Exploring the impact of antenatal micronutrients used as a treatment for maternal depression on infant temperament in the first year of life.

Antenatal depression and maternal nutrition can influence infant temperament. Although broad-spectrum-micronutrients (BSM: vitamins and minerals) given above Recommended Dietary Allowances during pregnancy can mitigate symptoms of antenatal depression, their associated effects on infant temperament are unknown. One hundred and fourteen New Zealand mother-infant dyads (45 infants exposed to BSM during pregnancy (range of exposure during pregnancy: 12-182 days) to treat antenatal depressive symptoms (measured by Edinburgh Postnatal Depression Scale) and 69 non-exposed infants) were followed antenatally and for 12 months postpartum to determine the influence of in utero BSM exposure on infant temperament. The Infant Behavior Questionnaire-Revised: Very Short-Form assessed temperament at 4 (T1), 6 (T2) and 12 (T3) months postpartum via online questionnaire. Latent growth curve modeling showed BSM exposure, antenatal depression and infant sex did not statistically significantly predict initial levels or longitudinal changes in orienting/regulatory capacity (ORC), positive affectivity/surgency (PAS) or negative affectivity (NEG). Higher gestational age was positively associated with initial PAS, and smaller increases between T1 and T3. Breastfeeding occurrence was positively associated with initial NEG. Although not significant, BSM exposure exerted small, positive effects on initial NEG (ß = -0.116) and longitudinal changes in ORC (ß = 0.266) and NEG (ß = -0.235). While BSM exposure did not significantly predict infant temperament, it may mitigate risks associated with antenatal depression. BSM-exposed infants displayed temperamental characteristics on par with typical pregnancies, supporting the safety of BSM treatment for antenatal depression.

Effect of antenatal micronutrient or antidepressant exposure on Brazelton neonatal behavioral assessment scale (NBAS) performance within one-month of birth.

BACKGROUND: Antenatal depression is a risk factor for poor infant outcomes. Broad-spectrum-micronutrients (vitamins and minerals) have shown efficacy in treating psychiatric symptoms in non-pregnant populations and are associated with reduced incidence of adverse birth outcomes, and improvements in neonatal development. We investigated the effects of treatment of antenatal depression with micronutrients above the Recommended Dietary Allowance on infant development compared to treatment with antidepressant medications and controls. METHOD: One-hundred-and-three infants were assessed using the Brazelton Neonatal Behavioral Assessment Scale (NBAS) within 28 days of birth: 37 exposed to micronutrients in-utero (50-182 days exposure), 18 to antidepressants in-utero (exposure for full gestation), and 48 controls whose mothers received neither treatment nor experienced depressive symptoms. RESULTS: Controlling for gestational age and parity, there were significant group differences on habituation, orientation, motor, state regulation, autonomic stability and reflexes (p < .05). Micronutrient-exposed performed better than antidepressant-exposed and controls on habituation, motor and autonomic stability (p < .05), effect sizes ranged 1.0-1.7 and 0.5-1.0, respectively. Antidepressant-exposed performed significantly worse on orientation and reflexes compared to micronutrient-exposed and controls. Micronutrient-exposed had significantly better state regulation compared to antidepressant-exposed. There was an association between micronutrient exposure length and better habituation (r = 0.41, p = .028). Micronutrient exposure was generally identified as a stronger predictor of neonatal performance over maternal depression, social adversity, gestational age and infant sex. CONCLUSION: In-utero micronutrient exposure appears to mitigate risks of depression on infant outcomes showing positive effects on infant behavior, on par with or better than typical pregnancies and superior to antidepressants. Limitations include differential exposure to micronutrients/antidepressants and lack of group blinding.

Patient and disease factors predictive of adverse perioperative outcomes after nephrectomy.

INTRODUCTION: The aim of this study was to determine the patient and disease factors predictive of adverse perioperative outcomes after nephrectomy using the British Association of Urological Surgeons (BAUS) audit database. METHODS: All nephrectomies entered on the BAUS database for the year 2012 were included and ten patient or disease factors were selected for analysis. Logistic regression was used to calculate the area under the receiver operating characteristic curve (AUC) (0.5 = no better than chance, 1.0 = perfect prediction) for each variable and 500 bootstrap samples were used to determine variable selection. RESULTS: Data were captured for 6,031 nephrectomies in 2012. World Health Organization performance status (WHO-PS) (AUC: 0.733) and anaemia (AUC: 0.696) were the most significant predictors of 30-day mortality in univariate analysis. WHO-PS (AUC: 0.626) and anaemia (AUC: 0.590) also predicted complications classified as Clavien-Dindo grades III-V. Anaemia (AUC: 0.722) and clinical T stage (AUC: 0.713) predicted need for transfusion. CONCLUSIONS: Adverse perioperative outcomes after nephrectomy are predicted by clinical presentation with haematuria, poor WHO-PS and higher TNM (tumour, lymph nodes, metastasis) stage. This study used surgeon collected data as opposed to an administrative database, which may have advantages in terms of accuracy and breadth of data fields. These data form a basis for preoperative patient counselling and informed consent for nephrectomy. They can also be used as a standard against which surgeons and hospitals can compare their own results.

Subtle cardiovascular dysfunction in the unilateral 6-hydroxydopamine-lesioned rat.

The present study evaluated whether the unilateral 6-hydroxydopamine (6-OHDA) model of Parkinson's disease produces autonomic deficits. Autonomic parameters were assessed by implanting a small radiofrequency telemetry device which measured heart rate variability (HRV), diurnal rhythms of heart rate (HR), core body temperature (cBT) and locomotor activity (LA). Rats then received 6-OHDA lesion or sham surgery. 6-OHDA lesioned rats exhibited head and body axis biases, defective sensorimotor function ("disengage" test), and prominent apomorphine rotation (all P < .05 versus controls). Diurnal rhythm of HR was lower for 6-OHDA lesioned rats (n = 8) versus controls (n = 6; P < .05). Whilst HR decreased similarly in both groups during the day, there was a greater decrease in HR for the 6-OHDA lesioned rats at night (by 38 b.p.m. relative to 17 b.p.m. for controls). LA and cBT did not differ between surgery groups. This study indicates the unilateral 6-OHDA model of PD shows subtle signs of cardiovascular autonomic dysfunction.

Behavioural effects of a selective NMDA NR1A/2B receptor antagonist in rats with unilateral 6-OHDA+parafascicular lesions.

Experimental lesions involving the parafascicular (Pf) nucleus and medial forebrain bundle (MFB) may model to some extent the pathological loss of glutamatergic neurons from the centromedian-parafascicular (CM-Pf) complex and nigral dopaminergic cell loss observed clinically at post-mortem in Parkinson's disease (PD) cases. Our study investigated whether there were alterations in symptomatology in such rats with unilateral 6-OHDA+Pf lesions after treatment with either a selective NR1A/NR2B NMDA antagonist and/or l-dopa. Rats were given dual surgery to the MFB with 6-hydroxydopamine (6-OHDA) and Pf with N-methyl-d-aspartate (NMDA). (i) An NR1A/NR2B selective NMDA antagonist (BZAD-01; 10mg/kg), (ii) l-dopa (25mg/kg), (iii) BZAD-01+l-dopa (10mg/kg; 25mg/kg) or (iv) vehicle solution were administered for 6 weeks, during which behavioural testing was performed. BZAD-01 improved postural asymmetry in the first month as well as apomorphine-induced rotation. The latter was also improved by l-dopa in this model. These data support the use of selective NR1/NR2B NMDA antagonists in the therapeutics of PD.

Evaluation of behavioural effects of a selective NMDA NR1A/2B receptor antagonist in the unilateral 6-OHDA lesion rat model.

The degeneration of the dopaminergic nigrostriatal pathway in Parkinson's disease (PD) is associated with altered transmission at striatal NMDA receptors containing NR2B subunits. We investigated a potential novel therapeutic compound, 4-trifluoromethoxy-N-(2-trifluoromethyl-benzyl)-benzamidine (BZAD-01), a selective NMDA NR1A/2B receptor antagonist for PD and compared it with levodopa, the standard treatment for PD. This study also evaluated whether combining levodopa and BZAD-01 gave better improvements of parkinsonian symptoms. Parkinsonism was induced by microinjection of the toxin, 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) of 40 Sprague-Dawley rats. Parkinsonism and the efficacy of drugs were assessed using a battery of behavioural tests including balance beam, apomorphine-induced rotation, body axis bias or "curling", head position bias and disengage sensorimotor latency test. Immunohistochemistry was performed on post-mortem tissue to estimate the loss of dopaminergic neurons. The main effects were that BZAD-01 co-administration prevented chronic levodopa-induced potentiation of apomorphine rotation. However levodopa-treated rats were slower than either controls or BZAD-01-treated rats in the locomotor test. The improvement in the apomorphine rotation test suggests that BZAD-01 may be a useful adjunct to levodopa monotherapy.

Neuroprotective effects of a selective N-methyl-D-aspartate NR2B receptor antagonist in the 6-hydroxydopamine rat model of Parkinson's disease.

1. Current pharmacotherapies for the treatment of Parkinson's disease (PD) are largely symptomatic and do not attenuate the characteristic nigral (dopamine) cell loss. 2. Using the 6-hydroxydopamine (6-OHDA) rat model of PD, we investigated the novel, potentially neuroprotective compound BZAD-01, which is an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist selective for the NR2B subunit. 3. Forty female Sprague-Dawley rats were pretreated with either 10 mg/kg BZAD-01 or vehicle (5% sucrose and 0.1% ascorbate) in their drinking water for 11 days prior to and for 3 days following 6-OHDA surgery. During surgery, rats received an injection of either a toxic dose of 16 microg 6-OHDA or a non-toxic dose of 1 microg 6-OHDA (sham) into the medial forebrain bundle. A series of behavioural tests, including curling (measuring body axis bias), head position bias and narrow beam, was performed fortnightly for 8 weeks after surgery to assess the effects of BZAD-01 pretreatment on parkinsonism. Drug-induced rotational asymmetry was also assessed just before rats were killed. Post-mortem immunohistochemistry was performed to quantify the degree of nigral dopamine cell loss. 4. Pretreatment of 6-OHDA-lesioned rats with BZAD-01 significantly reduced the amount of dopamine cell loss and significantly improved all behavioural measures. Furthermore, there was no significant difference in any of the behavioural measures between lesioned rats pretreated with BZAD-01 and rats that underwent sham surgery.

Leucine-rich repeat-containing G-protein-coupled receptor 8 in the rat brain: Enrichment in thalamic neurons and their efferent projections.

Leucine-rich repeat-containing G-protein-coupled receptor 8 (LGR8; also classified as relaxin family peptide 2 receptor; RXFP2) has been identified as a cognate receptor for the peptide hormone, insulin-like peptide 3 (INSL3) and INSL3-LGR8 signaling plays an essential role in testis descent and germ cell development in human and rodents. Lgr8 mRNA has been detected in human tissues including testis, kidney and brain, but its regional and cellular distribution in these tissues in human or other species is largely unknown. In an initial step to elucidate the physiological function of a putative INSL3-LGR8 system in rat brain, the localization of Lgr8 mRNA was investigated using in situ hybridization histochemistry, revealing a discrete distribution in forebrain, with expression highly enriched in the thalamus. High densities were detected in the parafascicular nucleus (Pf), the dorsolateral, ventrolateral and posterior thalamic nuclei, and in the medial habenula. Lgr8 transcripts were also detected in frontal and motor cortices. The comparative distribution of LGR8 (receptor protein) was examined by autoradiography of [125I]-human INSL3 binding sites, with high densities detected in the thalamus, especially in Pf, and in the entire striatum--the caudate putamen (CPmicro), islands of Calleja, olfactory tubercle, nucleus accumbens--with lower levels in distinct layers of cerebral cortex. Notably, these areas also receive dopaminergic projections. These findings demonstrate the existence of LGR8 in neuronal soma in the thalamus and axons/terminals in thalamic target areas such as the striatum and frontal cortex. LGR8 was also detected throughout the medial habenula-fasciculus retroflexus-interpeduncular nucleus pathway, further indicating that the receptor is transported from mRNA-expressing soma to remote axonal/terminal sites. These findings suggest the existence of a broadly distributed LGR8 signaling system in the rat involved in sensorimotor, limbic and cognitive functions. Further studies are now required to elucidate the precise function of LGR8, under normal and pathological conditions, as importantly, several of the equivalent receptor-positive areas in human brain are part of the pathology of neurodegenerative conditions including Parkinson's disease.

Mice with altered alpha-actinin-4 expression have distinct morphologic patterns of glomerular disease.

Mutations in ACTN4, encoding the actin-binding protein alpha-actinin-4, cause a form of familial focal segmental glomerulosclerosis. We had developed two strains of transgenic mice with distinct alterations in the expression of alpha-actinin-4. One strain carried a human disease-associated mutation in murine Actn4, whereas the other knockout strain did not express alpha-actinin-4 protein. Most adult homozygous Actn4 mutant and knockout mice developed collapsing glomerulopathy. Homozygous Actn4 mutant mice also exhibited actin and alpha-actinin-4-containing electron-dense cytoplasmic structures, that were present but less prominent in heterozygous Actn4 mutant mice and not consistently seen in wild-type or knockout mice. Heterozygous Actn4 mutant mice did not develop glomerulosclerosis, but did exhibit focal glomerular hypertrophy and mild glomerular ultrastructural changes. The ultrastructural abnormalities seen in heterozygous Actn4 mutant mice suggest low-level glomerular damage, which may increase susceptibility to injury caused by genetic or environmental stressors. Our studies show that different genetic defects in the same protein produce a spectrum of glomerular morphologic lesions depending on the specific combination of normal and/or defective alleles.

A 12-month prospective study of gasserian ganglion stimulation for trigeminal neuropathic pain.

AIMS: Trigeminal neuropathic pain is a broad diagnostic category that includes pain of several etiologies and excludes trigeminal neuralgia. The authors report a prospective series of percutaneous gasserian ganglion stimulation for trigeminal neuropathic pain. METHODS: Patients who experienced >50% reduction in pain from a 7- to 10-day trial period underwent permanent implantation and were prospectively followed. RESULTS: Eight of 10 trialed patients received a permanent implant. At the 12-month follow-up, 2 patients had been explanted and 1 was lost to follow-up. Three (all working at that the time) continued to experience >50% improvement in pain. DISCUSSION: The results in this series were variable but 3 patients showed long-term improvements. Patients who continued to work responded better to treatment.

Developing a preclinical model of Parkinson's disease: a study of behaviour in rats with graded 6-OHDA lesions.

Injection of increasing concentrations of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) can be used to establish a graded model of different clinical stages of Parkinson's disease (PD). We investigated the relationship between behavioural alterations and loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Forty female Sprague-Dawley rats were injected with either (i) 4 microg (ii) 8 microg or (iii) 16 microg 6-hydroxydopamine (6-OHDA) to mimic the preclinical, mild and advanced clinical stages of PD, respectively. Vehicle was injected in a separate control group. Behaviours analysed included postural asymmetry, balance, locomotion, sensorimotor deficits and apomorphine rotation. At post-mortem the degree of tyrosine immunoreactive dopaminergic cell (TH-ir) loss was then estimated. There was a graded and consistent trend in each of the behaviours studied with respect to cell loss between the different sized lesion groups when examined using correlation analysis (all comparisons, r > 0.8, p < 0.001). Rats with large lesions demonstrated more significant behavioural changes over 8 weeks of testing than those with intermediate and smaller lesions (group comparisons p < 0.001). PD symptomatology became overt when cell loss reached 70%, however some significant changes can be observed with as little as 40% dopaminergic cell loss. Thus, injection with increasing concentrations 6-OHDA into the MFB can produce increasing extents of cell loss and behavioural changes, which were well correlated. This graded model can be useful for testing potential neuroprotective compounds for PD.

Behavioural effects of parafascicular thalamic lesions in an animal model of parkinsonism.

We recently reported that the centromedian-parafascicular thalamic complex (CM-Pf) degenerates in Parkinson's disease and progressive supranuclear palsy. The contribution of such thalamic pathology to disease symptoms has not yet been established. The present study therefore investigated the behavioural impact of lesioning the corresponding thalamic region (termed Pf) on a range of behaviours present in rodents. There were four surgical groups: (1) sham medial forebrain bundle (mfb)+sham Pf, (2) 6-OHDA mfb lesion+sham Pf, (3) sham mfb+NMDA Pf lesion, (4) 6-OHDA+NMDA Pf lesions. Posture, sensory functions and apomorphine-induced rotational asymmetry were assessed before and after each surgery. Other assessments performed including a timed motivational task, grooming behaviours and piloerection. 6-OHDA lesions induced postural (ipsilateral curling and head position biases), sensorimotor (increased latency to respond to tactile stimulation of the contralateral side when eating or grooming) and rotational abnormalities (contralateral circling after apomorphine). The main effects of combined 6-OHDA+Pf lesions were improved performance in a motivational task (decreased latency to retrieve reward) but worsened piloerection, relative to animals with either 6-OHDA or Pf lesions alone. The thalamic zone common to all lesioned animals involved the posterior Pf. Our data suggests that the posterior CM-Pf may be involved in motivational responses and autonomic dysfunction in parkinsonian disorders.

Thrombotic microangiopathy and cytomegalovirus in liver transplant recipients: a case-based review.

BACKGROUND: Thrombotic microangiopathy (TMA) is a rare but potentially lethal complication encountered in solid organ and bone marrow transplant recipients, requiring rapid recognition, diagnosis, and initiation of therapy. Several potential causes have been identified in this setting, including viral infections and medications. METHODS: We report a case of TMA in a liver transplant recipient with active cytomegalovirus (CMV) gastritis. A 41-year-old female presented 3 months after liver transplantation with a 5-week history of nausea, vomiting, anorexia, and diarrhea. CMV serology was donor seropositive and recipient seronegative (D+/R-). The immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and prednisone. Evaluation revealed CMV viremia with a high viral load and intravenous ganciclovir was started. A decline in hemoglobin and platelets with an increase in lactate dehydrogenase (LDH) warranted hematologic evaluation, which revealed findings consistent with microangiopathic hemolytic anemia. Ganciclovir and tacrolimus were discontinued. Intravenous immunoglobulin was administered and daily plasmapheresis was initiated. As the patient's blood counts and LDH started to improve, ganciclovir was cautiously reinstituted. The patient's gastrointestinal symptoms gradually resolved and her blood counts continued to improve with prolonged plasmapheresis (a total of 23 plasmapheresis sessions). Tacrolimus and possibly CMV infection were suspected to be the cause for her TMA, and cyclosporine was substituted. CONCLUSIONS: TMA is an important entity in the differential diagnosis of acute hemolytic anemia in liver transplant recipients. Many cases seem to be medication-induced. However, in treatment-resistant or relapsing cases, a possibility of concomitant CMV infection should be considered.

Olfactory deficits and sleep disturbances in Parkinson's disease: a case-control survey.

BACKGROUND: Olfactory and sleep disturbances are common in Parkinson's disease, and may be early disease indicators. OBJECTIVE: To obtain information about olfactory and sleep deficits preceding the onset of motor symptoms in Parkinson's disease. SUBJECTS: 38 community dwelling patients with Parkinson's disease (73% response rate) and 32 age matched controls (60% response rate). METHODS: Using a questionnaire survey, the frequencies, timing, and relations between olfactory and sleep disturbances, drug treatment, mood, and motor deficits in Parkinson's disease were compared with those in age matched controls. Reliability of information was validated by informant interview in 9% of the sample. Interdependency of factors was assessed using Fisher's fourfold table test, and differences between populations were analysed using chi(2) and unpaired t tests. RESULTS: Microsmia was reported by 26 patients (68%) (and only one control), on average within a year of the diagnosis of Parkinson's disease. More patients than controls had excessive daytime somnolence (45% v 6%), restless legs (50% v 19%), and abnormal movements during sleep (34% v 0%), which generally occurred three to five years after diagnosis and were independent of mood disorders and drug treatment. CONCLUSIONS: Many patients with Parkinson's disease have microsmia at the onset of motor deficits, but some sleep disorders are a subsequent occurrence.

Relationships between various behavioural abnormalities and nigrostriatal dopamine depletion in the unilateral 6-OHDA-lesioned rat.

While rotational asymmetry is used as a characteristic behavioural sign of striatal dopamine (DA) loss in unilateral animal models of Parkinson's disease (PD), there is relatively little analysis of how other common behavioural deficits relate to nigrostriatal DA depletion. We analysed the relationships between several deficits induced by unilateral 6-OHDA lesions and striatal neurochemistry, as well as neuronal loss in the dopaminergic substantia nigra (SN). Behaviour was evaluated from before until 6 weeks after surgery and abnormalities appeared in body axis, head position and sensorimotor performance as well as apomorphine-induced rotation. As expected, rotational behaviour correlated with striatal DA loss and not with other striatal neurotransmitters measured. Similar observations were found for sensorimotor deficits ('disengage task'). Both deficits were observed in rats with >70% loss of TH+ nigral neurons and >80% loss of striatal DA. Additional postural abnormalities appeared with mean losses of 87% of nigral DA neurons and 97% striatal DA, consistent with observations in patients with advanced PD. The data show that the repertoire of behavioural abnormalities manifested by hemiparkinsonian rats relate directly to the degree of nigrostriatal DA loss and, therefore, mimic features of PD. Analysis of such behaviours are relevant for chronic therapeutic studies targeting PD.

Mushroom poisoning--from diarrhea to liver transplantation.

Mushroom poisoning from the genus Amanita is a medical emergency, with Amanita phalloides being the most common species. The typical symptoms of nausea, vomiting, abdominal pain, and diarrhea are nonspecific and can be mistaken for gastroenteritis. If not adequately treated, hepatic and renal failure may ensue within several days of ingestion. In this case series, patients poisoned with Amanita virosa are described with a spectrum of clinical presentations and outcomes ranging from complete recovery to fulminant hepatic failure. Although there are no controlled clinical trials, a few anecdotal studies provide the basis for regimens recommended to treat Amanita poisoning. Use of i.v. penicillin G is supported by most reports. Silibinin, although preferred over penicillin, is not easily available in the United States. In those with acute liver failure, liver transplantation can be life saving.

Salvage therapies for refractory variceal hemorrhage.

Refractory variceal bleeding is defined as bleeding that continues through adequate pharmacologic and endoscopic therapy. In patients with end-stage liver disease, the only option for long-term salvage is liver transplantation. In patients with well-preserved liver function (Child's class A and class B-7), other salvage options such as surgical shunt, TIPS, and devascularization procedures can achieve good outcome. The long-term survival depends on the underlying liver disease, rather than on the variceal bleeding per se.

Accuracy and utility of 3-dimensional computed tomography in evaluating donors for adult living related liver transplants.

Three-dimensional (3D) computed tomography (CT) is an imaging technique that renders anatomic detail in 3D images from helical computed tomographic scans. The purpose of this study is to assess 3D CT in the preoperative evaluation of adult living related liver transplant donors. Nine patients underwent right-lobe liver resection for adult living related liver transplants between October 1999 and September 2000. All donors underwent triphasic helical CT of the liver with 3D computed tomographic reconstruction and conventional angiography. The 3D images were correlated with angiography and intraoperative findings. The origin of vessels, relative length of segments, and position of branches were considered for accuracy. The 3D computed tomographic images were compared with angiograms to determine whether angiography could be replaced by 3D CT. 3D CT identified all variations of the hepatic vein confluences and portal vein trifurcations and all hepatic arterial variants. At surgery, the 3D computed tomographic images of hepatic and portal veins were judged to be accurate and helpful in 8 of 9 cases, and images of the hepatic artery, accurate and helpful in 5 of 9 cases. The 3D computed tomographic images of hepatic and portal veins were better than or equivalent to angiograms in nearly all cases. The 3D computed tomographic images of the hepatic artery were better than or equivalent to angiography in 5 of 9 cases. By providing an accurate 3D map of the liver and its vasculature, 3D computed tomographic reconstructions of the hepatic vasculature are a useful adjunct for surgical planning in adult living related liver donors. 3D CT clearly delineates portal and hepatic veins as well as or better than the angiogram and can identify the hepatic artery and its branches well enough to consider replacing angiography, thus reducing cost, inconvenience, and risk to the donor.