Clinical Significance of Serum COL6A3 in Pancreatic Ductal Adenocarcinoma

Type VI collagen (COL6) forms a microfibrillar network often associated with type I collagen and constitutes a major component of the desmoplastic reaction in pancreatic ductal adenocarcinoma (PDA). We have demonstrated recently that the α3 chain of COL6, COL6A3, is highly expressed in PDA tissue and undergoes tumor-specific alternative splicing. In this study, we investigated the diagnostic value and clinical significance of circulating COL6A3 protein and mRNA in PDA. COL6A3 levels in sera from patients with PDA (n?=?44), benign lesions (n?=?46) and age-matched healthy volunteers (n?=?30) were analyzed by enzyme-linked immunosorbent assays (ELISA). Predictive abilities of COL6A3 were examined using receiver operating characteristic (ROC) curves from logistic regression models for PDA versus normal or benign serum levels. Expression levels were correlated with clinicopathological parameters. Real-time PCR was used to analyze the presence of COL6A3 mRNA containing alternative spliced exons E3, E4, and E6. Circulating COL6A3 protein levels were significantly elevated in PDA patients when compared to healthy sera (p?=?0.0001) and benign lesions (p?=?0.0035). The overall area under the ROC was 0.975. Log(COL6A3) alone provided good discrimination between PDA and benign lesions (area under the curve (AUC)?=?0.817), but combined with CA19-9 provided excellent discrimination (AUC?=?0.904). Interestingly, high COL6A3 serum levels were significantly associated with perineural invasion and cigarette smoking. Combined E3, E4, and E6 serum RNA values provided good sensitivity but low specificity. Our data demonstrate for the first time the potential clinical significance of circulating COL6A3 in the diagnosis of pancreatic malignancy.     

Hemodynamic consequences of endogenous hyperinsulinism in obese rats with lesions of the ventromedial hypothalamus

The rat with ventromedian hypothalamus lesions (VMH) is characterized by massive obesity, hyperinsulinemia, increase in parasympathetic tonus and sympathetic depression. The aim of this study was to examine in this model the hemodynamic changes and the baroreflex response and to compare the data with the evaluation of beta adrenergic sensitivity. In VMH rats and Sham operated rats hemodynamic parameters were followed until 8 weeks after operation. Heart rate (HR) and blood pressure (BP) were monitored each week during 24 hours by a telemetric system, a catheter being implanted in aorta. In VMH, HR was significantly lower by the first week (p = 0.02) and until the last measurement. Systolic BP increased progressively in the two groups but was higher in VMH only at 8 weeks (p = 0.03). Compared with Sham rats, 5 days after operation, the percentage of HR acceleration in response to atropine and isoprenaline was significantly higher in VMH, whereas HR response to sodium nitroprussiate was similar in the two groups. Plasma epinephrine and norepinephrine levels were significantly higher in VMH rats. The density of cardiac beta receptors decreased from 15 days to 3 months after operation, similarly in VMH and Sham rats. The affinity of cardiac beta receptors remained stable during the same period and very similar in VMH and Sham rats. This study suggests that in VMH rats 1. bradycardia results mainly from an increase in parasympathetic tone; 2. the increase in reflex tachycardia described in normal rats after insulin infusion needs a normal activity of the sympathetic nervous system; 3. catecholamine levels may be increased despite sympathetic depression, probably as a result of an increase in adrenomedullary secretion possibly due to endogenous hyperinsulinemia; 4. the lack of hypertension in this model including a massive obesity is likely to result from the proper vasodilatory effect of insulin.     

M-mode echocardiographic observations in active bacterial endocarditis limited to the aortic valve

Analysis of 37 M-mode echocardiograms recorded during the period of active bacterial endocarditis (ABE) involving the aortic valve (AV) in 17 patients disclosed one or more echocardiographic abnormalities involving the aortic valve cusps or their immediate vicinity in 15 (88%), including “shaggy” echoes indicative of vegetations in 12 (71%). Of the 12 patients with echocardiographic evidence of AV vegetation, 11 developed overt congestive heart failure (CHF) and either died or had AV replacement, and seven had clinical events compatible with systemic emboll; of the five patients without echo-demonstrated vegetations, only one had CHF, none had AV replacement, two died, and one had a systemic embolus. In comparison to our previously reported echocardiographic observations in patients with ABE involving either the mitral (29 patients) or tricuspid valve (23 patients), infection involving the AV was far more liable to produce overt CHF and systemic emboll, to necessitate valve replacement, and to cause death during the period of active infection.     

Long-term results after aortic valve replacement in patients with congestive heart failure. Homografts vs prosthetic valves.

OBJECTIVES: The aim of this study was to assess the influence of valve substitute (homograft vs prosthetic valve) on the long-term survival and late valve-related complication rates following aortic valve replacement in patients with aortic valve disease and congestive heart failure. BACKGROUND: The effect of choice of valve substitute on outcome after aortic valve replacement in patients with pre-operative heart failure is unknown. The superior haemodynamic profile of homografts may be of particular benefit. METHODS: We retrospectively analysed pre-operative, operative and follow-up data on 518 adults in functional classes III and IV, who, over the 25 years 1969-1993, had their initial aortic valve replacement at Harefield hospital. Follow-up conducted during 1996 to April 1997 and totalling 4439 patient-years was 96.1% complete. Using multivariate analysis, independent risk factors for different complications and mortality were defined. RESULTS: Overall 5-, 10- and 20-year survival was 80+/-2%, 62+/-2% and 30+/-3%, respectively, with no significant difference between valve types. However, homografts (n=381) independently reduced the rate of serious complications and cardiac death, whereas mechanical valves were an independent adverse risk factor for late mortality. The rates of anticoagulant-related bleeding and thromboembolism were increased by mechanical valves, whereas primary tissue failure was the main complication of homografts. CONCLUSIONS: Long-term outcome of homograft aortic valve replacement in patients with congestive heart failure is acceptable, with a reduced rate of serious complications and cardiac death. Further improvements would be expected if the rate of primary tissue failure could be reduced.     

Intramedullary spinal tuberculoma

Spinal intradural intramedullary tuberculoma is extremely rare entity of tuberculosis involving the nervous system. Because of its atypical symptomatology, it must be considered in differential diagnosis of spinal cord lesions, especially where prevalence of tuberculosis is high. In this case report this atypical disease is described where good outcome was achieved by surgical excision of the intramedullary lesion followed by antituberculous therapy.     

Hepatitis C prevalence and elimination planning in Pakistan,a bottom-up approach accounting for provincial variation

In Pakistan, substantial changes to hepatitis C virus (HCV) programming and treatment have occurred since the 2008 nationwide serosurvey estimated a 4.8% anti-HCV prevalence. In the absence of an updated national study, this analysis uses provincial data to estimate a national prevalence and the interventions needed to achieve elimination. Using a Delphi process, epidemiologic HCV data for the four provinces of Pakistan (accounting for 97% of the population) were reviewed with 21 subject-matter experts in Pakistan. Province-level estimates were inputted into a mathematical model to estimate the national HCV disease burden in the absence of intervention (Base), and if the World Health Organization (WHO) elimination targets are achieved by 2030 (80% reduction in new infections, 90% diagnosis coverage, 80% treatment coverage, and 65% reduction in mortality: WHO Elimination). An estimated 9,746,000 (7,573,000–10,006,000) Pakistanis were living with viraemic HCV as of January 1, 2021; a viraemic prevalence of 4.3% (3.3–4.4). WHO Elimination would require an annual average of 18.8 million screens, 1.1 million treatments, and 46,700 new infections prevented anually between 2022 and 2030. Elimination would reduce total infections by 7,045,000, save 152,000 lives and prevent 104,000 incident cases of hepatocellular carcinoma from 2015 to 2030. Blood surveys, programmatic data, and expert panel input uncovered more HCV infections and lower treatment numbers in the provinces than estimated using national extrapolations, demonstrating the benefits of a bottom-up approach. Screening and treatment must increase 20 times and 5 times, respectively, to curb the HCV epidemic in Pakistan and achieve elimination by 2030.     

Mitochondrial nicotinamide adenine dinucleotide hydride dehydrogenase (NADH) subunit 4 (MTND4) polymorphisms and their association with male infertility

Journal of Assisted Reproduction and Genetics - The purpose of the present study was to determine the relationship between infertility and the polymorphisms of mitochondrial NADH dehydrogenase...     

Preparation and characterization of polyelectrolyte complex nanoparticles based on poly (malic acid), chitosan. A pH-dependent delivery system

The main objective of this work was to develop polyelectrolyte complex (PEC) nanoparticles based on poly (malic acid), chitosan (PMLA/CS) as pH-dependent delivery systems. The results indicated that the PMLA/CS Nps were successfully prepared. The prepared PMLA/CS Nps showed spherical morphology with a mean diameter of 212.81 nm and negative surface charge of ?24.60 mV, and revealing significant pH-sensitive properties as the mass ratio of PMLA to CS was 5:5. The prepared PMLA/CS Nps were characterized by FT-IR, TEM and DLS. The prepared PMLA/CS Nps remained stable over a temperature range of 4–53 °C. Doxorubicin (Dox) as a model drug was loaded on the nanoparticles through the physical adsorption method. The high drug loading efficiency (16.9%) and the sustained release patterns in acidic media were observed, and the release accelerated in alkaline solutions. MTT based cytotoxic analysis also depicted the non-toxic nature of PMLA/CS Nps, while Dox-PMLA/CS Nps showed dose-dependent cytotoxicity towards MDA-MB-231 cells. Hence, the nanoparticles could be potentially applied as pH sensitive drug vehicles for controlled release.     

Up-regulation of Ras/Raf/ERK1/2 signaling impairs cultured neuronal cell migration, neurogenesis, synapse formation, and dendritic spine development

The Ras/Raf/ERK1/2 signaling pathway controls many cellular responses such as cell proliferation, migration, differentiation, and death. In the nervous system, emerging evidence also points to a death-promoting role for ERK1/2 in both in vitro and in vivo models of neuronal death. Recent studies have suggested that abnormal apoptosis in the central nervous system may be involved in the pathogenesis of autism. Two studies reported that both a microdeletion and microduplication on chromosome 16, which includes the MAPK3 gene that encodes ERK1, are associated with autism. In addition, our recent work showed that Ras/Raf/ERK1/2 signaling activities were significantly up-regulated in the frontal cortex of autistic individuals and in the BTBR murine model of autism. To further investigate how Ras/Raf/ERK1/2 up-regulation may lead to the development of autism, we developed a cellular model of Raf/ERK up-regulation by over-expressing c-Raf in cultured cortical neurons (CNs) and cerebellar granule cells (CGCs). We found that Raf/ERK up-regulation stimulates the migration of both CNs and CGCs, and impairs the formation of excitatory synapses in CNs. In addition, we found that Raf/ERK up-regulation inhibits the development of mature dendritic spines in CNs. Investigating the possible mechanisms through which Raf/ERK up-regulation affects excitatory synapse formation and dendritic spine development, we discovered that Raf/ERK up-regulation suppresses the development and maturation of CNs. Together, these results suggest that the up-regulation of the Raf/ERK signaling pathway may contribute to the pathogenesis of autism through both its impairment of cortical neuron development and causing neural circuit imbalances.