger (mean +/- SD, 70.2 +/- 10.5 vs 73.3 +/- 8.5 years; P<.001) and were less likely to undergo elective repair (48.5% vs 73.3%; P<.001). The median length of hospital stay was longer in Canada (9.0 vs 7.0 days; P<.001), and mortality rates were similar (12.0% [Canada] vs 9.9% [United States]; P =.29). The mean +/- SEM cost of AAA repair was dollars 15 852 +/- dollars 790 in Canada compared with US dollars 23299 +/- US dollars 1410 in the United States. CONCLUSIONS: The cost of AAA repair is substantially higher in the United States compared with Canada, despite shorter lengths of stay and similar clinical outcomes. The difference in total treatment costs between Canadian and American hospitals was partially attributable to differences in direct costs, but was largely due to differences in overhead costs.     

Short report: Crimean-Congo hemorrhagic fever outbreak in Rawalpindi, Pakistan, February 2002

A nosocomial outbreak of Crimean-Congo hemorrhagic fever occurred in Rawalpindi, Pakistan in February 2002. The identified index case died shortly after admission to a hospital. Two of the health care workers became secondary cases; one of them died on day 13 after coming in contact with the index case. The other secondary case was successfully treated with oral ribavirin.