Hepatitis C genotype change after transplantation utilizing hepatitis C positive donor organs.

A shortage in organs for transplantation has led to the increased use of hepatitis C (HCV) infected donor organs for solid organ transplant recipients infected with HCV. However, the donor HCV genotype is not routinely checked or known prior to transplant. Here, we report 4 cases of genotype conversion after transplantation in patients receiving HCV infected donor organs. This change in genotype may potentially impact HCV progression as well as treatment choice for these patients.

Association Between Duration of Human Immunodeficiency Virus (HIV)-1 Viral Suppression Prior to Renal Transplantation and Acute Cellular Rejection.

Renal transplant has become an important option for human immunodeficiency virus (HIV)-infected patients with end-stage renal disease; however, these patients experience a high rate of acute cellular rejection (ACR). Guidelines do not currently exist for the optimal duration of viral suppression prior to transplantation. In a retrospective cohort analysis of 47 HIV-infected renal transplant recipients, we compared the rate of ACR between patients based on the length of time of viral suppression prior to transplantation. Of the patients who achieved viral suppression for >6 months but less than 2 years prior to transplantation (n = 15), 60% experienced ACR compared to 41% of patients suppressed at least 2 years or more (n = 32) prior to transplant (p = 0.21). Patients suppressed <2 years experienced ACR at 2.48 times the rate of those suppressed 2 years or longer. Induction immunosuppression, HLA mismatch and panel-reactive antibodies (PRAs) did not significantly differ between the two groups.

Evaluation of Adhesion Forces for the Manipulation of Micro-Objects in Submerged Environment through Deposition of pH Responsive Polyelectrolyte Layers.

Optimization of surface treatment for reversible adhesion of micro-objects in liquid environment for the need in microassembly processes is presented. A spherical borosilicate probe and planar oxidized silicon wafer substrates were modified by deposition of pH sensitive polyelectrolyte films through layer-by-layer technique. Branched polyethylenimine (b-PEI) and poly(sodium styrenesulfonate) (PSS) were deposited in alternating manner on surfaces, and the influence of polyelectrolyte concentration, pH of deposition, and number of layers on the adhesion were successively examined. The multilayer buildup was followed by optical reflectometry (OR) and dissipative quartz crystal microbalance (QCM-D). The adhesion forces were monitored in aqueous environment at variable pH values by colloidal probe AFM microscopy. The thermodynamic work of adhesion was derived from the pull-off forces by using the Johnson-Kendall-Roberts (JKR) model and compared to the work of adhesion determined from contact angle measurements. It was found out that they correlate well, however, the values accessed from JKR model were underestimated, which was attributed mainly to the effect of surface roughness. Obtained results have demonstrated that it is possible to achieve repeatable reversible adhesion with the change of pH of submerged environment by appropriately tailoring the surface properties and therefore the prevailing surface forces.

Clinical and pathological characteristics of a dog with scleromyxoedema.

An 8-year-old male cross-Labrador retriever was presented for a progressive appearance of folds all over the body of the dog. Scleromyxoedema was diagnosed based on clinical signs and histopathological features. Clinical signs were characterised by a papular and vesicular eruption and severe skin thickening causing exuberant folds along with concurrent severe osteoarthritis of the coxofemoral joints. Thyroid disorders were excluded and the condition was not associated with monoclonal gammopathy. Histopathological features consisted of mucin deposition, fibroblast proliferation and fibrosis. Prednisolone was prescribed to decrease mucin synthesis which allowed a marked clinical improvement. Due to the progressive inability to walk, the dog was euthanased 6 months after the first consultation.

Delayed post-traumatic alopecia of the dorso-lumbar area following a road accident in a cat without pelvic fracture.

An 11-month-old female, neutered domestic short-haired cat was presented for non-pruritic alopecia of the dorso-lumbar area which had appeared 1 month after a road accident. After the trauma, a fracture of the left hind limb was demonstrated without dermatological lesions on the dorso-lumbar area. One month later, hair loss was observed in this area. Four months later, clinical examination revealed dorso-lumbar alopecia. Histopathological findings included an absence of all adnexae, a mild fibroplasia and fibrosis without oriented collagen deposition, individual to coalescing pyogranulomas at the dermo-hypodermal junction and a moderately stenotic hypodermal artery. Clinical history, physical examination and histopathological findings were compatible with post-traumatic dorso-lumbar alopecia. Special features of this case include the location of the fracture and the more developed histopathological lesions with pyogranulomas at the dermo-hypodermal junction, the absence of hair follicles and a stenosing arteriopathy.

Force spectroscopy of a single artificial biomolecule bond: the Kramers' high-barrier limit holds close to the critical force.

We use a minimal system with a single micron-size bead trapped with optical tweezers to investigate the kinetics of escape under force. Surprisingly, the exponential decay of the off rate with the barrier energy is still valid close to the critical force. Hence, the high viscosity approximation derived by Kramers in the case of a high energy barrier holds even for an energy barrier close to the thermal energy. Several recent models describe a single biomolecule bond by a smooth single-barrier energy profile. When this approach is accurate enough, our result justifies the use of Kramers' approximation in the high-force regime, close to the critical force of the system, as done in recent single biomolecule bond studies.

Local anaesthetic use for the iliac crest-donor site: pharmacokinetic and pharmacodynamic evaluations.

During orthopaedic surgery of the limb, we performed a prospective, double blind controlled study on three parallel groups in 30 patients to evaluate the pharmacokinetic and pharmacodynamic effect of infiltration of the iliac crest bone graft harvest site with 20 ml of bupivacaine (100 mg), ropivacaine (150 mg) or saline as control group (n = 10 in each group). Then, in a sheep model of iliac crest infiltration, we compared the pharmacokinetics of single administration of plain bupivacaine (100 mg) and bupivacaine (500 mg)-loaded microspheres. In the clinical control group, pain from the iliac crest was worse than pain from the primary surgical site. Pain from the iliac crest was significantly reduced during the first 12 postoperative hours in local anaesthetic groups compared to the control group. However, during this period, pain from the primary surgical site was increased compared to the control group. Finally, there was no difference between the three groups in the average intake of PCA morphine. There was no significant pharmacokinetic and pharmacodynamic difference between plain bupivacaine and ropivacaine. The maximal plasma concentration (Cmax) of ropivacaine and bupivacaine were 964 (282) ng ml(-1) and 638 (366) ng ml(-1), respectively. In the sheep model, it was clearly shown that the release of bupivacaine from microspheres was controlled and prolonged despite the largest dose of bupivacaine used (500 mg; n = 4). Wound infiltration of iliac crest harvest site with local anaesthetic is an easy technique for postoperative analgesia. However, this effect lasts only 12 hours without reducing the morphine consumption due to an increase of pain from the primary surgical site. The local anaesthetic infiltration produced a significant peak of plasma level, which could be dangerous if another infiltration or regional anaesthetic technique was associated with it. Experimentally, as a drug delivery system, the use of local anaesthetic-loaded microspheres could be an interesting alternative.

Distinct mechanisms of nonhomologous end joining in the repair of site-directed chromosomal breaks with noncomplementary and complementary ends.

DNA double-strand breaks (DSBs) are considered the most important type of DNA damage inflicted by ionizing radiation. The molecular mechanisms of DSB repair by nonhomologous end joining (NHEJ) have not been well studied in live mammalian cells, due in part to the lack of suitable chromosomal repair assays. We previously introduced a novel plasmid-based assay to monitor NHEJ of site-directed chromosomal I-SceI breaks. In the current study, we expanded the analysis of chromosomal NHEJ products in murine fibroblasts to focus on the error-prone rejoining of DSBs with noncomplementary ends, which may serve as a model for radiation damage repair. We found that noncomplementary ends were efficiently repaired using microhomologies of 1-2 nucleotides (nt) present in the single-stranded overhangs, thereby keeping repair-associated end degradation to a minimum (2-3 nt). Microhomology-mediated end joining was disrupted by Wortmannin, a known inhibitor of DNA-PKcs. However, Wortmannin did not significantly impair the proficiency of end joining. In contrast to noncomplementary ends, the rejoining of cohesive ends showed only a minor dependence on microhomologies but produced fivefold larger deletions than the repair of noncomplementary ends. Together, these data suggest the presence of several distinct NHEJ mechanisms in live cells, which are characterized by the degree of sequence deletion and microhomology use. Our NHEJ assay should prove a useful system to further elucidate the genetic determinants and molecular mechanisms of site-directed DSBs in living cells.

[Association of Wolff-Parkinson-White syndrome with isolated non-compaction of the left ventricle: a case report]. / Association du syndrome de Wolff-Parkinson-White a une non-compaction isolée du ventricule gauche. A propos d'un cas.

The Wolff-Parkinson-White syndrome (WPW) may be associated with a number of cardiac pathologies, especially congenital disease, in 7.5 to 17% of cases. The authors report a rare association of the WPW syndrome with two Kent bundles, right and left septal, with non-compaction of the left ventricle in a 52 year old man. This was a chance finding during systematic echocardiography after ablation, and confirmed by cardiac MRI. The patient was asymptomatic.

[Severe Guillain-Barré syndrome and pregnancy: two cases with rapid improvement post-partum]. / Syndrome de Guillain-Barré sévère et grossesse: deux cas d'amélioration rapide en post-partum.

INTRODUCTION: Guillain-Barré syndrome can occur at any time of pregnancy with the same incidence as in the general population. Observations. We report two cases of patients who developed a progressive ascending paralysis during the second trimester of pregnancy. The worsening of the respiratory insufficiency for one of them required a transfer to an intensive care unit for artificial ventilation lasting 102 days. In the two cases, cerebrospinal fluid examination revealed albumin-cytological dissociation and repeated electrophysiological studies showed typical features of demyelinating neuropathy with conduction blocks. Biological investigations, especially CMV and Campylobacter jejuni serologies, were all negative. Intravenous immunoglobulin infusions, in one case associated with high doses of corticosteroïds, were ineffective. Rapid improvement was observed in the two patients after delivery. CONCLUSION: These cases raise the question of the relationships between the Guillain-Barré syndrome and pregnancy. The occurrence of the disease, as well as the rapid recovery in post-partum, could be consecutive to a partial failure of the maternal immunological tolerance toward the fetus.

Dynamic monitoring of cell mechanical properties using profile microindentation.

We have developed a simple and relatively inexpensive system to visualize adherent cells in profile while measuring their mechanical properties using microindentation. The setup allows simultaneous control of cell microenvironment by introducing a micropipette for the delivery of soluble factors or other cell types. We validate this technique against atomic force microscopy measurements and, as a proof of concept, measure the viscoelastic properties of vascular endothelial cells in terms of an apparent stiffness and a dimensionless parameter that describes stress relaxation. Furthermore, we use this technique to monitor the time evolution of these mechanical properties as the cells' actin is depolymerized using cytochalasin-D.

A review of the value of MRI signs in low back pain.

Low back pain is a common symptom that can lead to disability and major socio-professional repercussions. Despite advances in imaging, the etiology of the pain often remains unknown. Morphological changes related to normal ageing of the disc appear on MR imaging without any symptoms. The potential impact of changes seen on imaging, especially MRI, also warrants discussion. The purpose of this work is to review the state-of-the-art of this subject, underlining relevant key features for routine radiological practice. We will first discuss anterior and posterior segments of the spine with a focus on anatomical, physiopathological and semiological findings. Secondly we will discuss the diagnostic value of each sign.

The new steroid analog RU 486 inhibits glucocorticoid action in man.

RU 486 [17 beta-hydroxy-11 beta-(4- dimethylaminophenyl )-17 alpha-(prop-1- ynyl )-estra-4,9-dien-3-one] is a new steroid analog which antagonizes glucocorticoid action at the receptor level in animals. To assess its potential antiglucocorticoid activity in man we studied the pituitary-adrenal response to RU 486 in normal men. The compound was administered at 0200 h and plasma cortisol and lipotropins (LPH) were measured hourly for 10 h. After 400 mg RU 486 significant and sustained elevation of both hormones occurred during the 0700-1200 h period: mean (+/- SE) plasma levels after placebo or RU 486 during this interval were, respectively, for cortisol (ng/ml), 63.4 +/- 8.2 and 112.7 +/- 2.9 (P less than 0.02); and for LPH (pg/ml), 34.8 +/- 11.3 and 71.6 +/- 15.4 (P less than 0.01). The 200- and 100-mg doses induced only transient cortisol and LPH increases. Administration of RU 486 (400 mg) at 1400 h induced no increase in plasma cortisol compared to placebo in the corresponding 2000 to 2400 h period. When RU 486 was administered concomitantly with dexamethasone (1 mg) at 2400 h, dose-dependent blockade of the dexamethasone-induced cortisol suppression at 0900 h was found (r = 0.62, P less than 0.01); this blockade was partial after the 100-mg dose, but complete after the 400-mg dose. Plasma LPH and ACTH showed parallel variations. We conclude that RU 486 antagonizes the negative pituitary feedback of both the nocturnal endogenous cortisol rise and exogenously administered dexamethasone. These actions are consistent with an antiglucocorticoid activity of this compound in man.

Pituitary-adrenal response to the antiglucocorticoid action of RU 486 in Cushing's syndrome.

RU 486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one] is a steroid analog which antagonizes glucocorticoid action at the receptor level. The pituitary-adrenal response to RU 486 was evaluated in patients with Cushing's syndrome. The acute administration of 400 mg RU 486 at 0800 h in five patients with Cushing's disease induced no significant change in plasma cortisol during the next 10 h compared with the administration of placebo. However, prolonged administration (400 mg daily for 3 days) caused activation of the pituitary-adrenal axis; urinary cortisol increased the most from 727 to 5720, 830 to 8200, 610 to 1020, 110 to 570, and 300 to 990 micrograms/day. Plasma cortisol and lipotropins increased to a lesser extent. Hormone changes appeared on the second day of drug administration and lasted up to 3-4 days after the drug was discontinued. In two patients with nonpituitary-dependent Cushing's syndrome, RU 486 induced no significant change in steroid secretion. We conclude that RU 486 induced a delayed and prolonged pituitary-adrenal response in Cushing's disease; whether the resulting cortisol overproduction will overcome the peripheral effect of RU 486 remains to be determined.

Interaction between roxithromycin and cyclosporin in heart transplant patients.

Cyclosporin is an immunosuppressive agent commonly used in transplant patients. It is actively metabolised by the cytochrome P450 system and interactions with drugs metabolised by the same system are predictable. This is particularly relevant since cyclosporin has a low therapeutic index and its renal toxicity is concentration-related. Roxithromycin, a new, well-tolerated macrolide with a weak interactive profile, uses the same isoenzyme of the P450 system as cyclosporin. To evaluate its interaction potential in clinical practice, 8 heart transplant recipients treated with cyclosporin for at least 1 month received roxithromycin for 11 days (150 mg twice daily). Bi-weekly controls of plasma cyclosporin concentrations and creatinine levels were carried out before, during and after roxithromycin treatment. A slight nonsignificant rise in cyclosporin concentrations was observed, but creatinine levels remained stable during roxithromycin treatment. Values of cyclosporin concentrations diminished after withdrawal of roxithromycin. Cyclosporin dosage adjustment was not necessary. There was a minor pharmacokinetic interaction, which can be considered safe for the usual therapeutic dosage of roxithromycin used.

Estimating viral concentrations from dilution counts: a reliable computation method programmed on a pocket calculator.

A program for a Hewlett-Packard 41C calculator is described, applying the maximum likelihood method for the estimation of the density of a suspension of infective particles when counts are available for a number of independent dilutions of the original suspension. An unbiased estimate for the variance of the density, a suitable confidence interval and its corresponding confidence level are also given by the program. Moreover, after testing for the presence of overcrowding and/or clumping, the selection of suitable dilutions is fully automated so as to avoid recourse to statistical tables.

Estimating viral concentrations from dilution counts: an improved HP48SX version of the 'MLE2' program.

The recent withdrawal of the HP41C* calculator from the market necessitated a translation of the HP41C* 'MLE2' program published earlier (Roussel and Husson, 1991) into a version for its successor, the HP48SX. The existence of the HP41CV emulator module for the HP48SX offers no solution for continued support of the 'MLE2' program, because it does not accept synthetic HP41C instructions (cf. 'Warning' paragraph in (Roussel and Husson, 1991)). Moreover, the built-in HP48SX upper-tail probability functions (UTPC UTPF UTPN) are more accurate than the corresponding HP41C subprograms. The easy interfacing capabilities of the HP48SX with PC or Macintosh make transfer of the program itself, and its output (e.g. for reporting) straight-forward. This calls for a specific HP48SX implementation with ASCII text output of the algorithm presented by Roberts and Coote (1965), and extended by Roussel and Husson (1991). Finally, the probability distribution of the particle concentration lambda as a function of a given set of counts is shown to be chi 2, so that exact confidence bounds for lambda can be computed using the HP48SX UTPC and ROOT commands.

Effects of RU16117, an orally active weak oestrogenic compound, in postmenopausal women.

Daily oral administration of 1, 3 or 10 mg of RU16117 (11 alpha-methoxy ethinyl oestradiol) to normal postmenopausal women led to a progressive decrease of basal serum LH levels to 60.4 +/- 17.0, 35.1 +/- 9.1 and 20.1 +/- 2.8% of control (pretreatment values, P less than 0.01), respectively, after 4 wk of drug administration. Although the pattern was similar, the inhibitory effect of RU16117 was even more pronounced on FSH than LH levels: a 50% decrease of basal LH and FSH levels was obtained at the daily 1.8 and 1.2 mg doses of RU16117, respectively. No significant change of basal serum gonadotrophin levels was observed with the daily 0.3 mg dose. Administration of 1 mg of RU16117 every second day or 10 mg once a week led to a relatively small but significant (P less than 0.05) 20--25% decrease of basal serum LH levels after 4 wk of treatment in four out of five women. While daily 0.3 and 1.0 mg doses of RU16117 had no significant effect on the LH response to 100 microgram LHRH, the 3.0 mg dose delayed the response up to 90 min. The 10 mg dose, on the other hand, led to a markedly delayed and reduced response. Treatment for the same period (4 wk) with 1 mg RU16117 every second day or 10 mg once a week led to a small (20--25%, P less than 0.05) inhibition of the LH response to LHRH. At the dose of 10 mg once a week, RU16117 had no or minimal effect on endometrial histology. Since RU16117, an orally active weak oestrogenic compound, has been shown to have anticarcinogenic activity in the rat, the present findings suggest that this new steroid could be useful for the treatment of climacteric symptoms.

PIP: Daily oral administration of 1, 3, or 10 mg of RU16117 (11alpha-methoxy ethiyl estradiol) to normal postmenopausal women led to a progressive decrease of basal serum LH levels to 60.4 + or - 17.0, 35.1 + or - 9.1 and 20.1 + or - 2.8% of control (pretreatment values, P 0.01), respectively, after 4 weeks of drug administration. Although the pattern was similar, the inhibitory effect of RU16117 was even more pronounced on FSH than LH levels: a 50% decrease of basal LH and FSH levels was obtained at the daily 1.8 and 1.2 mg doses of RU16117, respectively. No significant change of basal serum gonadotrophin levels was observed with the daily 0.3 mg dose. Administration of 1 mg of RU16117 every 2nd day or 10 mg once a week led to a relatively small but significant (P 0.05) 20-25% decrease of basal serum LH levels after 4 weeks of treatment in 4 out of 5 women. While daily 0.3 and 1.0 mg doses of RU16117 had no significant effect on the LH response to 100 mcg LHRH, the 3.0 mg dose delayed the response up to 90 minutes. The 10 mg dose, on the other hand, led to a markedly delayed and reduced response. Treatment for the same period (4 weeks) with 1 mg RU16117 every 2nd day or 10 mg once a week, led to a small (20-25%, P 0.05) inhibition of the LH response to LHRH. At the dose of 10 mg once a week, RU16117 had no or minimal effect on endometrial histology. Since RU16117, an orally active weak estrogenic compound, has been shown to have anticarcinogenic activity in the rat, the present findings suggest that this new steroid could be useful for the treatment of climacteric synptoms.

Symptomatic spinal epidural lipomatosis induced by a long-term steroid treatment. Review of the literature and report of two additional cases.

Spinal epidural lipomatosis associated with Cushing's syndrome is an uncommon complication (11 reported cases). Two additional symptomatic cases with neurologic deficit are described. Steroid treatment was systemic in the first case and local with epidural injections in the second. The second case is unique because no similar observations have yet been reported. In most cases, a preoperative computed tomographic scan establishes the diagnosis by demonstrating dural compression by an adipose mass. Myelography is far less specific. In some cases, the exact diagnosis is made at the time of surgery. The treatment is primarily surgical, with laminectomy over the length of the compression and the removal of the compressing fat. Neurologic recovery is dependent on two factors: the level of the compression and the adequacy of decompression.

A radioreceptor assay for benzodiazepines.

A simple, rapid and sensitive radioreceptor assay for determining benzodiazepines in serum is based on the displacement by the drug of specific [3H]diazepam binding to a membrane fraction from rat brain. The limit of detection of the more active benzodiazepines is about 0.5 ng. Diazepam, nitrazepam, clobazam and HR 458 have been assayed in human serum after a single oral clinical dose. The results can be used for determining pharmacokinetic parameters. The technique measures not only the parent benzodiazepine but also clinically active metabolites.