Chemogenetic selective manipulation of nucleus accumbens medium spiny neurons bidirectionally controls alcohol intake in male and female rats.

The nucleus accumbens (NAc), considered the hub of reward circuitry, is comprised of two medium spiny neuron (MSN) subtypes that are classified by their enrichment of dopamine 1 (D1) or 2 (D2) receptors. While reports indicate that alcohol increases excitatory neurotransmission exclusively on NAc D1-MSNs in male rats, it remains unknown how NAc MSNs control alcohol intake in either sex. Therefore, this study investigated how NAc MSNs mediate alcohol intake by using Drd1a-iCre and Drd2-iCre transgenic rats of both sexes. Intra-NAc infusions of Cre-inducible viral vectors containing stimulatory (hM3Dq) or inhibitory (hM4Di) designer receptors exclusively activated by designer drugs (DREADDs) were delivered after 4-weeks of alcohol intake, and clozapine-N-oxide (CNO) was administered to selectively manipulate NAc MSNs. Our results show that activation of NAc D1-MSNs increased alcohol intake 1-, 4-, and 24-h after the start of drinking while inhibition decreased it 1-h after the start of drinking, with no sex differences observed at any time point. Activation of NAc D2-MSNs had no impact on alcohol intake while inhibition increased alcohol intake in Drd2-iCre rats for 1-h in males and 4-h in females. These findings suggest opposing roles for how NAc D1- and D2-MSNs modulate alcohol intake in rats of both sexes.

On the safety of repeated ketamine infusions for the treatment of depression: Effects of sex and developmental periods.

In this review, we will discuss the safety of repeated treatments with ketamine for patients with treatment-resistant depression (TRD), a condition in which patients with major depression do not show any clinical improvements following treatments with at least two antidepressant drugs. We will discuss the effects of these treatments in both sexes at different developmental periods. Numerous small clinical studies have shown that a single, low-dose ketamine infusion can rapidly alleviate depressive symptoms and thoughts of suicidality in patients with TRD, and these effects can last for about one week. Interestingly, the antidepressant effects of ketamine can be prolonged with intermittent, repeated infusion regimens and produce more robust therapeutic effects when compared to a single infusion. The safety of such repeated treatments with ketamine has not been thoroughly investigated. Although more studies are needed, some clinical and preclinical reports indicated that repeated infusions of low doses of ketamine may have addictive properties, and suggested that adolescent and adult female subjects may be more sensitive to ketamine's addictive effects. Additionally, during ketamine infusions, many TRD patients report hallucinations and feelings of dissociation and depersonalization, and therefore the effects of repeated treatments of ketamine on cognition must be further examined. Some clinical reports indicated that, compared to women, men are more sensitive to the psychomimetic effects of ketamine. Preclinical studies extended these findings to both adolescent and adult male rodents and showed that male rodents at both developmental periods are more sensitive to ketamine's cognitive-altering effects. Accordingly, in this review we shall focus our discussion on the potential addictive and cognitive-impairing effects of repeated ketamine infusions in both sexes at two important developmental periods: adolescence and adulthood. Although more work about the safety of ketamine is warranted, we hope this review will bring some answers about the safety of treating TRD with repeated ketamine infusions.

Locomotor sensitization to intermittent ketamine administration is associated with nucleus accumbens plasticity in male and female rats.

Clinical evidence suggests superior antidepressant response over time with a repeated, intermittent ketamine treatment regimen as compared to a single infusion. However, the club drug ketamine is commonly abused. Therefore, the abuse potential of repeated ketamine injections at low doses needs to be investigated. In this study, we investigated the abuse potential of repeated exposure to either 0, 2.5, or 5 mg/kg ketamine administered once weekly for seven weeks. Locomotor activity and conditioned place preference (CPP) were assayed to evaluate behavioral sensitization to the locomotor activating effects of ketamine and its rewarding properties, respectively. Our results show that while neither males nor females developed CPP, males treated with 5 mg/kg and females treated with either 2.5 or 5 mg/kg ketamine behaviorally sensitized. Furthermore, dendritic spine density was increased in the NAc of both males and females administered 5 mg/kg ketamine, an effect specific to the NAc shell (NAcSh) in males but to both the NAc core (NAcC) and NAcSh in females. Additionally, males administered 5 mg/kg ketamine displayed increased protein expression of ΔfosB, calcium calmodulin kinase II alpha (CaMKIIα), and brain-derived neurotrophic factor (BDNF), an effect not observed in females administered either dose of ketamine. However, males and females administered 5 mg/kg ketamine displayed increased protein expression of AMPA receptors (GluA1). Taken together, low-dose ketamine, when administered intermittently, induces behavioral sensitization at a lower dose in females than males, accompanied by an increase in spine density in the NAc and protein expression changes in pathways commonly implicated in addiction.

Chiari malformations: diagnosis, treatments and failures.

Chiari malformations refer to abnormalities of the hindbrain originally described by the Austrian pathologist Hans Chiari in the early 1890s. These malformations range from herniation of the cerebellar tonsils through the foramen magnum to complete agenesis of the cerebellum. In this review, we review the different classification schemes of Chiari malformations. We discuss the different signs and symptoms that the two most common malformations present with and diagnostic criteria. We next discuss current treatment paradigms, including the new measure of possible in utero surgery to help decrease the incidence of Chiari type II malformations. There is also a small discussion of treatment failures and salvage procedures in these difficult cases. Chiari malformations are a difficult clinical entity to treat. As more is learned about the genetic and environmental factors relating to their characteristics, it will be interesting if we are able to predict which treatments are better suited for different patients. Similarly, with the evolution of in utero techniques especially for Chiari II malformations, it will be interesting to see if the incidence and practice of treating these difficult patients will change.

Potential animal and environmental sources of Q fever infection for humans in Queensland.

Q fever is a vaccine-preventable disease; despite this, high annual notification numbers are still recorded in Australia. We have previously shown seroprevalence in Queensland metropolitan regions is approaching that of rural areas. This study investigated the presence of nucleic acid from Coxiella burnetii, the agent responsible for Q fever, in a number of animal and environmental samples collected throughout Queensland, to identify potential sources of human infection. Samples were collected from 129 geographical locations and included urine, faeces and whole blood from 22 different animal species; 45 ticks were removed from two species, canines and possums; 151 soil samples; 72 atmospheric dust samples collected from two locations and 50 dust swabs collected from domestic vacuum cleaners. PCR testing was performed targeting the IS1111 and COM1 genes for the specific detection of C. burnetii DNA. There were 85 detections from 1318 animal samples, giving a detection rate for each sample type ranging from 2.1 to 6.8%. Equine samples produced a detection rate of 11.9%, whilst feline and canine samples showed detection rates of 7.8% and 5.2%, respectively. Native animals had varying detection rates: pooled urines from flying foxes had 7.8%, whilst koalas had 5.1%, and 6.7% of ticks screened were positive. The soil and dust samples showed the presence of C. burnetii DNA ranging from 2.0 to 6.9%, respectively. These data show that specimens from a variety of animal species and the general environment provide a number of potential sources for C. burnetii infections of humans living in Queensland. These previously unrecognized sources may account for the high seroprevalence rates seen in putative low-risk communities, including Q fever patients with no direct animal contact and those subjects living in a low-risk urban environment.

A critique of "the best secular argument against abortion".

Don Marquis has put forward a non-religious argument against abortion based on what he claims is a morally relevant similarity between killing adult human beings and killing fetuses. He asserts that killing adults is wrong because it deprives them of their valuable futures. He points out that a fetus's future includes everything that is in an adult's future, given that fetuses naturally develop into adults. Thus, according to Marquis, killing a fetus deprives it of the same sort of valuable future that an adult is deprived of in being killed and this makes abortion seriously wrong. Commentators have raised a number of objections to Marquis's argument, to which he has satisfactorily responded. In this paper, difficulties with Marquis's argument that have not been considered by previous commentators are pointed out. A main thesis of this paper is that Marquis does not adequately defend his argument against several important objections that he himself has raised. These new considerations support the view that Marquis's argument is unsuccessful.

Reproductive cloning combined with genetic modification.

Although there is widespread opposition to reproductive cloning, some have argued that its use by infertile couples to have genetically related children would be ethically justifiable. Others have suggested that lesbian or gay couples might wish to use cloning to have genetically related children. Most of the main objections to human reproductive cloning are based on the child's lack of unique nuclear DNA. In the future, it may be possible safely to create children using cloning combined with genetic modifications, so that they have unique nuclear DNA. The genetic modifications could be aimed at giving such children genetic characteristics of both members of the couple concerned. Thus, cloning combined with genetic modification could be appealing to infertile, lesbian, or gay couples who seek genetically related children who have genetic characteristics of both members. In such scenarios, the various objections to human reproductive cloning that are based on the lack of genetic uniqueness would no longer be applicable. The author argues that it would be ethically justifiable for such couples to create children in this manner, assuming these techniques could be used safely.

Gynecologic cancer patients' psychosocial needs and their views on the physician's role in meeting those needs.

The aim of this study was to identify the psychosocial needs of patients after treatment for gynecological malignancies and their views concerning the role physicians should take in meeting those needs. Self-administered questionnaires were answered by 95 patients at least 6 months after completion of therapy. Topic areas included emotional needs, spiritual concerns, patient-family communication, patient participation in decision making, and advance directives. In addition, all participants completed the Functional Assessment of Cancer Therapy (FACT-G, version 4) quality of life questionnaire. Fifty-seven percent of respondents stated that they had needed help dealing with emotional problems, and 73% wanted the physician to ask whether help is needed. The most common emotional concerns were feeling nervous (40% of subjects), being worried (34%), fear (25%), needing someone to talk to (24%), sadness (21%), and loss of control (17%). Fifty-nine percent stated that physicians should ask whether help is needed in discussing spiritual matters. Sixty-one percent stated that physicians should ask patients whether they want help starting conversations with their families about difficult-to-raise topics such as the possibility of dying. Forty-six of 86 respondents (53%) stated that discussions about advance directives such as living wills should take place soon after the cancer diagnosis has been established. Most patients surveyed want physicians to take an active role in dealing with psychosocial needs.

Orbitally induced oscillations in the East Antarctic ice sheet at the Oligocene/Miocene boundary.

Between 34 and 15 million years (Myr) ago, when planetary temperatures were 3-4 degrees C warmer than at present and atmospheric CO2 concentrations were twice as high as today, the Antarctic ice sheets may have been unstable. Oxygen isotope records from deep-sea sediment cores suggest that during this time fluctuations in global temperatures and high-latitude continental ice volumes were influenced by orbital cycles. But it has hitherto not been possible to calibrate the inferred changes in ice volume with direct evidence for oscillations of the Antarctic ice sheets. Here we present sediment data from shallow marine cores in the western Ross Sea that exhibit well dated cyclic variations, and which link the extent of the East Antarctic ice sheet directly to orbital cycles during the Oligocene/Miocene transition (24.1-23.7 Myr ago). Three rapidly deposited glacimarine sequences are constrained to a period of less than 450 kyr by our age model, suggesting that orbital influences at the frequencies of obliquity (40 kyr) and eccentricity (125 kyr) controlled the oscillations of the ice margin at that time. An erosional hiatus covering 250 kyr provides direct evidence for a major episode of global cooling and ice-sheet expansion about 23.7 Myr ago, which had previously been inferred from oxygen isotope data (Mi1 event).

Purification and characterization of trans-permethrin metabolizing microsomal esterases from workers of the eastern subterranean termite, Reticulitermes flavipes (Kollar).

Three alpha-naphthyl acetate hydrolyzing esterase isozymes were purified from microsomes prepared from Reticulitermes flavipes workers. The two step process involved sequential preparative IEF followed by continuous elution preparative electrophoresis on a 5% non-denaturing polyacrylamide gel. The first IEF run resulted in 5.4-fold purification with a yield of 46.1%. Subsequent IEF further purified the esterases 14.3-fold and 12% yield. Preparative electrophoresis of the pooled IEF fractions produced three major peaks of alpha-naphthyl acetate hydrolyzing activity. The esterases were correspondingly designated microsomal esterase (ME) 1, ME 2, and ME 3 based on increasing molecular retention on a native PAGE gel. ME 1, ME 2, and ME 3 were acidic proteins with pI values of 4.61, 4.70, and 4.77, respectively. Molecular mass as determined by gel filtration chromatography of ME 1, ME 2, and ME 3 was 69, 64, and 62 kDa, respectively. SDS-PAGE gels produced a single band for each of the isozymes with a molecular mass of 63 kDa indicating that the esterases were monomers. Specific activities of ME 1, ME 2, and ME 3 increased with increasing pH and the enzymes were active over a broad temperature range (25-55 degrees C). The three purified isozymes were inhibited at low concentration by paraoxon (10(-10) M), chlorpyrifos (10(-6) M), DEF (10(-6) M), and PMSF (10(-6) M) indicating that they were "B" type serine esterases. Conversely, inhibition was not observed at 10(-4) M eserine, PHMB, or CaCl(2), further supporting the conclusion that the microsomal esterases were of the "B" type. None of the isozymes was inhibited by 10(-4) M imidacloprid, fipronil, or PBO. Quantitatively, ME 1, ME 2 and ME 3 metabolized t-permethrin at 21.8, 21.0, and 38.8 nmol/h/mg protein, representing a purification factor of 333-, 318-, and 591-fold over microsomes, respectively. The three isozymes produced the same type and number of t-permethrin metabolites.

Divalproex therapy in medication-naive and mood-stabilizer-naive bipolar II depression.

BACKGROUND: There have been few systematic studies of the treatment of bipolar II depression. While divalproex sodium (DVPX) is effective in acute mania, there are few data on the antidepressant effects of DVPX. Similarly, little is known regarding the use of DVPX administered in a single daily dose. METHOD: We performed a 12-week open trial of DVPX monotherapy (mean dose 882 mg qhs, mean level 80.7 mug/ml) in nineteen (thirteen women, six men, mean age 29) bipolar II depressed outpatients. Eleven patients (six women, five men) were medication-naive (MN) and eight (seven women, one man) were mood stabilizer-naive (MSN), having had prior trials of antidepressants or stimulants. Mean illness and current depressive episode duration were 15.4 years and 11.8 weeks, respectively. DVPX was given as a single dose each evening starting with 250 mg at bedtime and increased by 250 mg at bedtime every 4 days until symptom relief or adverse effects were noted. Weekly prospective Hamilton Depression, Young Mania and Clinical Global Impression ratings were obtained. RESULTS: DVPX therapy was generally well tolerated. Twelve of nineteen patients (63%) responded (>50% decrease in Hamilton Depression ratings). MN patients compared to MSN patients tended to have a higher response rate (9/11 versus 3/8, P<0.08). Mean Hamilton scores decreased from 22.2 to 9.6 (P<0.0001) in the entire group, from 20.6 to 6.6 (P<0.0003) in MN patients, and from 24.2 to 14.7 (P=0.008) in MSN patients. CONCLUSION: Single daily dose DVPX monotherapy appeared to be well tolerated and substantially benefited 63% of patients with bipolar II depression. The trend towards a higher rate of antidepressant response to DVPX in MN patients (82%) compared to MSN patients (38%) could be due to a milder form or earlier phase of illness and the lack of prior medication exposure or failures. This uncontrolled open pilot study must be viewed with caution, and randomized double-blind placebo controlled studies of DVPX in bipolar II depression are warranted to confirm the possibility that single daily dose DVPX is an effective, well-tolerated, first-line monotherapy in this population.

Experience with newborn intensive care deaths in a tertiary setting.

The purpose of this paper is to report the longitudinal experience with deaths in a United States' newborn intensive care unit. Retrospective analysis comparing infant deaths in two epochs: Epoch 1: 1985-1988 (n = 127) and Epoch 2: 1991-1994 (n = 75). Data included demographic factors, age at death, episodes of cardiopulmonary resuscitation, do not resuscitate status, and whether withdrawal of support occurred. Infants in Epoch 2 were significantly younger at birth (28.7 +/- 0.7 vs. 30.6 +/- 0.5 wks', p = 0.02) and death (31.5 +/- 0.9 vs. 34.0 +/- 0.7 wks', p = 0.02) than those in Epoch 1. There was no difference in length of stay (19.5 +/- 5.1 vs. 24.4 +/- 4.2 days, Epoch 2 vs. Epoch 1). Infants were more likely to receive cardiopulmonary resuscitation in Epoch 2 than Epoch 1 (60 vs. 41%, p = 0.008). However, more infants in Epoch 2 also had do not resuscitate status (80% vs. 59%, p = 0.002) or withdrawal of support (72% vs. 52%, p = 0.005). The majority of newborn intensive care deaths currently occur with do not resuscitate status and/or withdrawal of support.

Xbra3 induces mesoderm and neural tissue in Xenopus laevis.

Homologues of the murine Brachyury gene have been shown to be involved in mesoderm formation in several vertebrate species. In frogs, the Xenopus Brachyury homologue, Xbra, is required for normal formation of posterior mesoderm. We report the characterisation of a second Brachyury homologue from Xenopus, Xbra3, which has levels of identity with mouse Brachyury similar to those of Xbra. Xbra3 encodes a nuclear protein expressed in mesoderm in a temporal and spatial manner distinct from that observed for Xbra. Xbra3 expression is induced by mesoderm-inducing factors and overexpression of Xbra3 can induce mesoderm formation in animal caps. In contrast to Xbra, Xbra3 is also able to cause the formation of neural tissue in animal caps. Xbra3 overexpression induces both geminin and Xngnr-1, suggesting that Xbra3 can play a role in the earliest stages of neural induction. Xbra3 induces posterior nervous tissue by an FGF-dependent pathway; a complete switch to anterior neural tissue can be effected by the inhibition of FGF signalling. Neither noggin, chordin, follistatin, nor Xnr3 is induced by Xbra3 to an extent different from their induction by Xbra nor is BMP4 expression differentially affected.

Specified principlism: what is it, and does it really resolve cases better than casuistry?

Principlism has been advocated as an approach to resolving concrete cases and issues in bioethics, but critics have pointed out that a main problem for principlism is its lack of a method for assigning priorities to conflicting ethical principles. A version of principlism referred to as 'specified principlism' has been put forward in an attempt to overcome this problem. However, none of the advocates of specified principlism have attempted to demonstrate that the method actually works in resolving detailed clinical cases. This paper shows that when one tries to use it, specified principlism fails to provide practical assistance in deciding how to resolve concrete cases. Proponents of specified principlism have attempted to defend it by arguing that it is superior to casuistry, but it can be shown that their arguments are faulty. Because of these reasons, specified principlism should not be considered a leading contender in the search for methods of making justifiable decisions in clinical cases.

Documentation of decision-making during air transport.

INTRODUCTION: Decision-making is an integral part of quality patient care. The aim of this study was to evaluate decision-making documentation. METHODS: A retrospective descriptive design was used to examine the documentation for a convenience sample of 48 trauma patients transported by rotor-wing aircraft. RESULTS: A total of 1012 decisions were documented in the 48 records. The decisions were grouped into major conceptual problems. An average of 10.2 +/- 4.56 conceptual problems were identified in each record. The top 10 conceptual problems were evaluated. Adequate documentation was found to support all decision-making related to the top 10 problems. CONCLUSION: Although air medical personnel may not directly document statements of rationale for their decision-making, sufficient data were present in the records to support each documented decision.