Clonal diversity of recurrently mutated genes in myelodysplastic syndromes.

Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ≤0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS.

Recurrent DNMT3A mutations in patients with myelodysplastic syndromes.

Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides is mediated by DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. In this study, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A, was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of myeloblast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared with patients without DNMT3A mutations (P=0.005) and more rapid progression to AML (P=0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.

Spectral analysis of stress-induced change in blood pressure and heart rate in normotensive subjects.

Changes in spectral analysis of the variability in systolic blood pressure (SBP) and heart rate (HR) were investigated in 12 normotensive volunteers during a well-standardized stress test. BP was measured indirectly from the finger by a noninvasive device (Finapres). The stress test was a computerized version of the Stroop color word conflict test (CWT). The influences of acute (single dose) beta 1-selective blockade by bisoprolol or angiotensin-converting enzyme (ACE) inhibition by lisinopril were analyzed by a double-blind placebo-controlled trial. During the placebo phase, the efficiency of the stress test was confirmed by a significant increase in SBP (25 +/- 11%), HR (36 +/- 23%), and plasma concentrations of epinephrine (Epi, 54 +/- 37%) and norepinephrine (NE, 27 +/- 35%). Stress induced a significant increase in the amplitude of SBP and HR oscillations in the medium-frequency band (MF, 70- to 140-mHz range), which corresponds to the Mayer waves (27 +/- 32 and 42 +/- 43%, respectively for SBP-MF and HR-MF). The stress-induced increase in NE correlated significantly with the increase in HR (r = 0.68, p < 0.05). The stress-induced increase in SBP-MF correlated significantly with the increase in Epi (r = 0.69, p < 0.05) and in HR-MF (r = 0.69, p < 0.05). A significant decrease in SBP-MF at rest was observed with a single oral (p.o.) dose of bisoprolol, but not of lisinopril. As a noninvasive method, spectral analysis of the variability in SBP and HR may be of benefit in stress-induced modifications of the autonomic nervous system.

[Adaptive control of therapeutics using amikacin in very old patients: retrospective analysis of efficacy and toxicity]. / Contrôle adaptatif des thérapeutiques par l'amikacine chez des patients très âgés: analyse rétrospective de l'efficacité et de la toxicité.

UNLABELLED: The authors previously showed the precision of adaptive control of amikacin therapy in elderly patients. The present retrospective study evaluated the effects of such therapy on outcomes. 48 patients, aged 80 +/- 5 years, with estimated creatinine clearance (eCCR) of 48 +/- 15 ml/mn, received amikacin initial dosage of 13.3 +/- 3.5 mg/kg/d, alone or with other drugs. Efficacy outcomes were: E1 = changes in dosage during therapy; E2 = fever reduction within 3 days after therapy; E3 = eradication of infection by culture data; E4 = reduction of white blood cell count (WCB) to normal; E5 = overall recovery. Toxicity outcomes were: T1 = subjective ototoxicity; T2 = nephrotoxicity, variation of serum creatinine low (between 18 et 44 mumol/l) or high (over 0.5 mg/dl). RESULTS: E1: final dose = 11.8 +/- 5.1 mg/kg/d (NS), 57% reduced, 33% increased, during 15.1 +/- 9.3 days in therapy, with 88% having effective peaks over 15 micrograms/ml. E2: fever reduced within 3 days 16/37; after 12/37; no change, 9/37. E3: cultures became negative, 13/28. E4: WBC fell early, 10/21; late, 7/21; no change, 2/21. E5: recovery 36; death, 8; change in therapy, 3. T1: no clinical signs of ototoxicity. T2: low(+), 9/51; low(-), 11/51; high(-), 7/51. final eCCR: 48 +/- 14 ml/mn (NS); no nephrotoxicity. These results suggest that adaptive control of amikacin regimens yields good efficacy and avoid toxicity in the Elderly. However, prospective controlled clinical trials should be done for confirmation.

[Treatment of sub-levator rectocele by transrectal approach. Value of the automatic stapler with linear clamping]. / Traitement des rectocèles sus-lévatoriennes par voie endorectale. Intérêt de la pince automatique à agrafage linéaire.

Surgical treatment of rectocele causing outlet blockage is still a subject of controversy. A retrospective study of eight rectocele repairs endorectally using a surgical stapling device done over a two years period was performed. The most common indication was constipation. All patients underwent in the preoperative period complete physiologic examination including defecography, anorectal manometry, electromyography and colonic transit studies. All patients underwent colonoscopy to exclude an obvious physical disorder. There was no postoperative morbidity and the mean hospital stay was four days. Good functional results were obtained in seven patients with a one year follow-up. Endorectal resection using a stapling device is both a simple and effective technique to treat rectocele associated with difficulty in evacuation.

Compression (Salter-Harris Type V) physeal fracture: an experimental model in the rat.

Histologic evidence of damage to the proximal tibial physis of immature rats was documented in greater than 30% of hind limbs subjected to a valgus and compressive force. The lesion was consistent with that theorized for the Salter-Harris Type V fracture. Two additional groups of immature rats were subjected to the same insult and followed to maturity. One of the groups sustained an intentional concomitant ipsilateral femoral shaft fracture. No tibia demonstrated a growth disturbance in the absence of the femoral fracture, while similar angular deformities were noted in four tibiae (13%) in the presence of a fractured femur. Previously theorized traumatic physeal injuries, implicated in subsequent growth disturbances and seen clinically in association with ipsilateral long bone fractures, were identified in this animal study.

[Effects of treatment of female stress incontinence by intravaginal perineal retraining. Prospective study]. / Effets du traitement de l'incontinence féminine d'effort par rééducation périnéale endovaginale. Etude prospective.

31 stress incontinent women (stage 1 and 2 Ingelman-Sundberg) are treated with Kegel perineal reeducation (levator ani contractions are controlled with an intravaginal finger and with an intravaginal pressure biofeed-back). After a mean of 9 weeks treatments, one treatment 30 mm weekly, levator ani and urethral striated contract in a good way and their contractions are stronger. 64% women are continent. Continence prognostic after treatment is function of the age of incontinence before reeducation (75% stage 1 versus 45% stage 2 become continent) and function of the recovery of a minimal strength of peri-urethral striated sphincter.

[Relaxing effect of nicergoline on the female urethra in peripheral neurogenic vesicosphincter dysfunctions]. / Effet relaxateur sur l'urètre féminin de la nicergoline dans les dysfonctions vésico-sphinctériennes neurogènes périphériques.

The authors study the effect of Nicergoline (alpha 1-blocker) on the urethral profile of 13 women with a peripheral type of neurological bladder. With regard to the 3 parameters adopted (maximum urethral pressure, continence zone and continence area), they found decrease of 13%, 8% and 20% respectively.

[Medical practice in Indians of the Colombian Amazon. Epidemiology of intestinal parasitoses]. / Exercice de la médecine chez les indiens d'amazonie colombienne. Epidémiologie des parasitoses intestinales.

In spite of the presence of a physician, the real pathology of an indian population of Colombie is not very well known. Some of ill people are probably entrusted to the traditional "chaman". The western medicine is symptomatic, curative and not preventive. Intestinal nematodiasis and amoebiasis are the major problem. Prevalences are: ascaris 46%, trichuris 30%, ankylostoma 39%, strongyloides 40%, Entamoeba histolytica 30%. Among this slowly evoluting population parasitism is related with cultural factors.

[Presence of Angiostrongylus cantonensis in the Réunion Island. Isolation of the strain]. / Existence d'Angiostrongylus cantonensis a la Réunion Isolement de la souche

The detection of some cases of eosinophilic meningitis suggest that Angiostrongylus cantonensis is present in Reunion Island. Larvae of this nematode have been isolated after dissection of Achatina fulica and have been used to infest laboratory rats. 30 days later, the dissection of these animals shows the presence of young worms in the brain and in the pulmonary arteries. 45 days later, first-stage larvae are recovered from the feces of animals. Now, the strain is maintained in Biomphalaria glabrata and in the rat.