Dissociated effects of diazepam and lorazepam on short-latency afferent inhibition

Peripheral nerve inputs have an inhibitory effect on motor cortex excitability at short intervals (short-latency afferent inhibition, SAI). This can be tested by coupling electrical stimulation of peripheral nerve with transcranial magnetic stimulation (TMS) of the motor cortex. SAI is reduced by the anticholinergic drug scopolamine, and in patients with Alzheimer's disease. Therefore, it is possible that SAI is a marker of central cholinergic activity important for memory function. The benzodiazepine lorazepam also reduces SAI. Since benzodiazepines impair memory formation, but do not do so uniformly, with a maximum amnesic effect after lorazepam but less or no effect after diazepam, we were interested in testing in this non-behavioural study to what extent the effects of lorazepam and diazepam on circuits involved in SAI could be dissociated. In addition, and for control, we tested the effects of lorazepam and diazepam on short-interval intracortical inhibition (SICI), a motor cortical inhibition mediated through the GABA_A receptor. Lorazepam markedly reduced SAI, whereas diazepam slightly increased it. In contrast, both benzodiazepines uniformly increased SICI. Our findings demonstrate opposite effects of lorazepam and diazepam on SAI, an inhibition modulated by central cholinergic activity, but the same effects on SICI, a marker of neurotransmission through the GABA_A receptor. This dissociation suggests, for the first time, that TMS measures of cortical inhibition provide the opportunity to segregate differences of benzodiazepine action in human central nervous system circuits.     

Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6

Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder that affects the elastic tissue in the skin, eye, and cardiovascular system. Mutations in the ABCC6 gene cause PXE. We performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. This screen consisted of 170 PXE chromosomes in 81 families, and detected 59 distinct mutations (32 missense, eight nonsense, and six likely splice-site point mutations; one small insertion; and seven small and five large deletions). Forty-three of these mutations are novel variants, which increases the total number of PXE mutations to 121. While most mutations are rare, three nonsense mutations, a splice donor site mutation, and the large deletion comprising exons 23-29 (c.2996_4208del) were identified as relatively frequent PXE mutations at 26%, 5%, 3.5%, 3%, and 11%, respectively. Chromosomal haplotyping with two proximal and two distal polymorphic markers flanking ABCC6 demonstrated that most chromosomes that carry these relatively frequent PXE mutations have related haplotypes specific for these mutations, which suggests that these chromosomes originate from single founder mutations. The types of mutations found support loss-of-function as the molecular mechanism for the PXE phenotype. In 76 of the 81 families, the affected individuals were either homozygous for the same mutation or compound heterozygous for two mutations. In the remaining five families with one uncovered mutation, affected showed allelic compound heterozygosity for the cosegregating PXE haplotype. This demonstrates pseudo-dominance as the relevant inheritance mechanism, since disease transmission to the next generation always requires one mutant allelic variant from each parent. In contrast to other previous clinical and molecular claims, our results show evidence only for recessive PXE. This has profound consequences for the genetic counseling of families with PXE.     

Non-linearities in the pharmacokinetics of di-(2-ethylhexyl) phthalate and metabolites in male rats

The disposition of the plasticizer di-(2-ethylhexyl) phthalate (DEHP) and four of its major metabolites was studied in male rats given single infusions of a DEHP emulsion in doses of 5, 50 or 500 mg DEHP/kg body weight. Plasma concentrations of DEHP and metabolites were followed for 24 h after the start of the infusion. The kinetics of the primary metabolite mono-(2-ethylhexyl) phthalate (MEHP) was studied separately.The concentrations of DEHP in plasma were at all times considerably higher than those of MEHP, and the concentrations of MEHP were much higher than those of the other investigated metabolites. In animals given 500 mg DEHP/kg, the areas under the plasma concentration-time curves (AUCs) of the other investigated metabolites were at most 15% of that of MEHP. Parallel decreases in the plasma concentrations of DEHP, MEHP and the and (-1) oxidized metabolites indicated that the elimination of DEHP was the rate-limiting step in the disposition of the metabolites. This was partly supported by the observation that the clearance of MEHP was higher than that of DEHP. Nonlinear increases in the AUCs of DEHP and MEHP indicated saturation in the formation as well as the elimination of the potentially toxic metabolite MEHP.     

Substance P antagonists and mucociliary activity in rabbit

Summary Substance P (SP) is known to accelerate mucociliary (m.c.) activity in the rabbit maxillary sinus in vivo. The physiological significance of this finding was investigated by testing three putative SP antagonists. [Arg⁵, d-Trp^{7, 9}, Nle¹¹]SP_5–11 could not be used as an antagonist because it stimulated m.c. activity. [d-Arg¹, d-Trp^{7, 9}, Leu¹¹]SP had no effect on the m.c. activity changes induced by SP. [d-Pro², d-Trp^{7, 9}]SP was found to be an effective antagonist, 1 mg/kg of this drug reversibly inhibiting both the effects of 0.1 g/kg SP and the stimulating effect of 1.0 g/kg bradykinin and 30.0g/kg capsaicin; the stimulating effect of 0.5 g/kg methacholine was not inhibited. It is suggested that bradykinin and capsaicin stimulate m.c. activity at least partly by releasing SP.The results of this investigation also support the view that the accelerating effect of SP on m.c. activity reflects physiological SP-mediated protective mechanisms in the airways. It is concluded that [d-Pro², d-Trp^{7, 9}]SP is a useful pharmacological tool for studying the role of SP in the control of m.c. actvity in rabbits.     

Cellular Immunity in COVID-19 Convalescents with PCR-Confirmed Infection but with Undetectable SARS-CoV-2–Specific IgG

We investigated immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among a group of convalescent, potential blood donors in Germany who had PCR-confirmed SARS-CoV-2 infection. Sixty days after onset of symptoms, 13/78 (17%) study participants had borderline or negative results to an ELISA detecting IgG against the S1 protein of SARS-CoV-2. We analyzed participants with PCR-confirmed infection who had strong antibody responses (ratio >3) as positive controls and participants without symptoms of SARS-CoV-2 infection and without household contact with infected patients as negative controls. Using interferon-γ ELISpot, we observed that 78% of PCR-positive volunteers with undetectable antibodies showed T cell immunity against SARS-CoV-2. We observed a similar frequency (80%) of T-cell immunity in convalescent donors with strong antibody responses but did not detect immunity in negative controls. We concluded that, in convalescent patients with undetectable SARS-CoV-2 IgG, immunity may be mediated through T cells.     

The impact on quality of life of diet restrictions and disease symptoms associated with phenylketonuria: a time trade-off and discrete choice experiment study

The European Journal of Health Economics - Phenylketonuria (PKU) is a metabolic disorder leading to a deficiency in the metabolism of phenylalanine (Phe). Elevated Phe levels in the blood, tissue...     

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta?=??0.0264, p value?=?3.5?×?10^–8) in the discovery panel and was replicated in replication panel (beta?=??0.07, p value?=?0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value?=?1.4?×?10^–13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

     

Intrahepatic absorbable fine mesh packing of hepatic injuries: Preliminary clinical report

A previous report from the authors' institution reported the effectiveness of hepatic packing with absorbable fine mesh (AFMP) for the control of hemorrhage in an animal model with an otherwise lethal hepatic injury. The technique has subsequently been applied to 12 abdominal trauma patients with hemodynamic instability and actively hemorrhaging hepatic injuries. Two patients expired in the operating room owing to uncontrolled hemorrhage from hepatic and associated injuries for a mortality of 16.7%. AFMP was successful in controlling hemorrhage in the remaining 10 patients. Hepatic injuries ranged from grade II to grade V, and all were actively hemorrhaging at the time of exploration. None of the surviving 10 patients experienced early or late recurrent bleeding attributable to the hepatic injuries, and there were no intraabdominal abscesses or late deaths. Liver function studies returned to normal prior to discharge in all surviving patients. Follow-up included serial computed tomographic scans, which demonstrated fibrosis incorporating the mesh packing. Complete resolution of injury and mesh appears to proceed over approximately a 6-month period. AFMP is a safe, effective method for controlling hepatic hemorrhage. It is easy to perform in the operating room, offers an excellent matrix for hemostasis, provides tamponade of bleeding sites, and does not require reoperation for removal of packing material, as is necessary with conventional, nonabsorbable packing techniques.

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Resumen En una publicación previa se informó la eficacia del empaquetamiento hepático con una fina malla absorbible en el control de la hemorragia en un modelo animal experimental sometido a lesión hepática letal. Desde entonces la técnica ha sido aplicada en 12 pacientes con trauma abdominal e inestabilidad hemodinámica y lesiones hepáticas sangrantes. Dos pacientes expiraron en la mesa de operaciones por hemorragia no controlada proveniente de la arteria hepática y de otras lesiones asociadas, con una tasa de mortalidad de 16.7%. La malla fue eficaz en cuanto a controlar la hemorragia en el resto de los pacientes. Las lesiones hepáticas variaron en cuanto a severidad entre los Grados II a V y todas exhibían hemorragia activa en el momento de la exploración. Ninguno de los 10 sobrevivientes desarrolló sangrado recurrente temprano o tardío que pudiera ser atribuible a las lesiones hepáticas y no se observaron abscesos intraabdominales o muertes tardías. Las pruebas de función hepática retornaron a valores normales con anterioridad al egreso, en la totalidad de los sobrevivientes. El seguimiento incluyó tomografías computadorizadas seriadas, que demostraron fibrosis del área de empaquetamiento con la malla; la resolución completa de la lesión y de la malla parece tener lugar en el curso de seis meses, aproximadamente. La malla representa un método seguro y eficaz de control de la hemorragia hepática, es fácil de aplicar en el quirófano, ofrece una excelente matriz para la hemostasia, produce taponamiento de los sitos sangrantes y no requiere reoperación para remover el material de empaquetamiento, como sí lo requieren las técnicas convencionales de empaquetamiento con materiales no absorbibles.

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Résumé Nous avons déjà rapporté l'efficacité du packing périhépatique par un filet fin résorbable (FFA) pour contrôler l'hémorragic autrement mortelle provenant d'une lésion hépatique chez l'animal. Cette même technique a été utilisée utilisée chez 12 patients ayant un traumatisme sévère du foie avec une hémodynamique instable. Deux patients sont décédés en salle d'opération des lésions hépatiques et des structures avoisinantes soit une mortalité de 16.7%. La technique de FFA a été couronnée de succès chez les 10 autres patients. Les lésions ont été classées selon leur sévérité du grade II au grade V et toutes saignaient activement au moment de l'opération. Aueun des patients survivants n'a eu de récidive hémorragique attribuable à la lésion hépatique et il n'y a eu aucun abcès intra-abdominal ni de mortalité tardive. La fonction hépatique est redevenue normale avant la sortie chez tous les autres patients. La surveillance du suivi a comporté une tomodensitométrie montrant une fibrose autour du filet. La résolution complète de la lésion et la résorption du filet évoluent en général sur six mois. La technique de FFA est sûre et efficace dans le contrôle de l'hémoragie provenant des traumatismes du foie. La méthode est facile à appliquer en salle d'opération, procure une hémostase excellent par tamponnade et ne nécessite pas de réintervention pour enlever le packing comme quand on utilise le matériel traditionnel non résorbable.

     

Cadmium in kidneys in Swedes measured in vivo using X-ray fluorescence analysis

An X-ray fluorescence (XRF) technique using plane polarized X-rays for excitation was used for in vivo measurements of cadmium in the kidney cortex among non-occupationally exposed members of the general population in southern Sweden. The measured concentrations of cadmium in the kidney cortex of smokers (median 28 g/g, n = 10) were significantly higher (P = 0.0036) as compared to those in non-smokers (median 8 g/g, n = 10), and so were the cadmium concentrations in blood and urine. The results show that smoking considerably increases the cadmium concentration in the kidney cortex and that smoking is a major source of cadmium exposure in the general population of Sweden. Except in the presence of very deeply situated kidneys, where the minimum detectable concentration is high, non-invasive in vivo XRF analysis of kidney cadmium should be a useful tool for evaluating the effects of long-term low-level exposure to cadmium and the risk of kidney damage.