Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS.

HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 capsid (p26) amino acid polymorphisms are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific T cell responses common in slower progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. In this study we analysed 369 heterochronous HIV-2 p26 sequences from 12 participants with a median age of 30 years at enrolment. CD4% change over time was used to stratify participants into relative faster and slower progressor groups. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Median virus evolutionary rates were higher in faster than slower progressors - synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (ρ = -0.8, P=0.02), but not CD4% level. The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5α/p26 hexamer interface surface. p26 evolutionary rates were associated with progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate HIV-2 p26 may be an attractive therapeutic target.

The sensory and affective components of pain: are they differentially modifiable dimensions or inseparable aspects of a unitary experience? A systematic review.

BACKGROUND: Pain is recognised to have both a sensory dimension (intensity) and an affective dimension (unpleasantness). Pain feels like a single unpleasant bodily experience, but investigations of human pain have long considered these two dimensions of pain to be separable and differentially modifiable. The evidence underpinning this separability and differential modifiability is seldom presented. We aimed to fill this gap by evaluating the current evidence base for whether or not the sensory and affective dimensions of pain can be selectively modulated using cognitive manipulations. METHODS: A rigorous systematic search, based on a priori search terms and consultation with field experts, yielded 4270 articles. A detailed screening process was based on the following recommendations: (i) evaluation of effectiveness; (ii) examination of methodological rigour, including each study having an a priori intention to cognitively modulate one of the two dimensions of pain; and (iii) sound theoretical reasoning. These were used to ensure that included studies definitively answered the research question. RESULTS: After in-depth critique of all 12 articles that met the inclusion criteria, we found that there is no compelling evidence that the sensory and affective dimensions of pain can be selectively and intentionally modulated using cognitive manipulations in humans. CONCLUSIONS: We offer potential explanations for this discrepancy between assumptions and evidence and contend that this finding highlights several important questions for the field, from both the research and clinical perspectives.

Delayed disease progression in HIV-2: the importance of TRIM5α and the retroviral capsid.

HIV-2 is thought to have entered the human population in the 1930s through cross-species transmission of SIV from sooty mangabeys in West Africa. Unlike HIV-1, HIV-2 has not led to a global pandemic, and recent data suggest that HIV-2 prevalence is declining in some West African states where it was formerly endemic. Although many early isolates of HIV-2 were derived from patients presenting with AIDS-defining illnesses, it was noted that a much larger proportion of HIV-2-infected subjects behaved as long-term non-progressors (LTNP) than their HIV-1-infected counterparts. Many HIV-2-infected adults are asymptomatic, maintaining an undetectable viral load for over a decade. However, despite lower viral loads, HIV-2 progresses to clinical AIDS without therapeutic intervention in most patients. In addition, successful treatment with anti-retroviral therapy (ART) is more challenging than for HIV-1. HIV-2 is significantly more sensitive to restriction by host restriction factor tripartite motif TRIM5α than HIV-1, and this difference in sensitivity is linked to differences in capsid structure. In this review we discuss the determinants of HIV-2 disease progression and focus on the important interactions between TRIM5α and HIV-2 capsid in long-term viral control.

Pharmacokinetics and ex vivo anti-inflammatory effects of oral misoprostol in horses.

BACKGROUND: Misoprostol is an E prostanoid (EP) 2, 3 and 4 receptor agonist that is anecdotally used to treat and prevent NSAID-induced GI injury in horses. Misoprostol elicits anti-inflammatory effects in vivo in men and rodents, and inhibits TNFα production in equine leucocytes in vitro. OBJECTIVE: Define the pharmacokinetic parameters of oral misoprostol in horses, and determine the inhibitory effect of oral misoprostol administration on equine leucocyte TNFα production in an ex vivo inflammation model. STUDY DESIGN: Pharmacokinetic study, ex vivo experimental study. METHODS: Six healthy adult horses of mixed breeds were used. In phase one, horses were given 5 µg/kg misoprostol orally, and blood was collected at predetermined times for determination of misoprostol free acid (MFA) by UHPLC-MS/MS. Pharmacokinetic parameters were calculated. In phase two, horses were dosed as in phase one, and blood was collected at T0, 0.5, 1 and 4 h following misoprostol administration for leucocyte isolation. Leucocytes were stimulated with 100 ng/mL LPS, and TNFα mRNA concentrations were determined via quantitative real-time PCR. RESULTS: About 5 µg/kg oral misoprostol produced a rapid time to maximum concentration (Tmax ) of 23.4 ± 2.4 min, with a maximum concentration (Cmax ) of 0.29 ± 0.07 ng/mL and area under the curve (AUC0-∞ ) of 0.4 ± 0.12 h ng/mL. LPS stimulation of equine leucocytes ex vivo significantly increased TNFα mRNA concentrations, and there was no significant effect of misoprostol even at the Tmax . MAIN LIMITATIONS: Only a single dose was used, and sample size was small. CONCLUSIONS: Misoprostol is rapidly absorbed following oral administration in horses, and a single 5 µg/kg dose had no significant inhibitory effect on ex vivo LPS-stimulated TNFα mRNA production in leucocytes. Further studies analysing different dosing strategies, including repeat administration or combination with other anti-inflammatory drugs, are warranted.

Ionoregulatory Characteristics of Non-Rio Negro Characiforms and Cichlids.

We examined ionoregulatory characteristics of two species of characiform fish and two species of cichlids that are not native to the Rio Negro, an extremely ion-poor, acidic tributary of the Amazon River, in order to gain insight into the origin of the specializations possessed by Rio Negro fish. The two characiform species examined, Congo tetras (Phenacogrammus interruptus) and black neon tetras (Hyphessobrycon herbertaxelrodi), had high-affinity/high-capacity transporters that produce high rates of uptake in dilute water. Na+ uptake for both was pH insensitive (down to pH 3.5). Exposure to 100 µmol L-1 phenamil had no effect on Na+ uptake in either species, while exposure to 1 mmol L-1 NH4Cl- (high external ammonia [HEA]) slightly stimulated Na+ uptake in Congo tetras. Exposure to "Na+-free" water significantly inhibited Na+ uptake (by 65%-85%) but had no effect on net ammonia flux. The two cichlid species examined, convict cichlids (Amatitlania siquia) and red point cichlids (Archocentrus sp.), had high-affinity but low-capacity transporters that yield low rates of uptake in dilute media. Sodium transport was pH sensitive and completely inhibited at pH 3.5. Phenamil exposure inhibited Na+ uptake by 60% in convict cichlids but had no effect on red point cichlids, and exposure to HEA reduced Na+ uptake in both species by 70%-85%. Exposure to "Na+-free" water reduced Na+ uptake by 80%-85%, and in convict cichlids it also reduced net ammonia flux by about 50%. The ionoregulatory characteristics described for both groups are strikingly similar to those for Rio Negro species, and we suggest that they may be ancestral physiological traits for these two groups. Further, if this is the case, it seems likely that these traits existed before the Rio Negro and may explain the great success of these species-rich groups in colonizing the river despite its challenging chemistry.

Childhood body mass index at 5.5 years mediates the effect of prenatal maternal stress on daughters' age at menarche: Project Ice Storm.

Early pubertal timing is known to put women at greater risk for adverse physiological and psychological health outcomes. Of the factors that influence girls' pubertal timing, stress experienced during childhood has been found to advance age at menarche (AAM). However, it is not known if stress experienced by mothers during or in the months before conception can be similarly associated with earlier pubertal timing. Prenatal maternal stress (PNMS) is associated with metabolic changes, such as increased childhood adiposity and risk of obesity, that have been associated with earlier menarchal age. Using a prospective longitudinal design, the present study tested whether PNMS induced by a natural disaster is either directly associated with earlier AAM, or whether there is an indirect association mediated through increased girls' body mass index (BMI) during childhood. A total of 31 girls, whose mothers were exposed to the Quebec's January 1998 ice storm during pregnancy were followed from 6 months to 15.5 years of age. Mother's stress was measured within 6 months of the storm. BMI was measured at 5.5 years, and AAM was assessed through teen's self-report at 13.5 and 15.5 years of age. Results revealed that greater BMI at 5.5 years mediated the effect of PNMS on decreasing AAM [B=-0.059, 95% confidence intervals (-0.18, -0.0035)]. The present study is the first to demonstrate that maternal experience of stressful conditions during pregnancy reduces AAM in the offspring through its effects on childhood BMI. Future research should consider the impact of AAM on other measures of reproductive ability.

Characteristics and expectations of fluid bolus therapy: a bi-national survey of acute care physicians.

There is little consensus on the definition or optimal constituents of fluid bolus therapy (FBT), and there is uncertainty regarding its physiological effects. The aims of this study were to determine clinician-reported definitions of FBT and to explore the physiological responses clinicians expect from such FBT. In June and October 2014, intensive care and emergency physicians in Australia and New Zealand were asked to participate in an electronic questionnaire of the reported practice and expectations of FBT. Two hundred and fifty-one questionnaires were completed, 65.3% from intensivists. We identified the prototypical FBT given by intensivists is more than 250 ml of compound sodium lactate, saline or 4% albumin given in less than 30 minutes, while that given by emergency department physicians is a similar volume of saline delivered over a similar time frame. Intensive care and emergency physicians expected significantly different changes in mean arterial pressure (P=0.001) and heart rate (P=0.033) following FBT. Substantial variation was demonstrated in the magnitude of expected response within both specialties for each variable. Major variations exist in self-reported FBT practice, both within and between acute specialties, and wide variation can be demonstrated in the expected physiological responses to FBT. International explorations of practice and prospective quantification of the actual physiological response to FBT are warranted.

RU486 facilitates or disrupts the sensitization of sexual behaviors by estradiol in the ovariectomized Long-Evans rat: Effect of timecourse.

An acute injection of estradiol benzoate (EB) to the ovariectomized (OVX) rat activates low levels of lordosis, and subsequent progesterone (P) administration augments lordosis and recruits a complete pattern of sexual behavior including appetitive behaviors (e.g., hops/darts and solicitations). However, repeated injections of 5µg or 10µg EB (but not 2µg EB), administered every 4days to sexually-experienced OVX rats results in a behavioral sensitization, such that lordosis quotients (LQs) and appetitive behaviors progressively increase. We have shown that adrenal P does not play a critical role because behavioral sensitization to EB is not prevented by adrenalectomy. Here we tested whether P receptors play a role by examining the effect of chronic administration of the P receptor antagonist RU486 at a dose that reliably inhibits sexual behavior in fully primed OVX rats. Females were treated with EB (5 or 10µg), and 5mg RU486 dissolved in 0.4mL vehicle (VEH; 80% sesame oil, 15% benzyl benzoate, 5% benzyl alcohol) 48h and 5h prior to each of 7 tests, respectively, occurring at 4-day intervals in unilevel 4-hole pacing chambers. Control animals were treated with 2, 5, or 10µg EB+VEH. As expected, sensitization did not occur in females treated with 2µg EB+VEH, and those females received fewer intromissions and ejaculations than all other groups. RU486 did not prevent the sensitization of LQ, moderate and high lordosis magnitudes (LM2 and LM3) or appetitive sexual behaviors on early tests, and in fact potentiated appetitive behaviors, LQ, LM2 and LM3, consistent with its facilitative actions in females treated with EB-alone, as we and others have reported previously. However, despite the initial facilitation, blocking P receptors by chronic administration of RU486 inhibited the maintenance of behavioral sensitization to EB.

KIR3DL1*0040102 ­ a novel three-domain KIR subtype isolated from donors of African descent.

KIR3DL1*0040102 allele differs from KIR3DL1*0040101 by a single-nucleotide change at position 12356 (intron 6).

KIR3DS1*0130109: a novel activating three-domain KIR identified using sequence-based typing.

KIR3DS1*0130109 is similar to KIR3DS1*0130101 except for a A > G change in intron 4.

Detection of a novel KIR3DL1*0150210 allele by sequencing.

KIR3DL1*0150210 has seven point mutations compared to the common Asian allele KIR3DL1*0150201.

Full-length sequence of KIR3DL1*0310102 detected in DNA samples from West Africa.

KIR3DL1*0310102 differs from KIR3DL1*0150101 with 11 nucleotide substitutions.

Behavioral defeminization by prenatal androgen treatment in rats can be overcome by sexual experience in adulthood.

Exposure to testosterone during a critical period of prenatal development disrupts the normal display of sexual behaviors in adult ovariectomized (OVX) rats treated with estradiol benzoate (EB) followed by progesterone (P). The organizational hypothesis posits that prenatally androgenized females (PNAFs) are desensitized to EB. We tested this hypothesis by first treating PNAFs with varying doses of EB (2.5, 5, 10, 20µg) followed by P (500µg), and second by subjecting females to an established EB behavioral sensitization paradigm where females are first given sexual experience with EB (10µg) and P prior to repeated sexual behavior testing with EB alone. Long-Evans females were androgenized in utero by a s.c. injection of 500µg testosterone propionate or the oil control to pregnant dams on gestational day 18. Female offspring were OVX on postnatal day 80 and tested one week later in the unilevel 4-hole pacing chamber. Genital tissue was defeminized in PNAFs, and the lordosis quotient (LQ) and partial (i.e., hops/darts) and full solicitations were significantly lower, while defensive behaviors were higher, in PNAF females, relative to non-PNAF females regardless of the acute EB priming dose. However, repeated testing with EB alone (10µg), or EB and P eliminated the differences between groups on LQ and hops/darts, indicating that the behavioral deficit can be overcome by sexual experience. These results suggest that PNAFs are not desensitized to EB, and despite disruptions in sexual differentiation of anatomical structures, the deficiency in sexual behavior in response to acute EB and P can be experientially overcome. PNAFs appear, however, to have a chronic deficit in the expression of full solicitations.

A novel KIR3DL1*0150103 subtype identified in West Africa.

A novel KIR3DL1*0150103 found in West Africa with five single nucleotide polymorphisms compared to KIR3DL1*0150101.

The identification of a killer cell immunoglobulin-like receptor 3DL1*0150209 in an Asian population using molecular techniques.

Full-length sequences of KIR3DL1*0150209 differ from those of KIR3DL1*0150201 with seven single-nucleotide polymorphisms.

KIR3DL1*0250103: a novel three-domain KIR allele isolated in West African samples.

The full length sequence of KIR3DL1*0250103 differs from that of KIR3DL1*0150101 with nine single-nucleotide polymorphisms.

KIR3DS1*0130111: a novel KIR allele identified using molecular typing methods.

KIR3DS1*0130111 differs from KIR3DS1*0130101 with two previously undescribed single nucleotide polymorphisms.