Constituents and bioactive principles of Polygonum chinensis.
Isolation and characterization of the chemical constituents of Polygonum chinensis L. gave the new 25R-spirost-4-ene-3,12-dione. The known compounds stigmast-4-ene-3,6-dione, stigmastane-3,6-dione, hecogenin and aurantiamide acetate were also isolated from for the first time from this species. Their anti-inflammatory and anti-allergic properties are described.


Role of the small proteoglycan bikunin in human reproduction.
Female reproductive events, including ovulation, menstruation, implantation, and delivery, are physiologically characterized by deep tissue remodeling and display hallmark signs of inflammation. This review discusses the pleiotropic roles played by bikunin in human reproduction. A comprehensive literature search of the Medline/PubMed database was performed on the following topics: bikunin structure, roles in pathophysiological conditions and involvement in human reproduction, and usefulness as a marker of gestational complications or as a drug to improve pregnancy outcomes. Bikunin is a small chondroitin sulfate proteoglycan found in blood, urine, and amniotic and cerebrospinal fluids, known for its anti-inflammatory and anti-proteolytic activities. Its levels are usually low, but they can increase several-fold in both acute and chronic inflammatory diseases. Bikunin plays key roles in reproductive events, such as cumulus-oocyte complex formation, pregnancy, and delivery. Its levels have been associated with the most common pregnancy complications such as preterm delivery, pre-eclampsia, and gestational diabetes mellitus. Finally, its intravaginal administration has been reported to reduce the risk of preterm delivery and to improve neonatal outcomes. Because of its pleiotropic roles in several reproductive events and its association with some life-threatening pathological conditions of pregnancy, bikunin may represent a non-invasive marker for improving follow-up and early diagnosis. Studies showing its usefulness as a drug for reducing the risk of preterm delivery and improving neonatal outcomes have yielded interesting results that deserve to be investigated through further research.


Liver inflammatory cells, apoptosis, regeneration and stellate cell activation in non-alcoholic steatohepatitis.
The pathogenesis of non-alcoholic steatohepatitis remains unclear from several points of view. Minimal diagnostic criteria are still not defined. To gather information useful for diagnosis and to improve the understanding of pathogenic mechanisms. A series of 14 patients with non-alcoholic steatohepatitis, identified among liver outpatients, were paired for age, sex and alanine amino transferase values with 14 patients with hepatitis C virus infection without steatosis. Clinical, biochemical and immunohistological examination, including characterisation of inflammatory cell population, evaluation of type III collagen and tenascin deposition, activation of stellate cells, hepatocellular apoptosis and proliferation. Patients with non-alcoholic steatohepatitis were more frequently obese, had higher triglyceride concentrations and lower gamma-globulins. T lymphocytes outnumbered polymorphonuclear cells, both in hepatitis C and in steatohepatitis, with a larger number of CD8 lymphocytes in patients with viral hepatitis but a comparable number of granulocytes. This resulted in a higher granulocytes to T cells ratio in steatohepatitis, possibly making these cells more easily detectable in spite of similar absolute numbers. Portal fibrosis and piecemeal necrosis were prevalent in hepatitis C virus infection, pericentral fibrosis was similar Hepatocellular apoptosis and proliferation as well as stellate cell activation were less relevant in steatohepatitis than in hepatitis C virus infection in spite of similar alanine amino transferase levels. These data provide a possible explanation for the relatively low tendency to progression of non-alcoholic steatohepatitis in most patients despite increased alanine amino transferase and suggest that non-death-related release of alanine amino transferase might occur in non-alcoholic steatohepatitis. This makes liver biopsy an essential part of the clinical setting supporting diagnosis, evaluation of severity and possibly definition of the evolutionary trend.


Enhanced ethanol formation by Clostridium thermocellum via pyruvate decarboxylase.
Pyruvate decarboxylase (PDC) is a well-known pathway for ethanol production, but has not been demonstrated for high titer ethanol production at temperatures above 50 °C. Here we examined the thermostability of eight PDCs. The purified bacterial enzymes retained 20% of activity after incubation for 30 min at 55 °C. Expression of these PDC genes, except the one from Zymomonas mobilis, improved ethanol production by Clostridium thermocellum. Ethanol production was further improved by expression of the heterologous alcohol dehydrogenase gene adhA from Thermoanaerobacterium saccharolyticum. The best PDC enzyme was from Acetobactor pasteurianus. A strain of C. thermocellum expressing the pdc gene from A. pasteurianus and the adhA gene from T. saccharolyticum was able to produce 21.3 g/L ethanol from 60 g/L cellulose, which is 70% of the theoretical maximum yield.


Optimizing Narrowband UVB Phototherapy Regimens for Psoriasis.
Psoriasis is a chronic, autoimmune condition characterized by abnormal epidermal hyperproliferation affecting about 3.2% of adults in the United States. Narrowband UVB (NBUVB) is a commonly used phototherapy option for patients with psoriasis and is an effective first-line therapy for generalized plaque psoriasis. This article covers fundamental considerations for physicians using NBUVB and highlights changes in the newest guideline recommendations for phototherapy treatment. Protocols for treatment initiation, maintenance, dose increases, and maintenance are compared and discussed. Readers will achieve a greater understanding of the fundamentals of NBUVB phototherapy and promising advances in the field, including home phototherapy and combination treatment.


[Histologic risk factors of basal cell carcinoma of the face, about 184 cases].
Basal cell carcinoma is the most common type of skin cancer in humans. The aim of our study was to determine the histologic risk factors involved in recurrence of basal cell carcinomas of the face. We conducted a retrospective study of patients with primary basal cell carcinoma (BCC) of the face treated between March 2003 and December 2005. We analyzed the size of lateral and deep margins of tumor, histologic subtype, perineural invasion, and ulcerations. Clinical follow-up was observed until June 2011. We note that 184 cases of BCC were included. Eleven recurrences occurred during the follow-up, i.e. 6%. The population was divided into two groups according to histologic safety margins (1 mm for all basal cell carcinomas, 0.8 mm for nodular and 2 mm for aggressive-growth (AG-BCC) subtypes). There was a significant difference between groups in regards to cancer recurrence. Tumor size above 2 cm and presence of perineural invasion increased the risk of recurrence. Low histological safety margins appear to be critical on tumor recurrence. Depending on the tumor characteristics, and the patient, we advocate a re-excision in cases of histological safety margins inferior to 0.8 mm for the nodular subtypes and 2 mm for aggressive subtypes. Tumor size, and perineural invasion should be taken into consideration so as to make a well-informed decision between re-excision and a watching strategy in critical cases.


Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11beta-HSD1: novel therapeutic agents for the treatment of metabolic syndrome.
Replacement of the pentyl chain on our original bicyclo[2.2.2]octyltriazole leads 1 and 2 has led to the discovery that heteroaryl substituted bicyclo[2.2.2]octyltriazoles are potent and selective 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1) inhibitors with excellent pharmacokinetic profiles.


Orbital reconstruction in hypertelorism.
Orbital hypertelorism as defined by increased bony interorbital distance is a complex manifestation of many congenital anomalies. As such, it is associated with a multitude of orbital, adnexal, and surrounding soft-tissue deformities. Treatment of these problems requires extensive experience and a comprehensive team, permitting adequate preoperative evaluation, diagnosis, and treatment. The results obtained may be dramatic. The overall safety of the procedures has been demonstrated. Continued refinements and long-term follow-up will undoubtedly continue to make significant improvements.


Wavelet transform for analysis of heart rate variability preceding ventricular arrhythmias in patients with ischemic heart disease.
Studies evaluating changes in HRV preceding the onset of ventricular arrhythmias using conventional techniques have shown inconsistent results. Time-frequency analysis of HRV is traditionally performed using short-term Fourier transform (STFT). Wavelet transform (WT) may however be better suited for analyzing non-stationary signals such as heart rate recordings. We studied patients with a history of myocardial infarction implanted with a defibrillator with an extended memory. The RR intervals during the 51 min preceding ventricular events requiring electrical therapy were retrieved, and HRV studied by WT and STFT. 111 episodes of ventricular arrhythmia were retrieved from 41 patients (38 males, age 64 +/- 8 years). Heart rate increased significantly before arrhythmia. There was no significant variation in low frequency / high frequency components (LF/HF) observed for the group as a whole, probably due to a great degree of heterogeneity amongst individuals. A subset of 30 patients also had heart rate recordings performed during normal ICD follow-up. WT did not show any difference in HRV before arrhythmia onset and during control conditions. Variations in HRV before onset of ventricular arrhythmias were not apparent in this large dataset, despite use of optimal tools for studying time-frequency analysis.


AID mutant analyses indicate requirement for class-switch-specific cofactors.
Activation-induced cytidine deaminase (AID) is the essential and sole B cell-specific factor required for class-switch recombination (CSR) and somatic hypermutation (SHM). However, it is not known how AID differentially regulates these two independent events. Involvement of several cofactors interacting with AID has been indicated by scattered distribution of loss-of-function point mutations and evolutionary conservation of the entire 198-amino-acid protein. Here, we report that human AID mutant proteins with insertions, replacements or truncations in the C-terminal region retained strong SHM activity but almost completely lost CSR activity. These results indicate that AID requires interaction with a cofactor(s) specific to CSR.


Ultrasound diagnosis of tunica albuginea cyst: clinical perspective.
Two case reports of tunica albuginea cysts are presented. Imaging of this lesion by high resolution ultrasonography and the impact of this technique on management are considered.


Magnetic resonance imaging for chylothorax after esophagectomy.
A 75-year-old man underwent esophagectomy for thoracic esophageal cancer. After the operation, the output fluid from the right chest drain increased, and laboratory analysis confirmed the fluid to be chyle. Magnetic resonance imaging (MRI) was then carried out to identify the leakage point and the size of the injury to the thoracic duct. The MRI clearly showed the leak point to be in the lower thoracic region. It thus appears that this non-invasive new approach using MRI is effective and suitable for diagnosis and establishment of an appropriate treatment plan for chylothorax after thoracic surgery.


Plasminogen activator inhibitor type 1 inhibits smooth muscle cell proliferation in pulmonary arterial hypertension.
Pulmonary arterial smooth muscle cells (PASMCs) in the medial layer of the vessel wall are responsible for vessel homeostasis, but also for pathologic vascular remodelling in diseases, such as idiopathic pulmonary arterial hypertension (IPAH). Vascular remodelling in IPAH results in vessel stiffness, occlusion, and increased vascular resistance, but its underlying mechanisms remain to be fully elucidated. In this study, we investigated the expression and function of plasminogen activator inhibitor (PAI)-1, an inhibitor of the plasminogen activator system and target gene of the transforming growth factor (TGF)-beta1 signalling cascade, in PASMC in IPAH. RNA and protein analysis from lung tissues of donors and patients with IPAH (n=7 each) revealed a significant downregulation of PAI-1 in IPAH lungs. Immunohistochemical analysis localised PAI-1 to the bronchial and alveolar epithelium, as well as to vascular and airway smooth muscle cells. PAI-1 was also downregulated in primary PASMC derived from IPAH lungs as compared with donor-derived PASMC. In order to elucidate PAI-1 function, primary PASMC were stimulated with active recombinant (r)PAI-1, or transfected with PAI-1-specific siRNA. Stimulation with rPAI-1 led to decreased PASMC proliferation and adhesion to vitronectin, and increased PASMC migration. In contrast, PAI-1 knock-down with siRNA increased PASMC proliferation and decreased PASMC migration. PAI-1 is significantly downregulated in PASMC in IPAH, on the mRNA and protein level. PAI-1 negatively regulates PASMC proliferation, while it increases PASMC migration. Thus, its loss in IPAH may therefore contribute to pathologic vascular remodelling in IPAH.


Decerebrate mammalian preparations: unalleviated or fully alleviated pain? A review and opinion.
In experimental decerebration of mammals, the cerebral cortex and thalamus are surgically or otherwise inactivated under traditional (pharmacologic) general anesthesia. Once the effects of the pharmacologic anesthesia have dissipated, the animal remains alive, but there is neither pain sensation nor consciousness. Because the Animal Welfare Act and its regulations recognize drugs as the only means to alleviate pain, it is unclear whether a decerebrate animal should be placed in U.S. Department of Agriculture (USDA) pain and distress category D (pain or distress alleviated by drugs) or E (unalleviated pain or distress). We present a rationale for including decerebrate animals in USDA category D. We also provide a general review of decerebration and suggestions for institutional animal care and use committees having to evaluate decerebration protocols.


Development and validation of a patient-based health-related quality of life questionnaire in schizophrenia: the S-QoL.
We developed a self-administered instrument to assess health-related quality of life (HRQL) among people with schizophrenia. The S-QoL, based on Calman's approach to the subject's point of view, is a multidimensional instrument that is sensitive to change. The scale is a 41-item questionnaire with eight subscales (psychological well-being, self-esteem, family relationships, relationships with friends, resilience, physical well-being, autonomy and sentimental life) and a total score. In-depth interviews with patients determined the pertinent issues for item development. The validation study, performed with 207 patients, showed high internal consistency reliability, reproducibility and responsiveness. Construct validity was confirmed using established clinical and HRQL measures. S-QoL covers domains that differ from areas tapped in other measures, with greater responsiveness. The S-QoL is an efficient instrument for the measurement of the impact of schizophrenia on individuals' lives.


Role of relaxin-3/RXFP3 system in stress-induced binge-like eating in female rats.
Binge eating is frequently stimulated by stress. The neuropeptide relaxin-3 (RLN3) and its native receptor RXFP3 are implicated in stress and appetitive behaviors. We investigated the dynamics of the central RLN3/RXFP3 system in a newly established model of stress-induced binge eating. Female Sprague-Dawley rats were subjected to unpredictable intermittent 1-h access to 10% sucrose. When sucrose intake stabilized, rats were assessed for consistency of higher or lower sucrose intake in response to three unpredictable episodes of foot-shock stress; and assigned as binge-like eating prone (BEP) or binge-like eating resistant (BER). BEP rats displayed elevated consumption of sucrose under non-stressful conditions (30% > BER) and an additional marked increase in sucrose intake (60% > BER) in response to stress. Conversely, sucrose intake in BER rats was unaltered by stress. Chow intake was similar in both phenotypes on 'non-stress' days, but was significantly reduced by stress in BER, but not BEP, rats. After stress, BEP, but not BER, rats displayed a significant increase in RLN3 mRNA levels in the nucleus incertus. In addition, in response to stress, BEP, but not BER, rats had increased RXFP3 mRNA levels in the paraventricular and supraoptic nuclei of the hypothalamus. Intracerebroventricular administration of a selective RXFP3 antagonist, R3(B1-22)R, blocked the stress-induced increase in sucrose intake in BEP rats and had no effect on sucrose intake in BER rats. These results provide important evidence for a role of the central RLN3/RXFP3 system in the regulation of stress-induced binge eating in rats, and have therapeutic implications for eating disorders.


Computational study of the conformational ensemble of CX3C chemokine receptor 1 (CX3CR1) and its interactions with antagonist and agonist ligands.
The CX3C chemokine receptor 1 (CX3CR1), a member of the class A of G Protein-Coupled Receptors (GPCR) superfamily, and its ligand fractalkine constitute an important biochemical axis that influence many cellular pathways involving homeostatic and inflammatory processes. They participate in the activation, chemotaxis and recruitment of multiple immunological cells such as microglia, macrophages and monocytes, and play a critical role in neuroinflammatory conditions such as Alzheimer's disease and multiple sclerosis, in the recovery from central nervous system injuries, in several chronic, peripheral inflammatory entities and in some infective processes including HIV-AIDS. In this work we present the study of the CX3CR1 receptor employing extensive atomistic Molecular Dynamics (MD) simulations with the aim to characterize the conformational ensemble of the receptor in the presence of its antagonist and agonist ligands. We analyzed the receptor conformational changes and described interactions within its key regions and the bounded ligands to identify their notable differences. Finally, we classify the features that would allow the identification of patterns that characterize a functional state to contribute to the understanding of the complexity of the GPCR superfamily.


Ordering markers in the region of the ataxia-telangiectasia gene (11q22-q23) by fluorescence in situ hybridization (FISH) to interphase nuclei.
Fluorescence in situ hybridization (FISH) to interphase nuclei was performed to order probes corresponding to bands 11q22-q23 where the ataxia-telangiectasia (AT) gene(s) have been located. Cosmid probes and one phage probe previously localized to this chromosome 11 region by FISH to metaphase chromosomes, were hybridized to interphase nuclei of the somatic cell hybrid J1a, which contains chromosome 11 as the only human chromosome. Two-color FISH was used with a centromeric reference probe marker. The following order was obtained: cen-D11S385 (CJ52.75)-CJ52.3-D11S384 (CJ52.193)-CJ52.114-D11S424 (CJ52.77)-D11S132-NCAM-D11S351 (CJ52.208)-tel. The validity of using the centromeric probe was illustrated by showing that a probe corresponding to 11p13 hybridized more closely to the centromere than a probe corresponding to 11q22-q23, and by using cosmids hybridized three by three.


The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection.
Surveillance, Epidemiology and End Results (SEER) data indicate that number of lymph nodes removed impacts survival in gastric cancer. Our aim was to study this relationship in esophageal cancer. The study population included 2303 esophageal cancer patients (1381 adenocarcinoma, 922 squamous) from 9 international centers that had R0 esophagectomy prior to 2002 and were followed at regular intervals for 5 years or until death. Patients treated with neoadjuvant or adjuvant therapy were excluded. Operations consisted of esophagectomy with (1700) and without (603) thoracotomy. Median number of nodes removed was 17 (IQR10-29). There were 508 patients with stage I, 853 stage II, and 942 stage III. Five-year survival was 40%. Cox regression analysis showed that the number of lymph nodes removed was an independent predictor of survival (P < 0.0001). The optimal threshold predicted by Cox regression for this survival benefit was removal of a minimum of 23 nodes. Other independent predictors of survival were the number of involved nodes, depth of invasion, presence of nodal metastasis, and cell type. The number of lymph nodes removed is an independent predictor of survival after esophagectomy for cancer. To maximize this survival benefit a minimum of 23 regional lymph nodes must be removed.


COVID-19 and dys-regulation of pulmonary endothelium: implications for vascular remodeling.
Coronavirus disease-2019 (COVID-19), the disease caused by severe acute respiratory syndrome-coronavirus-2, has claimed more than 4.4 million lives worldwide (as of 20 August 2021). Severe cases of the disease often result in respiratory distress due to cytokine storm, and mechanical ventilation is required. Although, the lungs are the primary organs affected by the disease, more evidence on damage to the heart, kidney, and liver is emerging. A common link in these connections is the cardiovascular network. Inner lining of the blood vessels, called endothelium, is formed by a single layer of endothelial cells. Several clinical manifestations involving the endothelium have been reported, such as its activation via immunomodulation, endotheliitis, thrombosis, vasoconstriction, and distinct intussusceptive angiogenesis (IA), a unique and rapid process of blood-vessel formation by splitting a vessel into two lumens. In fact, the virus directly infects the endothelium via TMPRSS2 spike glycoprotein priming to facilitate ACE-2-mediated viral entry. Recent studies have indicated a significant increase in remodeling of the pulmonary vascular bed via intussusception in patients with COVID-19. However, the lack of circulatory biomarkers for IA limits its detection in COVID-19 pathogenesis. In this review, we describe the implications of angiogenesis in COVID-19, unique features of the pulmonary vascular bed and its remodeling, and a rapid and non-invasive assessment of IA to overcome the technical limitations in patients with COVID-19.


Test-retest reliability and validity of self-reported duration of computer use at work.
The aims of this study were to evaluate the test-retest reliability and the validity of self-reported duration of computer use at work. Test-retest reliability was studied among 81 employees of a research department of a university medical center. The employees filled out a web-based questionnaire twice with an in-between period of 14 days. Validity was studied among a group of 572 office workers who participated in an epidemiologic field study. A software program recorded the duration of computer use at work during the 3 months preceding the questionnaire. The percentages of agreement for test-retest reliability were 75% [95% confidence interval (95% CI) 64-84] for total computer use and 67% (95% CI 55-77) for mouse use. The percentages of agreement between self-report and registration were 18% (95% CI 15-21) for total computer use and 16% (95% CI 13-19) for mouse use. Misclassification was mainly nondifferential in nature, since all of the evaluated subgroups showed at least 75% misclassification. The use of self-reports lead to the misclassification of exposure to computer use for more than 80% of all persons. This misclassification is predominantly nondifferential in nature and can only partly be explained by limited test-retest reliability.


Continuous monitoring of cerebral oxygenation in acute brain injury: injection of mannitol during hyperventilation.
Global cerebral oxygenation, perfusion pressure, and expired pCO2 were continuously monitored in 10 adults with acute severe closed head trauma. Cerebral oxygenation was monitored by fiberoptic catheter oximetry, which allowed simultaneous measurements of arterial and jugular bulb oxyhemoglobin saturation. Intracranial pressure levels over 20 mm Hg were recorded several times in all patients, in spite of sedation, muscle paralysis, and profound hyperventilation. Intracranial hypertension was frequently associated with oligemic cerebral hypoxia, identified as abnormally low jugular oxygen saturation in the presence of normal arterial oxygenation. Intracranial hypertension was then managed with intravenous administration of mannitol boluses, which yielded simultaneous decreases in intracranial pressure and increases in cerebral oxygenation to highly statistically significant levels. Monitoring cerebral oxygenation was clinically useful because it allowed identification of impaired cerebral oxygenation even when cerebral perfusion pressure was normal. It is therefore proposed as a new monitoring technique, to supplement conventional monitoring of cerebral perfusion pressure.


Clarifying Misconceptions of the Zone of Latent Solutions Hypothesis: A Response to Haidle and Schlaudt: Miriam Noël Haidle and Oliver Schlaudt: Where Does Cumulative Culture Begin? A Plea for a Sociologically Informed Perspective (Biological Theory 15: 161-174, 2020).
The critical examination of current hypotheses is one of the key ways in which scientific fields develop and grow. Therefore, any critique, including Haidle and Schlaudt's article, "Where Does Cumulative Culture Begin? A Plea for a Sociologically Informed Perspective," represents a welcome addition to the literature. However, critiques must also be evaluated. In their article, Haidle and Schlaudt (Biol Theory 15:161-174, 2020. 10.1007/s13752-020-00351-w; henceforth H&S) review some approaches to culture and cumulative culture in both human and nonhuman primates. H&S discuss the "zone of latent solutions" (ZLS) hypothesis as applied to nonhuman primates and stone-toolmaking premodern hominins. Here, we will evaluate whether H&S's critique addresses its target.


Strong spatial segregation between wildcats and domestic cats may explain low hybridization rates on the Iberian Peninsula.
The European wildcat (Felis silvestris silvestris) is an endangered felid impacted by genetic introgression with the domestic cat (Felis silvestris catus). The problem of hybridization has had different effects in different areas. In non-Mediterranean regions pure forms of wildcats became almost extinct, while in Mediterranean regions genetic introgression is a rare phenomenon. The study of the potential factors that prevent the gene flow in areas of lower hybridization may be key to wildcat conservation. We studied the population size and spatial segregation of wildcats and domestic cats in a typical Mediterranean area of ancient sympatry, where no evidence of hybridization had been detected by genetic studies. Camera trapping of wild-living cats and walking surveys of stray cats in villages were used for capture-recapture estimations of abundance and spatial segregation. Results showed (i) a low density of wildcats and no apparent presence of putative hybrids; (ii) a very low abundance of feral cats in spite of the widespread and large population sources of domestic cats inhabiting villages; (iii) strong spatial segregation between wildcats and domestic/feral cats; and (iv) no relationship between the size of the potential population sources and the abundance of feral cats. Hence, domestic cats were limited in their ability to become integrated into the local habitat of wildcats. Ecological barriers (habitat preferences, food limitations, intra-specific and intra-guild competition, predation) may explain the severe divergences of hybridization impact observed at a biogeographic level. This has a direct effect on key conservation strategies for wildcats (i.e., control of domestic cats).


Outcomes from patients with multi-vessel disease following primary PCI: staged PCI imparts very low mortality.
CABG and PCI are effective means for revascularization of patients with multi-vessel coronary artery disease, but previous studies have not focused on treatment of patients that first undergo primary PCI. Among patients enrolled in the global registry of acute coronary events (GRACE), clinical outcomes for patients presenting with STEMI treated with primary PCI were compared according to whether residual stenoses were treated medically, surgically, or with staged PCI. Clinical characteristics and data pertaining to major adverse cardiac events during hospitalization and 6 months after discharge were collected. Of the 1,705 patients included, 1,345 (79%) patients were treated medically, 303 (18%) underwent staged PCI, and 57 (3.3%) underwent CABG following primary PCI. Hospital mortality was lowest among patients treated with staged PCI (Medical = 5.7%; PCI = 0.7%; CABG = 3.5%; P < 0.001 [PCI vs. Medical]), a finding that persisted after risk adjustment (Odds Ratio PCI vs. Medical 5 0.16, [0.04-0.68]; P 5 0.01). Six month postdischarge mortality likewise was lowest in the staged PCI group (Medical = 3.1%; PCI = 0.8%; CABG = 4.0%; P = 0.04 [PCI vs. Medical]). Patients revascularized surgically were rehospitalized less frequently (Medical = 20%; PCI = 19%; CABG = 6.3%; P < 0.05) and underwent fewer unscheduled procedures (Medical 5 9.8%; PCI = 10.0%; CABG = 0.0%; P < 0.02). The results of this multinational registry demonstrate that hospital mortality in patients who undergo staged percutaneous revascularization of multivessel coronary disease following primary PCI is very low. Patients undergoing CABG following primary PCI are hospitalized less frequently and undergo fewer unplanned catheter-based procedures.


Nucleic acid biomarkers of β cell stress and death in type 1 diabetes.
The purpose of this review is to summarize recent advances in the development of nucleic acid-based biomarkers of type 1 diabetes (T1D). Recent rodent and human studies have identified new roles for stress pathways intrinsic to the β cell during the development of T1D. As such, methods to identify an authentic nucleic acid signature of β cell stress and/or death may improve our ability to predict T1D at earlier timepoints, allowing for optimal timing of immunomodulatory interventions. To this end, both targeted and unbiased approaches have begun to identify changes in microRNA expression patterns in T1D. Moreover, a number of groups have developed distinct assays that quantitatively detect circulating unmethylated insulin DNA, which is thought to primarily emanate from dying β cells. Here we highlight unique blood and urine microRNA signatures identified in T1D cohorts, compare differences between first, second, and third-generation assays that detect circulating unmethylated insulin DNA, and review recent technological advances that have the capacity to improve T1D biomarker development.


An audit of COVID-19 death reporting in counties Cork and Kerry, Ireland, winter 2021-2022.
In Ireland, a 'COVID-19 death' is defined as any death in which the decedent was COVID-19 positive and had no clear alternative cause of death unrelated to COVID-19, a definition based on World Health Organization guidance. The objectives of this audit were to determine the proportion of COVID-19 deaths notified in the Cork/Kerry region of Ireland during winter 2021-2022 which adhered to this national definition, and to determine whether COVID-19 was deemed to be the primary cause of death, or a contributory or incidental factor. A review of all deaths in individuals who were COVID-19 positive at the time of death notified to the Department of Public Health for Cork and Kerry between 22 November 2021 and 31 January 2022 was conducted to determine whether each death adhered to the national COVID-19 death definition. The clinical opinion on cause of death was obtained by contacting decedents' clinicians. Sixty deaths in individuals who were COVID-19 positive at the time of death were notified to the Department in the study period. Of deaths notified as being due to COVID-19, COVID-19 was deemed the primary cause of death, a contributory factor or an incidental factor in 72.7%, 21.8%, and 5.5% of cases, respectively. Most (93.3%) notified deaths adhered to the national COVID-19 death definition. The COVID-19 death definition in Ireland may require revision so it can distinguish between deaths caused by COVID-19 and those in which COVID-19 played a less direct role. The current COVID-19 mortality reporting system may also need updating to capture more clinical nuance.


Prediction of disability progression in fingolimod-treated patients.
The aim of the study was to evaluate whether early disease activity during fingolimod treatment could predict disease progression in patients with relapsing-remitting multiple sclerosis (RRMS). We included RRMS patients who received fingolimod for at least 12 months with a ≥36 months of follow-up. Early disease activity was assessed by the modified Rio score (MRS). Association between MRS at 12 months and time to disability progression over the following two years was assessed using Kaplan-Meier survival curves analysis and Cox proportional hazards model. At 1 year from starting treatment, 14 (58.3%), 5 (20.8%), 3 (12.5%) and 2 (8.3%) subjects had a MRS=0, 1, 2, and 3, respectively. The risk of disability progression in the next 2 years was associated to the MRS and increased from 21.1% in patients with MRS=0-1 to 80% in those with MRS≥2 (adjusted HR=19.67; 95% CI=2.30-167.79; p=0.006). Early disease activity is suggested to be associated with the risk of disease progression in patients receiving fingolimod and MRS could be a reliable tool to identify the subjects at higher risk of unfavorable course.


Development and evaluation of different complex media for phytoplasma isolation and growth.
The focus of this research was the development and evaluation of different complex liquid and solid media for the isolation and growth of phytoplasma strains infecting grapevine plants. Previously reported media supporting phytoplasma isolation are commercial and not easy to modify in order to improve performance and selectivity towards obtaining pure cultures of 'Candidatus Phytoplasma' species. Three media (Piv®, CB and MB) were therefore evaluated for phytoplasma isolation and colony formation under microaerophilic growing conditions, using grapevine canes from plants showing yellows symptoms, and infected by "flavescence dorée", "bois noir" and aster yellows phytoplasmas as sources. The newly developed methodology was applied for two years at three sample collection times. Broad applicability and a good repeatability in supporting phytoplasma colony formation were obtained in Pivs® and CBs media. While the MB medium did not support phytoplasma isolation and growth, the CB media support a phytoplasma growth comparable to the one obtained in the previously reported media. This medium has the advantage of a formulation that allow its modification to implement specificity towards selective phytoplasma growth. Moreover preliminary trials on serial dilutions and tetracycline addition confirmed some phytoplasma growth behaviours.


Tri-iodothyronine (T3) and dexamethasone interact to modulate osteoprogenitor cell differentiation in fetal rat calvaria cell cultures.
We investigated the role of 3,5,3'-tri-iodothyronine (T3) in regulating differentiation of osteoprogenitor cells and also studied the effects of the glucocorticoid hormone dexamethasone (Dex) on the T3-induced effects on osteoprogenitor populations. This was done by determining the effects of either hormone alone, or of combinations of the two hormones, on the number of bone nodules formed in long-term cultures of rat calvaria cells. In this system, Dex has been shown to increase bone nodule formation, the maximal effective dose being 10 nM (Bellows et al. Endocrinology 121: 1985-1992; 1987). In standard culture medium containing 15% fetal bovine serum FBS), low concentrations of T3 (0.001-0.1 nM) had no effect on the number of bone nodules, while higher concentrations of 1-100 nM inhibited. However, in culture medium containing 10 nM Dex, the lower concentrations of T3 markedly increased the number of nodules. Short term pulse experiments with these low concentrations of T3 in the presence of Dex indicated that stimulation of nodule formation occurred only when T3 was present prior to confluency. Higher concentrations of T3 (1-100 nM) decreased nodule number whether or not Dex was added. We then cultured cells in medium containing FBS from which T3 and T4 were removed by treatment with AG-1 chi-10 resin. In both + or - Dex conditions, bone nodule formulation was increased 1.5 to 2-fold in T3, T4-depleted medium when compared with cultures maintained in standard culture medium.(ABSTRACT TRUNCATED AT 250 WORDS)


30-day readmission prevention program in heart failure patients (RAP-HF) in a community hospital: creating a task force to improve performance in achieving CMS target goals.
In 2012, Centers for Medicare and Medicaid Services (CMS) announced it would penalize any hospitals that had 30-day readmission rates for heart failure (HF) patients above 20%. Mather Hospital Northwell Health, a community teaching hospital, organized a proactive task force to meet these goals. We describe our hospital-wide Readmission Prevention in Heart Failure (RAP-HF) project. We focused on the following interventions: early identification of patients at risk for readmission, discipline-specific mitigation planning by the interdisciplinary rounding team, enhanced medication education for heart failure patients, education of family/caregivers on medication and heart failure symptoms, facilitation in scheduling of post-discharge follow up visits and hard-wired communication between hospital and post-discharge care providers. We saw a 25.53% decrease in 30-day readmission rates.


Enhancement of hypoxia-induced gene expression in fish liver by the aryl hydrocarbon receptor (AhR) ligand, benzo[a]pyrene (BaP).
Fish in polluted coastal habitats commonly suffer simultaneous exposure to both hypoxia and xenobiotics. Although the adaptive molecular responses to each stress have been described, little is known about the interaction between the signaling pathways mediating these responses. Previous studies in mammalian hepatoma cell lines have shown that hypoxia-inducible factor (HIF)- and/or aryl hydrocarbon receptor (AhR)-activated gene expression is suppressed following co-exposure to hypoxia and the hallmark AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, whether similar crosstalk exists in the non-tumor liver tissues of fish and whether other non-TCDD ligands also play the same inhibitory role in this crosstalk remain unknown. Here, the in vivo hepatic mRNA expression profiles of multiple hypoxia- and AhR-responsive genes (later gene expression=mRNA expression of the gene) were examined in the orange-spotted grouper (Epinephelus coioides) upon single and combined exposures to hypoxia and benzo[a]pyrene (BaP). Combined exposure enhanced hypoxia-induced gene expression but did not significantly alter BaP-induced gene expression. Protein carbonyl content was markedly elevated in fish subjected to combined exposure, indicating accumulation of reactive oxygen species (ROS). Application of diethyldithiocarbamate (DDC) to hypoxia-treated grouper liver explants similarly exaggerated hypoxia-induced gene expression as in the combined stress tissues in vivo. These observations suggest that ROS derived from the combined hypoxia and BaP stress have a role in enhancing hypoxia-induced gene expression.


A Simple Route to Synthesize Cu@Ag Core-Shell Bimetallic Nanoparticles and Their Surface-Enhanced Raman Scattering Properties.
Water-dispersed Cu@Ag core-shell nanoparticles (NPs) with 15 nm-diameter Cu core and 5 nm-thick Ag shell can be synthesized by a facile one-step chemical reduction at room temperature without any protective atmosphere. To obtain a homogeneous Ag coating on Cu, the influence of [Cu/Ag] molar ratio was investigated. Transmission electron microscopy (TEM) and X-ray diffraction (XRD) confirmed that Ag formed a dense coating on the surface of Cu, and that phase-pure spherical Cu@Ag core-shell bimetallic NPs were prepared when the [Cu/Ag] molar ratio was between 1/0.5 and 1/0.75. The time dependence of ultraviolet-visible (UV-Vis) spectra and XRD patterns of six-month stored Cu@Ag NPs showed that the as-prepared Cu@Ag NPs have a long-term antioxidant activity. Also, the surface-enhanced Raman scattering (SERS) signals had a high stability and reproducibility for the substrates. Hence, the as-prepared Cu@Ag nanostructures can be used as an efficient substrate for SERS signals.


Psychological manifestations of gastrointestinal disorders. Comments.
This article reviews the literature regarding the interplay between gastrointestinal complaints and psychological factors, an increasingly recognized and therapeutically important aspect of referral practice. Knowledge in this field is distilled to broad principles and approaches that can be applied to the different clinical entities affecting the gut, from the esophagus to the rectum. The management of these challenging problems is discussed, with special attention paid to the relationship between the physician and his or her patient. This article is highly relevant and applicable to the often complicated referral case seen by the gastroenterology subspecialist.


Lakes as nitrous oxide sources in the boreal landscape.
Estimates of regional and global freshwater N2 O emissions have remained inaccurate due to scarce data and complexity of the multiple processes driving N2 O fluxes the focus predominantly being on summer time measurements from emission hot spots, agricultural streams. Here, we present four-season data of N2 O concentrations in the water columns of randomly selected boreal lakes covering a large variation in latitude, lake type, area, depth, water chemistry, and land use cover. Nitrate was the key driver for N2 O dynamics, explaining as much as 78% of the variation of the seasonal mean N2 O concentrations across all lakes. Nitrate concentrations varied among seasons being highest in winter and lowest in summer. Of the surface water samples, 71% were oversaturated with N2 O relative to the atmosphere. Largest oversaturation was measured in winter and lowest in summer stressing the importance to include full year N2 O measurements in annual emission estimates. Including winter data resulted in fourfold annual N2 O emission estimates compared to summer only measurements. Nutrient-rich calcareous and large humic lakes had the highest annual N2 O emissions. Our emission estimates for Finnish and boreal lakes are 0.6 and 29 Gg N2 O-N/year, respectively. The global warming potential of N2 O from lakes cannot be neglected in the boreal landscape, being 35% of that of diffusive CH4 emission in Finnish lakes.


Left heart pacing--experience with several types of coronary vein leads.
Our experience with 121 coronary vein (CV) leads in 116 patients shows that CV leads are the leads of choice for pacing the left ventricle (LV). The information gained from pre-operative venous angiography permits individual selection of the most appropriate lead model for each case. The use of steerable electrophysiology catheters facilitates guide catheter cannulation of the coronary sinus (CS) when the anatomy is difficult and reduces the risk of complications. By selecting the CV lead model most suitable for each individual patient, we achieved successful implantation in 99.1% of patients. In this day and age, epicardial electrodes should be restricted to cases with CS anomalies which make CS cannulation impossible, and to LV lead implantation during heart surgery.


Effects of Vaspin on Insulin Resistance in Rats and Underlying Mechanisms.
Insulin resistance (IR) is the main pathogenesis of metabolic syndrome and a shared pathophysiological change in conditions such as diabetes mellitus, adiposity, hypertension, and atherosclerosis. Visceral adipose tissue-derived serpin (Vaspin) is a newly discovered adipocytokine with insulin-sensitizing and anti-inflammatory effects. To examine if vaspin can improve insulin resistance in rats fed a high-fat diet via the insulin receptor substrate/phosphatidylinositol 3 kinase/protein kinase B/glucose transport (IRS/PI3K/Akt/Glut) and inhibitory κB alpha/nuclear factor-kappa B (IκBα/NF-κB) signalling pathways, thirty male Sprague-Dawley (SD) rats were randomly divided into three groups: the normal control group (NC group, n = 10), high-fat diet group (HFD group, n = 10) and vaspin intervention group (HFD + vaspin group, n = 10). Results showed that intervention with vaspin significantly decreased fasting blood glucose (FBG) and fasting insulin (FINS) concentrations in HFD - fed rats without significantly affecting body weight or triglyceride (TG) or total cholesterol (TC) levels. The areas under the intraperitoneal glucose tolerance test (IPGTT) and the insulin tolerance test (ITT) curves were significantly decreased in HFD + vaspin group compared with the HFD group, and the glucose infusion rate (GIR) showed the same trends. Western blot, real-time polymerase chain reaction (RT-PCR) and immunofluorescence staining showed that vaspin could improve insulin resistance in liver, skeletal muscle and adipose tissue by activating the IRS/PI3K/Akt/Glut signalling pathway and inhibiting the IκBα/NF-κB signalling pathway.


Loss of dimethylated H3K27 (H3K27me2) expression is not a specific marker of malignant peripheral nerve sheath tumor (MPNST): An immunohistochemical study of 137 cases, with emphasis on MPNST and melanocytic tumors.
Loss-of-function mutations in EED and SUZ12, core components of the polycomb repressive complex 2 (PRC2), occur in >90% of sporadic and radiation-associated malignant peripheral nerve sheath tumors (MPNST) and in roughly 70% of NF1-related tumors. PRC2 inactivation results in loss of H3K27me3 expression and aberrant downstream transcription. H3K27me3 expression is lost in 40-90% of spindle cell MPNST but is not specific. A single study has suggested that dimethylated H3K27 (H3K27me2) is a more specific marker of MPNST. We compared the expression of H3K27me3 and H3K27me2 by immunohistochemistry in a series of MPNST (n = 26), neurofibroma (n = 11), conventional dermatofibrosarcoma protuberans (n = 8), fibrosarcomatous dermatofibrosarcoma protuberans (n = 7), spindle cell rhabdomyosarcoma (n = 6), high-risk solitary fibrous tumor (n = 9), dedifferentiated chondrosarcoma (n = 7), synovial sarcoma (n = 9), diffuse midline glioma, H3K27-altered (n = 13), conventional diffuse astrocytoma (n = 2), conventional cutaneous melanoma (n = 8), uveal melanoma (n = 8), cellular blue nevus (n = 17) and melanoma arising in blue nevus (n = 6). H3K27me3 and H3K27me2 expression patterns were concordant in 115/137 (84%) with 85 cases (62%) expressing both markers and 30 cases (22%) showing loss of both. Discordant results were seen in 22 cases (H3K27me3 loss with retained H3K27me2, 10 cases (7%); H3K27me3 expression with H3K27me2 loss, 12 cases (9%)). H3K27me2 loss was not specific for MPNST and was also seen in certain other tumors, in particular those in the "blue nevus family". We conclude that H3K27me2 loss is not specific for MPNST, and like H3K27me3, should be used in the appropriate clinicopathologic, immunohistochemical and molecular genetic context. Loss of H3K27me2 with retained H3K27me3 is a common feature of "blue nevus family" melanocytic tumors known to harbor GNAQ/GNA11 mutations.


Treatment of Febrile illness with artemisinin combination therapy: prevalence and predictors in five African household surveys.
To evaluate the determinants of compliance with national policies recommending Artemisinin Combination Therapy (ACT) for the treatment of uncomplicated malaria in the community. We used data from Gambia, Ghana, Kenya, Nigeria, and Uganda national household surveys that were conducted with a standardized World Health Organization (WHO) methodology to measure access to and use of medicines. We analyzed all episodes of acute fever reported in the five surveys. We used logistic regression models accounting for the clustered design of the surveys to identify determinants of seeking care in public healthcare facilities, of being treated with antimalarials, and of receiving ACT. Overall, 92% of individuals with a febrile episode sought care outside the home, 96% received medicines, 67% were treated with antimalarials, and 16% received ACT. The choice of provider was influenced by perceptions about medicines availability and affordability. In addition, seeking care in a public healthcare facility was the single most important predictor of treatment with ACT [odds ratio (OR): 4.64, 95% confidence intervals (CI): 2.98-7.22, P < 0.001]. Children under 5 years old were more likely than adults to be treated with antimalarials [OR: 1.28, CI: 0.91-1.79, not significant (NS)] but less likely to receive ACT (OR: 0.80, CI: 0.57-1.13, NS). Our results confirm the high prevalence of presumptive antimalarial treatment for acute fever, especially in public healthcare facilities where poor people seek care. They show that perceptions about access to medicines shape behaviors by directing patients and caregivers to sources of care where they believe medicines are accessible. The success of national policies recommending ACT for the treatment of uncomplicated malaria depends not only on restricting ACT to confirmed malaria cases, but also on ensuring that ACT is available and affordable for those who need it.


Fused-Ring Acceptors with Asymmetric Side Chains for High-Performance Thick-Film Organic Solar Cells.
A kind of new fused-ring electron acceptor, IDT-OB, bearing asymmetric side chains, is synthesized for high-efficiency thick-film organic solar cells. The introduction of asymmetric side chains can increase the solubility of acceptor molecules, enable the acceptor molecules to pack closely in a dislocated way, and form favorable phase separation when blended with PBDB-T. As expected, PBDB-T:IDT-OB-based devices exhibit high and balanced hole and electron mobility and give a high power conversion efficiency (PCE) of 10.12%. More importantly, the IDT-OB-based devices are not very sensitive to the film thickness, a PCE of 9.17% can still be obtained even the thickness of active layer is up to 210 nm.


Penile Autophotography Underestimates the Degree of Penile Curvature in Peyronie's Disease.
Penile curvature is the most debilitating symptom of Peyronie's disease (PD); the evaluation of the degree of angulation is essential for planning treatment strategy. However, the most used method of penile at-home autophotography (AHP) is associated with some potential pitfalls and discrepancies compared with different assessment methods. To compare the degree of penile curvature quantified by AHP and in-office intracavernosal alprostadil injection (ICI) prior to therapy. Data from 55 PD patients of a single tertiary referral center were analyzed. All patients provided standardized AHP of the erect phallus. Clinic-based assessment included ICI with curvature measurement and completion of the International Index of Erectile Function (IIEF-15). The Wilcoxon and/or chi-square test was used to compare the degree of curvature obtained using AHP and ICI, and to evaluate whether erectile dysfunction was a predictor of a relevant difference of >10° in curvature assessment between AHP and ICI. Our study showed a significant (p < 0.001) difference in the degree of penile curvature between AHP (48° [38°; 55°]) and ICI (50° [40°; 65°]). Patients suffering from erectile dysfunction tend to have a higher difference in the degree of penile curvature between AHP and ICI than patients with good erectile function (p < 0.001). Our study is not devoid of limitations. First, we did not use Peyronie's Disease Questionnaire, as suggested by the European Association of Urology guidelines. Second, we did not evaluate inter- and intraobserver variations in the measurements. AHP tends to underestimate the extent of penile curvature compared to ICI. Erectile dysfunction is an independent predictor of measurement differences of >10° between AHP and ICI. It is necessary to evaluate the degree of penile curvature in Peyronie's disease prior to therapy decision. The at-home self-photography underestimates the real degree of penile curvature compared with an erection by in-office penile drug injection. Especially men suffering from erectile dysfunction carry the risk of a high difference in the measured degree of penile curvature, with a potential impact on the further treatment.


Investigation of Hot Spot Region in XIAP Inhibitor Binding Site by Fragment Molecular Orbital Method.
X-linked inhibitor of apoptosis protein (XIAP) is an important regulator of cancer cell survival whose BIR3 domain (XIAP-BIR3) recognizes the Smac N-terminal tetrapeptide sequence (AVPI), making it an attractive protein-protein interaction (PPI) target for cancer therapies. We used the fragment molecular orbital (FMO) method to study the binding modes and affinities between XIAP-BIR3 and a series of its inhibitors (1-8) that mimic the AVPI binding motif; the inhibitors had common interactions with key residues in a hot spot region of XIAP-BIR3 (P1-P4 subpockets) with increased binding affinity mainly attributed to specific interactions with the P1 and P4 subpockets. Based on the structural information from FMO results, we proposed a novel XIAP natural product inhibitor, neoeriocitrin 10, which was derived from our preciously reported XIAP-BIR3 inhibitor 9, can be used as a highly potent candidate for XIAP-BIR3 inhibition. We also performed pair interaction energy decomposition analysis to investigate the binding energies between specific binding residues and individual ligands, showing that the novel natural product neoeriocitrin 10 had a higher binding affinity than epicatechin gallate 9. Molecular docking and dynamics simulations were performed to explore the mode of binding between 10 and XIAP-BIR3, demonstrating that 10 binds more strongly to the P1 and P4 pockets than 9. Overall, we present a novel natural product, neoeriocitrin 10, and demonstrate that the FMO method can be used to identify hot spots in PPIs and design new compounds for XIAP inhibition.


Biventricular thrombi in dilated cardiomyopathy in a patient with human immunodeficiency virus infection: a case report.
Sub-Saharan Africa is undergoing epidemiological transition with an increase in the prevalence of cardiovascular diseases that will add to the already devastating burden of infectious diseases such as human immunodeficiency virus infection. Human immunodeficiency virus infection is increasingly being recognized as an important etiological factor for dilated cardiomyopathy with the potential complication of intraventricular thrombus. However, biventricular thrombi are extremely rare. We report on a rare finding of biventricular thrombi in dilated cardiomyopathy in a patient with human immunodeficiency virus infection in Cameroon. A 52-year old Cameroonian male patient with human immunodeficiency virus infection since 4 years, longstanding heavy alcohol consumption and cigarette smoking presented with gradually worsening shortness of breath, fatigue, persistent dry cough and lower extremity swelling of about two weeks duration. Congestive heart failure was diagnosed. Echocardiography showed left ventricular chamber enlargement with severe left ventricular systolic dysfunction and biventricular thrombi. The thrombi were immobile and regular in configuration, suggesting they were old. He was treated with a conventional heart failure treatment including loop diuretics and angiotensin converting enzyme inhibitors and anticoagulants for the biventricular thrombi. Six months later, a control echocardiography showed a significant decrease in the size of the thrombi. There was no evidence of systemic or pulmonary embolization during follow up. Dilated cardiomyopathy may be seen in patients with human immunodeficiency virus infection, although other mechanisms needs to be assessed, but the occurrence of biventricular thrombi is rare.


Diagnosis of Carpal Tunnel Syndrome using Shear Wave Elastography and High-frequency Ultrasound Imaging.
The performance of ultrasound features from shear wave elastography (SWE) and high-frequency ultrasound imaging was evaluated independently and in combination to diagnose carpal tunnel syndrome (CTS). Twenty-five subjects were imaged in a sitting position with an arm extended and palm facing up. SWE of the medial nerve (MN) was acquired at the wrist level (site 1) and proximal to the pronator quadratus muscle (site 2). Cross-sectional area (CSA) and vascularity of the MN were assessed at the wrist using a 24 MHz probe. Color and power Doppler imaging (CDI and PDI), monochrome and color-coded Superb Microvascular Imaging (SMI) were performed for vascularity assessments. The diagnosis and severity of CTS was determined by clinical and electrodiagnostic tests. Diagnostic performance of the ultrasound features was assessed by t-tests, ANOVAs, and ROC analysis. The study included 20 control hands and 27 hands with CTS. All ultrasound features except for the stiffness ratio were significantly different between the CTS and control wrists (p<0.04). The stiffness of MN at site 1 showed a higher accuracy than at site 2. The combination of CSA and MN stiffness from site 2 showed an overall accuracy of 95% with a specificity and sensitivity of 100% and 93%, respectively. The CSA, MN stiffness from site 2, and CDI combination improved the accuracy to 96% with specificity and sensitivity of 100% and 93%, respectively. However, no ultrasound features (independently or in combination) differentiated all stages of CTS severity. SWE with high-frequency ultrasound imaging showed potential for the diagnosis of CTS.


Timing of seed germination and the reproductive effort in Xanthium canadense.
The effect of different dates of germination on the timing of flowering and the final reproductive yield was examined in a short-day annual plant Xanthium canadense (cocklebur). Delays in germination of 30 and 60 days deferred flower initiation by 2 and 9 days, respectively. Although plants that germinated later were smaller because of the shorter growing period, the reproductive yields did not show as much reduction as the vegetative biomass. The reproductive effort (RE, defined as the ratio of final reproductive yield to the vegetative biomass at the end of the growing season) increased 1.5 and 2.5 times with delays in germination of 30 and 60 days, respectively. A simple model of plant growth was used to analyse the factors involved in the control of RE, which depends only on the dry mass productivity and its partitioning in the reproductive phase, and is independent of the productivity and partitioning in the vegetative phase. Since relative allocation of dry mass to the reproductive part in the reproductive phase was similar for plants with different germination dates, the different REs could be ascribed mainly to differences in productivity of the vegetative parts in the reproductive period. The dependence of RE on plant size is discussed.


The aging of the retina.
This mini-review summarizes our current knowledge concerning the age-related changes that affect the retina. Over the last 10 years, our understanding of the genetics of hereditary retinal diseases has improved considerably. However, the modifications that occur in the retina as a result of aging are still under investigation. In this review, we place particular emphasis on the normal retinal alterations that occur with aging (gene modulation; psychophysical, structural and cellular alterations). We describe the events that occur during the pathological aging process, such as in age-related macular degeneration. Understanding these different modifications is essential if we are to find key players on which to base therapeutic interventions that may help to prevent the passage of normal aging process to the pathological aging process.


[3H]thymidine-labeled colonic epithelial cells and mucosa in mice and man.
Since normal epithelial cell proliferation occurs chiefly in the lower two thirds of colonic crypts, the presence of aberrant DNA-synthesizing cells (tritiated thymidine labeled) at the mouth and on the surface of colonic crypts is being assessed as a predictive indicator of the development of neoplasia in patients at high risk. These would include patients with previous polyps or colon cancer or family history of either or both. Surface cells are obtained by pulsatile saline lavage of the lower bowel and incubated with tritiated thymidine ([3H]TdR) for autoradiographic observation. Findings in each high-risk category are presented and compared with [3H]TdR labeling data from a biopsy taken at the close of the procedure. The lavage technique has also been carried out on mice injected with the colon carcinogen 1,2-dimethylhydrazine (DMH). Mice were demonstrated to have [3H]TdR-labeled cells and cellular atypic while being hemoccult negative and asymptomatic for overt disease. Evaluation of human material preliminarily demonstrated the presence of surface-labeled epithelial cells in a high percentage of patients at risk for colon cancer.


AKAP79 increases the functional expression of skeletal muscle Ca2+ channels in Xenopus oocytes.
The actions of the kinase A anchoring protein, AKAP79, a key element in the regulation of the cardiac L-type Ca2+ channel, were assessed on skeletal muscle Ca2+ channels expressed in Xenopus oocytes. The channels were reconstituted by expressing the pore forming alpha1s subunit and its accessory subunits, alpha2-delta, beta, and gamma. We report, for the first time, that peak Ca2+ channel currents are greatly increased (3.5-fold) by AKAP79 when co-expressed with the truncated form of the alpha1s subunit. Immunoblots revealed that the increase in current amplitude is not accompanied by a corresponding increase in the membrane levels of the alpha1s subunit. This suggests that AKAP79 does not increase the trafficking of the channel. In addition, we show that the transcript of AKAP150, the rat ortholog of the human AKAP79, is expressed in rat skeletal muscle and propose that AKAP79/150 modulates Ca2+ channel function.


Surface-enhanced Raman spectroscopy with monolithic nanoporous gold disk substrates.
Monolithic hierarchical nanoporous gold disks, 500 nm in diameter, 75 nm in thickness and 3.5 nm in pore radius, have been fabricated by hybrid processes. A surface-enhanced Raman scattering enhancement factor of at least 10(8) has been obtained on individual disks using benzenethiol self-assembled monolayer with 785 nm laser excitation.


Ventricular fibrillation arrest after blunt chest trauma in a 33-year-old man, commotio cordis?
Commotio cordis is an event in which a blunt, non-penetrating blow to the chest occurs, triggering a life-threatening arrhythmia and often sudden death. This phenomenon is often seen in young, male athletes and has become increasingly well-known over the past few decades. We present a unique case in which ventricular fibrillation occurs in an older male athlete after blunt trauma. Patient with no known medical history was brought to the ER after being found unconscious after a soccer ball kick to the chest. He was found to be in ventricular fibrillation and successfully resuscitated on the soccer field. Patient was admitted to the hospital and lab workup and initial imaging were unremarkable, except elevated troponin and lactate, which returned to normal levels. An echocardiogram showed global left ventricular systolic dysfunction with a visually estimated ejection fraction of 45-50%. Coronary showed angiographically nonobstructive coronary arteries. The patient was diagnosed with commotio cordis and discharged from the hospital in stable condition. Follow-up echocardiogram continued to show low ejection fraction and event monitor demonstrated frequent polymorphic ventricular tachycardia with periods of asystole. This case is unique in that blunt trauma to the chest from a soccer ball immediately triggered ventricular fibrillation in a patient with a possible cardiomyopathy. It is possible that the blunt trauma caused primary commotio cordis that led to cardiomyopathy in a previous healthy man, or that an underlying cardiomyopathy made it more likely for this to occur. Overall, increased awareness and prevention efforts of blunt chest trauma are required to reduce the high mortality associated life-threatening arrhythmias. There is limited data regarding the interplay between these two entities.


Plasma catecholamine concentrations and hemodynamic responses to vasoconstrictor during conventional or Gow-Gates mandibular anesthesia.
The literature supports that systemic responses to injected vasoconstrictors depend on the volume and concentration administered, patient's age and health status, as well as site of injection. Thus, the influence of mandibular anesthesia technique on hemodynamic and plasma responses to epinephrine-containing local anesthetics was investigated. Conventional or Gow-Gates anesthesia with 2% lidocaine and epinephrine, 1:100,000, was performed in 18 subjects who required third molar extraction. A control group of 9 subjects was submitted to conventional anesthesia with plain 3% mepivacaine. Blood pressure, heart rate, and plasma catecholamines were measured. Analysis of variance showed that plasma epinephrine level after conventional lidocaine anesthesia was significantly elevated (P < .01), while there was no difference between the Gow-Gates and control groups. The hemodynamic parameters did not demonstrate correlation to the injection technique. Presumably, there was less exogenous epinephrine absorption in the Gow-Gates technique than in the conventional mandibular anesthesia injection.


First bioelectronic immunoplatform for quantitative secretomic analysis of total and metastasis-driven glycosylated haptoglobin.
The glycosylation status of proteins is increasingly used as biomarker to improve the reliability in the diagnosis and prognosis of diseases as relevant as cancer. This feeds the need for tools that allow its simple and reliable analysis and are compatible with applicability in the clinic. With this objective in mind, this work reports the first bioelectronic immunoplatforms described to date for the determination of glycosylated haptoglobin (Hp) and the simultaneous determination of total and glycosylated Hp. The bioelectronic immunoplatform is based on the implementation of non-competitive bioassays using two different antibodies or an antibody and a lectin on the surface of commercial magnetic microcarriers. The resulting bioconjugates are labeled with the horseradish peroxidase (HRP) enzyme, and after their magnetic capture on disposable electroplatforms, the amperometric transduction using the H2O2/hydroquinone (HQ) system allows the single or multiple detection. The developed immunoplatform achieves limits of detection (LODs) of 0.07 and 0.46 ng mL-1 for total and glycosylated Hp in buffer solution, respectively. The immunoplatform allows accurate determination using simple and relatively short protocols (approx. 75 min) of total and glycosylated Hp in the secretomes of in vitro-cultured colorectal cancer (CRC) cells with different metastatic potentials, which is not feasible, due to lack of sensitivity, by means of some commercial ELISA kits and Western blot methodology.


Popliteal artery perforation during low dose intra-arterial streptokinase infusion.
There has been a recent increase in the use of low dose intra-arterial streptokinase infusion for the management of patients with acute peripheral arterial occlusions. Though serious complications using this technique occur less frequently than when using systemic thrombolytic therapy, a case is reported where the catheter used to infuse streptokinase perforated the popliteal artery 36 hours after the infusion commenced. The use of softer arterial catheters and restriction of patient movement where possible may prevent the recurrence of this previously unreported hazard.


[cDNA microarray to identify the significance of DNA replication and damage repair genes associated with benzene poisoning].
To screen DNA replication, and damage repair genes associated with benzene poisoning by using gene expression profile analysis. Leucocytes in peripheral blood of seven patients and seven normal controls were collected and total RNA was extracted. The cDNA probes were prepared by labeling cell RNA with Cy3-dUTP and Cy5-dUTP with reverse transcription. The arrays with 141 genes were hybridized against the cDNA probe mixture, and the fluorescent signals were scanned. Twenty five differentially expressed genes were screened out. Among these genes, 16 genes were up-regulated and 9 down-regulated. They were DNA replication genes such as PRIM2A, ORC1L etc; DNA synthesis, recombination and repair genes such as POLK etc; DNA damage signaling/repair proteins and DNA ligases such as RECQL, PRKDC, G22P1, ERCC3, ERCC1, CRY1, CHES1, BRCA2, APEX etc; proteins involved in recombination such as RECQL; and other DNA synthesis, recombination, and repair proteins such as SKIV2L, RBMS1, SON, SET. Some DNA replication, and damage repair genes associated with benzene poisoning show differential expression, which provides the basis for screening biomarkers of benzene poisoning.


Activity of pemetrexed in pre-clinical chordoma models and humans.
Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no effective standard medical therapy exists. Thymidylate synthase (TS), an intracellular enzyme, is a key rate-limiting enzyme of DNA biosynthesis and repair which is primarily active in proliferating and metabolically active cells. Eighty-four percent of chordoma samples had loss of TS expression which may predict response to anti-folates. Pemetrexed suppresses tumor growth by inhibiting enzymes involved in folate metabolism, resulting in decreased availability of thymidine which is necessary for DNA synthesis. Pemetrexed inhibited growth in a preclinical mouse xenograft model of human chordoma. We report three cases of metastatic chordoma that had been heavily treated previously with a variety of standard therapies with poor response. In two cases, pemetrexed was added and objective responses were observed on imaging with one patient on continuous treatment for > 2 years with continued shrinkage. One case demonstrated tumor growth after treatment with pemetrexed. The two cases which had a favorable response had a loss of TS expression, whereas the one case with progressive disease had TS present. These results demonstrate the activity of pemetrexed in recurrent chordoma and warrant a prospective clinical trial which is ongoing (NCT03955042).


The productivity assessment tool: computer-based cost benefit analysis model for the economic assessment of occupational health and safety interventions in the workplace.
This paper describes the concepts behind cost benefit analysis in occupational health and safety and introduces the Productivity Assessment Tool, a method by which an analysis may be performed relatively easily in a service or manufacturing workplace. The advantage of using such analyses is to show the important financial role that safe and efficient workplaces play in the workplace. By using analytical tools, the effectiveness of an intervention (workplace change) may be estimated prior to its introduction. This places occupational health and safety on the same financial footing as other proposed workplace changes and thus places occupational health and safety in a strong position to attract scarce resources.


A rare 47 XXY/46 XX mosaicism with clinical features of Klinefelter syndrome.
47 XXY/46 XX mosaicism with characteristics suggesting Klinefelter syndrome is very rare and at present, only seven cases have been reported in the literature. We report an Indian boy diagnosed as variant of Klinefelter syndrome with 47 XXY/46 XX mosaicism at age 12 years. He was noted to have right cryptorchidism and chordae at birth, but did not have surgery for these until age 3 years. During surgery, the right gonad was atrophic and removed. Histology revealed atrophic ovarian tissue. Pelvic ultrasound showed no Mullerian structures. There was however no clinical follow up and he was raised as a boy. At 12 years old he was re-evaluated because of parental concern about his 'female' body habitus. He was slightly overweight, had eunuchoid body habitus with mild gynaecomastia. The right scrotal sac was empty and a 2mls testis was present in the left scrotum. Penile length was 5.2 cm and width 2.0 cm. There was absent pubic or axillary hair. Pronation and supination of his upper limbs were reduced and x-ray of both elbow joints revealed bilateral radioulnar synostosis. The baseline laboratory data were LH < 0.1 mIU/ml, FSH 1.4 mIU/ml, testosterone 0.6 nmol/L with raised estradiol, 96 pmol/L. HCG stimulation test showed poor Leydig cell response. The karyotype based on 76 cells was 47 XXY[9]/46 XX[67] with SRY positive. Laparoscopic examination revealed no Mullerian structures. Insisting on an adequate number of cells (at least 50) to be examined during karyotyping is important so as not to miss diagnosing mosaicism.


Metabolomics and the Microbiome as Biomarkers in Sepsis.
Metabolomics is an emerging field of research interest in sepsis. Metabolomics provides new ways of exploring the diagnosis, mechanism, and prognosis of sepsis. Advancements in technologies have enabled significant improvements in identifying novel biomarkers associated with the disease progress of sepsis. The use of metabolomics in the critically ill may provide new approaches to enable precision medicine. Furthermore, the dynamic interactions of the host and its microbiome can lead to further progression of sepsis. Understanding these interactions and the changes in the host's genomics and the microbiome can provide novel preventive and therapeutic strategies against sepsis.


Effects of salinity acclimation and eyestalk ablation on Na(+), K(+), 2Cl(-) cotransporter gene expression in the gill of Portunus trituberculatus:a molecular correlate for salt-tolerant trait.
The Na(+), K(+), 2Cl(-) cotransporter (NKCC) is an important gene in ion transport. In order to elucidate its function, and regulatory mechanisms, in salinity acclimation, the complete cDNA sequence of NKCC (4218 bp) from Portunus trituberculatus (PtNKCC) was first cloned and characterized. It was found to encode 1055 amino acids containing conserved AA-permease and SLC12 motifs. Results show that PtNKCC is expressed to the greatest extent in gills. High salinity stress exposure led to significant increases (9.6-fold) of PtNKCC mRNA expression in the gills 12 h after treatment, declining to less than the levels seen in the control group between 48 and 72 h. During low salinity stress, expression levels of PtNKCC in gills were found to be upregulated at each sampling time, reaching their peak after 6 h (a 12.4-fold increase). Eyestalk ablation also triggered an 11.3-fold increase in PtNKCC mRNA, while re-injection with eyestalk homogenates significantly reduced the expression of PtNKCC mRNA. Four single nucleotide polymorphisms (SNPs) were detected in the PtNKCC open reading frame, and one SNP was associated with salt tolerance. Our results indicate that PtNKCC plays an important role in the salinity acclimation of P. trituberculatus, while there may be a compound present in the XOSG that inhibits the expression of PtNKCC.


Peritoneal drainage under local anesthesia for perforations from necrotizing enterocolitis.
During 1974 and 1975, five newborn infants weighing between 760 and 1600 g developed severe intraabdominal complications of NEC due to necrotic bowel with perforation and peritonitis. Because these tiny neonates were very ill with sepsis and other severe medical problems, no attempt at laparotomy under general anesthesia was carried out. Instead, using local anesthesia, the contaminated peritoneal cavity was drained via a small incision, usually in the right lower quadrant. This permitted evacuation of air, pus, and stool. In all babies there was improvement evident in the abdomen within one wk, although two of the five newborns died from other causes. The three survivors are well and have normally functioning intestinal tracts 1-2 yr following surgery. One of these surviving babies developed a bowel stricture which subsequently required resection. We feel this method is preferable in the handling of the tiny sick neonate with a bowel perforation from NEC.


Variations in the compartmental location of the superficial fibular nerve: a cadaveric study with meta-analysis.
To investigate variations in the course of the superficial fibular nerve (SFN) and its branches-the medial dorsal cutaneous nerve (MDCN) and intermediate dorsal cutaneous nerve (IDCN)-concerning the leg compartments by means of a meta-analysis supplemented with an original anatomical study. A literature survey was conducted in the PubMed, Scopus, Web of Science, and Lilacs databases on October 14th, 2021, to obtain anatomical data, and the PRISMA statement was adopted as a methodological guideline. We used MetaXL software for data analysis. We classified the anatomical data into three location patterns: in Type 1, the SFN courses through the lateral compartment; in Type 2, the SFN courses through the anterior compartment; in Type 3, the MDCN courses through the anterior compartment and the IDCN courses in the lateral compartment. Twelve studies (n = 837 lower limbs) comprised the current review. The SFN location was normal (Type 1 variation) in 77% (95% CI 72.9-78.9) of the cases, while Type 2 had a pooled prevalence of 14.3% (95% CI 11.1-15.9). Type 3 was the less common course, with a prevalence of 8.7% (95% CI 5.9-9.7). We found differences among the geographical subgroups analyzed. The SFN courses through the lateral compartment of the leg most times, and the prevalence of this pattern varies significantly between the different geographical subgroups evaluated. These results are of great clinical and surgical relevance.


Psychopharmacological Effects of Alkaloid Z77 under Conditions of Posthypoxic Encephalopathy and Mechanisms of Their Development.
Psychopharmacological effects of atisine-type diterpene alkaloid Z77 were studied under conditions of experimental posthypoxic encephalopathy. The preparation had a pronounced cerebroprotective effect consisting in normalization of orientation and exploratory behavior and conditioned activity in experimental animals. These changes were accompanied by significant increase in the number of neural stem cells in the paraventricular region of the brain and markedly enhanced production of neurotrophic growth factors by neural tissue microenvironment cells.


Psychological and other mechanisms for end-of-day soft lens symptoms.
To examine psychological factors and other mechanisms for soft contact lens (CL)-related end-of-day symptoms of dryness and associated dropping out from lens wear. A PubMed search for articles related to dryness, comfort, and discomfort in CLs was conducted. Comparisons with rigid lens adaptation have been used to construct and examine a hypothesis that high levels of initial soft lens comfort increase expectations of an absence of lens awareness that result in end-of-day symptoms being more difficult to tolerate. Relevant reports were referenced in this review having been located using the 143 listed by PubMed. Contact lens-induced corneal hypoalgesia and the association between the influence on blink function of end-of-day general and ocular fatigue, lens front surface degradation, a dysfunctional pre-lens tear layer, and symptoms of dryness suggest that lid wiper friction has a prime role in determining the level of lens awareness. Rather than dry eye symptoms, end-of-day discomfort in CL wearers might be more appropriately described as dry lens symptoms. Apart from tear function, lens condition, compliance with lens care instructions, and symptom strength, lens awareness may also be determined by psychological factors such as motivation, high expectations for comfort, and sense of subjective well-being. For example, high levels of comfort experienced on lens insertion may increase expectations of the level of comfort to be experienced at the end of the day. In addition, patient management seems to require a thorough assessment of lens comfort, which may indicate the need to review a patient's understanding of the relation between compliance and other factors, which could influence CL performance negatively. For example, increased use of digital devices, especially in air conditioning, and any associated reduced blink efficiency seem likely to be important contributors to dry lens symptoms.


miR-129-3p alleviates chondrocyte apoptosis in knee joint fracture-induced osteoarthritis through CPEB1.
Osteoarthritis (OA), a refractory disease, is one of the leading contributors for disability worldwide. Since chondrocyte is the only resident cell in cartilage, this study aims to explore the roles of miR-129-3p and CPEB1 in chondrocyte apoptosis in knee joint fracture-induced OA. Cartilage was collected from 20 OA patients who underwent total knee replacement (OA group) and 20 patients with knee contusion (normal group). Then, miR-129-3p and CPEB1 levels in the cartilage were quantified by qRT-PCR. Primary rat chondrocytes in the knee were isolated and identified by toluidine blue staining and immunofluorescent staining of type II collagen. OA cellular models were induced by TNF-α treatment, in which miR-129-3p and CPEB1 expressions were assessed. Subsequently, cell viability, apoptosis, and the expression levels of apoptotic protein and caspase-3 were measured. Dual luciferase reporter assay identified the interaction between miR-129-3p and CPEB1. Patients in the OA group had decreased miR-129-3p expression and increased CPEB1 expression than those in the normal group. TNF-α treatment successfully induced the OA cellular model. Downregulated miR-129-3p and upregulated CPEB1 expressions were found in OA-treated chondrocytes. miR-129-3p overexpression or CPEB1 knockdown improved chondrocyte viability and attenuated apoptosis, and vice versa. miR-129-3p negatively regulated CPEB1, thus ameliorating apoptosis and enhancing cell viability. miR-129-3p negatively targeted CPEB1 to facilitate chondrocyte viability and hamper apoptosis.


The proximal and distal click syndrome of the superior oblique tendon.
In the following case report we describe a healthy 25-year-old woman suffering from the "click" syndrome with pseudoparesis of the superior oblique muscle and a concomitant inflammatory ocular disorder. No etiology of the chorioretinitic changes or click syndrome could be ascertained. Based on the different topographic conditions present, we suggest the introduction of two new subgroups involving a proximal and a distal click syndrome.


An autonomous mobile system for the management of COPD.
Managing chronic disease through automated systems has the potential to both benefit the patient and reduce health-care costs. We have developed and evaluated a disease management system for patients with chronic obstructive pulmonary disease (COPD). Its aim is to predict and detect exacerbations and, through this, help patients self-manage their disease to prevent hospitalisation. The carefully crafted intelligent system consists of a mobile device that is able to collect case-specific, subjective and objective, physiological data, and to alert the patient by a patient-specific interpretation of the data by means of probabilistic reasoning. Collected data are also sent to a central server for inspection by health-care professionals. We evaluated the probabilistic model using cross-validation and ROC analyses on data from an earlier study and by an independent data set. Furthermore a pilot with actual COPD patients has been conducted to test technical feasibility and to obtain user feedback. Model evaluation results show that we can reliably detect exacerbations. Pilot study results suggest that an intervention based on this system could be successful.


Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation.
Lamivudine has become a main therapeutic option for treating hepatitis B virus (HBV) infection. Although drug resistance develops, the clinical course after selection of antiviral-resistant HBV mutants seems to be benign. However, we observed a severe clinical course of hepatitis B infection in several liver transplant recipients after the emergence of lamivudine resistance. This was associated with high viral load in the blood. In this report, we characterize the molecular mechanisms underlying drug-dependent enhanced replication of particular lamivudine-resistant HBV mutants selected in these patients, which were associated with sudden onset of liver failure. The clinical course was characterized by a sudden rise in serum bilirubin, prothrombin time, and transaminase. HBV sequence analysis of these patients revealed both mutations in the "a-determinant" of the envelope and the YMDD (tyrosine, methionine, aspartate, aspartate) motif (domain C) of the polymerase protein. Transfection experiments with replication competent vectors indicated that the "a-determinant" changes were not associated with resistance, whereas mutations in the YMDD motif conferred resistance to lamivudine. More importantly, combinations of mutations in the "a-determinant" and the YMDD motif in patients with a severe hepatitis were not only resistant to lamivudine treatment, but showed enhanced replication in vitro in the presence of lamivudine. This observation was confirmed in separate laboratories. Severe and fatal hepatitis B infection can occur during lamivudine therapy and may be associated with certain HBV mutants selected during sequential nucleoside and HBIg treatment. The lamivudine-enhanced replication shown by these mutants suggests that continuation of therapy with lamivudine could be deleterious in some patients.


A Retrospective Analysis of 10 Years of Liver Surveillance Undertaken in Uveal Melanoma Patients Treated at the Supraregional "Liverpool Ocular Oncology Centre", UK.
To determine liver screening frequency and modality in UM patients following primary treatment, and the characteristics of detected metastases. A 10-year retrospective study of 615 UM patients undergoing liver surveillance in Liverpool. Information was collected from liver scan reports of these patients. Of 615 UM patients analyzed, there were 337 men (55%) and 278 women (45%). Median age at primary treatment was 61 years (range, 22-94). At study end, median follow-up was 5.1 years, with 375 patients (61%) alive and 240 deceased (39%). Of the deceased patients, 187 (78%) died due to metastatic UM; 24 (10%) deaths were due to other causes; and 29 (12%) patients died of unknown conditions. In total, 3854 liver scans were performed in the 615 UM patients, with a median of 6.2 scans per patient (range, 1-40). Liver MRI was most frequently performed (62.8%). In total, 229 (37%) UM patients developed metastases during the study period: 150 were detected via liver surveillance and 79 were observed post-mortem. Metastatic UM onset is related to the size and genetic profiles of the primary UM, and can be predicted using the model LUMPO3. Regular liver surveillance allowed for timely detection of metastases, and through metastasectomy can lead to prolongation of life in some patients.


The contribution of primary and secondary neuronal degeneration to prenatally-induced micrencephaly.
Prenatal exposure of rats to the alkylating agent methylazoxymethanol acetate (MAM Ac) induces severe micrencephaly in the offspring. The aim of the present study was to examine the contribution of primary cell death (due to a direct action of MAM Ac on the neuroepithelium), and secondary (target-dependent) cell death to the subsequent cell deficits in the visual system following prenatal exposure to MAM Ac on embryonic day 11, 12, 13, 14, 15 or 16. The results showed that when primary cell death substantially reduced the neuronal population of a target structure then there was increased target-dependent cell death in the neurons which normally project to that target. This was particularly evident in the dorsal lateral geniculate nucleus following exposure to MAM Ac on E15. Although the MAM Ac caused virtually no primary cell death in the embryonic precursor cells of the dLGN, the nucleus in the adult offspring was reduced by 87% compared with controls. This reduction was shown to be due to increased postnatal target-dependent, or secondary, cell death due to a severe reduction in layers III and IV of the occipital cortex. The cortical damage was due to primary cell death. Hence, primary cell death only partly accounts for the degree of micrencephaly seen in the offspring, consideration of secondary cell death is necessary to understand the total deficit.


Inhibition of transition metal ion-catalysed ascorbate oxidation and lipid peroxidation by allopurinol and oxypurinol.
Allopurinol and its metabolite oxypurinol inhibited basal oxidation of ascorbate and exerted comparable concentration-dependent inhibitory effects on the oxidation of ascorbate catalysed by cupric ion, but the stimulation produced by ferric ion was affected minimally. UV spectral analysis suggested the formation of an allopurinol-ascorbate-copper ion complex. The oxidation of erythrocyte membrane lipids by ferric ion and cupric ion-t-butylhydroperoxide was also inhibited by allopurinol and oxypurinol, by the metal chelators EDTA and uric acid, and by the antioxidant butylated hydroxytoluene. The metal chelating actions of allopurinol and oxypurinol may be relevant to their protective actions against ischemia/reperfusion injury.


[Characteristics of the abstinence syndrome induced by the administration of the benzodiazepine antagonist CGS 8216 to rats following chronic treatment with diazepam].
Male rats were treated with 5 and 10 mg/kg diazepam once daily for 5-30 days. After the drug discontinuation a benzodiazepine receptor antagonist CGS 8216 (2.5-10 mg/kg) induced a behavioural syndrome that might be characterized as an abstinence syndrome. The most typical signs of abstinence were head twitches, myoclonic seizures of forepaws, emotional hyperirritability, increased muscle tone of the tail, sniffing and chewing. These behavioural changes could be observed within 1-1.5 hours after CGS 8216 injection. The abstinence syndrome was induced by repeated CGS 8216 injections for 10-15 days after diazepam discontinuation. Further analysis has shown that that the intensity of abstinence was dependent on the dose and duration of chronic diazepam, as well as on CGS 8216 dose. It is suggested that CGS 8216-induced abstinence syndrome in rats chronically treated with diazepam might be used as a tool for studying the addictive potential of benzodiazepines.


Pericollicular syndromes.
Five cases of pericollicular focal hemorrhages are presented with a description of their effect on vision and consciousness. Loss of vision, loss of consciousness, extraocular muscle dysfunction, mutism, and dyslexia may result from expansive lesions near the collicular plate.


Barriers to Engagement in Opioid Use Disorder Treatment After Buprenorphine Induction.
Expanded access to buprenorphine induction, including via emergency departments, increases the likelihood of treatment engagement for patients with opioid use disorder (OUD). However, longer-term retention among these patients remains a challenge. In this study, we aimed to identify barriers to engaging and retaining patients with OUD in care and additional services that might improve retention. We surveyed counselors at an urban safety net addictions treatment clinic. Twenty-five of 27 (93%) eligible counselors responded. Counselors described patients who were homeless, had no prior treatment history, or lacked health insurance as hardest to retain in treatment. Housing assistance, residential treatment placement, regular access to a phone, and mental health services were thought to be most beneficial for improving retention. Respondents most often reported that screening for services should happen at intake, and almost all respondents agreed that "retention of patients receiving treatment for OUD would improve with a dedicated case manager and/or more coordinated case management services." Engagement in OUD treatment would be improved with interventions to mitigate the significant social and psychiatric comorbidities of addiction. Community- and emergency department-initiated buprenorphine is a promising intervention whose full promise cannot be realized without interventions to improve treatment retention.


Immunohistochemical and ultrastructural observations of desmoplastic trichoepithelioma with a special reference to a morphological comparison with normal apocrine acrosyringeum.
Desmoplastic trichoepithelioma is a benign neoplasm considered to have follicular differentiation. Its sweat gland- or sebaceous-lines of differentiation have been also reported. There have been, however, only a few reports regarding extensive immunohistochemical and ultrastructural investigations of this neoplasm. Histopathological and immunohistochemical studies were performed on three cases of desmoplastic trichoepithelioma, comparing it with normal skin. One of these cases was ultrastructurally investigated. The cord-like basaloid nests were reacted with the anti-cytokeratin (CK)1/5/10/14, -CK5/8, -CK14 and -CK15 antibodies, but not with the anti-CK6 antibody. Similar findings were observed in the outer layers of the normal follicular outer root sheath. Basaloid cell nests in one case, which showed ductal structures in the nests, also expressed CK7, CK8/18 and CK19. These keratins were also detected in the normal sweat glands. In addition, CK8/18 and CK19 were expressed in the basal cells of the outer root sheath. Keratinous cysts had inner reactions with the anti-CK10/11 and -CK6 antibodies, and outer reactions with anti-CK5/8 and -CK14 antibodies. Ultrastructurally, the cells in the cord-like nests were basically immature and basaloid in appearance. A few cells contained Odland bodies, which were also observed in the normal apocrine acrosyringeum. The ductal structure was lined by the cells which bore numerous microvilli in the luminal surface. The cells in desmoplastic trichoepithelioma are suggested to be in close association with the basal cells in the outer root sheath, which can differentiate into various parts of the folliculosebaceous apocrine unit.


Radiometric assay for cytochrome P-450-catalyzed progesterone 16 alpha-hydroxylation and determination of an apparent isotope effect.
In the course of studies on the oxygenation of steroids by purified P-450 cytochromes, particularly rabbit liver microsomal cytochrome P-450 form 3b, a rapid and reliable radiometric assay has been devised for progesterone 16 alpha-hydroxylation. In view of the lack of a commercially available, suitably tritiated substrate, [1,2,6,7,16,17-3H]progesterone was treated with alkali to remove the label from potential hydroxylation sites other than the 16 alpha position. The resulting [1,7,16-3H]progesterone was added to a reconstituted enzyme system containing cytochrome P-450 form 3b, NADPH-cytochrome P-450 reductase, and NADPH, and the rate of 16 alpha-hydroxylation was measured by the formation of 3H2O. This reaction was shown to be linear with respect to time and to the cytochrome P-450 concentration. An apparent tritium isotope effect of 2.1 was observed by comparison of the rates of formation of tritium oxide and 16 alpha-hydroxyprogesterone, and the magnitude of the isotope effect was confirmed by an isotope competition assay in which a mixture of [1,7,16-3H]progesterone and [4-14C]progesterone was employed.


Developmental processes in early adolescence. Relations among chronologic age, pubertal stage, height, weight, and serum levels of gonadotropins, sex steroids, and adrenal androgens.
Cross-sectional data are presented on 108 young adolescents (56 boys, 52 girls), ages 9 to 14 years. The measures were: for all subjects, pubertal stage (Tanner criteria for genital/breast and pubic hair stage); height and weight; serum hormone concentrations for gonadotropins (luteinizing hormone and follicle-stimulating hormone), sex steroids (testosterone, estradiol, and the computed testosterone to estradiol ratio), adrenal androgens (dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione), and testosterone-estradiol binding globulin. In addition, testicular volume for boys and menarchial status for girls are reported. The study goal was to provide interrelations among these measures, based on the same sample, and examine their interchangeability. Results suggest that it would be reasonable to compare research across as well as within studies based on different markers. Multiple regression analysis showed that the strongest hormone correlates of pubertal development were androgen levels (primarily testosterone in boys and primarily dehydroepiandrosterone sulphate and androstenedione in girls). Estradiol level in girls was the strongest correlate only for menarchial status. Level of testosterone-estradiol binding globulin, which was lower at successive pubertal stages for boys and showed no consistent differences for girls, may be a useful measure for studying the developmental processes and gender differences during puberty.