Thoughts on the importance of being different.
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Biomedical subjects
Publications and source records attributed to C Richard.
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The authors report a case of a 25 years old woman in whom a coin lesion was fortuitously discovered. Initial investigations were negative and an exploratory thoracotomy was performed which enabled a benign clear cell tumour of the lung to be found (sugar tumour). This rare benign tumour whose cellular origin remains indeterminate is in general discovered in a fortuitous manner after a chest x-ray has been performed showing a round peripheral opacity. The diagnosis is confirmed following the excision of the tumour, complementary examinations are not helpful.
We evaluated the efficacy and safety of 0.1% indomethacin and 0.1% diclofenac solutions, in controlling pain post excimer laser photorefractive keratectomy (PRK). After written consent, 61 informed patients (23 males, 38 females; mean age = 33.5 +/- 8.4 yrs) were enrolled in a double-masked, randomized, comparative study and assigned to either indomethacin or diclofenac treatment. Subjective preoperative evaluation of individual susceptibility to pain evoked by topical application of 1% tetracaine vs saline served as reference for further post-operative pain measurement using a visual analog rating scale. Ocular and cephalic pain, itching, foreign body sensation, insomnia, photophobia, blepharospasm as well as systemic analgesic medication and alcohol intake were monitored for 3 days following photoablation as well as the re-epithelialization process. Both solutions significantly reduced pain on the first day following excimer laser PRK, and this activity was maintained until the end of the observation period. At Day 0 the first measure of pain level was slightly higher in the indomethacin group (p < 0.05) and could be related to a possible anaesthetic effect of Diclofenac. During the follow-up the oral intake of analgesics was higher in the diclofenac group, however this difference was not significant. Wound healing rate was not affected by indomethacin or diclofenac administration. These data suggest that both 0.1% indomethacin and 0.1% diclofenac ophthalmic solutions may help to control the pain induced by excimer laser PRK without any deleterious effect on corneal wound healing.
The chromatographic behaviour of various saturated and unsaturated oligouronates obtained by acid or enzymatic degradation of homopolymeric blocks of alginates was investigated by isocratic anion exchange liquid chromatography. This approach was then applied to the determination of the catalytic properties of Haliotis tuberculata alginate lyase. This enzyme presents a high affinity for poly-beta-D-mannuronate blocks, leading to the release of O-(4-deoxy-alpha-L-erythro-hex-4-enopyranosyluronic acid)-(1-->4)-O-(beta-D-mannopyranosyluronic acid)-(1-->4)-O-beta-D-mannopyranuronic acid as the main end reaction product. Kinetic analysis with oligomannuronates of various sizes indicate that the catalytic site of Haliotis tuberculata lyase (abalone) best accommodates an oligomannuronate pentamer. The abalone lyase, however, is also capable of cleaving the G-M linkages of alginate heteropolymeric sequences. In contrast, it does not degrade the G-G nor the M-G diads. This lyase should therefore be referred to as a mannuronate beta-eliminase, indicating that the enzyme performs beta-elimination on mannuronate residues only, from both the M-M and G-M diads of alginates.
Erythropoietin (Epo), the hormone that is the principal regulator of red blood cell production, interacts with high-affinity receptors on the surface of erythroid progenitor cells and maintains their survival. Epo has been shown to promote cell viability by repressing apoptosis; however, the molecular mechanism involved is unclear. In the present studies we have examined whether Epo acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. We addressed this issue in HCD-57, a murine erythroid progenitor cell line that requires Epo for proliferation and survival. When HCD-57 cells were cultured in the absence of Epo, Bcl-2 and Bcl-XL but not Bax were downregulated, and the cells underwent apoptotic cell death. HCD-57 cells infected with a retroviral vector encoding human Bcl-XL or Bcl-2 rapidly stopped proliferating but remained viable in the absence of Epo. Furthermore, endogenous levels of bcl-2 and bcl-XL were downregulated after Epo withdrawal in HCD-57 cells that remained viable through ectopic expression of human Bcl-XL, further indicating that Epo specifically maintains the expression of bcl-2 and bcl-XL. We also show that HCD-57 rescued from apoptosis by ectopic expression of Bcl-XL can undergo erythroid differentiation in the absence of Epo, demonstrating that a survival signal but not Epo itself is necessary for erythroid differentiation of HCD-57 progenitor cells. Thus, we propose a model whereby Epo functions as a survival factor by repressing apoptosis through Bcl-XL and Bcl-2 during proliferation and differentiation of erythroid progenitors.
1-O-Octadecyl-2-O-methyl-glycerophosphocholine (ET18-OCH3) is an ether lipid with selective antiproliferative properties whose mechanism of action is still unresolved. We hypothesized that since ET18-OCH3 affects a wide variety of cells, its mechanism of action was likely to involve the inhibition of a common widely used pathway for transducing growth signals such as the mitogen-activated protein kinase (MAPK) cascade. To test this, we established conditions whereby quiescent MCF-7 cells took up ET18-OCH3 in sufficient quantities that inhibited cell proliferation subsequent to the addition of growth medium and examined the activation of components of the MAPK cascade under these conditions. ET18-OCH3 inhibited the sustained phosphorylation of MAPK resulting in a decrease in the magnitude and duration of activation of MAPK in cells stimulated with serum or EGF. ET18-OCH3 had no effect on the binding of EGF to its receptors, their activation, or p21ras activation. However, an interference in the association of Raf-1 with membranes and a resultant decrease in Raf-1 kinase activity in membranes of ET18-OCH3-treated cells was observed. ET18-OCH3 had no direct effect on MAPK or Raf-1 kinase activity. A direct correlation between ET18-OCH3 accumulation, inhibition of cell proliferation, Raf association with the membrane, and MAPK activation was also established. These results suggest that inhibition of the MAPK cascade by ET18-OCH3 as a result of its effect on Raf-1 activation may be an important mechanism by which ET18-OCH3 inhibits cell proliferation.
Axonal atrophy may reflect earlier and more reversible events in neurodegeneration and ageing than somatic atrophy. Innervation density by sympathetic fibres from the rat superior cervical ganglion (SCG) to the middle cerebral artery (MCA) decreases dramatically in old age, while that to the iris is largely unchanged. In situ hybridization was used in conjunction with retrograde tracers to examine the role of the neuronal cytoskeleton in this selective axonal vulnerability. Using a riboprobe complementary to neurofilament light chain (NF-L) mRNA, there was a 22-25% decrease in the mean grain density in aged neurones when all neurones were examined. A small subset of these neurones was shown to project to the MCA and another to the iris. In young SCG, both subpopulations expressed intermediate grain densities for NF-L mRNA. In MCA-projecting neurones, there was a 40% decline in grain density with ageing (p < 0.05), with no change in iris-projecting neurones. Our results demonstrate that major decreases in NF-L expression may represent cellular markers of selective axonal hypotrophy by aged neurones.
In the green unicellular alga Chlamydomonas reinhardtii, as in higher plants, the expression of the genes encoding the chlorophyll a/b-binding (CAB) polypeptides associated with photosystem I (PSI) and photosystem II (PSII) is regulated by endogenous (circadian clock) and exogenous signals (light and temperature). The circadian clock ensures that the oscillation in the levels of the different cab mRNAs is continuously kept in phase with light/dark (LD) cycles and is maximal by the middle of the day. On the other hand, light controls the amplitude of the oscillations. We report here the cloning and characterization of the C. reinhardtii LI818 gene, which identifies a CAB-related polypeptide and whose expression is regulated quite differently from the cab I/II genes. We show: (1) that in LD synchronized Chlamydomonas cells LI818 mRNA accumulation is subject to dual regulation that involves separable regulation by light and an endogenous oscillator; (2) that LI818 mRNA is fully expressed several hours before the cab I/II mRNAs and that the latter accumulate concomitantly; (3) that blocking the electron flow through PSII using DCMU prevents cells from accumulating cab I/II mRNAs but not LI818 mRNA and (4) that the accumulation of LI818 mRNA is abolished by blocking cytoplasmic protein synthesis, suggesting that these regulatory mechanisms are mediated by labile proteins.
Previous studies found that months after clorimipramine (CLI) treatment of male neonatal rats, the mature animals developed behavioral deficits and REM sleep abnormalities that modeled human endogenous depression. In the initial studies neonatal rats received CLI 30 mg/kg/IP daily from age 8 through 21 days. Diminished sexual activity of the adult rats treated neonatally in this manner was a behavioral deficit that supported the depression model. However, in subsequent studies in our laboratory, the same neonatal treatment occasionally failed to produce adult sexual deficiencies found in the initial studies. The inconsistency raised the possibility that neonatal CLI treatment was not a reliable method to produce an animal model of depression. An alternative hypothesis was that the CLI dose was too low. The present study tested this hypothesis. Placebo or one of four CLI doses was administered daily to male neonatal rats (n = 12/treatment group) from age 8 days through 21 days: 30 (the original dose), 40, 50, and 60 mg/kg/IP. Six components of adult sexual behavior were measured at age 5 months. Deficiency of each sexual behavior was found to be dose-dependent (r = 0.5, p < 0.001). The 30 mg/kg/day dose caused deficiencies in some, but not all, sexual behavior measures. Higher doses caused deficiencies in all measures of sexual behavior. The results support the hypothesis that neonatal CLI treatment at doses higher than the original 30 mg/kg/day caused reliable impairments in adult male rat sexual behavior, and therby support the reliability of neonatal CLI treatment to produce an animal model of endogenous depression.
Recombinant human erythropoietin (rHuEPO) has been demonstrated to be effective in ameliorating anemia among persons with chronic renal failure, and is associated with improved functional status and quality of life. Access to rHuEPO has been examined by a variety of clinical, demographic, geographic, and facility characteristics. However, rHuEPO utilization based on insurance status has not been previously examined. All Medicare and Medicaid prevalent end-stage renal disease (ESRD) patients receiving dialysis services in California, Georgia, and Michigan in December 1991 were identified using state and federal administrative program data. The population in each state was stratified by insurance status as follows: Medicare-entitled, Medicare/Medicaid dually entitled, and Medicaid-only entitled. Insurance coverage of the ESRD population by Medicaid, as either a primary or secondary payer, differed greatly by state. In December 1991, the proportion of Medicaid-only and Medicaid/Medicare dually eligible dialysis patients ranged, respectively, from 8% and 43% in California, to 3% and 26% in Michigan, and to 3% and 18% in Georgia. Compared with the Medicare-entitled population, the Medicaid/Medicare dually eligible and Medicaid-only populations disproportionately comprised women, black patients, and individuals younger than 20 years. Using Lee's two-stage binary logit model, dual-eligibility was found to be associated with an increased access to rHuEPO. Compared with their state-specific, dually eligible counterparts, the odds of receiving rHuEPO was lower for Medicare-entitled patients in California (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.76,0.93) and Georgia (OR, 0.65; 95% CI, 0.53,0.80), and lower for Medicaid-only patients in Georgia (OR, 0.02; 95% CI, 0.01,0.05) and Michigan (OR, 0.34; 95% CI, 0.23,0.52). We hypothesize that the absence of substantial copayments associated with rHuEPO, approximately $1,000 per year for a portion of Medicare-entitled patients, resulted in increased access among the dually eligible ESRD population. Dosing of rHuEPO was associated primarily with patient hematocrit level (P < 0.0001) and was unrelated to insurance status. Regardless of insurance status, an unexpectedly large number of Medicare prevalent dialysis patients receiving rHuEPO in each state (31%, 42%, and 41% in California, Georgia, and Michigan, respectively) had hematocrit values lower than 0.28, indicating inadequate treatment of anemia. Eleven percent of all patients receiving rHuEPO in California and nearly 20% in Georgia and Michigan were deemed to be severely anemic (hematocrit < 0.25). The wide variability in access to rHuEPO among the Medicaid-only populations may be indicative of state-specific differences in Medicaid prior approval, copayments, and other drug restrictions. We conclude that the Medicaid-only ESRD population excluded from Medicare coverage is particularly vulnerable to cost-containment measures that focus on expensive technologies such as rHuEPO.
Arousal is an important protective response during sleep, and arousal deficit is hypothesized to play a role in the etiology of sudden infant death syndrome (SIDS). Because environmental or caretaking factors have been shown to exert powerful effects on susceptibility to SIDS, manipulations that facilitate arousability might be protective against SIDS. All-night laboratory polysomnographic recordings were performed in 20 routinely bedsharing and 15 routinely solitary sleeping healthy breast-feeding Latino infants within the peak age range for SIDS, in both bedsharing (with mother) and solitary sleeping environments. The most important findings revealed by repeated measures analyses of variance were a significant reduction in stage 3/4 sleep and an inverse increase in stage 1/2 sleep on the bedsharing night compared to the solitary night, irrespective of routine sleeping arrangement. Shorter mean duration episodes of stage 3/4 sleep and longer mean stage 1/2 sleep episodes accounted for these differences. Because the arousal threshold is high in the electroencephalographic delta range, by limiting the amount of stage 3/4 sleep, bedsharing should promote infant arousability and might be protective against SIDS. The results also suggest that accepted normative values for infant sleep established in solitary sleeping infants may not be representative of infants raised in social sleeping environments.
The impact of mother-infant bedsharing on infant sleeping position, orientation, and proximity to the mother was assessed in 12 breast-feeding Latino mother-infant pairs. Six routinely bedsharing and six routinely solitary-sleeping pairs slept 3 nights in the sleep laboratory. The first night matched the routine home condition, followed by 1 bedsharing night and 1 solitary-sleeping night in random order. During bedsharing infants were never placed prone, regardless of their routine sleeping condition. On the bedsharing night, mothers and infants spent most of the night oriented toward each other; seven of 12 infants remained oriented toward their mothers the entire night. While sleeping in a face-to-face orientation, most pairs slept most of the time less than 30 cm apart with appreciable amounts of time at less than 20 cm. This orientation and proximity should facilitate sensory exchanges between mother and infant which, we hypothesize, influence the infant's sleep physiology and nocturnal behavior. We conclude that bedsharing minimizes the use of the prone infant sleeping position, probably in part to facilitate breast feeding. By promoting nonprone positions, bedsharing may protect some infants from sudden infant death syndrome (SIDS), since prone sleeping is a known risk factor for SIDS. The large percentage of the night that mothers spent oriented toward their infants suggests that a higher degree of maternal vigilance may also result from bedsharing.
During the final phases of chronic renal disease, inpatient care comprises an enormous share of morbidity and direct medical costs. Using an attributable risk methodology, this study calculated inpatient resource utilization and associated costs for chronic renal failure (CRF) and ESRD. A national hospital survey was used to identify the 348,962 hospitalizations for patients with renal failure in 1991. Among persons under the age of 65, pre-ESRD CRF patients had the same number of hospitalizations (nearly 75,000) as ESRD patients. Age-adjusted relative risk calculations indicate that patients with renal failure experience greater inpatient morbidity compared with other populations with chronic, progressive diseases. For example, compared with persons with diabetes, ischemic heart disease, hypertension, and emphysema, renal patients were at significantly higher risk of hospitalization for congestive heart failure, pneumonia, sepsis, electrolyte disorders, and gastrointestinal hemorrhage. Overall, renal failure patients were ten times more likely to be hospitalized (relative risk, 10.0; 95% confidence interval, 10.00 to 10.04) and, on average, were hospitalized nearly 1 day longer (P < 0.01) compared with the non-renal failure population in 1991. As a result, the economic consequences of inpatient care for the treatment of renal failure were enormous. In 1991, 222,827 hospitalizations, 1.5 million days of inpatient care, and $2.2 billion were attributable to renal failure. Further studies that examine other components of direct medical costs (e.g., long-term care, outpatient care, and pharmaceuticals) as well as indirect costs associated with the treatment and care of renal failure patients are warranted.
OBJECTIVE: The objective of this retrospective study was to determine whether the difference between the donor's weight (wd) and the recipient's dry weight (wr) could influence the function of renal transplants. METHODS: Between 1987 and 1994, 185 patients with a mean age of 43.3 years +/- 12 were transplanted with a locally harvested cadaver kidney, corresponding to 120 men (42.2 years +/- 1.4) and 65 women (45 years +/- 12.8). The weight variation between donors and recipients (wd - wr) was 0.06 for men and 0.22 for women. The serum creatinine of recipients at 1 year was 147 mumol +/- 41.7. We used analysis of variance for univariate statistical analysis and multiple linear regression for multivariate analysis. RESULTS: On univariate analysis, the serum creatinine at 1 and 2 years was significantly higher (p < 0.02 and p < 0.035 respectively) when the donor's weight was 10% lower than the recipient's weight. Multivariate analysis, taking into account the donor's age and sex and the recipient's serum creatinine, confirmed the influence of the donor-recipient weight difference on serum creatinine at 2 years (p0.03), but also the role of the donor's age at 1 and 2 years (p < 0.0001 and p < 0.0004, respectively). CONCLUSION: In our study, the donor-recipient weight difference was a factor influencing the recipient's serum creatinine at 2 years. The donor's age also influences the recipient's serum creatinine, 1 and 2 years after renal transplantation.
We report four patients with chronic myeloid leukemia (CML) that showed poor graft function after a non-T-depleted bone marrow transplantation (BMT) from an HLA-compatible sibling donor and who were successfully treated with splenectomy. Conditioning was done with cyclophosphamide (CY) and total body irradiation (TBI) without additional splenic irradiation. Three patients had enlarged spleens before BMT. The nucleated cell dose infused ranged from 2.3-3.2 x 10(8)/kg. Bone marrow (BM) examination prior to splenectomy showed BM aplasia (three cases) or hypocellularity (one case). At splenectomy no patient had evidence of cytomegalovirus (CMV) infection or severe acute GVHD; and three patients had moderately enlarged spleens. All patients were transfusion dependent. Complete hematological recovery was obtained in all patients. BM cellularity was normal 1 month after splenectomy. Complete chimerism of donor origin was documented. The four patients are alive (+16 to +58 months after BMT). Thus, in patients with CML, a poor graft function may be successfully corrected by splenectomy.
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A 52-year-old male diagnosed with acute myeloid leukemia (AML) developed an invasive middle-ear mucormycosis during the neutropenic period after consolidation chemotherapy which resolved successfully with surgery and antifungal therapy. The patient underwent autologous peripheral blood stem cell transplantation (APBSCT) in first complete remission with antifungal prophylaxis with liposomal amphotericin B (AmB). There was no clinical, radiological or microbiological data of mycotic reactivation. This is the first reported stem cell transplantation (SCT) in a patient with prior invasive mucormycosis.