Impact of COVID-19 & Response Measures on HIV-HCV Prevention Services and Social Determinants in People Who Inject Drugs in 13 Sites with Recent HIV Outbreaks in Europe, North America and Israel.

HIV/HCV prevention among people who inject drugs (PWID) is of key public health importance. We aimed to assess the impact of COVID-19 and associated response measures on HIV/HCV prevention services and socio-economic status of PWID in high-HIV-risk sites. Sites with recent (2011-2019) HIV outbreaks among PWID in Europe North America and Israel, that had been previously identified, were contacted early May 2020. Out of 17 sites invited to participate, 13 accepted. Semi-structured qualitative site reports were prepared covering data from March to May 2020, analyzed/coded and confirmed with a structured questionnaire, in which all sites explicitly responded to all 103 issues reported in the qualitative reports. Opioid maintenance treatment, needle/syringe programs and antiretroviral treatment /hepatitis C treatment continued, but with important reductions and operational changes. Increases in overdoses, widespread difficulties with food and hygiene needs, disruptions in drug supply, and increased homelessness were reported. Service programs rapidly reformed long established, and politically entrenched, restrictive service delivery policies. Future epidemic control measures should include mitigation of negative side-effects on service provision and socio-economic determinants in PWID.

RESUMEN: La prevención del VIH/VHC entre las personas que se inyectan drogas (PWID) es de vital importancia para la salud pública. Nuestro objetivo fue evaluar el impacto de COVID-19 y las medidas de respuesta asociadas en los servicios de prevención del VIH/VHC y el estado socioeconómico de las PWID en sitios de alto riesgo de VIH. Se contactó con sitios con brotes recientes (2011­2019) de VIH entre PWID en Europa, América del Norte e Israel, que habían sido previamente identificados, a principios de mayo de 2020. De los 17 sitios invitados a participar, 13 aceptaron. Se prepararon informes cualitativos semiestructurados del sitio que cubrían los datos de marzo a mayo de 2020, analizados/codificados y confirmados con un cuestionario estructurado, en el que todos los sitios respondieron explícitamente a los 103 asuntos reportados en los informes cualitativos. El tratamiento de mantenimiento con opiáceos, los programas de agujas/jeringas y el tratamiento antirretroviral/tratamiento de la hepatitis C continuaron, pero con importantes reducciones y cambios operativos. Se reportaron aumentos en las sobredosis, dificultades generalizadas con las necesidades alimentarias y de higiene, interrupciones en el suministro de medicamentos y aumento de personas sin hogar. Los programas de servicios reformaron rápidamente las políticas restrictivas de prestación de servicios, establecidas desde hace mucho tiempo y políticamente arraigadas. Las futuras medidas de control de epidemias deben incluir la mitigación de los efectos secundarios negativos en la prestación de servicios y los determinantes socioeconómicos en las PWID.

Sharp Edge Eye Syndrome: A Case Report and Survey of Self-Identified Individuals.

BACKGROUND: Sharp edge eye syndrome (SEES), sometimes known as visual looming syndrome, is a condition in which the patient experiences ocular pain or discomfort when viewing or mentally picturing sharp objects and edges. Patients may present for medical care because they perceive the condition to represent an ophthalmic problem or a sign of a more serious underlying condition. An individual case report of SEES is included to aid in illustrating syndrome characteristics. Our aim is to describe the syndrome, vision-related quality of life (VRQOL), and psychosocial characteristics in patients with self-identified SEES. METHODS: A cross-sectional web-based survey was made available on social media webpages dedicated to SEES. The study included 22 questions developed by the research team, demographic questions, and 4 standardized questionnaires [ID Migraine, the National Eye Institute's Visual Function Questionnaire (NEI-VFQ-25), General Anxiety Disorder-2 (GAD-2), and Patient Health Questionnaire (depression) Scale-2]. RESULTS: Seventy-seven respondents had an average age of 29 and were 57% male. 92% reported symptoms before age 18. The main site of pain or discomfort was the eyes, with onset resulting from viewing or thinking of sharp objects and edges. Symptoms lasted from seconds to hours and could be prolonged even after closing eyes or avoiding viewing the trigger. The composite and subscale scores on the NEI-VFQ-25 were low, with a mean composite score of 78 and selected subscores of general health (61), general vision (73), ocular pain (68), driving (79), mental health (61), and role difficulties (72). Anxiety was reported in 58% of participants, and depression in 57%. Migraine or headache was reported in 46% of participants. Participants reported Alice in Wonderland syndrome, visual snow, obsessive-compulsive disorder, attention deficit hyperactivity disorder, stripe-induced visual discomfort, and synesthesia. CONCLUSION: From this survey, we have the beginnings of an understanding of the characteristics of SEES, as well as VRQOL impacts. These survey responses lead us to postulate that SEES may be a distinct visual phenomenon and to propose SEES criteria. Systematic studies of this condition's clinical features and treatment responses will be additional steps toward improving patient care.

Antiseizure effects of the cannabinoids in the amygdala-kindling model.

OBJECTIVE: Focal impaired awareness seizures (FIASs) are the most common seizure type in adults and are often refractory to medication. Management of FIASs is clinically challenging, and new interventions are needed for better seizure control. The amygdala-kindling model is a preclinical model of FIASs with secondary generalization. The present study assessed the efficacy of cannabidiol (CBD), ∆9-tetrahydrocannabinol (THC), and a combination of CBD and THC in a 15:1 ratio at suppressing focal and secondarily generalized seizures in the amygdala-kindled rat. METHODS: Fully kindled, male Sprague Dawley rats, with bipolar electrodes implanted in the right amygdala, were given either CBD (0-320 mg/kg), THC (0-40 mg/kg), or a combination of CBD and THC (15:1 ratio, multiple doses) intraperitoneally. Suprathreshold kindling stimulation was administered 1 h (THC) or 2 h (CBD) after drug injection, and outcomes were assessed using focal electroencephalographic recording and the Racine seizure scale. RESULTS: CBD alone produced a partial suppression of both generalized seizures (median effective dose [ED50 ] = 283 mg/kg) and focal seizures (ED40 = 320 mg/kg) at doses that did not produce ataxia. THC alone also produced partial suppression of generalized (ED50 = 10 mg/kg) and focal (ED50 = 30 mg/kg) seizures, but doses of 10 mg/kg and above produced hypolocomotion, although not ataxia. The addition of a low dose of THC to CBD (15:1) left-shifted the CBD dose-response curve, producing much lower ED50 s for both generalized (ED50 = 26 + 1.73 mg/kg) and focal (ED50 = 40 + 2.66 mg/kg) seizures. No ataxia or hypolocomotion was seen at these doses of the CBD + THC combination. SIGNIFICANCE: CBD and THC both have antiseizure properties in the amygdala-kindling model, although THC produces suppression of the amygdala focus only at doses that produce hypolocomotion. The addition of small amounts of THC greatly improves the effectiveness of CBD. A combination of CBD and THC might be useful for the management of FIASs.

Interpreting the Tests of Focal Cortical Dysplasia for Epilepsy Surgery Referral.

OBJECTIVE: Focal cortical dysplasia (FCD) is a common cause of refractory, focal onset epilepsy in children. Interictal, scalp electroencephalograph (EEG) markers have been associated with these pathologies and epilepsy surgery may be an option for some patients. We aim to study how scalp EEG and magnetic resonance imaging (MRI) markers of FCD affect referral of these patients for surgical evaluation. METHODS: A single-center, retrospective review of children with focal onset epilepsy. Patients were included if they were between 1 month and 18 years of age, had focal onset seizures, prolonged scalp EEG monitoring, and an MRI conducted after 2 years of age. Statistics were carried out using the chi-squared and student's t-test, as well as a logistic regression model. RESULTS: Sixty-eight patients were included in the study. Thirty-seven of these patients were referred to a comprehensive pediatric epilepsy program (CPEP) for surgical evaluation, and of these 22% showed FCD EEG markers, 32% FCD MRI markers, and 10% had both. These markers were also present in patients not referred to a CPEP. The MRI markers were significantly associated with CPEP referral, whereas EEG markers were not. Neither marker type was associated with epilepsy surgery. CONCLUSION: This study found that children with focal onset epilepsy were more likely to be referred for surgical evaluation if they were medically refractory, or were diagnosed with FCD or tumor on MRI. Scalp EEG markers of FCD were not associated with CPEP referral. The online tool CASES may be a useful physician guide for identifying appropriate children for epilepsy surgery referral.

Interpréter les tests de détection de la dysplasie corticale focale en vue d'une évaluation préopératoire du traitement de l'épilepsie.Objectif: La dysplasie corticale focale (DCF) constitue une des causes communes des crises convulsives partielles réfractaires chez l'enfant. À la suite d'EEG effectués au niveau du cuir chevelu, des marqueurs de l'activité épileptique interictale ont été associés avec ce trouble pour lequel une intervention chirurgicale peut constituer, dans le cas de certains patients, une option. Nous voulons nous pencher sur la façon dont ces marqueurs et les marqueurs utilisés lors d'examens d'IRM pour la DCF peuvent affecter l'aiguillage de ces patients en vue d'une évaluation préopératoire. Méthodes: Dans un seul établissement hospitalier, nous avons effectué une analyse rétrospective de cas d'enfants chez qui sont apparues des crises convulsives partielles. Pour être inclus, les patients devaient être âgés de 1 mois à 18 ans, avoir été victimes de telles crises convulsives, avoir bénéficié de surveillance prolongée par EEG et avoir subi un examen d'IRM après l'âge de deux ans. Nous avons enfin effectué une analyse statistique à l'aide d'un modèle de régression logistique et des tests du X2 et de Student. Résultats: Au total, nous avons inclus soixante-huit patients dans cette étude. Trente-sept d'entre eux ont été redirigés vers un programme pédiatrique complet de traitement de l'épilepsie (comprehensive pediatric epilepsy program) en vue d'une évaluation préopératoire. Sur ces trente-sept patients, on a observé chez 22 % d'entre eux les marqueurs électroencéphalographiques associés à la DCF ; ce pourcentage atteignait 32 % dans le cas des marqueurs de la DCF utilisés en imagerie ; enfin, on a pu détecter ces deux types de marqueurs chez 10 % de ces trente-sept patients. Fait à souligner, ces marqueurs étaient aussi présents chez des patients n'ayant pas été orientés vers le type de programme cité ci-dessus. En outre, les marqueurs utilisés en imagerie se sont avérés étroitement associés au fait d'orienter des patients vers ce programme tandis que les marqueurs électroencéphalographiques ne l'étaient pas. Finalement, aucun de ces types de marqueurs n'a pu être associé à une intervention chirurgicale visant à traiter l'épilepsie. Conclusion: Cette étude a donc permis de constater que les enfants atteints de crises convulsives partielles étaient plus susceptibles d'être orientés en vue d'une évaluation préopératoire si leur trouble était de nature réfractaire ou s'ils avaient reçu un diagnostic de DCF ou de tumeur cancéreuse à la suite d'un examend'IRM. Les marqueurs électroencéphalographiques de la DCF n'ont pas été associés à un aiguillage vers un programme pédiatrique complet de traitement de l'épilepsie. Il se pourrait à cet égard que l'outil en ligne CASES soit un guide utile pour les médecins souhaitant identifier les enfants convenant à un aiguillage en vue d'un traitement chirurgical de l'épilepsie.

ß-Cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion.

ß-Cell insulin secretion is dependent on proper mitochondrial function. Various studies have clearly shown that the Nr4a family of orphan nuclear receptors is essential for fuel utilization and mitochondrial function in liver, muscle, and adipose. Previously, we have demonstrated that overexpression of Nr4a1 or Nr4a3 is sufficient to induce proliferation of pancreatic ß-cells. In this study, we examined whether Nr4a expression impacts pancreatic ß-cell mitochondrial function. Here, we show that ß-cell mitochondrial respiration is dependent on the nuclear receptors Nr4a1 and Nr4a3. Mitochondrial respiration in permeabilized cells was significantly decreased in ß-cells lacking Nr4a1 or Nr4a3. Furthermore, respiration rates of intact cells deficient for Nr4a1 or Nr4a3 in the presence of 16 mM glucose resulted in decreased glucose mediated oxygen consumption. Consistent with this reduction in respiration, a significant decrease in glucose-stimulated insulin secretion rates is observed with deletion of Nr4a1 or Nr4a3. Interestingly, the changes in respiration and insulin secretion occur without a reduction in mitochondrial content, suggesting decreased mitochondrial function. We establish that knockdown of Nr4a1 and Nr4a3 results in decreased expression of the mitochondrial dehydrogenase subunits Idh3g and Sdhb. We demonstrate that loss of Nr4a1 and Nr4a3 impedes production of ATP and ultimately inhibits glucose-stimulated insulin secretion. These data demonstrate for the first time that the orphan nuclear receptors Nr4a1 and Nr4a3 are critical for ß-cell mitochondrial function and insulin secretion.

Head and neck cancer patients' experiences of percutaneous endoscopic gastrostomy feeding: a Q-methodology study.

Head and neck cancer patients are at high risk of malnutrition and its complications and therefore often undergo non-oral nasogastric or percutaneous endoscopic gastrostomy (PEG) nutrition support. However, there is little evidence that either approach is effective in this group. While one possible explanation for these findings relates to the relationship between artificial tube feeding and poor quality of life, there is little research that examines the patient's subjective experience of nutrition support. This study investigated the experiences of PEG tube feeding in head and neck cancer patients undergoing radical treatment. Conventional Q-methodology was used with 15 head and neck cancer patients, who rank-ordered 36 statements according to the extent to which these reflected their experiences of PEG tube feeding. The sorted statements were factor-analysed case-wise to provide clusters of similar experiences. Three perspectives emerged. Factor 1, labelled 'Constructive cognitive appraisal', focused around positive adaptation to, and acceptance of, PEG feeding. Factor 2, labelled 'Cognitive-affective dissonance', reflected ambivalence between cognitive acceptance and affective rejection of the PEG tube. Factor 3, labelled 'Emotion-focused appraisal', was characterised by tube-focused anxiety and fear. The findings broadly confirm Levanthal et al.'s Self-Regulatory Model of coping and support the need for genuine and individualised patient-centred nutritional care.

Mitochondrial brain proteome acetylation levels and behavioural responsiveness to amphetamine are altered in mice lacking Sirt3.

Post-translational modification of mitochondrial proteins represents one mechanism by which the functional activity of mitochondria can be regulated. In the brain, these modifications can influence the functional properties of different neural circuitries. Given that the sirtuin family member Sirt3 represents the primary protein deacetylase enzyme in mitochondria, we tested whether brain mitochondrial proteome acetylation would increase in male or female mice lacking Sirt3. Our results confirm that whole brain mitochondrial proteome acetylation levels are indeed elevated in both sexes of Sirt3-KO mice relative to controls. Consistently, we found the mitochondria of mouse embryonic fibroblast (MEF) cells derived from Sirt3-KO mice were smaller in size, and fewer in number than in wild-type MEFs, and that mitochondrial free calcium levels were elevated within the mitochondria of these cells. As protein acetylation can influence mitochondrial function, and changes in mitochondrial function have been linked to alterations in neural circuit function regulating motor activity and anxiety-like behavior, we tested whether Sirt3-deficient mice would display sensitized responsiveness to the stimulant amphetamine. Both male and female Sirt3-KO mice displayed hyper-locomotion and attenuated anxiety-like behavior in response to a dose of amphetamine that was insufficient to promote any behavioural responses in wild-type mice. Collectively, these results confirm that Sirt3 regulates mitochondrial proteome acetylation levels in brain tissue, and that the absence of Sirt3 increases the sensitivity of neural systems to amphetamine-induced behavioural responses.

Seizures in Mouse Models of Rare Neurodevelopmental Disorders.

Genetic neurodevelopmental disorders - that often include epilepsy as part of their phenotype - are a heterogeneous and clinically challenging spectrum of disorders in children. Although seizures often contribute significantly to morbidity in these affected populations, the mechanisms of epileptogenesis in these conditions remain poorly understood. Different model systems have been developed to aid in unraveling these mechanisms, which include a number of specific mutant mouse lines which genocopy specific general types of mutations present in patients. These mouse models have not only allowed for assessments of behavioral and electrographic seizure phenotypes to be ascertained, but also have allowed effects on the neurodevelopmental alterations and cognitive impairments associated with these disorders to be examined. In addition, these models play a role in advancing our understanding of these epileptic processes and developing preclinical therapeutics. The concordance of seizure phenotypes - in a select group of rare, genetic, neurodevelopmental disorders and epileptic encephalopathies - found between human patients and their model counterparts will be summarized. This review aims to assess whether models of Rett syndrome, CDKL5 deficiency disorder, Fragile-X syndrome, Dravet syndrome, and Ohtahara syndrome phenocopy the seizures seen in human patients.

Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders.

Epigenetic processes are critical for governing the complex spatiotemporal patterns of gene expression in neurodevelopment. One such mechanism is the dynamic network of post-translational histone modifications that facilitate recruitment of transcription factors or even directly alter chromatin structure to modulate gene expression. This is a tightly regulated system, and mutations affecting the function of a single histone-modifying enzyme can shift the normal epigenetic balance and cause detrimental developmental consequences. In this review, we will examine select neurodevelopmental conditions that arise from mutations in genes encoding enzymes that regulate histone methylation and acetylation. The methylation-related conditions discussed include Wiedemann-Steiner, Kabuki, and Sotos syndromes, and the acetylation-related conditions include Rubinstein-Taybi, KAT6A, genitopatellar/Say-Barber-Biesecker-Young-Simpson, and brachydactyly mental retardation syndromes. In particular, we will discuss the clinical/phenotypic and genetic basis of these conditions and the model systems that have been developed to better elucidate cellular and systemic pathological mechanisms.

Identification of each human chromosome with a modified Giemsa stain.

Differential staining of human chromosomes can be obtained when the pH of Giemsa stain is changed to 9.0 from the usual 6.8. Such staining permits identification of all homolog pairs and distinct regions within chromosome arms. In most instances, the pattern is quite similar to that obtained with quinacrine mustard fluorescence staining. Certain regions, such as the paracentric constrictions in chromosomes Al and C9, and the distal end of the long arm of the Y chromosome stain differently with the Giemsa 9 technique. The technique is considerably simpler than the quinacrine mustard fluorescence technique and identification of homologs is also easier than in cells stained by the latter.

Atypical Antipsychotics for Irritability in Pediatric Autism: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: Irritability is common in pediatric autism spectrum disorder (ASD) patients. This can have major implications in child development, receptivity to behavioral therapy, as well as child and caregiver well-being. A systematic review and network meta-analysis were conducted to assess the efficacy and safety of atypical antipsychotics in treating irritability in these patients. METHODS: Studies were identified from Medline, Embase, and PsycINFO from inception to March 2018. The clinical trials database was reviewed. Studies were included if they were a double-blind, randomized controlled trial utilizing the Aberrant Behavior Checklist Irritability (ABC-I) to measure the efficacy of atypical antipsychotic monotherapy. Data extraction was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-analyses for network meta-analysis guidelines. The main outcome was the reduction in irritability score using the ABC-I subscale from baseline. RESULTS: Eight trials comparing four interventions-risperidone, aripiprazole, lurasidone, and placebo in 878 patients, were included. Both risperidone and aripiprazole had significantly reduced ABC-I scores than placebo. Estimates of mean differences (95% credible intervals) were risperidone, -6.89 (-11.14, -2.54); aripiprazole, -6.62 (-10.88, -2.22); and lurasidone, -1.61 (-9.50, 6.23). Both risperidone and aripiprazole had similar safety. There were only eight studies included in the analysis, however, sample sizes were not small. Variance in reporting of adverse effects limited the quality of safety analysis. CONCLUSION: Risperidone and aripiprazole were the two best drugs, with comparable efficacy and safety in pediatric ASD patients. These two medications could be beneficial in improving irritability in these patients.

Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding.

Abnormally phosphorylated tau proteins (A68) are the building blocks of Alzheimer's disease (AD) paired helical filaments. The biological consequences of the conversion of normal adult tau to A68 remain unknown. Here we demonstrate that native A68 does not bind to microtubules (MTs), yet dephosphorylated A68 regains the ability to bind to MTs. Ser396 is phosphorylated in A68, but not in normal adult tau, whereas fetal tau is phosphorylated transiently at this site. Phosphorylation of tau at Ser396 by protein kinases in CHO cells and rat brain produces an electrophoretic mobility similar to that of A68. Using CHO cells transfected with an Ala396 mutant, we show that the phosphorylation of tau at Ser396 reduces its affinity for MTs and its ability to stabilize MTs against nocodazole-induced depolymerization. Our results demonstrate that the abnormal phosphorylation of tau in AD involves Ser396, and we suggest that this may be mediated by the inappropriate activation of fetal kinases or the reduced activity of tau protein phosphatases. Thus, phosphorylation of Ser396 may destabilize MTs in AD, resulting in the degeneration of affected cells.

Automated crystal mounting and data collection for protein crystallography.

To increase the efficiency of diffraction data collection for protein crystallographic studies, an automated system designed to store frozen protein crystals, mount them sequentially, align them to the X-ray beam, collect complete data sets, and return the crystals to storage has been developed. Advances in X-ray data collection technology including more brilliant X-ray sources, improved focusing optics, and faster-readout detectors have reduced diffraction data acquisition times from days to hours at a typical protein crystallography laboratory [1,2]. In addition, the number of high-brilliance synchrotron X-ray beam lines dedicated to macromolecular crystallography has increased significantly, and data collection times at these facilities can be routinely less than an hour per crystal. Because the number of protein crystals that may be collected in a 24 hr period has substantially increased, unattended X-ray data acquisition, including automated crystal mounting and alignment, is a desirable goal for protein crystallography. The ability to complete X-ray data collection more efficiently should impact a number of fields, including the emerging structural genomics field [3], structure-directed drug design, and the newly developed screening by X-ray crystallography [4], as well as small molecule applications.

Structure-directed discovery of potent non-peptidic inhibitors of human urokinase that access a novel binding subsite.

BACKGROUND: Human urokinase-type plasminogen activator has been implicated in the regulation and control of basement membrane and interstitial protein degradation. Because of its role in tissue remodeling, urokinase is a central player in the disease progression of cancer, making it an attractive target for design of an anticancer clinical agent: Few urokinase inhibitors have been described, which suggests that discovery of such a compound is in the early stages. Towards integrating structural data into this process, a new human urokinase crystal form amenable to structure-based drug design has been used to discover potent urokinase inhibitors. RESULTS: On the basis of crystallographic data, 2-naphthamidine was chosen as the lead scaffold for structure-directed optimization. This co-crystal structure shows the compound binding at the primary specificity pocket of the trypsin-like protease and at a novel binding subsite that is accessible from the 8-position of 2-napthamidine. This novel subsite was characterized and used to design two compounds with very different 8-substituents that inhibit urokinase with K(i) values of 30-40 nM. CONCLUSIONS: Utilization of a novel subsite yielded two potent urokinase inhibitors even though this site has not been widely used in inhibitor optimization with other trypsin-like proteases, such as those reported for thrombin or factor Xa. The extensive binding pockets present at the substrate-binding groove of these other proteins are blocked by unique insertion loops in urokinase, thus necessitating the utilization of additional binding subsites. Successful implementation of this strategy and characterization of the novel site provides a significant step towards the discovery of an anticancer clinical agent.

A human squamous cell carcinoma cell line.

An epithelial cell line COLO 16 has been established from a human squamous carcinoma, characterized and maintained for over two years. The cells produce a parathyroid-like hormone and carcinoembryonic antigen. The line is definitely not a "HeLa contaminant." The cell line is available to other investigators.

Ventricular contraction abnormalities in dilated cardiomyopathy: effect of biventricular pacing to correct interventricular dyssynchrony.

OBJECTIVE: To measure ventricular contractile synchrony in patients with dilated cardiomyopathy (DCM) and to evaluate the effects of biventricular pacing on contractile synchrony and ejection fraction. BACKGROUND: Dilated cardiomyopathy is characterized by abnormal ventricular activation and contraction. Biventricular pacing may promote a more coordinated ventricular contraction pattern in these patients. We hypothesized that biventricular pacing would improve synchrony of right ventricular and left ventricular (RV/LV) contraction, resulting in improved ventricular ejection fraction. METHODS: Thirteen patients with DCM and intraventricular conduction delay underwent multiple gated equilibrium blood pool scintigraphy. Phase image analysis was applied to the scintigraphic data and mean phase angles computed for the RV and LV. Phase measures of interventricular (RV/LV) synchrony were computed in sinus rhythm and during atrial sensed biventricular pacing (BiV). RESULTS: The degree of interventricular dyssynchrony present in normal sinus rhythm correlated with LV ejection fraction (r = -0.69, p < 0.01). During BiV, interventricular contractile synchrony improved overall from 27.5 +/- 23.1 degrees to 14.1 +/- 13 degrees (p = 0.01). The degree of interventricular dyssynchrony present in sinus rhythm correlated with the magnitude of improvement in synchrony during BiV (r = 0.83, p < 0.001). Left ventricular ejection fraction increased in all thirteen patients during BiV, from 17.2 +/- 7.9% to 22.5 +/- 8.3% (p < 0.0001) and correlated significantly with improvement in RV/LV synchrony during BiV (r = 0.86, p < 0.001). CONCLUSIONS: Dilated cardiomyopathy with intraventricular conduction delay is associated with significant interventricular dyssynchrony. Improvements in interventricular synchrony during biventricular pacing correlate with acute improvements in LV ejection fraction.

Glial cells of the lamprey nervous system contain keratin-like proteins.

Lamprey axons regenerate following spinal cord transection despite the formation of a glial scar. As we were unable to detect a lamprey homologue of glial fibrillary acidic protein (GFAP), a major constituent of astrocytes, we studied the composition of intermediate filament (IF) proteins of lamprey glia. Monoclonal antibodies (mAbs) were raised to lamprey spinal cord cytoskeletal extracts and these mAbs were characterized by using Western blotting and immunocytochemistry. On two-dimensional (2-D) Western blots, five of the mAbs detected three major IF polypeptides in the molecular weight (MW) range of 45-56 kD. Further studies were conducted to determine the relationship between the lamprey glial-specific antigen and other mammalian IF proteins. Antikeratin 8 antibody recognized two of the three polypeptides. Several of the glial-specific mAbs reacted with human keratins 8 and 18 on Western blots. Keratin-like immunoreactivity was found in all parts of the central and peripheral nervous systems in both larval and adult lampreys. The immunocytochemical staining patterns of glial-specific mAbs were indistinguishable on lamprey spinal cord sections. However, on brain sections, two distinct patterns were observed. A subset of mAbs stained only a few glial fibers in the brain, whereas others stained many more brain glia, particularly the ependymal cells. The former group of mAbs recognized only the two lower MW polypeptides on 2-D Western blots, but the latter group of mAbs recognized all three major IF polypeptides. This correlation is supported by the observation that the highest MW IF polypeptide has an increased level of expression in the brain relative to the spinal cord. Thus, in the lamprey, the glial cells of both spinal cord and brain express molecules similar to simple epithelial cytokeratins, but their IFs may contain these keratins in different stoichiometric proportions. The widespread presence in the lamprey of primitive glial cells containing keratin-like intermediate filaments may have significance for the extraordinary ability of lamprey spinal axons to regenerate.

Determination of cardiac output by thermodilution during hypothermia.

The thermodilution method for estimating cardiac output was compared with the electromagnetic flowmeter technique in 10 mongrel dogs at normothermia and during surface-induced deep hypothermia. Thermodilution curves obtained during cooling or rewarming must be corrected for the baseline drift caused by changing core temperature. At normothermia, the correlation coefficient between the two methods was 0.96 and the reproducibility of the thermodilution technique was 5 percent. Comparable correlation was present during hypothermia. Curves corrected for baseline drift resulted in significantly different output values from those derived from uncorrected curves (p < 0.05). The thermodilution method is valid at low body temperatures. Clinical confirmation of these results, particularly during open heart surgery in infants, is warranted.

The safety and efficacy of ten percent pentastarch as a cardiopulmonary bypass priming solution. A randomized clinical trial.

Ten percent pentastarch is a low-molecular-weight hydroxyethyl starch with greater oncotic pressure and shorter intravascular persistence than 6% hetastarch. To evaluate its safety and efficacy as a component of cardiopulmonary bypass priming solution, we prospectively studied 90 patients undergoing coronary artery bypass grafting or valve replacement necessitating cardiopulmonary bypass (bubble oxygenator and moderate systemic hypothermia). Sixty patients were randomized to receive 75 gm of either 10% pentastarch (group P) or 25% albumin (group A), and 30 patients received lactated Ringer's solution alone (group C). Intravascular colloid osmotic pressure during cardiopulmonary bypass was highest with either of the colloid primes (15-minute measurement: group P, 15.7 +/- 2.2 mm Hg (mean +/- standard deviation); group A, 15.2 +/- 2.0 mm Hg; group C, 11.3 +/- 1.7 mm Hg; p less than 0.05, groups P and A compared with group C). This was associated with a lower volume requirement during cardiopulmonary bypass to maintain the venous reservoir (group P, 333 +/- 318 ml; group A, 483 +/- 472 ml; group C, 1332 +/- 1013 ml; p less than 0.05, groups P and A compared with group C). Urine output during cardiopulmonary bypass was similar in each group. Net intraoperative fluid balance was lowest in the colloid groups (groups P and A, 5.7 +/- 1.4 L; group C, 6.9 +/- 1.3 L; p less than 0.05, groups P and A compared with group C). Cardiac index shortly after weaning from cardiopulmonary bypass was greatest in group P (group P, 3.2 +/- 0.9; group A, 2.8 +/- 0.8; group C, 2.7 +/- 0.6 dyne.sec.cm-5; p less than 0.05, group P compared with group C). Changes in alveolar-arterial oxygen gradients, shunt fraction, and effective compliance were similar in all groups. During cardiopulmonary bypass, pentastarch appeared to cause the greatest degree of hemodilution, as suggested by the lowest hemoglobin, factor VII and IX levels and platelet count. The activated partial thromboplastin time was significantly prolonged during and immediately after cardiopulmonary bypass in group P relative to groups A and C (p less than 0.05), although there were no significant differences in the activated clotting time before cardiopulmonary bypass, during cardiopulmonary bypass, or after heparin neutralization. As well, clinical indices of hemostasis, including mediastinal drainage, red cell, platelet, and fresh frozen plasma requirements, and reoperation for excessive postoperative bleeding, were similar. We conclude that pentastarch, when used in cardiopulmonary bypass prime, is as safe as either albumin or Ringer's solution alone.(ABSTRACT TRUNCATED AT 400 WORDS)

The Mustard procedure in infants (less than 100 days of age). Ten-year follow-up.

Surgical treatment of transposition of the great arteries and intact ventricular septum has changed markedly in the past 10 years. However, long-term follow-up on new approaches is not available. In a unique group of patients, operated on in the first 100 days of life with the Mustard procedure, such follow-up is available, and the results of these true infant repairs represent a benchmark against which subsequent techniques applied to infants should be compared. During the period of 1975 to 1980, 36 infants, less than 100 days of age, who had transposition of the great arteries and intact ventricular septum, underwent Mustard repair at the University of California, San Francisco. Ages ranged from 4 to 98 days (mean 46 days) and weights from 2.3 to 6.6 kg (mean 3.5 kg). There were no early deaths, and late follow-up was available from 8 to 13 years (mean 10 years). The late survival rate was 97% (mean 10 years). There was a 62% rhythm disturbance-free survival rate, 89% reoperation-free survival rate, and 91% pacemaker-free survival rate. Echocardiographic evaluation revealed obstruction of the superior vena cava in eight patients, tricuspid insufficiency in four, right ventricular dysfunction in two, and left ventricular outflow tract obstruction in three. The Mustard procedure, performed in the first 100 days of life, results in a high rate of survival (early 100% and late 97%, at a mean of 10 years) and a low incidence of late complications against which other techniques of infant repair should be compared.