Effect of the 21-aminosteroid, U-74389F, on hyperoxic lung injury in rats.
Hyperoxia (> 95% oxygen) in rats caused an increase in lung weight and an accumulation of fluid in the thorax. The mean lung wet weight of air-breathing controls at 60 h was 1.2 +/- 0.01 g, and that of vehicle-treated, oxygen-exposed animals was 2.45 +/- 0.05 g. Treatment with the 21-aminosteroid U-74389F, 3, 10, and 30 mg/kg twice daily throughout oxygen exposure, produced 8, 42, and 18% inhibition of the oxygen-induced increase in lung weight, respectively. However, U-74389F did not inhibit the hyperoxia-induced accumulation of neutrophils in bronchoalveolar lavage fluid. No pleural fluid could be aspirated from the thorax of air-breathing controls. The volume of pleural fluid in oxygen-exposed, vehicle-treated animals and animals treated with 3, 10, and 30 mg/kg U-74389F b.i.d. was 6.5 +/- 0.9, 2.6 +/- 0.6, 0.8 +/- 0.3, and 1.3 +/- 0.5 ml, respectively. U-74389F or its biologs are of potential value for the treatment of lung diseases in which oxidant damage has been implicated.


Reversal of myocardial injury using genetically modulated human skeletal myoblasts in a rodent cryoinjured heart model.
We hypothesized that combination therapy using human myoblasts and VEGF165 will lead to better prognosis in a failing heart. Forty-eight female Wistar rats with cryoinjured hearts were randomized into non-treated normal (group-1, n=12), DMEM injected (group-2, n=10), myoblast-transplanted (group-3, n=12) and myoblast-hVEGF(165) (group-4, n=14). Ten days after cryoinjury, 200 microl DMEM containing 3x10(6) cells or without cells was injected into the injured myocardium. Animals were maintained on cyclosporine for 6 weeks post cell transplantation. Heart function was assessed by echocardiography. Animals were sacrificed and hearts were processed for histochemical and immunohistochemical studies. Histological examination showed survival of the donor myoblasts expressing lac-z and hVEGF165 in rat cardiac tissue. Fluorescent immunostaining for vWillebrand Factor-VIII and smooth muscle actin expression at low power microscope (x100) showed significantly higher blood vessel density in group-4 (31.25+/-1.82; 24.63+/-0.92) as compared to group-2 (13.29+/-1.0; p<0.001; 9.71+/-0.81, p<0.001) and group-3 (16.50+/-1.43, p<0.001; 14.5+/-1.34, p<0.001). Echocardiography showed that ejection fraction and fractional shortening of group-3 (93.36+/-1.52%, p=0.005; 75+/-3.75%, p=0.024) and group-4 (94.8+/-1.62%, p=0.003; 76.13+/-2.15%, p=0.011) significantly improved as compared to group-2 (81.8+/-3.3%, 55.1+/-7.18%). Myoblasts carrying of hVEGF165 are potential therapeutic transgene carriers for cardiac repair.


The effect of cocaine on the expression of motor activity and conditioned place preference in high and low alcohol-preferring Wistar rats.
Outbred rats show significant variability in their propensity to consume alcohol. These experiments were designed to examine the effect of cocaine on the expression of motor activation or place preference in outbred Wistar rats that consumed either high or low quantities of alcohol. These rats were exposed to a 2-bottle limited access procedure and dichotomized into 2 groups, high (mean 0.91 g/kg/h) and low alcohol consumption (0.36 g/kg/h), and then exposed to repeated daily cocaine, 10 or 20 mg/kg, or saline injections. The low alcohol-consuming rats showed a significant increase in motor behavior to a cocaine challenge across both doses of cocaine, which did not differ from each other. The high alcohol-consuming rats showed a significant increase in motor behavior only at the high dose of cocaine. In Experiment 2 both high and low alcohol-consuming rats were exposed to a conditioned place preference procedure using cocaine 10 mg/kg. High alcohol-consuming rats showed a significant place preference to the cocaine-paired side while low consuming rats did not. The differential effects of cocaine on motor activating behavior and reward obtained in these experiments suggest that those factors determining whether an outbred Wistar rat will consume high or low amounts of alcohol are related, in part, to differential sensitivity of those neural systems underlying the effects of those drugs.


Selection for insecticide resistance can promote Plasmodium falciparum infection in Anopheles.
Insecticide resistance is under strong selective pressure in Anopheles mosquitoes due to widespread usage of insecticides in vector control strategies. Resistance mechanisms likely cause changes that profoundly affect mosquito physiology, yet it remains poorly understood how selective pressures imposed by insecticides may alter the ability of the mosquito to host and transmit a Plasmodium infection. From pyrethroid-resistant field-derived Anopheles gambiae s.l. mosquitoes, we established resistant (RES) and susceptible (SUS) colonies by either selection for, or loss of insecticide resistance. We show increased oocyst intensity and growth rate as well as increased sporozoite prevalence and intensity in RES compared to SUS females infected with Plasmodium falciparum. The increase in infection intensity in RES females was not associated with the presence of the kdrL1014F mutation and was not impacted by inhibition of Cytochrome P450s. The lipid transporter lipophorin (Lp), which was upregulated in RES compared to SUS, was at least partly implicated in the increased intensity of P. falciparum but not directly involved in the insecticide resistance phenotype. Interestingly, we observed that although P. falciparum infections were not affected when RES females were exposed to permethrin, these females had decreased lipid abundance in the fat body following exposure, pointing to a possible role for lipid mobilization in response to damage caused by insecticide challenge. The finding that selection for insecticide resistance can increase P. falciparum infection intensities and growth rate reinforces the need to assess the overall impact on malaria transmission dynamics caused by selective pressures mosquitoes experience during repeated insecticide challenge.


The clinical results of a novel method for minimal invasive dynamic hip screw fixation of intertrochanteric fractures compared to the conventional one.
Hip intertrochanteric fractures are very frequent. Early mobilization reduces the associated mortality and morbidity rate. DHS is still commonly used in many centers. We describe a new minimal invasive DHS technique (MIDHS) depending on radiological land marks, facilitating the application of DHS in a proper way without the use of an angle guide and we retrospectively compared the functional results of the new technique with that of the conventional DHS (CDHS) technique. 116 patients (MIDHS n = 56; CDHS n = 60) with stable intertrochanteric fractures were followed up for at least 12 months. The motoric function using the Barthel index, the post-operative pain using the VAS, and the time of bone healing of the new MIDHS group were compared to that of the CDHS group. The 1st, 2nd, 3rd, 7th, 15th, and 45th days showed a higher motoric function of the MIDHS compared with the CDHS, P (0.001, 0.032, 0.012, 0.001, 0.028 and 0.041), respectively. VAS demonstrated less scores of the MIDHS group in the 1st, 2nd, 3rd, 7th, 15th, and 45th days when compared with that of the CDHS group, P (0.001, 0.032, 0.012, 0.001, 0.028, and 0.041), respectively. However, no statistical significance was detected in bone-healing time between the two groups. The new MIDHS technique is a trustable procedure that may help the surgeon to perform DHS fixation in a proper way. It offers a better motoric function, less pain. However, further studies should be conducted to evaluate the validity of such radiological land marks in proximal femoral surgery.


Type beta transforming growth factor and epidermal growth factor suppress the plasminogen activator activity in a human glioblastoma cell line.
In the human glioblastoma cell line, T-MG1, plasminogen activator activity (PA-activity) was demonstrated by using the chromogenic substrate S-2251. Using monoclonal antibodies against human urokinase type PA (u-PA) and human tissue type PA (t-PA), only u-PA activity was found in T-MG1 cell extracts. The u-PA activity in T-MG1 cells was suppressed in a dose-dependent manner by B-TGF and EGF after 24 hours of exposure to these growth factors. Twenty units of B-TGF caused a decrease in PA-activity of 80%, while 10 ng/ml EGF gave a decrease in PA-activity of 60%. The suppressive effects of B-TGF and EGF were observed after 2 hours and 4 hours of incubation, respectively and sustained for at least 24 hours. The effects of B-TGF and EGF were not antienzymatic, but rather mediated through regulatory mechanisms. In view of the capacity of invasive growth of gliomas and the potential role of PA in invasive growth, the suppression of PA-activity in gliomas by B-TGF and EGF may be of importance.


Hypothermic circulatory arrest versus aortic clamping in thoracic and thoracoabdominal aortic aneurysm repair.
To compare perioperative and midterm outcomes in thoracic and thoraco-abdominal aortic aneurysm (TAA and TAAA) repair using hypothermic circulatory arrest (HCA) or aortic clamping (AC) with mild hypothermia. From 2012 to 2021 there were 180 open repairs of a TAA or TAAA, of which 90 (50%) were done with HCA and 90 (50%) with aortic clamping with mild hypothermia. The indications for HCA were arch aneurysm, TAA from chronic aortic dissection, and inability to clamp the aorta for proximal anastomosis. Compared to AC, the HCA group had less prior descending aorta replacement/repair (9.1% vs. 32%, p = 0.0001). Intraoperatively, the HCA group had more TAAs (70% vs. 20%, p < 0.0001) while the AC group had more TAAAs (80% vs. 30%, p < 0.0001). HCA group had longer cardiopulmonary bypass times (242 vs. 181 min, p < 0.0001) but shorter cross-clamp time (39 vs. 120 min, p < 0.0001) and lower temperatures (18°C vs. 34°C, p < 0.0001). Postoperatively, the HCA group had longer intubation times (31 vs. 26 h, p = 0.002), but all other postoperative outcomes including paralysis (2.2% vs. 8.9%, p = 0.08), and operative mortality (4.4% vs. 2.2%, p = 0.68) were similar between HCA and AC groups. Patient age was an independent risk factor for postoperative paralysis (OR 1.07, p = 0.03) while HCA was not significant (OR 0.37, p = 0.21). Five-year survival was similar between HCA and AC groups (85% vs. 80%, p = 0.36). Postoperative outcomes and midterm survival were acceptable in thoracic and thoracoabdominal aneurysm patients after HCA or AC. Both HCA and AC with mild hypothermia were valid approaches in TAA/A repair.


Donor nerve selection in free gracilis muscle transfer for facial reanimation. A systematic review and meta-analysis of clinical outcomes.
One of the critical factors in facial reanimation is selecting the donor nerve. The most favored neurotizers are the contralateral facial nerve with a cross-face nerve graft (CFNG) and motor nerve to the masseter (MNM). A relatively new dual innervation (DI) method has shown successful results. This study aimed to compare the clinical outcomes of different neurotization strategies for free gracilis muscle transfer (FGMT). The Scopus and WoS databases were queried with 21 keywords. Three-stage article selection was performed for the systematic review. Articles presenting quantitative data for commissure excursion and facial symmetry were included in meta-analysis, using random-effects model. ROBINS-I tool and Newcastle-Ottawa scale were used to assess bias and study quality. One hundred forty-seven articles containing FGMT were systematically reviewed. Most studies indicated CFNG as the first choice. MNM was primarily indicated in bilateral palsy and in elderly. Clinical outcomes of DI studies were promising. 13 studies including 435 observations (179 CFNG, 182 MNM, 74 DI) were eligible for meta-analysis. The mean change in commissure excursion was 7.15 mm (95% CI: 4.57-9.72) for CFNG, 8.46 mm (95% CI: 6.86-10.06) for MNM, and 5.18 mm (95% CI: 4.01-6.34) for DI. In pairwise comparisons, a significant difference was found between MNM and DI (p = 0.0011), despite the superior outcomes described in DI studies. No statistically significant difference was found in resting and smile symmetry (p = 0.625, p = 0.780). CFNG is the most preferred neurotizer, and MNM is a reliable second option. Outcomes of DI studies are promising, but more comparison studies are needed to draw conclusions. Our meta-analysis was limited by incompatibility of the assessment scales. Consensus on a standardized assessment system would add value to future studies.


The natural history of subarachnoid haemorrhage with negative angiography: a prospective study and 3-year follow-up.
One hundred and forty-eight patients with negative cerebral angiography after subarachnoid haemorrhage are reported. Good grade, normotension and normal CT are associated with a favourable outcome. In 89 patients with negative four-vessel angiography the overall annual risks of rebleeding and fatal rebleeding were 1.5% and 0.4% respectively. In 52 patients undergoing appropriate limited angiography corresponding risks were 2.5% and 1.9%. No fatal rebleeds occurred after 6 months. Initial CT scanning in 104 patients was abnormal in 34. Of these, 14 had SAH alone, in whom no episodes of rebleeding occurred, although SAH on CT was associated with an increased chance of a poor outcome. Twenty had other abnormalities, three of whom rebled, two (both with ICH on CT) being fatal. The annual risks of rebleeding and fatal rebleeding in patients with these CT abnormalities were 5.0% and 3.33% respectively. Fifty-two patients were hypertensive, of whom six rebled, four fatally. Two of the 89 normotensive patients rebled, neither fatally.


Right atrial thrombus formation associated with central venous catheters utilization in hemodialysis patients.
To report five patients on hemodialysis via an indwelling central venous catheter who developed a thrombus located exclusively on the right atrial wall opposing the emptying site of the superior vena cava and to determine the possible cause of this location. Transthoracic echocardiography was performed in four of the patients as work-up for suspected endocarditis or pulmonary embolism and in one patient for syncope evaluation. The right atrial clots were confirmed in all the patients by transesophageal echocardiography. General intensive care unit of a university hospital, tertiary referral center. Five patients with end-stage chronic renal failure on hemodialysis via subclavian or internal jugular vein catheter. Three of these patients underwent surgical thrombectomy, and two others were medically treated. The clots were 2-4 cm in length and three of them were infected. Two of the three surgically treated patients and one of the two medically treated patients died. All the patients had the catheter tip in the right atrium, in two of them the bent catheter rubbed the atrial endocardium, and in all the cases the clot was located on the atrial free wall facing the superior vena cava emptying. We postulate that the mechanism of thrombus formation at this location is related to friction of the catheter on the atrial endocardium, and therefore positioning the distal segment of the central venous catheters in the right atrium should be avoided.


Molecular mechanisms underlying oncogenic RET fusion in lung adenocarcinoma.
Oncogenic RET fusion, caused by an inversion in chromosome 10, was recently identified as a driver mutation for the development of lung adenocarcinoma (LADC). Nevertheless, the molecular mechanism(s) underlying the rearrangement of the RET locus during lung carcinogenesis are unknown. Genomic segments containing breakpoint junctions for RET fusions were cloned and analyzed by genomic polymerase chain reaction and genome capture sequencing using a next-generation sequencer to identify the mechanisms involved in DNA strand breaks and illegitimate joining of DNA ends. Of the 18 cases studied, 16 were identified by screening 671 LADC cases and two were previously published. Almost all (17 of 18, 94%) of the breakpoints in RET were located within a 2.0-kb region spanning exon 11 to intron 11 and no breakpoint occurred within 4 bp of any other. This suggested that as in papillary thyroid carcinoma, DNA strand breaks formed at nonspecific sites within this region trigger RET fusion. Just over half of the RET fusions in LADC (10 of 18, 56%) were caused by simple reciprocal inversion, and two DNA-repair mechanisms, namely nonhomologous end joining and break-induced replication, were deduced to have contributed to the illegitimate joining of the DNA ends. Oncogenic RET fusion in LADC occurs through multiple pathways and involves the illegitimate repair of DNA strand breaks through mechanisms different from those identified in papillary thyroid carcinoma, where RET fusion also functions as a driver mutation.


Distinct Gag interaction properties of HIV-1 RNA 5' leader conformers reveal a mechanism for dimeric genome selection.
During HIV-1 assembly, two copies of viral genomic RNAs (gRNAs) are selectively packaged into new viral particles. This process is mediated by specific interactions between HIV-1 Gag and the packaging signals at the 5' leader (5'L) of viral gRNA. 5'L is able to adopt different conformations, which promotes either gRNA dimerization and packaging or Gag translation. Dimerization and packaging are coupled. Whether the selective packaging of the gRNA dimer is due to favorable interactions between Gag and 5'L in the packaging conformation is not known. Here, using RNAs mimicking the two 5'L conformers, we show that the 5'L conformation dramatically affects Gag-RNA interactions. Compared to the RNA in the translation conformation (5'LT), the RNA in the packaging conformation (5'LP) can bind more Gag molecules. Gag associates with 5'LP faster than it binds to 5'LT, whereas Gag dissociates from 5'LP more slowly. The Gag-5'LP complex is more stable at high salt concentrations. The NC-SP2-p6 region of Gag likely accounts for the faster association and slower dissociation kinetics for the Gag-5'LP interaction and for the higher stability. In summary, our data suggest that conformational changes play an important role in the selection of dimeric genomes, probably by affecting the binding kinetics and stability of the Gag-5'L complex.


Determination of the minimum effective volume of bupivacaine for ultrasound-guided infraclavicular brachial plexus block: a prospective, observer-blind, controlled study.
We aimed to determine the minimum effective volume (MEV) of 0.5% bupivacaine for infraclavicular brachial plexus block. We assigned patients to volume groups consisting of five consecutive patients. Local anesthetic was sequentially reduced from a starting dose of 30 mL by 2 mL to form the volume groups. Five patients were included in each volume group, and at least 3 of 5 injections had to be successful to consider the volume of the anesthetic as sufficient. The study ended when the anesthetic volume of a group was determined to be unsuccessful (two or fewer successful blocks). Block was successful if the patient reported a sensorial block score of 7 or more on an 8-point scale and sensorial and motor block's total score of 14 on a 16-point scale. The MEV of 0.5% bupivacaine for infraclavicular brachial plexus block was 14 mL. A successful block was achieved in all patients (n = 45) in 9 volume groups, which received 30 mL down to 14 mL. Three blocks were unsuccessful in the 12-mL group. Time to onset of block and time to first postoperative anesthetic administration was 15 (10-15) min and more than 24 h in the 30-mL bupivacaine group, but 40 (30-45) min and 14 (10-24) h were determined for the 14-mL group, respectively. The MEV of 0.5% bupivacaine for ultrasound-guided infraclavicular brachial plexus block was 14 mL. However, this low-dose block has a long onset time of 40 (30-45) min on average.


The plasma membrane of epididymal epithelial cells has a specific receptor which binds to androgen-binding protein and sex steroid-binding protein.
The binding of [3H] delta 6-testosterone photoaffinity-labelled rat androgen-binding protein (rABP) has been studied in an enriched fraction of plasma membranes of epithelial epididymal cells in immature (15 days) and adult rats (40 days). The binding was maximal in less than 30 min and more rapid at 4 degrees C than at 34 degrees C. It was calcium and pH dependent. Scatchard plots of the binding data gave curvilinear plots with two types of binding sites corresponding to a K(ass1) of 18.2 nM-1 and K(ass2) of 1.6 nM-1 (2.2 x 10(11) sites/mg protein and 5.4 x 10(11) sites/mg protein, respectively). In adult rats, only one type of binding site was found, with a K(ass) of 3.7 nM-1 (4.5 x 10(11) sites/mg protein). The number of receptors was 5-fold lower in the cauda than in the caput of the epididymis. The pretreatment of the isolated intact cells with streptozotocin induced a 45% reduction of the binding. Only unlabelled rABP and hSBP (human sex steroid-binding protein) but not other proteins (lactotransferrin, serotransferrin, asialofetuine, fetuine and bovine serum albumin) competed with the labelled ligand to bind plasma membranes. The membrane fraction was solubilized by triton X-100. Its incubation with labelled rABP and hSBP provoked the elution of the tracer as an aggregate into the void volume fraction of superose 6B mini-gel filtration columns. Structural homology between hSBP and rABP could be responsible for the common behaviour of the steroid-carrier molecules for the ABP receptor of rat epididymal epithelial cells.


Analysis of sequence specificity of 5-bromodeoxyuridine-induced reversion in cells containing multiple copies of a mutant gpt gene.
For studies on molecular mechanisms of mutagenesis, it would be advantageous to transfer mutant genes with specific alterations into mammalian cells and use the transformed cells in reversion analyses. In the present paper, we describe an efficient method for analyzing reversion events occurring in cells that possess multiple copies of a mutational target gene. This method involves amplification of the chromosomally integrated target genes with the polymerase chain reaction (PCR) and restriction endonuclease digestion of the amplified product. Single reversion events that either create or destroy restriction endonuclease recognition sequences that encompass the site of the original mutation can be identified in a background of 10-20 copies of the gene that retain the mutant sequence. Using this method, we have analyzed revertants induced by 5-bromodeoxyuridine (BrdU) in a Chinese hamster ovary cell line that possesses multiple copies of a mutant bacterial gpt gene containing a specific alteration. The results of this study not only demonstrate the effectiveness of this method for analyzing reversion of a single gene copy in transfectants possessing multiple copies of a mutant target gene, but also demonstrate that the sequence specificity for BrdU-induced mutations is the same in Chinese hamster cells as previously observed with mouse cells.


Efficient synthesis and biological evaluation of some 2,4-diamino-furo[2,3-d]pyrimidine derivatives.
The carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aromatic isocyanates, reacted with ammonia to give ethyl 3,4-dihydro-6-methyl-4-oxo-2-arylamino-furo[2,3-d]pyrimidine-5-carboxylate 3. Further reaction of 3 with POCl(3) and various amines generated ethyl 4-alkylamino-2-arylamino-6-methyl-furo[2,3-d]pyrimidine-5-carboxylate 5 in good yields. Their structures were confirmed by (1)H NMR, EI-Ms, IR and elemental analysis. Compound 5b was further analyzed by single crystal X-ray diffraction. Compound 5 exhibited cytotoxicity against two lung cancer cell lines. For example, compound 5a showed the best inhibition activities against A459 with IC(50) 0.8μM.


Molecular typing of Mycobacterium chelonae isolates from a pseudo-outbreak involving an automated bronchoscope washer.
We describe a pseudo-outbreak of Mycobacterium chelonae infection in bronchoalveolar lavage fluid from 9 patients that was traced to contamination of an automated bronchoscope washer. Molecular typing using repetitive extragenic palindromic polymerase chain reaction was helpful in confirming epidemiologic and clinical findings.


Oral complications during treatment of malignant diseases in childhood: effects of tooth brushing.
During anticancer treatment, oral lesions considerably aggravate the child's clinical condition and increase the risk of infection. This prospective study evaluated the incidence, nature and chronology of oral complications arising during the first 6 weeks of chemotherapy. 131 children were included in this study, and their oral and dental health evaluated on enrolment. Each child was observed once a week, for 6 weeks. Fifty-two per cent (68/131) of the children presented with at least one oral lesion. Two oral healthcare regimens (with or without tooth brushing) were evaluated. Tooth brushing significantly reduced the number of children affected. Standardised multicentre studies should permit the definition of oral care regimens which would eliminate pain and reduce the risk of infection in children hospitalised for cancer.


Celecoxib and rofecoxib potentiate chronic colitis and premalignant changes in interleukin 10 knockout mice.
Nonsteroidal anti-inflammatory drugs decrease sporadic colorectal carcinoma and adenomas in patients with familial adenomatous polyposis and in rodent models of sporadic colon cancer and familial adenomatous polyposis. Similarly, selective cyclooxygenase 2 inhibitors decrease adenomas in humans and rodents. However, their effects on chronic colitis and colitis-associated neoplasia are unknown. Interleukin 10-/- mice (C57/B6) were fed regular chow (n = 20) or chow with celecoxib (1,500 ppm, n = 18) or rofecoxib (75 ppm, n = 20) for 12 weeks. Twenty-eight percent of the celecoxib group died versus 5% of the control and rofecoxib groups (p < 0.05 compared with control). Celecoxib and rofecoxib increased the incidence of colitis (26% vs. 92% and 68%, p < 0.01), colitis score (0.4 +/- 0.2 vs. 2.5 +/- 0.3 and 2 +/- 0.4, p < 0.01), aberrant crypt foci (0.5 +/- 0.3 vs. 3.7 +/- 2.6 and 2.8 +/- 0.7, p < 0.01), aberrant crypts per mouse (4.11 +/- 2.1 vs. 41.2 +/- 9.7 and 27.1 +/- 7.5, p < 0.01) and dysplasia (11% vs. 54% and 42%, p < 0.01). Similarly, indomethacin (9 ppm, n = 15) increased colitis score, aberrant crypt foci, and dysplasia after 27 days of treatment. Two selective cyclooxygenase 2 inhibitors exacerbate colitis and premalignant changes in the interleukin 10-/- mouse model of chronic colitis and colitis-associated colon carcinoma.


A palmar-hinged flap for reconstruction of traumatic thumb defects.
Destructive terminal palmar wounds of the thumb should be reconstructed if possible with like tissue; palmar glabrous skin served by the thumb's own median nerve branches. Such tissue is usually available, and no free flap or adjacent flap can serve as well. Seventeen thumbs of seventeen patients have been repaired with this method. The average follow-up was over 3 years. Sixteen of the 17 thumbs regained excellent sensibility and excellent pinch power based on current standard methods of evaluation; all patients returned to the same or similar occupations they had performed before the injury.


Absence of in vivo generalized pro-inflammatory endothelial activation in severe, early-onset preeclampsia.
At present it is unclear whether endothelial activation is systematically present in preeclampsia or restricted to specialized vascular beds. Therefore, this study aimed to investigate the presence of generalized proinflammatory endothelial activation in severe, early-onset preeclampsia in vivo. During caesarean section, biopsies were obtained from abdominal subcutaneous fat, abdominal fascia, and myometrium from 11 severe, early-onset preeclamptic and 19 healthy pregnant women. Prior to caesarean, section plasma levels of von Willebrand Factor (vWF), sVCAM-1, and C-reactive protein (CRP) were measured by ELISA. Consecutive cryostat sections were stained immunohistochemically for CD31, E-selectin, VCAM-1, and ICAM-1. For subcutaneous fat tissue, endothelial gene expression levels of E-selectin, VCAM-1, ICAM-1, endothelin-1 (ET-1), and endothelial nitric oxide synthase (eNOS) were quantified by real-time RT-PCR, using normalization to the endothelium-specific housekeeping genes CD31 and VE-cadherin. Plasma levels of vWF, sVCAM-1, and CRP were elevated in the preeclampsia group compared to the control group, indicating enhanced endothelial activation and inflammatory response in the severely diseased preeclamptic women. By immunohistochemical analysis, no E-selectin and VCAM-1 expression could be detected in, and no differences in endothelial ICAM-1 staining could be observed between the preeclampsia and the control group for all tissues studied. Endothelial gene expression levels of E-selectin, VCAM-1, ICAM-1, ET-1, and eNOS were comparable between the preeclampsia and control group. Protein and gene expression analysis of E-selectin, VCAM-1, ICAM-1, ET-1, and eNOS, key mediators involved in pro-inflammatory endothelial activation, could not identify endothelial activation in severe, early-onset preeclampsia in the tissues studied. However, elevated plasma levels of markers of endothelial activation and inflammation were observed. These results may suggest that in severe, early-onset preeclampsia pro-inflammatory endothelial cell activation is not a generalized phenomenon, but is likely restricted to (possibly organ-specific) specialized vascular beds.


Single Cell Proteolytic Assays to Investigate Cancer Clonal Heterogeneity and Cell Dynamics Using an Efficient Cell Loading Scheme.
Proteolytic degradation of the extracellular matrix (ECM) is critical in cancer invasion, and recent work suggests that heterogeneous cancer populations cooperate in this process. Despite the importance of cell heterogeneity, conventional proteolytic assays measure average activity, requiring thousands of cells and providing limited information about heterogeneity and dynamics. Here, we developed a microfluidic platform that provides high-efficiency cell loading and simple valveless isolation, so the proteolytic activity of a small sample (10-100 cells) can be easily characterized. Combined with a single cell derived (clonal) sphere formation platform, we have successfully demonstrated the importance of microenvironmental cues for proteolytic activity and also investigated the difference between clones. Furthermore, the platform allows monitoring single cells at multiple time points, unveiling different cancer cell line dynamics in proteolytic activity. The presented tool facilitates single cell proteolytic analysis using small samples, and our findings illuminate the heterogeneous and dynamic nature of proteolytic activity.


The potentiometric and spectrophotometric determination of dissociation constants for same 2-mercapto-5-R-amino-1,3,4-thiadiazole derivatives.
In order to establish the dissociation constants of organic compounds, the spectrophotometric and potentiometric methods are the most precise and useful ones. Comparing the results, we used both methods for three derivatives of 2-mercapto-5-R-amino-1,3,4-thiadiazole. For the pKa determination by the spectrophotometric method we measured the ratio between the concentration of dissociated and undissociated forms. The ratio was calculated from spectral data. The potentiometric method for pKa consists of measuring the pH values within a potentiometric titration with 0.1 M NaOH. The results proved a very low acid character of the derivatives. The pKa values were influenced by the properties of the amino group substituents, and the results confirm the theoretical considerations. The study confirms the thion-thiolic tautometry of the 2-mercapto-5-R-amino-1,3,4-thiadiazole derivates and their property of being ligands for the coordination of the cations of some representative and transitional metals, with application in the preconcentration, in the detection and the quantitative determination of polluting and toxic cations in environmental analysis.


Vertical stratification of Culicoides biting midges at a Florida big game preserve.
Many important vector arthropods are known to stratify vertically in forest environments, a phenomenon which has important implications for vector-borne disease transmission and vector control. Culicoides Latreille biting midges (Diptera: Ceratopogonidae) have been documented using the forest canopy; however, studies of this phenomenon are lacking for many Culicoides species found in great abundance in the state of Florida, USA, some of which have been implicated as suspected vectors of hemorrhagic diseases of white-tailed deer. The present study aimed to determine whether common Culicoides species in Florida stratify vertically and to determine whether strata used by midges corresponded to host use. Trapping was conducted at a big game preserve in Gadsden County, FL, USA. Over two summer field seasons in 2016 and 2017, CDC miniature light traps were set at two levels, one set at 1.37 m, designated as the ground trap, and a nearby trap in the forest canopy set at 6 m during 2016 and 9 m during 2017. Species abundance, physiological status, and blood-meal sources were analyzed and compared between trap heights. Species abundances for C. haematopotus, C. stellifer and C. venustus were not significantly different between trap heights during the 2016 season; however, canopy traps were found to have significantly higher abundance of C. arboricola, C. biguttatus, C. debilipalpis, C. haematopotus, C. insignis and C. stellifer than ground traps in 2017. Greater numbers of blood-engorged midges were collected in the canopy compared with ground traps during both study years, and 98.6% and 98.7% of blood meals from canopy collected midges were taken from ground-dwelling mammals in 2016 and 2017, respectively. Culicoides species in Florida, including species implicated as vectors of hemorrhagic disease viruses, are found in great abundance in the forest canopy. Many midges are feeding on host species that are known reservoirs of hemorrhagic disease and then moving into the forest canopy, which has implications for the calculation of vectorial capacity. These data contribute valuable ecological information on Culicoides species found in Florida and provide a framework for developing effective vector control strategies to target these species.


Epistaxis.
Epistaxis is discussed. Three unusual cases are reported. The first was a patient with a basal skull fracture due to a motor vehicle accident. He developed a carotid-cavernous fistula causing epistaxis severe enough to cause a cardiac arrest on one of his bouts of severe bleeding. The second was an unusual complication of a rhinoplasty due to damage to the anterior ethmoidal artery from the medial osteotomy. The third was due to psychopathology causing an adult female to traumatize her nose as an attention-getting or defence mechanism causing epistaxis with anemia requiring bi-annual blood transfusions of more than 175 units of blood over a 20 year period. Management is described.


Suppressive effect of cyclophosphamide-induced toxicity by Withania somnifera extract in mice.
Administration of Withania somnifera extract (Solanaceae) was found to significantly reduce leucopenia induced by cyclophosphamide (CTX) treatment. The total WBC count on the 12th day of the CTX-treated group was 3720 cells/mm3 and that of CTX along with Withania was 6120 cells/mm3. Treatment of Withania along with CTX was found to significantly (P < 0.001) increase the bone marrow cellularity (13.1 x 10(6) cells/femur) compared to CTX alone treated group (8 x 10(6) cells/femur). Administration of Withania extract increased the number of alpha-esterase positive cells (1130/4000 cells) in the bone marrow of CTX treated animals, compared to the CTX-alone treated group (687/4000 cells). The major activity of Withania somnifera may be the stimulation of stem cell proliferation. These studies indicate that Withania somnifera could reduce the cyclophosphamide induced toxicity and its usefulness in cancer therapy.


[Percutaneous transthoracic aspiration biopsy: the reliability of cytological diagnosis of intrathoracic tumors].
The authors evaluated percutaneous aspiration biopsies of intrathoracic lesions in 348 patients where the obtained cytological results were compared with the histological finding from resections or post-mortem preparations. In 274 patients malignant and in 74 benign disease was confirmed. In the differentiation of malignant and benign disease the sensitivity of cytology was 84.3%, the specificity 91.9% and the accuracy 85.9%. The type of bronchogenic carcinoma was correctly diagnosed by cytological examination in 69.5%, in squamous cell carcinoma in 76.8%, in small-cell carcinoma in 80% and in adenocarcinoma in 59.1%. The same cytological finding as in the primary tumour was recorded in 73.5% of the patients with metastases in the lungs. Less favourable results as regards assessment of the type of tumour were obtained in other tumours, in particular in lymphogranulomas and non-Hodgkin lymphomas. In 25% it proved possible to assess by cytological examination the type of benign lung tumour.


Enteral nutrition by tube.
When oral intake is unsatisfactory or contraindicated, maintenance of nutrition by tube feeding is an alternative to the parenteral route. A large volume of research data supports the decision to use the enteral route whenever possible. Entry of food into the alimentary tract is a stimulus to structural and functional maintenance of that tract. Enteral nutrition can be given via indwelling nasoesophageal, pharyngostomy, esophagostomy, percutaneous or surgical gastrostomy, or enterostomy tube. Use of an appropriate catheter, familiarity with the technique used, and careful patient selection and monitoring are important factors in successful tube feeding. Blenderized pet food diets should be fed whenever possible; commercially available liquid diets provide an alternative when tube caliber or patient factors preclude the use of blenderized foods.


The Impact of RNA-DNA Hybrids on Genome Integrity in Bacteria.
During the essential processes of DNA replication and transcription, RNA-DNA hybrid intermediates are formed that pose significant risks to genome integrity when left unresolved. To manage RNA-DNA hybrids, all cells rely on RNase H family enzymes that specifically cleave the RNA portion of the many different types of hybrids that form in vivo. Recent experimental advances have provided new insight into how RNA-DNA hybrids form and the consequences to genome integrity that ensue when persistent hybrids remain unresolved. Here we review the types of RNA-DNA hybrids, including R-loops, RNA primers, and ribonucleotide misincorporations, that form during DNA replication and transcription and discuss how each type of hybrid can contribute to genome instability in bacteria. Further, we discuss how bacterial RNase HI, HII, and HIII and bacterial FEN enzymes contribute to genome maintenance through the resolution of hybrids.


Rotavirus infections in adults in association with acute gastroenteritis.
During an epidemic of acute gastroenteritis in Helsinki, in March--May 1976, 18 out of 40 adult patients showed electron microscopic and/or serologic evidence for rotavirus infection. Rotavirus was most frequently seen in the fecal suspensions from 2 to 6 days after the onset of the symptoms but persisted in one patient for as long as 10 days. An increase in the complement-fixing (CF) serum antibody titers against the related Nebraska calf diarrhea virus (NCDV), or an initially high titer and subsequent significant decrease, was seen in all but one patient with rotavirus-positive feces, and in 6 additional patients. This suggests that using electron microscopy as the only diagnostic procedure a considerable number of rotavirus infections in adults remain undetected. Immune response against autologous or homologous rotavirus was also documented by immunoelectron microscopy. Complement-fixing antibody titers against NCDV decreased significantly from the convalescence values over a half-year observation period, but still remained clearly above the titers of a gastroenteritis-negative control population.


Oral supplementation with L-glutamine alters gut microbiota of obese and overweight adults: A pilot study.
The aim of this study was to determine whether oral supplementation with L-glutamine (GLN) modifies the gut microbiota composition in overweight and obese adults. Thirty-three overweight and obese adults, ages between 23 and 59 y and body mass index between 25.03 and 47.12 kg/m(2), were randomly assigned to receive either oral supplementation with 30 g of L-alanine (ALA group control) or 30 g of GLN (GLN group) daily for 14 d. We analyzed the gut microbiota composition with new-generation sequencing techniques and bioinformatics analysis. After 14 d of supplementation, adults in the GLN group exhibited statistically significant differences in the Firmicutes and Actinobacteria phyla compared with those in the ALA group. The ratio of Firmicutes to Bacteroidetes, a good biomarker for obesity, decreased in the GLN group from 0.85 to 0.57, whereas it increased from 0.91 to 1.12 in the ALA group. At the genus level, Dialister, Dorea, Pseudobutyrivibrio, and Veillonella, belonging to the Firmicutes phylum, had statistically significant reduction. Oral supplementation with GLN, for a short time, altered the composition of the gut microbiota in overweight and obese humans reducing the Firmicutes to Bacteroidetes ratio, which resembled weight loss programs already seen in the literature.


Leydig cell function in streptozotocin-induced diabetic rats.
Streptozotocin diabetic rats were infertile as a result of decreased Leydig cell function of the testes. The major changes found were: decreased number of Leydig cells and their spontaneous secretion of testosterone. No change in the receptors to LH on the Leydig cells was observed. LH was found to be obligatory for the regulation of Leydig cell function and fertility.


Cellular and Humoral Responses to a Second Dose of Herpes Zoster Vaccine Administered 10 Years After the First Dose Among Older Adults.
Herpes zoster vaccine (ZV) was administered as a second dose to 200 participants ≥ 70 years old who had received a dose of ZV ≥ 10 years previously (NCT01245751). Varicella zoster virus (VZV) antibody titers (measured by a VZV glycoprotein-based enzyme-linked immunosorbent assay [gpELISA]) and levels of interferon γ (IFN-γ) and interleukin 2 (IL-2; markers of VZV-specific cell-mediated immunity [CMI], measured by means of ELISPOT analysis) in individuals aged ≥ 70 years who received a booster dose of ZV were compared to responses of 100 participants aged 50-59 years, 100 aged 60-69 years, and 200 aged ≥ 70 years who received their first dose of ZV. The study was powered to demonstrate noninferiority of the VZV antibody response at 6 weeks in the booster-dose group, compared with the age-matched first-dose group. Antibody responses were similar at baseline and after vaccination across all age and treatment groups. Both baseline and postvaccination VZV-specific CMI were lower in the older age groups. Peak gpELISA titers and their fold rise from baseline generally correlated with higher baseline and postvaccination VZV-specific CMI. IFN-γ and IL-2 results for subjects ≥ 70 years old were significantly higher at baseline and after vaccination in the booster-dose group, compared with the first-dose group, indicating that a residual effect of ZV on VZV-specific CMI persisted for ≥ 10 years and was enhanced by the booster dose. These findings support further investigation of ZV administration in early versus later age and of booster doses for elderly individuals at an appropriate interval after initial immunization against HZ. NCT01245751.


Photoperiodic light pulse induces ovarian development in the catfish, Mystus cavasius: Possible roles of dopamine and melatonin in the brain.
In the freshwater catfish, Mystus cavasius, locally known as gulsha, ovarian maturation is triggered by long-day conditions. Using dopaminergic neuronal activity in the brain, the purpose of this study was to identify the brain's detection of a nocturnal light pulse that induced ovarian development. Since direct inhibition of pituitary gonadotropin release is exerted by dopamine (DA), it may serve as a neuromodulator of photoperiodic stimulation in teleosts. We studied functional effects of photoperiodicity on dopaminergic rhythmicity in gulsha brain. Nocturnal illumination and Nanda-Hamner photocycles revealed that ovarian development is induced by a 1 h light pulse between zeitgeber time (ZT) 12 and 13. Daily fluctuations in DA, 3, 4-dihydroxyphenylacetic acid (DOPAC) and DOPAC/DA were observed under a 12L:12D photoperiod. Fish exhibited increased levels during the daytime and decreased levels at night. Rhythmic patterns of dopaminergic activity also showed clear circadian oscillations under constant light, but not constant dark conditions. After 7 days of exposure to long photoperiod (14L:10D), DA, DOPAC and DOPAC/DA in the brain at ZT12 and ZT16 were significantly higher than during a short photoperiod (10L:14D). Melatonin-containing water inhibited the release of DA and DOPAC 6 h and 24 h after treatment, respectively, and DOPAC/DA 6 h after treatment. This inhibition was blocked by the melatonin receptor antagonist, luzindole. These results suggest that a 1 h nocturnal light pulse induces ovarian development through alteration of dopaminergic neuronal excitability in the brain, via oscillation in melatonin triggered by photic stimuli, which may interfere with the reproductive endocrine axis in gulsha.


Mitral Valve Replacement Adopting Chimney Technique in Mitral Insufficiency And Extensive Mitral Annular Calcification: A Case Report.
Extensive and serious mitral annular calcification represents a troublesome obstacle in intracardiac mitral valve replacement due to time-consuming requirements and the potential of decalcification-associated complications. We report the case of a high-risk patient with extremely severe mitral insufficiency and difficult-to-debride annular calcification who received mitral replacement using a chimney technique. This approach enabled not only the minimization of mitral calcification debridement but also the reduction of surgery time. Consequently, the surgery was successful with a great postoperative outcome. Thus, this technique is a safe and feasible option to deal with intractable mitral annular calcification during mitral valve surgery.


Inorganic PM2.5 at a U.S. agricultural site.
In this study, we present approximately two years (January 1999-December 2000) of atmospheric NH3, NH4+, HCl, Cl-, HNO3, NO3-, SO2, and SO4= concentrations measured by the annular denuder/filter pack method at an agricultural site in eastern North Carolina. This site is influenced by high NH3 emissions from animal production and fertilizer use in the surrounding area and neighboring counties. The two-year mean NH3 concentration is 5.6 (+/-5.13) microg m(-3). The mean concentration of total inorganic PM2.5, which includes SO4=, NO3-, NH4+, and Cl-, is 8.0 (+/-5.84) microg m(-3). SO4=, NO3-, NH4+, and Cl- represent, respectively, 53, 24, 22, and 1% of measured inorganic PM2.5. NH3 contributes 72% of total NH3 + NH4+, on an average. Equilibrium modeling of the gas+aerosol NH3/H2SO4/HNO3 system shows that inorganic PM2.5 is more sensitive to reductions in gas + aerosol concentrations of sulfate and nitrate relative to NH3.


[Continence after low anterior resection (author's transl)].
In 28 patients we studied the fecal continence after low anterior resection of the rectum. After an usual proctological investigation we did in all patients measurements of the anorectal function, such as pressure measurement, electromyography and determination of the anal-rectal angle. In 12 patients a defecatogram was performed. Of the 28 patients with anastomoses lower than 8 cm only one was after 2 years still incontinent. All the other patients were completely continent. This fact could be proven objectively.


Out of synch: Clock mutation causes obesity in mice.
The Clock gene encodes an essential component of the "master clock" driving circadian rhythm in the hypothalamic suprachiasmatic nucleus (SCN). New evidence that Clock mutant mice are hyperphagic and obese suggests a previously unrecognized link between molecular controls of circadian rhythm and energy homeostasis.


Lap simulator, animal studies, and the Laptent. Bridging the gap between open and laparoscopic surgery.
In an effort to ensure proper training and to establish a routine amongst the surgical team right from the start, we began practicing laparoscopic techniques with the lap simulator. After having acquainted ourselves with the fundamentals of this minimal-invasive method, we applied our newfound experience to the animal model. Even though the subsequent studies with pigs were the best learning model in which to practice different surgical techniques--e.g., ureter clipping and renal vessel triple stapling with the Endo-GIA--various problems can arise in a true clinical situation since anatomical diversity exists between an animal and human situs. We found that a compromise could be reached by simulating laparoscopic conditions during open surgery without endangering the safety of the patient during any point of the operation. After open surgical exposure of the Gerota fascia was carried out, the operative site was completely covered with the Laptent. From this moment on, all operative steps were performed with laparoscopic instruments under continuous video monitoring. Our step-by-step training program has exposed the surgeon and OR staff to the complexity of this new surgical technique. The use of the Laptent has successfully bridged the gap between open and laparoscopic surgery. Most important of all, those surgical centers without access to extensive experimental studies will realize that Laptent-assisted surgery can be of benefit and facilitate the clinical introduction of this minimal-invasive method.


Temporal and spatial changes in macromolecular uptake in rat thoracic aorta and relation to [3H]thymidine uptake.
Leaky endothelial junctions associated with cell turnover have been suggested to be a hydrophilic pathway for the transport of macromolecules across the vascular endothelium. To demonstrate focal increases in endothelial permeability, the occurrence of localized uptake of macromolecules in the rat thoracic aorta was studied at various time periods after intravascular administration of Evans blue-albumin (EBA) complexes. With fluorescence microscopy, EBA uptake in the rat thoracic aorta was visible either as discrete spots or as larger areas in both en face and cross-sectional preparations. The average size of EBA leaky spots increased with dye circulation time, indicating that there is a continuous influx of macromolecules through the transiently leaky junctions in these foci with subsequent diffusion in the vessel wall. There was heterogeneity in EBA spot size distribution, suggesting that endothelial cells undergoing turnover in different phases of the cell cycle might exhibit different extents of junctional leakage to macromolecules. The technique of [3H]thymidine labeling autoradiography was applied to en face preparations of the rat thoracic aorta for identifying replicating endothelial cells. The correlation of EBA leakage with [3H]thymidine-labeled endothelial cells was determined. Only 26% of endothelial cells with nuclear incorporation of [3H]thymidine were shown to be associated with EBA leaky foci. This lack of correlation suggests that alterations in endothelial junctional permeability accompanying cell turnover might occur only in some limited time periods of the cell cycle, e.g., the mitotic (M) phase, rather than the whole period of [3H]thymidine labeling.


Isotype-specific regulation of human lymphocyte production of immunoglobulins by sustained exposure to vasoactive intestinal peptide.
Exposure of lymphocytes to nanomolar to micromolar concentrations of vasoactive intestinal peptide (VIP) for 1 to 3 days only modestly suppressed or enhanced the production of IgA and IgM, but not IgG. The effects of twice daily additions of 10(-12) to 10(-7) mol/L VIP for up to 18 days on pokeweed mitogen-stimulated peripheral blood mononuclear cells (PBMCs) from normal human subjects was examined by quantifying the production of IgG, IgM, and IgA. The maximum suppression of IgG by 10(-9) mol/L VIP was 79% +/- 33% (mean +/- SD) (range, 41% to 97%; p < 0.015) on day 9 and 84% +/- 1% (range, 74% to 96%; p < 0.0001) on day 14 and was significant at 6 x 10(-10) to 4 x 10(-9) mol/L VIP. Suppression of IgM production by 10(-9) mol/L VIP was significant and was observed first on day 5 and persisted through day 14. VIP did not alter IgA production or affect the proliferation or viability of PBMCs. The production of IgE by interleukin-4 stimulated PBMCs was enhanced consistently in two subjects but not in two other subjects. The duration of exposure to nanomolar concentrations of VIP is thus a critical determinant of its immunoregulatory effect, as manifested by late suppression of production of IgG and IgM and concurrent enhancement of production of IgE in some subjects.


[Vitreous cyst: a case presentation].
We report a case of a 12-year-old patient who complained about visual disturbances in left eye for 6 months. His visual acuity was 1/0.9, funduscopy in left eye revealed a free-floating cyst in the anterior vitreous. Magnetic resonance showed a low intense image in T1, and B-scan ultrasound confirmed a hypoechogenic cyst of 3.2 × 4.3 mm; ultrasound biomicroscopy revealed a normal ciliary body. Given the good VA the patient will be monitored periodically. If the cyst interferes with visual axis, management with Nd:YAG or Argon laser photocystotomy or remove it by pars plana vitrectomy has been advocated.


Characterization of novel loci controlling seed oil content in Brassica napus by marker metabolite-based multi-omics analysis.
Seed oil content is an important agronomic trait of Brassica napus (B. napus), and metabolites are considered as the bridge between genotype and phenotype for physical traits. Using a widely targeted metabolomics analysis in a natural population of 388 B. napus inbred lines, we quantify 2172 metabolites in mature seeds by liquid chromatography mass spectrometry, in which 131 marker metabolites are identified to be correlated with seed oil content. These metabolites are then selected for further metabolite genome-wide association study and metabolite transcriptome-wide association study. Combined with weighted correlation network analysis, we construct a triple relationship network, which includes 21,000 edges and 4384 nodes among metabolites, metabolite quantitative trait loci, genes, and co-expression modules. We validate the function of BnaA03.TT4, BnaC02.TT4, and BnaC05.UK, three candidate genes predicted by multi-omics analysis, which show significant impacts on seed oil content through regulating flavonoid metabolism in B. napus. This study demonstrates the advantage of utilizing marker metabolites integrated with multi-omics analysis to dissect the genetic basis of agronomic traits in crops.


Getting out of our own way.
This paper, a follow-up from a 2009 panel discussion at ABCT's Annual Convention, focuses on the choices that women make (or don't make) that can affect their careers. Women are particularly prone to feeling guilty about their choices, and while a few decades ago there was a great deal of sexism in the workplace, at this point in time, I believe that we are more likely to make assumptions that impede our careers rather than face external barriers. The paper covers some "stuck points" that stop women from advocating for themselves or results in guilt regardless of their choice.


Histological grading and prognosis in dogs with mammary carcinomas: application of a human grading method.
The human "Elston and Ellis grading method" was used in dogs with mammary carcinoma to examine its relation to prognosis in this species, based on a 2-year follow-up period. Of the 85 cases examined, 27(31.8%) had well-differentiated (grade I), 28 (32.9%) had moderately differentiated (grade II) and 30 (35.3%) had poorly differentiated (grade III) carcinomas. Two years after mastectomy, significant differences in survival between cases with different tumour grade were found; thus, survival was worse in dogs with grade III carcinomas than in those with grade II (P<0.05) or grade I (P<0.001) tumours. However, in dogs with simple carcinomas which had a less favourable prognosis than that of other carcinomas (P<0.001), there was no significant difference in survival between grade II and grade III cases (P=0.878), both having a very poor prognosis. Undifferentiated (grade III) carcinoma cases had a 21-fold increased risk of death as compared with differentiated (grade I and II) carcinoma cases. An increased risk (about 10-fold) was also associated with undifferentiated simple carcinomas as compared with differentiated ones. The predictive value of histological grade was not influenced by tumour size or age of the dog at mastectomy; nodal metastasis, however, worsened the prognosis (P<0.001). Routine use of this human grading method would help the clinician to make a more accurate prognosis in the interests of post-surgical management in dogs with mammary carcinomas.


Editorial Commentary: Determinants of Outcome After Repair of Knee Medial Meniscus Posterior Root Tear Are Multifactorial.
Medial meniscus posterior root tears alter tibiofemoral contact, leading to medial knee osteoarthritis. Repair can restore kinematics and biomechanics. Female sex, age, obesity, high posterior tibial slope, varus malalignment >5°, and Outerbridge grade ≥3 chondral lesions in the medial compartment are associated with risk for medial meniscus posterior root tears and poor healing after repair. Extrusion, degeneration, and tear gap may increase tension across the repair site, resulting in poor outcome.


Clinical features of hepatitis B virus genotype A in Japanese patients.
Hepatitis B virus (HBV) genotype A is predominant in northern Europe and central Africa. In the present study, we examined the clinical features associated with HBV genotype A disease in the Tokyo metropolitan area. We investigated 53 cases of HBV surface antigen (HBsAg)-positive Japanese patients with HBV genotype A. The 53 cases were further classified as to their serum alanine aminotransferase (ALT) status being within the normal range (asymptomatic carriers, n = 17), chronic hepatitis (n = 15), liver cirrhosis (n = 4), and acute hepatitis (n = 17). Chronic hepatitis patients had significantly higher HBV DNA levels (P = 0.003) and hepatitis B e antigen (HBeAg) positivity rates at the initial visit than did asymptomatic carriers or patients with liver cirrhosis (P = 0.003 and P = 0.054, respectively). The efficacy of treatment (HBeAg seroconversion rate) was 75% in 12 chronic hepatitis patients, which was excellent. A family history of HBsAg positivity was identified in eight (15%) families (five asymptomatic carriers, three with chronic hepatitis). However, none of the mothers in the study was positive for HBV genotype A. Maternal transmission of HBV has often been reported in Japan, but our present findings suggest that horizontal infection of HBV genotype A is more prevalent in the Tokyo metropolitan area. Our data indicate that HBV genotype A exhibits a mode of infection different from that of conventional HBV previously seen in Japan.


NMDA induced glutamate release from the suprachiasmatic nucleus: an in vitro study in the rat.
The suprachiasmatic nucleus (SCN) has been identified as a pacemaker for mammalian circadian rhythms. Excitatory amino acid receptors, especially N-methyl-D-aspartate (NMDA) receptors, have been considered to play an important role in the transmission of light information from the retina to the circadian clocks in the SCN. In the present study, we showed that application of NMDA at circadian time (CT) 12-15 induced significant glutamate release from the SCN region in vitro. The NMDA-induced glutamate release was blocked by co-application of the NMDA receptor antagonist MK-801, but not by that of tetrodotoxin. These results suggested that glutamate stimulated its own release by activating NMDA receptors. This NMDA-induced glutamate release through NMDA receptor-mediated mechanisms might be involved in NMDA-induced potent phase shifts.


Solitary plasmacytoma of the rib: A rare tumor to keep in mind: Case report.
Around 5% of plasma cell neoplasias are solitary plasmacytomas, a tumor that is fairly rare. The presence of a localized tumor composed of monoclonal plasma cells that are the same as those found in multiple myeloma and the absence of symptoms that would suggest a disseminated form are used to establish the diagnosis. The thoracolumbar spine is the area most affected. Costal origin is infrequently described. In our case, the patient manifested a right anterosuperior chest wall mass. Imaging showed a mass of tissue with a significant zone of osteolysis of the first rib and no chest wall infiltration. Blood protein immunoelectrophoresis disclosed a monoclonal kappa type IgG. Bence-Jones proteinuria was positive, further suggesting a plasmacytoma of the rib. A percutaneous needle biopsy for pathology study and immunohistochemistry enabled the diagnosis of costal plasmacytoma. Search for other localizations was negative and the diagnosis of solitary plasmacytoma was retained. The patient received radiotherapy and has remained in remission for over a year. The pathology and imaging findings are used to make the diagnosis. Radiotherapy is the therapy of choice, but it presents a risk of progression to other bone lesions, medullary plasmacytosis, and multiple myeloma. There are no known factors that predict systemic recurrence. Surveillance is essential on a regular basis.


Evaluation of glucose tolerance, insulin secretion, and insulin action in patients with primary hyperparathyroidism before and after surgery.
Glucose tolerance, insulin secretion, and insulin sensitivity were evaluated in 8 asymptomatic patients with primary hyperparathyroidism (PHPT) before and at least 8 weeks after surgical correction of PHPT by means of the hyperglycemic clamp technique. In addition, 15 sex- and age-matched control subjects were investigated for comparative reasons by the same technique. Glucose metabolized (M) during the hyperglycemic clamp was not significantly (NS) different between patients with PHPT and controls (7.9 +/- 2.3 vs. 6.3 +/- 1.9 mg/kg/min). However, insulin secretion (I) was significantly elevated in patients with PHPT compared to controls (87 +/- 17 vs. 45 +/- 12 microU/ml, P less than 0.05). The calculated insulin sensitivity index (M/I) was significantly reduced in PHPT compared to controls (11.0 +/- 2.1 vs. 15.2 +/- 1.4 mg/kg/min per microU/ml x 100, P less than 0.05). Comparing patients with PHPT before and after surgery, the M value, which is a measure of glucose tolerance, was not significantly different (7.9 +/- 2.3 vs. 7.8 +/- 1.5 mg/kg/min). However, insulin secretion was significantly lower after surgical correction of PHPT compared to the preoperative situation (48 +/- 9 microU/ml vs. 87 +/- 17 microU/7 ml, P less than 0.01). The calculated M/I rose significantly after surgery compared to the preoperative value (11 +/- 2.1 vs. 17.6 +/- 2.7 mg/kg/min per microU/ml x 100, P less than 0.001). We conclude that disturbed carbohydrate metabolism, such as insulin hypersecretion and insulin resistance, in patients with PHPT is an early finding in this disease and that these early disturbances in glucose metabolism are, however, fully reversible.(ABSTRACT TRUNCATED AT 250 WORDS)


Distribution of angiotensin II receptors in the brain of nonhuman primates.
Angiotensin II binding sites were demonstrated at discrete nuclei in the brain of three nonhuman primate species by autoradiography, using the agonist ligand, [Sar1]AII. Although there were some differences in location of the binding sites, all three species exhibited a characteristic pattern of distribution in areas related to water intake, vasopressin secretion, and blood pressure regulation through modulation of sympathetic activity. Studies in the cynomolgus monkey with the antagonist ligand, [Sar1,Ile8]AII, which localizes in pathways as well as nuclei, revealed novel regions of binding including the habenular-interpeduncular pathway, ventral bundle, and XII nerve, in addition to the X nerve. These data indicated that AII, as in other species, has a role in the central homeostatic control mechanisms in the primate.


The effect of portable HEPA filter air cleaner use during pregnancy on fetal growth: The UGAAR randomized controlled trial.
Fine particulate matter (PM2.5) exposure may impair fetal growth. Our aim was to assess the effect of portable high efficiency particulate air (HEPA) filter air cleaner use during pregnancy on fetal growth. The Ulaanbaatar Gestation and Air Pollution Research (UGAAR) study is a single-blind randomized controlled trial conducted in Ulaanbaatar, Mongolia. Non-smoking pregnant women recruited at ≤18 weeks gestation were randomized to an intervention (1-2 air cleaners in homes from early pregnancy until childbirth) or control (no air cleaners) group. Participants were not blinded to their intervention status. Demographic, health, and birth outcome data were obtained via questionnaires and clinic records. We used unadjusted linear and logistic regression and time-to-event analysis to evaluate the intervention. Our primary outcome was birth weight. Secondary outcomes were gestational age-adjusted birth weight, birth length, head circumference, gestational age at birth, and small for gestational age. The study is registered at ClinicalTrials.gov (NCT01741051). We recruited 540 participants (272 control and 268 intervention) from January 9, 2014 to May 1, 2015. There were 465 live births and 28 losses to follow up. We previously reported a 29% (95% CI: 21, 37%) reduction in indoor PM2.5 concentrations with portable HEPA filter air cleaner use. The median (25th, 75th percentile) birth weights for control and intervention participants were 3450 g (3150, 3800 g) and 3550 g (3200, 3800 g), respectively (p = 0.34). The intervention was not associated with birth weight (18 g; 95% CI: -84, 120 g), but in a pre-specified subgroup analysis of 429 term births the intervention was associated with an 85 g (95% CI: 3, 167 g) increase in mean birth weight. HEPA filter air cleaner use in a high pollution setting was associated with greater birth weight only among babies born at term.


Eigenvector Centrality Characterization on fMRI Data: Gender and Node Differences in Normal and ASD Subjects : Author name.
With the budding interests of structural and functional network characteristics as potential parameters for abnormal brains, an essential and thus simpler representation and evaluations have become necessary. Eigenvector centrality measure of functional magnetic resonance imaging (fMRI) offer region wise network representations through fMRI diagnostic maps. The article investigates the suitability of network node centrality values to discriminate ASD subject groups compared to typically developing controls following a boxplot formalism and a classification and regression tree model. Region wise differences between normal and ASD subjects primarily belong to the frontoparietal, limbic, ventral attention, default mode and visual networks. The reduced number of regions-of-interests (ROI) clearly suggests the benefit of automated supervised machine learning algorithm over the manual classification method.


Changes in fluorescein angiogram early after surgical removal of choroidal neovascularization in age-related macular degeneration.
Retinal pigment epithelial (RPE) defects inevitably occur in surgical removal of choroidal neovascularization (CNV) in age-related macular degeneration (AMD). RPE can proliferate and cover the denuded area, but the healing process has not been investigated in humans. To understand the RPE wound-healing process, we estimated the changes in fluorescein angiograms early after CNV removal. Ten consecutive patients with exudative AMD underwent CNV removal without gas tamponade. Fluorescein angiography was performed within 4 days of surgery and again 1 or 2 weeks postoperatively. Areas of leakage were measured using a computer-assisted image analyser. The decreasing rate of leakage was calculated as the change in disc areas of leakage per day (DA/day). The rates of decreasing leakage ranged from 0 to 0.42 DA/day (mean, 0.24 +/- 0.15 DA/day; median, 0.26 DA/day). The rate of decreasing leakage correlated with changes in visual acuity (r = 0.642, P = 0.0456). The retinal pigment epithelial wound after surgical removal of choroidal neovascularization may heal at the rate of 0.24 disc areas/day based on the blood retinal barrier function in patients with age-related macular degeneration. A faster rate of decreasing leakage may be associated with better visual prognosis.


Acute responses of renal nerve activity to microgravity induced by free drop in anesthetized rats.
To examine acute cardiovascular and autonomic responses to microgravity (microG), arterial pressure (AP), aortic flow velocity (AFV), central venous pressure (CVP), and renal nerve activity (RNA) were measured in anesthetized rats during 4.5 s of microG produced by free drop. A smooth and immediate reduction in gravity occurred during free drop, microG being achieved 100 ms after the start of the drop. Acute microG elicited an immediate and striking, but transient, decrease in RNA with no significant change in AP and AFV, but a significant decrease in CVP. The decrease in RNA lasted 2 s, then RNA recovered to the control level despite the G value remaining at < 0.001 for 4.5 s. The RNA decrease was attenuated or completely abolished by sinoaortic denervation, vagotomy, or sinoaortic denervation plus vagotomy. These results suggest that acute microG conditions stimulate sinoaortic and cardiopulmonary mechanoreceptors and suppress RNA.


Stem cell reconstitution of autoimmune T cell repertoires.
Maintenance of T cell memory in autoimmune disease may be complex because the unending renewable supply of self provides an inherent high antigen load that effectively precludes clearance, and because the broad array of potential immunogenic targets provides extensive self-recognition plasticity. Autoimmunity is characterized by a dynamic self-recognition process in which the primary autoreactivity initiating disease is soon followed and often displaced by secondary neoautoreactivities, or epitope spreading, that emerge as a result of endogenous self-priming. Here we show that the autoimmune disease process involves a tertiary phase of self recognition characterized by stem cell reconstitution of autoreactive T cells that recapitulates the myelin self recognition process involved in disease initiation and spreading during experimental autoimmune encephalomyelitis (EAE). Our study indicates that sustained autoimmune memory may not simply be due to the persistence of long-lived memory T cells, but may also involve bone marrow regeneration and replacement of the autoreactive T cell repertoire.


Influence of jejunoileal and common limb length on weight loss following Roux-en-Y gastric bypass.
Capella surgery is one of the technical variations of Roux-en-Y gastric bypass. The method includes the preparation of an alimentary (Roux) limb with a standardized length (110 cm) in order to induce deficiencies in the absorption of macronutrients and thereby contribute to weight loss. The recognized variation in jejunoileal length in humans (approximately 4 to 9 m) is not considered, although this range correlates with the wide variation in the length of the common limb. In order to assess the influence of variations in jejunoileal and common limb lengths on weight loss, intra-operative measurements were made of these segments on 100 patients undergoing Capella surgery. Patients were followed for a period of 1 year. Statistical analysis included subdivisions of the population by gender and body mass index. Average jejunoileal length was 671.4 +/- 115.7 cm (434-990 cm). Average common limb length was 505.3 +/- 113.3 cm (268-829 cm). No correlation was detected between jejunoileal length and weight loss at 6 months or 1 year following surgery. A weak negative correlation was detected between weight loss and common limb length at 1 year following surgery in male and super-obese patients. Jejunoileal and common limb length vary widely in gastric bypass patients. To make modifications in the alimentary and/or biliopancreatic limb length, surgeons must consider the variability of the jejunoileal and common limb length.


Effect of COVID-19 virus on reducing GHG emission and increasing energy generated by renewable energy sources: A brief study in Malaysian context.
Coronavirus 2019 (COVID-19) has globally affected the human mortality rate and economic history of the modern world. According to the World Health Organization, COVID-19 has caused a severe threat to the health of the vulnerable groups, notably the elderly. There is still some disagreements regarding the source of the virus and its intermediate host. However, the spread of this disease has caused most countries to enforce strict curfew laws and close most industrial and recreational centres. This study aims to show the potential positive effects of COVID-19 on the environment and the increase of renewable energy generation in Malaysia. To prevent the spread of this disease, Malaysia enacted the Movement Control Order (MCO) law in March 2020. Implementation of this law led to a reduction in environmental pollution, especially air pollution, in this country. The greenhouse gases (GHG) emission , which was 8 Mt CO2 eq. from January 2020 to March 2020, reduced to <1 Mt CO2 eq. for April and May. The reduction of GHG emission and pollutant gases allowed more sunlight to reach photovoltaic panels, hence increasing the renewable energy generation.


Household drinking water quality and its predictors in flood-prone settings of Northwest Ethiopia: A cross-sectional community-based study.
Globally, the deterioration of drinking water quality is a major public health problem that contributes to the spread of disease and causes death. Therefore, it is important to have regular quality control monitoring. This study aimed to assess the level of physicochemical and bacteriological quality of household drinking water and its contributing factors in flood-prone settlements of South Gondar Zone, Ethiopia. A community-based cross-sectional study was conducted in flood-prone settings of Northwest Ethiopia from January 17 to March 30, 2021. Structured questionnaires were used to gather the sociodemographic, environmental, and behavioral data. A total of 675 drinking water samples were collected from water storage containers of selected households. Logistic regression models were used for both univariate and multivariable studies. The survey included a total of 675 households. The mean values of pH (5.9 ± 1.03), turbidity (6.7 ± 2.21 NTU), and free residual chlorine (0.02 ± 0.01 mg/l) did not meet the WHO recommended limits for drinking water. The prevalence of fecal contamination of drinking water in the study area was 62.2% with [95% CI (53-60%)]. Family size [AOR = 2.205, 95% CI (1.375-3.536), absence of latrine [AOR = 3.449, 95% CI (1.349-8.823)], and lack of a separate container to draw water from its storage [AOR = 0.454, 95% CI (0.249-0.827)] were significant predictors for fecal contamination of household drinking water. In conclusion, the water quality in terms of pH, turbidity, residual chlorine, and bacteriological parameters was poor and not suitable for consumption. High prevalence of fecal contamination of water was found, and it was significantly associated with family size, the absence of a latrine, and the lack of a separate cap to take water from the storage. Therefore, continuous chlorination and monitoring its concentration, educating the community on how to use stored water, educating the advantage of having a latrine, and promoting point-of-use treatments such as filtration and boiling are needed.


A comparative study of metabolic engineering anti-metabolite tolerance in Escherichia coli.
A problem in strain engineering is that mutations that benefit the expression of a phenotype in one environment may impose a cost to biological fitness in a new environment. The overall objective of this study was to improve understanding of this phenomenon within the context of a classic anti-metabolite selection strategy. We have engineered Escherichia coli using three mutagenesis techniques (chemical mutagenesis, insertional mutagenesis, and plasmid-based overexpression) and assessed the relative costs and benefits to biological fitness of mutants selected for tolerance to five amino acid analogs whose target amino acids (glutamatic acid, aspartic acid, tryptophan, glycine, and serine) differ in metabolic connectivity and biosynthetic energy requirements. Our major findings include (i) the fold increase in anti-metabolite tolerance, independent of mutagenesis strategy, was much greater for aspartic acid beta-hydroxamate (AAH) compared to all other tested hydroxamates, (ii) increased tolerance to glutamic acid gamma-hydroxamate (GAH) was not achieved using any of the mutagenesis strategies, and (iii) characteristics of the anti-metabolite, rather than those of the corresponding metabolite, were more important in determining the ability to increase tolerance.


BTW: a web server for Boltzmann time warping of gene expression time series.
Dynamic time warping (DTW) is a well-known quadratic time algorithm to determine the smallest distance and optimal alignment between two numerical sequences, possibly of different length. Originally developed for speech recognition, this method has been used in data mining, medicine and bioinformatics. For gene expression time series data, time warping distance is arguably a more flexible tool to determine genes having similar temporal expression, hence possibly related biological function, than either Euclidean distance or correlation coefficient--especially since time warping accommodates sequences of different length. The BTW web server allows a user to upload two tab-separated text files A,B of gene expression data, each possibly having a different number of time intervals of different durations. BTW then computes time warping distance between each gene of A with each gene of B, using a recently developed symmetric algorithm which additionally computes the Boltzmann partition function and outputs Boltzmann pair probabilities. The Boltzmann pair probabilities, not available with any other existent software, suggest possible biological significance of certain positions in an optimal time warping alignment. http://bioinformatics.bc.edu/clotelab/BTW/.


Cellulitis in complicated pneumococcal pneumonia.
Serious complications of pneumococcal pneumonia have become uncommon. This has been attributed to decline in pneumococcal infection (van Roy et al. 1971; Foy et al. 1975), but in this country it is more likely to be due to effective antibiotic therapy. We report a case of pneumococcal pneumonia with severe complications (including a very unusual one) which probably arose through antibiotic failure.


Unconventional Molecular Design Approach of High-Efficiency Deep Blue Thermally Activated Delayed Fluorescent Emitters Using Indolocarbazole as an Acceptor.
Unconventional blue thermally activated delayed fluorescent emitters having electron-donating type indolocarbazole as an acceptor were developed by attaching carbazolylcarbazole or acridine donors to the indolocarbazole acceptor. Three compounds were derived from the indolocarbazole acceptor. The indolocarbazole-acridine combined products showed efficient delayed fluorescent behavior and a high quantum efficiency of 19.5% with a color coordinate of (0.15, 0.16) when they were evaluated as thermally activated delayed fluorescent emitters in deep blue fluorescent devices. This is the first demonstration of the use of electron-donating carbazole-derived moieties as efficient acceptor units of blue thermally activated delayed fluorescent emitters.


Vaping Restrictions: Is Priority to the Young Justified?
The vast majority of smokers become dependent on nicotine in youth. Preventing dependence has therefore been crucial to the recent decline in youth smoking. The advent of vaping creates an opportunity for harm reduction to existing smokers (mostly adults) but simultaneously also undermines prevention efforts by becoming a new vehicle for young people to become dependent on nicotine, creating an ethical dilemma. Restrictions to access to some vaping products enacted in response to the increase in vaping among youth observed in the United States since 2018 have arguably prioritized prevention of new cases of dependence-protecting the young-over harm reduction to already dependent adults. Can this prioritization of the young be justified? This article surveys the main bioethical arguments for prioritizing giving health benefits to the young and finds that none can justify prioritizing dependence prevention over harm reduction: any reasons for prioritizing the current cohort of young people at risk from vaping will equally apply to current adult smokers, who are overwhelmingly likely to have become nicotine-dependent in their own youth. Public health authorities' current tendency to prioritize the young, therefore, does not seem to be ethically justified. This article argues that commonsense reasons for prioritizing the young do not apply to the ethical dilemma surrounding restricting access to vaping products.


Rapidly metabolized glycoproteins in a neuroblastoma cell line.
The metabolism of neuroblastoma cell glycoproteins was examined using L-E13H]fucose. Incubation of monolayer cultures with [3H]fucose resulted in a rapid uptake of the radioactive precursor and its incorporation into acid-insoluble macromolecules. Less than 3% of the [3H]fucose that was isolated from neuroblastoma cells by trichloroacetic acid precipitation was associated with glycolipids. The metabolism of fucosylated macromolecules was studied in cells which were labelled to a steady state, and then reincubated under conditions which limited reutilization of the radioactive precursor (40 mM unlabelled fucose). During reincubation of the cells, we observed a rapid metabolism (27% by 2 h) of the prelabelled macromolecules which stabilized within a cell generation time to give an overall rate of turnover of 9%. This rapid loss of radioactivity from the cells was not due to exocytosis since less than 4% of the [3H]-fucose was lost into the media as macromolecules during a 5 h reincubation period. The presence of 40 mM fucose in the media did not affect cell growth until after 24 h of incubation or cellular protein synthesis until after 15 h of incubation. When the metabolism of neuroblastoma cell glycoproteins was measured in the presence of 1.8 - 10(-4) M cycloheximide, there appeared to be a less rapid decrease in cell-associated specific activity, and an increased reutilization of [3H]fucose. Although the major proportion of the radioactivity remained as e13H]fucose, extensive incubation of neuroblastoma cells with this radioactive precursor led to increased amounts of tritium associated with other cellular components; However, a rapid rate of glycoprotein metabolism could also be demonstrated with cells incubated with [14C]fucose. This eliminated the possibility that the above results were restricted to the tritiated precursor and merely a reflection of hydrogen-tritium exchange.


The cardiovascular effects of centrally administered taurine in anaesthetised and conscious rats.
The effects of pentobarbitone anaesthesia on the cardiovascular changes induced by centrally administered taurine have been investigated in spontaneously hypertensive (SHR) and normotensive rats. Administration of taurine (100-400 micrograms) into the lateral cerebral ventricle (i.c.v.) of anaesthetised SHR and normotensive rats induced a dose-related fall in systemic blood pressure and heart rate, which tended to be of a greater magnitude in the SHR. In anaesthetised rats attached to a ventilator, taurine was not as potent at inducing a fall in systemic blood pressure, approximately double the dose being required to produce the same cardiovascular changes as that which occurred in anaesthetised rats without a ventilator. In conscious normotensive rats taurine had no effect on blood pressure until a dose of 800 micrograms was administered i.c.v., whereas in conscious SHR, a small, but significant depressor response was evident with 400 micrograms. These findings demonstrate that pentobarbitone anaesthesia sensitises the rats to the cardiovascular effects of taurine, partially through a mechanism which involves respiratory depression. Conversely in conscious rats a much higher dose of taurine is required to induce a fall in arterial pressure and heart rate per se.


The effects of physical activity, fast-mimicking diet and psychological interventions on cancer survival: A systematic review and meta-analysis of randomized controlled trials.
Health professionals are often asked if non-pharmacological interventions prolong life. This review aims to evaluate the effects of physical activity, fast-mimicking diet (FMD) and psychological interventions on survival in all cancers. A systematic review and meta-analysis of randomized controlled trials (RCTs). Only RCTs of physical activity, FMD and psychological interventions (including counselling, cognitive and other psychotherapies) in cancer patients that reported survival outcomes were included. CENTRAL, MEDLINE, Embase, CINAHL, APA PsycINFO, Web of Science, ICTRP and ClinicalTrials.gov from inception to January 2020 were searched without language restrictions. The protocol was prospectively registered at PROSPERO (CRD42019160944). Thirty-one RCTs (9 on physical activity and 22 on psychological interventions) were included in the final analysis after evaluation of 60,207 records from our initial search. No eligible RCT on FMD was reported. RCTs on group psychological interventions (41.9 %) and in patients with breast cancer (38.7 %) were the most common. Most evaluated short-term interventions and in primary or adjuvant settings. Only one of 9 (11 %) RCTs on physical activity and 8 of 22 (36 %) RCTs on psychological interventions were associated with improved overall survival. Only group psychological interventions in breast cancer had adequate number of RCTs to allow a meta-analysis to be performed. It demonstrated a trend towards improved overall survival (HR -0.20, 95 %CI -0.49 to 0.10), particularly in RCTs that evaluated long-term (>6 months) therapies (HR -0.29, 95 %CI -0.59 to 0.01). Longer term interventions starting early in the patients' care journey in primary and adjuvant settings have shown the most promise for improving survival. Better designed RCTs including survival outcomes are particularly needed in non-breast cancers.


[Efficacy and safety of simvastatin in patients with hypercholesterolemia (results of a Multicenter Clinical Study)].
To assess efficacy and safety of a generic preparation of simvastatin Vasilip (KRKA) in ischemic heart disease patients with hypercholesterolemia or combined hyperlipidemia. Patients (n=167, age 36-73 years) with ischemic heart disease and moderate hypercholesterolemia or combined hyperlipidemia. Duration of simvastatin administration was 12 weeks. All patients received 20 mg/day for 6 weeks. Then those patients who did not achieve target low density lipoprotein (LDL) cholesterol level (3.0 mmol/l) were given 40 mg/day for 6 more weeks. Other patients continued to take 20 mg/day. The use of Vasilip was associated with lowering of total, LDL cholesterol and triglycerides (by 28, 39 and 10%, respectively) and 18% elevation of high density lipoprotein cholesterol. Target LDL CH level was achieved in 107 patients (66.9%). In 47 patients (29.4%) LDL CH concentration remained higher than target level but decrease of LDL CH exceeded 10%. Six patients (3.8%) did not respond to therapy. Treatment was stopped because of adverse effects in 2.4% of patients. A generic preparation of simvastatin Vasilip in a 12-week open noncomparative study demonstrated substantial lipid lowering activity and did not induce serious adverse reactions.


Biotransformation of amitriptyline in alcoholic depressive patients.
The biotransformation of amitriptyline (AMT) during steady state conditions was studied in plasma and urine from 11 nonalcoholic and 10 alcoholic depressive inpatients treated with oral AMT. The 2 groups of patients had a different pattern of biotransformation. The Demethylation of AMT was lower in alcoholic than in nonalcoholic depressive patients, and conjugation and hydroxylation of AMT were also more marked in the former group. The results may be of clinical relevance since the conjugates of AMT are inactive.


Differential toxicity and localization of arginine-rich C9ORF72 dipeptide repeat proteins depend on de-clustering of positive charges.
Arginine-rich dipeptide repeat proteins (R-DPRs), poly(PR) and poly(GR), translated from the hexanucleotide repeat expansion in the amyotrophic lateral sclerosis (ALS)-causative C9ORF72 gene, contribute significantly to pathogenesis of ALS. Although both R-DPRs share many similarities, there are critical differences in their subcellular localization, phase separation, and toxicity mechanisms. We analyzed localization, protein-protein interactions, and phase separation of R-DPR variants and found that sufficient segregation of arginine charges is necessary for nucleolar distribution. Proline not only efficiently separated the charges, but also allowed for weak, but highly multivalent binding. In contrast, because of its high flexibility, glycine cannot fully separate the charges, and poly(GR) behaves similarly to the contiguous arginines, being trapped in the cytoplasm. We conclude that the amino acid that spaces the arginine charges determines the strength and multivalency of the binding, leading to differences in localization and toxicity mechanisms.


Influence of bovine manure on dissipation of hexazinone in soil.
The effects of bovine manure (BM) on the degradation of hexazinone and formation of three of its major metabolites were investigated in sandy loam soil. The degradation half-life of hexazinone was 29.6 days in unamended soil, while it decreased to 21.8 days in BM-amended soil. The major metabolites formed in unamended soil were [3-cyclohexyl-6-(methylamino)-1-methyl-1,3,5-triazine-2,4(1, 3H)-dione] (metabolite A) and [3-cyclohexyl-1-methyl-1,3,5-triazine-2,4,6(1, 3, 5H)-trione] (metabolite C), while metabolite B [3-(4-hydroxycyclohexyl)-6-(dimethylamino)-1-methyl-1,3,5-triazine-2,4(1, 3H)-dione] was not detected over the entire experimental period. However, in BM-amended soil, metabolite B was detected at 20 and 40 days after incubation, suggesting that BM contributed to formation of this metabolite. N-demethylation, removal of the dimethylamino group with formation of a carbonyl group at the 6-position of the triazine ring appeared to be the principal mechanisms involved in hexazinone metabolism in unamended soil. However, hydroxylation at the 4-positon of the cyclohexyl group as well as the above two modes were the principal pathways in BM-amended soil.


Motivational control of latent inhibition in flavor preference conditioning.
In three experiments, rats given pairings of a neutral flavor with sucrose showed a preference for that flavor when subsequently allowed to choose between it and water. Preexposure to the flavor produced a latent inhibition effect (reduced the size of the preference) when the rats were hungry during the test (Experiments 1 and 2). Rats that were not hungry during the test failed to show latent inhibition (Experiments 1-3). Experiment 3 confirmed that sucrose-flavor pairings were capable of producing a preference even in nonhungry rats. It is argued that the preference shown by rats that are hungry on test depends on a flavor-nutrient association, a form of learning that is susceptible to latent inhibition in the same way as standard conditioning procedures are. The failure to obtain latent inhibition in nonhungry rats suggests that the preference obtained in these conditions depends on a different form of learning that is less susceptible to the effects of stimulus exposure.


STEMI: Considerations for Left Main Culprit Lesions.
There is a paucity of data regarding the prevalence, clinical characteristics, and outcomes of patients presenting with ST elevation myocardial infarction (STEMI) due to left main (LM) culprit vessel. LM culprit STEMI (LMCSTEMI) is an uncommon, but frequently catastrophic event. Prior meta-analyses and registries have described a varying prevalence of LMCSTEMI, associated cardiogenic shock, and in-hospital mortality among those surviving to hospital presentation. These observed clinical discrepancies may be partially attributable to diverse clinical and angiographical subsets among this STEMI population. STEMI due to LM culprit artery disease represents a clinically high-risk subset of patients with substantial in-hospital mortality. In this paper, we summarize the available clinical data pertaining to STEMI with LM culprit, discuss unique ECG characteristics, and discuss contemporary revascularization therapy. We also report the preliminary findings from a contemporary, STEMI database describing clinical characteristics and angiographically defined subsets of LM culprit STEMI.


Health risks and perceptions of residents exposed to multiple sources of air pollutions: A cross-sectional study on landfill and stone mining in Danang city, Vietnam.
Health risks and perceptions of residents living nearby landfills or stone mines/quarries have been well documented; however, the multiple impacts of these two pollution sources have yet to be investigated. This study aims at giving insights into the impacts of residents exposed to two pollution sources in Danang city, Vietnam: Khanh Son landfill and Phuoc Tuong quarry. In this cross-sectional study, 7-point-Likert scale questionnaires were used to collect information from 314 respondents which were divided into three groups: i) Landfill-Stone mine (LS) exposed group within 1 km from both sources, ii) Stone mine (ST) exposed group within 1 km from the stone mine, and iii) the far-exposed group about 2-3 km from the two emission sites. Air pollutants (including H2S, CH4, and total suspended particles (TSP)) and noise levels were also sampled. In addition, we estimated the potential health risk assessment due to the exposure to hydrogen sulphide in the study areas. The findings have shown that 1) There is a statistical difference (p-value < 0.001) between the two exposed groups and far-exposed group regarding health risks and residents' perceptions; 2) Compared to the ST exposed group, the LS exposed group statistically showed a higher perception to bad odours and skin diseases; lower satisfaction with regards to the personal health condition and the operation of the landfill; and higher willingness to change current living locations; and 3) There is evidence to indicate that elevated concentrations of air pollutants are associated with the high self-reported health risks and residents' perceptions. Urgent actions should be focused on the LS exposed group, landfill and quarry operations to prevent further adverse health effects.


The impact of reactive oxygen species and genetic mitochondrial mutations in Parkinson's disease.
The exact pathogenesis of Parkinson's disease (PD) is still unknown and proper mechanisms that correspond to the disease remain unidentified. It is understood that PD is age-related; as age increases, the chance of onset responds accordingly. Although there are no current means of curing PD, the understanding of reactive oxygen species (ROS) provides significant insight to possible treatments. Complex I deficiencies of the respiratory chain account for the majority of unfavorable neural apoptosis generation in PD. Dopaminergic neurons are severely damaged as a result of the deficiency. Symptoms such as inhibited cognitive ability and loss of smooth motor function are the results of such impairment. The genetic mutations of Parkinson's related proteins such as PINK1 and LRRK2 contribute to mitochondrial dysfunction which precedes ROS formation. Various pathways are inhibited by these mutations, and inevitably causing neural cell damage. Antioxidants are known to negate the damaging effects of free radical overexpression. This paper expands on the specific impact of mitochondrial genetic change and production of free radicals as well as its correlation to the neurodegeneration in Parkinson's disease.