Vaccine protection against HIV-2 infection in cynomolgus monkeys

The aim of this study was to determine if protection against an infectious human immunodeficiency virus type 2 (HIV-2) challenge could be obtained in cynomolgus macaques by active immunization using whole killed virus vaccine. Four monkeys were immunized with killed HIV-2SBL-6669, two of them with five intramuscular (im) injections of viral preparation containing 100 or 300 micrograms protein emulsified in incomplete Freund's adjuvant (IFA) and the two remaining received four im injections of 25-50 micrograms viral protein in iscoms. Each of the four vaccinated cynomolgus monkeys, along with four unvaccinated controls, were challenged intravenously two weeks after the last booster with approximately 100 animal infectious doses (ID50) of live HIV-2SBL-6669. All four immunized monkeys developed antibodies to HIV-2 envelope and core proteins before challenge exposure to HIV-2, but only the two animals vaccinated with virus in IFA developed detectable neutralizing antibodies. The two monkeys immunized with killed virus in IFA have shown no evidence of infection nine months after challenge with live virus. When blood and lymph node cells from these animals were transfused into naive cynomolgus monkeys, the recipients remained free of infection. In contrast, virus was recovered repeatedly in all nonimmunized animals and in the two animals immunized with iscom-associated viral antigens, which had a low content of envelope gp125 antigen. The demonstration of vaccine-induced protection against HIV-2 in a nonhuman primate raises hope for effective immunization against HIV infections in humans as well.     

HLA-haploidentical blood progenitor cell transplantation in osteopetrosis

Infantile osteopetrosis (OP) carries an extremely poor prognosis unless treated early by hematopoietic stem cell transplantation. We explored the use of purified blood progenitor cells from HLA-haploidentical parents in 7 patients lacking suitable matched donors. Blood progenitor cells were purified by positive selection and by additional T-cell depletion using rosette formation. For conditioning, patients received busulfan, thiotepa, and either cyclophosphamide (5 patients) or fludarabine (2 patients). Stable donor engraftment developed in 6 of 7 patients. Graft-versus-host disease was not observed. Three of the 7 patients had no major complications and 4 of 7 had both veno-occlusive disease and respiratory failure. Five of 7 patients survive with complete cure of OP at a median of 4 years. Patients with OP lacking HLA-matched donors can be successfully treated by transplantation of purified blood progenitor cells from HLA-haploidentical donors.     

Effectiveness of diclofenac versus paracetamol in knee osteoarthritis: a randomised controlled trial in primary care

Background

The effectiveness of diclofenac versus paracetamol in primary care patients with pain caused by knee osteoarthritis is unclear.

Aim

To assess the effectiveness of diclofenac compared with paracetamol over a period of 2, 4, and 12 weeks in patients with knee osteoarthritis.

Design and setting

Randomised controlled trial in general practice.

Method

There were 104 patients included in the study, they were aged ≥45 years consulting their GP with knee pain caused by knee osteoarthritis. Patients were randomly allocated to diclofenac (n = 52) or paracetamol (n = 52) for at least 2 weeks. Primary outcomes were daily knee pain severity, and knee pain and function measured with the Knee Injury and Osteoarthritis Outcome Score (KOOS).

Results

Over a period of 2- and 4-weeks follow-up, no significant difference in daily knee pain was found between the patient groups: estimated differences of 0.5 (95% CI = −0.2 to 1.3) and −0.2 (95% CI = −1.0 to 0.7), respectively. Over the 12-weeks follow-up, no significant differences were found between both groups for KOOS pain: estimated difference of −2.8 (95% CI = −10.7 to 5.1) and KOOS function of −2.7 (−10.6 to 5.0).

Conclusion

Over a period of 2- and 4-weeks follow-up no significant difference in daily measured knee pain severity was found between primary care patients with knee osteoarthritis taking paracetamol or diclofenac. Also, over a period of 12-weeks follow-up no significant differences were found regarding KOOS pain and KOOS function between both groups. Patients more frequently reported minor adverse events after taking diclofenac (64%) than paracetamol (46%).     

Differential effects of nitric oxide on erythroid and myeloid colony growth from CD34+ human bone marrow cells

Nitric oxide (NO) is a reactive molecule with numerous physiologic and pathophysiologic roles affecting the nervous, cardiovascular, and immune systems. In previous work, we have demonstrated that NO inhibits the growth and induces the monocytic differentiation of cells of the HL- 60 cell line. We have also demonstrated that NO inhibits the growth of acute nonlymphocytic leukemia cells freshly isolated from untreated patients and increases monocytic differentiation antigens in some. In the present work, we studied the effect of NO on the growth and differentiation of normal human bone marrow cells in vitro. Mononuclear cells isolated from human bone marrow were cultured in semisolid media and treated with the NO-donating agents sodium nitroprusside (SNP) or S- nitroso-acetyl penicillamine (SNAP) (0.25 to 1 mmol/L). Both agents decreased colony-forming unit-erythroid (CFU-E) and colony-forming unit- granulocyte macrophage (CFU-GM) formation by 34% to 100%. When CD34+ cells were examined, we noted that these cells responded to SNP and SNAP differently than did the mononuclear cells. At a concentration range of 0.25 to 1 mmol/L, SNP inhibited the growth of CFU-E by 30% to 75%. However, at the same concentration range, SNP increased the number of CFU-GM by up to 94%. At concentrations of 0.25 to 1 mmol/L, SNAP inhibited the growth of CFU-E by 33% to 100%. At a concentration of 0.25 mmol/L, SNAP did not affect CFU-GM. At higher concentrations, SNAP inhibited the growth of CFU-GM. Although SNP increased intracellular levels of cGMP in bone marrow cells, increasing cGMP in cells by addition of 8-Br-cGMP (a membrane permeable cGMP analogue) did not reproduce the observed NO effects on bone marrow colonies. These results demonstrate that NO can influence the growth and differentiation of normal human bone marrow cells. NO (generated in the bone marrow microenvironment) may play an important role modulating the growth and differentiation of bone marrow cells in vivo.     

Heller''s esophagomyotomy with or without a 360° floppy Nissen fundoplication for achalasia. Long-term results from a prospective randomized study

Heller's esophagomyotomy relieves dysphagia but does not restore esophageal peristalsis. The myotomy may induce reflux and the addition of a 360 degrees fundoplication may be hazardous with regard to the remaining aperistaltic esophagus. The aim of this prospectively randomized clinical trial was to compare the outcome for patients with uncomplicated achalasia who underwent an anterior Heller's esophagomyotomy (H group) with or without an additional floppy Nissen fundoplication (H + N group). Between 1984 and 1995, 20 patients were prospectively randomized to one or other of the performed operations, 10 patients per group. Esophagitis including Barrett's esophagus (n = 2) was seen under medical treatment, in 6 of 9 in the H group but none in the H + N group. No patient in the H + N group required postoperative continuous acid-reducing drugs. Twenty-four-hour esophageal pH-studies in median 3.4 years after surgery showed pathological reflux expressed as a percentage of time below pH 4 of 13.1% in the H group compared to 0.15% (P < 0.001) in H + N group. One patient with recurrent dysphagia in the H + N group later had an esophagectomy. The remaining patients reported significant improvement of dysphagia without symptoms of reflux at 8.0 years follow-up. Heller's esophagomyotomy eliminates dysphagia, but can induce advanced reflux that requires medical treatment. The addition of a 360 degrees fundoplication eliminates reflux without adding dysphagia in the majority of patients and can be recommended for most patients with uncomplicated achalasia.     

Dysphagia after pharyngolaryngeal cancer surgery. Part I: Pathophysiology of postsurgical deglutition

Eighty-one patients were examined after laryngopharyngeal cancer surgery with a sequential computer manometry system using 4-channel-pressure probes. The general swallowing coordination is neither a matter of the oropharyngeal pressure thrust nor of the pharyngeal transit time, but mainly depends on swallowing initiation. The points of interest are both the pharyngeal inlet and outlet. The topographic correlates are the base of the tongue and the upper esophageal sphincter (UES). Resections of the base of the tongue lead to a decrease of volume available for pressure generation, thus reducing the tongue driving force. The swallowing reflex is uncoordinated resulting in dyskinesia of the UES. Compensation may be achieved with a stronger oropharyngeal thrust and/or repeated swallows. Distal resections alter the pharyngoesophageal segment so that a functional obstruction results, combined with lower pressure amplitudes in the hypopharynx, reducing the pressure gradient necessary for bolus flow. This increasing resistance can be overcome by higher propulsive forces in the base of the tongue region. In case of additional lingual defects, deglutition is subject to decompensation, highlighting the major role of the tongue as a pressure generator for bolus passage.     

Interleukin-10 promoter polymorphisms in rheumatoid arthritis and Felty's syndrome

OBJECTIVE: To examine whether promoter polymorphisms associated with variation in interleukin-10 (IL-10) production are relevant to the development of rheumatoid arthritis (RA) or Felty's syndrome (FS). METHODS: DNA was obtained from 44 FS patients, 117 RA patients and 295 controls. The promoter region between -533 and - 1120 was amplified by polymerase chain reaction, and polymorphisms detected by restriction enzyme digest or sequence-specific oligonucleotide probing. RESULTS: We found no significant difference in allele or haplotype frequencies between the groups. CONCLUSION: There is no association between FS or RA and these recently identified IL-10 promoter polymorphisms. Other genetic or environmental factors could explain the alterations in IL-10 levels seen in these conditions.