Differential Effect of Diarrhea on FK506 Versus Cyclosporine A Trough Levels and Resultant Prevention of Allograft Rejection in Renal Transplant Recipients

Diarrhea is the most frequently reported adverse event in patients treated with mycophenolate mofetil. Twenty-six renal transplant patients on a mycophenolate mofetil-based immunosuppressive regime with persistent afebrile diarrhea were examined. Diarrhea caused a significant rise in FK-506 trough levels despite intake of stable doses, necessitating FK-506 dose reductions of 30% to obtain pre-diarrhea trough levels. In contrast, trough levels of cyclosporine A remained stable without dose adjustments. This suggests that absorption and/or metabolism is differentially altered for FK506 compared with cyclosporine A in patients with diarrhea. In nine patients mycophenolate mofetil was reduced or stopped because of persistent diarrhea without identifiable cause. This resulted in end-stage renal disease because of chronic rejection in two patients, and in acute rejection in two patients, all taking FK506 and steroids. Therefore, dose adjustments of FK506 in patients with diarrhea must be carefully monitored, especially when doses of mycophenolate mofetil are also reduced.     

Proteolytic Processing Mechanisms in the Biosynthesis of Neuroendocrine Peptides: The Subtilisin-like Proprotein Convertases

The recent discovery of a novel family of precursor processing endoproteases has greatly accelerated progress in understanding the complex mechanisms underlying the maturation of prohormones, neuropeptides, and many other precursor-derived proteins. At least six members of this family have been found thus far in mammalian species, several having alternatively spliced isoforms, and related enzymes have been identified in many invertebrates, including molluscs, insects, nematodes, and coelenterates. The proprotein convertases are all dependent on calcium for activity and all possess highly conserved subtilisin-like domains with the characteristic catalytic triad of this serine protease (ordered Asp, His, and Ser along the polypeptide chain). Two members of this family, PC2(SPC2) and PC1/PC3(SPC3), appear to play a preeminent role in neuroendocrine precursor processing. Both convertases are expressed only in the brain and in the extended neuroendocrine system, while another important family member—furin/PACE (SPC1)—is expressed more ubiquitously, in almost all tissues, and at high levels in liver. SPC2 and SPC3 exhibit acidic pH optima and other properties which enhance their activity in the acidic, calcium-enriched environment of the dense-core secretory granules of the regulated pathway in neuroendocrine cells, while furin has a neutral pH optimum and is localized predominantly to the trans Golgi network where it is retained by a C-terminal transmembrane domain. Furin processes a wide variety of precursors in the constitutive pathway, such as those of growth factors, receptors, coagulation factors, and viral glycoproteins. Recent findings on the processing of proopiomelanocortin, proinsulin, proglucagon, and several other neuroendocrine precursors by SPC2 and SPC3 are discussed, along with information on the structure, properties, evolution, developmental expression, and regulation or the convertases. An inherited defect in the fat/fat mouse which affects the processing of proinsulin, and probably also many other prohormones, due to a point mutation in carboxypeptidase E has recently been identified and has begun to provide new insights into the functional integration of the individual processing steps.     

Ascending cluster pinning of the humerus inserted through the deltoid tuberosity

Summary Goal of Surgery Stable internal fixation of extraarticular proximal humeral fractures. Indications Extraarticular fractures angulated more than 30° which can be reduced closely or through a small incision. Epiphysiolysis. Fracture-dislocation of the humeral head. Contraindications Pathological fractures. Four part fractures. Segmental fractures of the humerus. Positioning and Anaesthesia Supine; the affected shoulder overhanging the edge of the table and supported by a radiolucent board. General or regional anaesthesia. Surgical Technique Closed pinning of two part and certain three part fractures of the proximal humerus being displaced, unstable, and mainly at the metaphyseal level. Introduction of Kirschner wires through a diaphyseal window and advancement into the proximal fragments after reduction which is controlled by image intensification. Postoperative Management Temporary immobilization in a sling. Passive and active assisted movements after a few days. Active movements after 2 weeks. Removal of wires after 3 months. Possible Complications Fracture of the humerus at the site of the cortical window. Injury to the radial nerve. Results 32 patients, mean age 49 years, 30 two part fractures and 2 three part fractures. Number of Kirschner wires used: 3 to 6, mean 4. Two out of 3 patients complained of pain at the site of wire insertion. All fractures consolidated. No avascular necrosis nor infection. Complications: Partial loss of internal fixation in 3 patients. One fracture of the humeral shaft. Sympathetic reflex dystrophy in 3 patients. Half of the patients had a normal range of motion. Time of follow-up: 6 to 24 (mean 10) months. Division of Orthopaedics and Traumatology, Purpan Hospital, Toulouse, France.     

Comparative effects of ischemia and acute hypoxemia on muscle afferents from tibialis anterior in cats

Comparative effects of ischemia and acute hypoxemia (PaO₂ = 24 mm Hg) were studied in anesthetized cats on afferents from the tibialis anterior limb muscle. Metaboreceptors (groups III and IV fibers) and mechanoreceptors were identified by their activation by an intraarterial injection of lactic acid (LA) or high-frequency vibrations (HFV) applied to the extremity of the muscle tendon, respectively. Ischemia and hypoxemia exerted opposite influences on the two categories of muscle afferents: they depressed the response of mechanoreceptors to HFV, but markedly enhanced the spontaneous tonic activity of metaboreceptors. The effects of hypoxamia were delayed but slightly greater and lasted longer during the recovery period than those exerted by ischemia. The inhibitory action on mechanoreceptors exerted by a reduced oxyden supply to muscle is interpreted as a result from local acidosis. Indeed, under normoxic conditions, a LA bolus injection during the HFV test also reduced the firing rate of these receptors. © 1993 John Wiley & Sons, Inc.     

Comparison of cord blood immunoglobulin E concentrations and maternal allergy for the prediction of atopic diseases in infancy

Total serum IgE levels were determined in 136 newborns and their mothers and in 54 of their fathers, using the paper radioimmunosorbent test (PRIST) technique. IgE specific antibodies for house dust (Dermatophagoides pteronyssinus), orchard grass, timothy grass, and cow's milk were measured with the radioallergosorbent test (RAST). One hundred thirty-three RAST assays were negative in newborns, and in three cases RAST for cow's milk was positive. Cord blood IgE ranged from 0 to 5.5 IU/ml (mean 0.32 ± 0.54 IU/ml); levels were significantly (p < 0.05) higher when maternal IgE was over 100 IU/ml and when mothers had received progesterone therapy during the pregnancy. Salbutamol administration or tobacco smoking during pregnancy did not influence newborn IgE. A clinical follow-up study was conducted in 83 infants for 9 mo. Nine infants developed definite atopic disease, and possible allergic diseases were noted in eight other infants. The IgE level at birth appeared to be more predictive for the development of allergy in infancy than the family history.     

Is one assessment enough? Patterns of helping alliance development and outcome

Early therapeutic alliance is usually measured by the rating of a single session (between the third and the fifth sessions). However, there is a strong argument in favor of viewing early alliance as a developing process. This study examined the relationship between patient's rating of the helping alliance (HAq) at each session and therapy outcome. This comparison was repeated using patterns of alliance over the course of treatment. Patterns of therapeutic alliance development were detected by clustering ratings of a sample of N = 70 outpatients across four sessions of very brief psychotherapeutic intervention. Cluster analysis revealed two main patterns (shapes) of alliance development: (i) stable alliance, and (ii) linear growth pattern. These patterns are more predictive of symptom improvement and social adjustment than single ratings, whereas single ratings measuring the strength of alliance are more correlated with patient's satisfaction. Copyright © 2004 John Wiley & Sons, Ltd.     

Human cytomegalovirus UL144 gene polymorphisms in congenital infections

The human cytomegalovirus (HCMV) UL144 gene is a tumor necrosis factor-like receptor with the potential to affect HCMV virulence. HCMV strains display genetic variability in the UL144 region, and the analysis of a potential link between UL144 gene polymorphisms and disease severity has scarcely been studied. However, a correlation between the UL144 genotype and congenital-disease outcome has been reported in one previous study, with the observation that all asymptomatic infants had a single UL144 genotype. In order to confirm or refute this finding, we determined the UL144 polymorphisms of HCMV strains recovered from the amniotic fluids of 38 infected fetuses and compared them to HCMV strains obtained from 30 viremic adult controls. The UL144 sequences were distributed among five genotypes (A, B, C, AC, and AB), as previously described. We observed similar percentages of the three major genotypes A (37%), B (33%), and C (27%) in our population. The UL144 genotype distributions were similar among the group of infected adults and the group of infected fetuses and among symptomatic and asymptomatic fetuses (P < 0.05). In our series, all five UL144 genotypes could be vertically transmitted from mothers to fetuses, and all could cause symptomatic congenital infection. We concluded that determination of UL144 polymorphisms in cases of congenital infection is not relevant, since it is unlikely to help predict the outcome of the infection.     

Focal expression and final activity of matrix metalloproteinases may explain irregular dysfunctional endometrial bleeding

Irregular dysfunctional bleeding of the endometrium (ie, metrorrhagia without organic lesion) is common in women, whether treated or not with ovarian hormones. Several matrix metalloproteinases (MMPs) become normally expressed and/or activated at menstruation and cause extracellular matrix breakdown. We therefore explored whether episodes of irregular dysfunctional bleeding could be associated with untimely MMP activity. By histology, foci of stromal breakdown were exclusively found in the endometrium of metrorrhagic women at bleeding. In these foci, 1) expression of estrogen receptor-alpha and progesterone receptor was altered; 2) collagenase-1 (MMP-1), stromelysin-1 (MMP-3), and gelatinase B (MMP-9) became detected in stromal cells, together with MMP-9 in neutrophils; and 3) gelatinase A (MMP-2) was more expressed and immunolocalized at the membrane of stromal cells. By biochemistry, endometrial lysates from nonbleeding metrorrhagic patients contained more latent and active MMP-2 and -9 than age-matched controls; at bleeding, collagenase activity, MMP-9, and active MMP-2 were strikingly increased whereas tissue inhibitor of metalloproteinases-1 (TIMP-1) was considerably decreased. As a functional assay, in situ gelatin zymography revealed large areas of gelatinolytic activity only in endometrium of bleeding patients. Altogether, these results strongly suggest that inappropriate focal expression and activation of several MMPs, combined with decreased inhibition, trigger irregular dysfunctional endometrial bleeding.     

Persistent increase in the incidence of acute male urethritis diagnosed in general practices in France

BACKGROUND: At-risk sexual behaviour seems to have increased in Europe, possibly due to the reassuring efficacy of highly active antiretroviral treatments. AIM: To follow, from 1990 to 2003, in France, the trends in the incidence of acute male urethritis diagnosed in general practice, a marker of at-risk sexual behaviour. DESIGN OF STUDY: Electronic disease surveillance. SETTING: General practices located all over mainland France. METHOD: The GPs of the French Sentinelles network reported, via online computer systems, the acute urethritis cases they diagnosed, and for each case the characteristics of the patients. RESULTS: After a striking decrease between 1990 and 1995 from 460 per 100 000 men aged 15-64 years (95% confidence interval [CI] = 390 to 520) to 180 (95% CI = 150 to 200), when antiretroviral drugs became available on the French market, the incidence of acute male urethritis stopped decreasing. Between 1996 and 2003, it may have risen again from 190 per 100 000 men (95% CI = 160 to 210) to 325 per 100 000 men (95% CI = 280 to 370) aged 15-64 years. The percentage of homosexual/bisexual men among the cases reported was higher than in the general population (10% versus 4%, P<0.001). Homosexual/bisexual patients were younger than heterosexual patients (34 versus 37 years, P = 0.04), more of them had a discharge (88% versus 59%, P<0.001), a history of sexually transmitted disease (65% versus 32%, P<0.001), and at least two sexual partners (74% versus 38%, P<0.001). The most frequent pathogens were Chlamydia trachomatis (25%), Neisseria gonorrhoea (21%), Mycoplasma genitalium (8%), Ureaplasma urealyticum (5%), Trichomonas vaginalis (3%) and other bacteria (32%). Presence of co-infections was observed in 8.3% of patients. CONCLUSIONS: This increase in the incidence of urethritis, shows that the sexual health of men has worsened in France, and calls for urgent new preventive measures.     

Spontaneous increase of DNA turnover in murine systemic lupus erythematosus

DNA synthesis and release was studied in unstimulated splenocytes of strains of mice known to develop spontaneous systemic lupus erythematosus (SLE)-like disease and in non-SLE age- and sex-matched strains as well. Newly synthesized DNA was measured as total acid-insoluble radioactive material present in cell pellet plus supernatant of unstimulated 0–72 h cell cultures [³H]thymidine-pulsed, whereas DNA release was measured as amount of acid-precipitable radioactivity found in supernatant of those cultures. In all strains known to develop spontaneous murine SLE the amount of newly synthesized DNA was 1.3–2.1-fold increased when compared to normal strains studied concomitantly. Furthermore, a significant increase in DNA release into medium, unrelated to cell viability, was observed in those strains as well. These observations clearly demonstrate different metabolic rates of synthesis and release of DNA in murine SLE. This difference suggests the existance of an underlying mechanism responsible for extracellular DNA abundancy, which may be important for the formation of circulating DNA-anti-DNA immune complexes.