N-3 Polyunsaturated Fatty Acids (PUFAs) Reverse the Impact of Early-Life Stress on the Gut Microbiota

Supporting Information S1 File. Microbiota Data Set. NS.S, NS.LD, NS.HD stand for non-separated Saline, non-separated Low Dose, non-separated High Dose, respectively. MS.S, MS.LD, MS.HD stand for maternally separated Saline, maternally separated Low Dose, maternally separated High Dose, respectively. (ZIP)peer-reviewedBackground Early life stress is a risk factor for many psychiatric disorders ranging from depression to anxiety. Stress, especially during early life, can induce dysbiosis in the gut microbiota, the key modulators of the bidirectional signalling pathways in the gut-brain axis that underline several neurodevelopmental and psychiatric disorders. Despite their critical role in the development and function of the central nervous system, the effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) on the regulation of gut-microbiota in early-life stress has not been explored. Methods and Results Here, we show that long-term supplementation of eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) (80% EPA, 20% DHA) n-3 PUFAs mixture could restore the disturbed gut-microbiota composition of maternally separated (MS) female rats. Sprague-Dawley female rats were subjected to an early-life stress, maternal separation procedure from postnatal days 2 to 12. Non-separated (NS) and MS rats were administered saline, EPA/DHA 0.4 g/kg/day or EPA/DHA 1 g/kg/day, respectively. Analysis of the gut microbiota in adult rats revealed that EPA/DHA changes composition in the MS, and to a lesser extent the NS rats, and was associated with attenuation of the corticosterone response to acute stress. Conclusions In conclusion, EPA/DHA intervention alters the gut microbiota composition of both neurodevelopmentally normal and early-life stressed animals. This study offers insights into the interaction between n-3 PUFAs and gut microbes, which may play an important role in advancing our understanding of disorders of mood and cognitive functioning, such as anxiety and depression.Research was funded by Food Institutional Research Measure (FIRM) under Grant No. 10/RD/TMFRC/709, the APC Microbiome Institute under Grant No. 07/CE/B1368 and 12/RC/2273, Science Foundation Ireland (SFI) under Grant No. 12/IA/1537

Ovarian dysgenesis associated with an unbalanced X;6 translocation: first characterisation of reproductive anatomy and cytogenetic evaluation in partial trisomy 6 with breakpoints at Xq22 and 6p23.

The aim of this study was to describe the clinical and laboratory findings associated with a previously unreported unbalanced X;6 translocation. Physical examination, reproductive history and cytogenetic techniques were used to characterise a novel chromosomal anomaly associated with gonadal dysgenesis. A healthy non-dysmorphic 23 year-old phenotypic female with primary amenorrhea and infertility presented for reproductive endocrinology evaluation. No discrete ovarian tissue was identified on transvaginal ultrasound, although the uterus appeared essentially normal. BMI was 19 kg/m2. Serum FSH and oestradiol were 111 mIU/ml and 15 pmol/l, respectively. TSH, prolactin and all infectious serologies were all normal. The karyotype of 46,X,der(X)t(X;6)(q22;p23) was determined following cytogenetic analysis of peripheral blood lymphocytes via fluorescence in situ hybridisation (FISH) with whole chromosome paint for chromosome 6, and a separate FISH analysis using a 6p subtelomeric probe. The patient was continued on hormone replacement therapy and underwent genetic counselling; the patient subsequently enrolled as a recipient in an anonymous donor oocyte IVF treatment. Translocations involving autosomes and chromosome X are rare. While female carriers of balanced X;autosome translocations are generally phenotypically normal, the impact of unbalanced X;autosome translocations can be severe. This is the first known report of an unbalanced translocation involving X;6. This abnormality was associated with ovarian dysgenesis, but an otherwise normal female phenotype. From this investigation, the observed developmental impact of the unbalanced translocation with breakpoints at Xq22 and 6p23 appears to be limited to ovarian failure

Genome Sequence of Geobacillus stearothermophilus DSM 458, an Antimicrobial-Producing Thermophilic Bacterium, Isolated from a Sugar Beet Factory

peer-reviewedThis paper reports the full genome sequence of the antimicrobial-producing bacterium Geobacillus stearothermophilus DSM 458, isolated in a sugar beet factory in Austria. In silico analysis reveals the presence of a number of novel bacteriocin biosynthetic genes

Ventricular structure, function, and mechanics at high altitude: chronic remodeling in Sherpa vs. short-term lowlander adaptation

Short-term, high-altitude (HA) exposure raises pulmonary artery systolic pressure (PASP) and decreases left-ventricular (LV) volumes. However, relatively little is known of the long-term cardiac consequences of prolonged exposure in Sherpa, a highly adapted HA population. To investigate short-term adaptation and potential long-term cardiac remodeling, we studied ventricular structure and function in Sherpa at 5,050 m (n = 11; 31 ± 13 yr; mass 68 ± 10 kg; height 169 ± 6 cm) and lowlanders at sea level (SL) and following 10 ± 3 days at 5,050 m (n = 9; 34 ± 7 yr; mass 82 ± 10 kg; height 177 ± 6 cm) using conventional and speckle-tracking echocardiography. At HA, PASP was higher in Sherpa and lowlanders compared with lowlanders at SL (both P < 0.05). Sherpa had smaller right-ventricular (RV) and LV stroke volumes than lowlanders at SL with lower RV systolic strain (P < 0.05) but similar LV systolic mechanics. In contrast to LV systolic mechanics, LV diastolic, untwisting velocity was significantly lower in Sherpa compared with lowlanders at both SL and HA. After partial acclimatization, lowlanders demonstrated no change in the RV end-diastolic area; however, both RV strain and LV end-diastolic volume were reduced. In conclusion, short-term hypoxia induced a reduction in RV systolic function that was also evident in Sherpa following chronic exposure. We propose that this was consequent to a persistently higher PASP. In contrast to the RV, remodeling of LV volumes and normalization of systolic mechanics indicate structural and functional adaptation to HA. However, altered LV diastolic relaxation after chronic hypoxic exposure may reflect differential remodeling of systolic and diastolic LV function. exposure to high altitude (HA) challenges the cardiovascular system to meet the metabolic demand for oxygen (O2) in an environment where arterial O2 content is markedly reduced. The drop in arterial O2 has both direct and indirect consequences for the heart, including depressed inotropy of cardiac muscle (40, 44), changes in blood volume and viscosity, and vasoconstriction of the pulmonary arteries (33). Despite these broad physiological changes, which have been reviewed previously (28, 49), there is evidence that the heart copes relatively well at HA (29, 34). Short-term HA exposure in lowland natives is characterized by a decreased plasma volume (PV), an increased sympathetic nerve activity, and pulmonary vasoconstriction (17, 30, 37), all of which have considerable impact on cardiac function and in time, could stimulate cardiac remodeling. Himalayan native Sherpa, who are of Tibetan lineage and have resided at HA for ∼25,000 yr (2), are well adapted to life at HA, demonstrating greater lung-diffusing capacity (11) and an absence of polycythemia compared with acclimatized lowlanders (4). Previous studies have also reported Sherpa to have higher maximal heart rates (HRs) and only moderate pulmonary hypertension compared with lowlanders at HA (11, 25). Due to their longevity at HA, Sherpa provide an excellent model to investigate the effects of chronic hypoxic exposure. Despite this, neither the acute nor lifelong effects of HA on right- and left-ventricular (RV and LV, respectively) structure and function have been fully assessed in lowlanders or the unique Sherpa population. Due to the unique arrangement of myofibers, cardiac form and function are intrinsically linked, as reflected in the cardiac mechanics (LV twist and rotation and ventricular strain) that underpin ventricular function. In response to altered physiological demand, ventricular mechanics acutely change (16, 41) and chronically remodel (31, 42) to reduce myofiber stress and achieve efficient ejection (5, 47). Therefore, concomitant examination of myocardial mechanics and ventricular structure in both the acute and chronic HA setting will provide novel insight into human adaptation to hypoxia. To investigate the effects of chronic hypoxic exposure, we compared ventricular volumes and mechanics in Sherpa at 5,050 m with lowlanders at sea level (SL). In addition, to reveal potential stimuli for remodeling and to examine the time course of adaptation, we compared Sherpa with lowlanders after short-term HA exposure. We hypothesized that: 1) Sherpa would exhibit smaller LV volumes and a higher RV/LV ratio than lowlanders at SL, 2) LV mechanics in Sherpa will closely resemble those of lowlanders at SL, and 3) following partial acclimatization to HA, LV volumes would be reduced in lowlanders and LV mechanics acutely increased

Assignment of human erythroid [delta]-aminolevulinate synthase (ALAS2) to a distal subregion of band Xp11.21 by PCR analysis of somatic cell hybrids containing X;Autosome translocations

The erythroid-specific (ALAS2) and housekeeping (ALAS1) genes encoding [delta]-aminolevulinate synthase have recently been mapped to chromosomes Xq21.1--&gt;q21 and 3p21, respectively. The erythroid-specific gene is a candidate for mutations resulting in X-linked sideroblastic anemia. Analysis of DNA from hybrid clones containing translocations in the region Xp11.21--&gt;Xq21.3 permitted the finer localization of the ALAS2 gene with respect to other loci and breakpoints within this region. These studies localized the ALAS2 gene to the distal subregion of Xp11.21 in Interval 5 indicating the following gene order: Xpter-OATL2-[L62-3A, Xp11.21; A62-1A-4b, Xp11.21]-(ALAS2, DXS323)-[B13-3, Xp11.21; C9-5, Xp11.21]-(DXS14, DXS429)-DXS422-(DXZ1, Xcen). Thus, the reported linkage of acquired sideroblastic anemia and sideroblastic anemia with ataxia to Xq13 presumably results from genes other than ALAS2.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30074/1/0000444.pd

Mass Azithromycin and Malaria Parasitemia in Niger: Results from a Community-Randomized Trial.

Studies designed to determine the effects of mass administration of azithromycin on trachoma have suggested that mass azithromycin distributions may also reduce the prevalence of malaria. These studies have typically examined the impact of a small number of treatments over short durations. In this prespecified substudy of a cluster-randomized trial for trachoma, we compared malaria parasitemia prevalence in 24 communities in Niger randomized to receive either annual or biannual mass azithromycin distributions over 3 years. The 12 communities randomized to annual azithromycin received three treatments during the high-transmission season, and the 12 communities randomized to biannual azithromycin received a total of six treatments: three during the high-transmission season and three during the low-transmission season. Blood samples were taken to assess malariometric indices among children in all study communities at a single time point during the high-transmission season after 3 years of the intervention. No significant differences were identified in malaria parasitemia, parasite density, or hemoglobin concentration between the annual and biannual treatment arms. When compared with annual mass azithromycin alone, additional mass azithromycin distributions given during the low-transmission season did not significantly reduce the subsequent prevalence of malaria parasitemia or parasite density after 3 years, as measured during the high-transmission season

Impaired myocardial function does not explain reduced left ventricular filling and stroke volume at rest or during exercise at high altitude

Impaired myocardial systolic contraction and diastolic relaxation have been suggested as possible mechanisms contributing to the decreased stroke volume (SV) observed at high altitude (HA). To determine whether intrinsic myocardial performance is a limiting factor in the generation of SV at HA, we assessed left ventricular (LV) systolic and diastolic mechanics and volumes in 10 healthy participants (aged 32 ± 7; mean ± SD) at rest and during exercise at sea level (SL; 344 m) and after 10 days at 5,050 m. In contrast to SL, LV end-diastolic volume was ∼19% lower at rest (P = 0.004) and did not increase during exercise despite a greater untwisting velocity. Furthermore, resting SV was lower at HA (∼17%; 60 ± 10 vs. 70 ± 8 ml) despite higher LV twist (43%), apical rotation (115%), and circumferential strain (17%). With exercise at HA, the increase in SV was limited (12 vs. 22 ml at SL), and LV apical rotation failed to augment. For the first time, we have demonstrated that EDV does not increase upon exercise at high altitude despite enhanced in vivo diastolic relaxation. The increase in LV mechanics at rest may represent a mechanism by which SV is defended in the presence of a reduced EDV. However, likely because of the higher LV mechanics at rest, no further increase was observed up to 50% peak power. Consequently, although hypoxia does not suppress systolic function per se, the capacity to increase SV through greater deformation during submaximal exercise at HA is restricted. during initial exposure to hypobaric hypoxia at high altitude (HA), cardiac output for a given absolute workload is increased to compensate for a lower arterial oxygen content before returning to baseline levels with acclimatization (8). However, after 2-5 days of acclimatization, the required cardiac output is generated through a lower stroke volume (SV) and higher heart rate (38). The reduced SV is suggestive of either lower ventricular filling, potentially caused in part by an impaired myocardial relaxation, or impaired ejection secondary to systolic contractile dysfunction. There is, however, a paucity of data in humans supporting a direct effect of hypoxia on myocardial function at HA (25, 41). The suggestion that hypoxia may impair myocardial systolic function during exercise was proposed nearly 50 years ago (3) and has been revisited more recently (27–29). Negative inotropic effects of hypoxia (arterial oxygen tension of 44 mmHg) have been shown in intact animal models (39) and isolated myocardial fibers under severe hypoxia (1% O2) (33). Exercise training under hypobaric hypoxia is also associated with altered mechanical properties at a cellular level in rodents (9), although chronic hypoxia alone did not decrease myofilament sensitivity to calcium. However, in contrast to animal studies, data in humans indicate that systolic function is maintained or enhanced at HA. For example, Suarez et al. (37) reported the maintenance of systolic function after gradual decompression to a barometric pressure of 282 mmHg, a finding that was subsequently confirmed by numerous investigations during acute and prolonged hypoxic exposure (6, 10, 12, 23, 31). However, of these studies, only Suarez et al. (37) investigated systolic function during light exercise (60 W), where function appeared to be maintained. It is not known whether systolic function is maintained at higher exercise intensities. It has also been speculated that reduced oxygen availability may impair diastolic relaxation at HA (15, 18) and thus explain the decreased left ventricular (LV) end-diastolic volume (EDV) commonly observed (2, 6, 18). However, despite numerous studies reporting a decrease in plasma volume and altered transmitral filling patterns (2, 6, 20), myocardial relaxation was only previously investigated during hypoxia in dogs (15), and no data exist examining LV relaxation during exercise at high altitude. By using sensitive, noninvasive imaging techniques (two-dimensional speckle tracking), it is now possible to examine the LV deformation mechanics (strain, twist, and untwist velocity) that underpin LV systolic and diastolic function. LV strain and twist have been shown to be sensitive measures of global and regional myocardial function, and reveal subclinical dysfunction in patients where ejection fraction is unchanged (16, 22). In addition, diastolic LV untwist velocity correlates well with invasive measures of LV stiffness and provides a temporal link between relaxation and the development of intraventricular pressure gradients (30, 43). Therefore, examination of LV mechanics at HA may determine whether the decreased SV observed at HA is dependent on impaired myocardial relaxation and/or myocardial contractile dysfunction or confirm previous findings of preserved ventricular function during exercise (37). We therefore assessed systolic and diastolic ventricular mechanics during incremental exercise at sea level and HA to examine whether impaired myocardial relaxation or systolic dysfunction explains the previously reported reduction in SV at HA. We hypothesized that at HA, 1) ventricular filling would be lower at rest and during exercise and would be accompanied by a reduction in untwist velocity and 2) systolic mechanics would be impaired during exercise at HA