Sharma's sigmoid colonic adhesive band - A new laparoscopic sign in female genital tuberculosis.
Female genital tuberculosis (FGTB) is a form of extra pulmonary tuberculosis (EPTB) affecting women of reproductive age group. It causes significant morbidity in women especially infertility particularly in developing countries. Diagnosis is by endometrial sampling for acid fast bacilli (AFB) microscopy, culture, gene Xpert, polymerase chain reaction (PCR), histopathological evidence of epithelioid granuloma and by laparoscopic findings suggestive of tuberculosis. Present study was conducted to observe the prevalence of a new "Sharma's Sigmoid colonic adhesive band "in FGTB on laparoscopy. It was a prospective study in a tertiary referral center as a part of our ongoing tuberculosis project on 148 infertile women found to have FGTB on microbiological or laparoscopic findings over previous 10 years. A new laparoscopic "Sharma's Sigmoid colonic adhesive band" was looked for in these cases on laparoscopy. The mean age, parity and duration of infertility and incidence of poor socioeconomic status was 26.9 years, 0.49, 5.3 years and 65.54% respectively. All patients had infertility with 83.78% primary and 16.22% secondary infertility while menstrual dysfuction especially hypomenorrhoea (31.75%), oligomenorrhoea (32.48%) were seen in respective cases. Constitutional symptoms like pyrexia (21.62%), weight loss (31.75%) appetite loss (33.5%) and abdominal pain (11.48%) and pelvic pain (27.70%) or abdominal mass (8.78%) and pelvic masses (35.81%) were also seen. Diagnosis of FGTB was made on endometrial or peritoneal biopsy microscopy or culture for AFB or positive gene Xpert or positive polymerase chain reaction (PCR) or histopathological demonstration of epithelioid granuloma or on laparoscopic findings of FGTB. Various laparoscopic findings were tubercles on pelvic organs (45.27%), shaggy areas (white deposits) on pelvic organs (43.91%),beaded or convoluted tubes (9.45%), hyperemic tubes (29.05%), caseous nodules in pelvis (29.72%), encysted ascites (14.18%), abdominal adhesions (32.43%), pelvic adhesions (42.56%), calcified and rigid tubes (6.08%). The new laparoscopic sigmoid colonic adhesive band was seen in 49 (33.10%) patients of FGTB. The new laparoscopic "Sharma's Sigmoid colonic adhesive band" appears to be an important finding in patients with FGTB.


Histamine-releasing properties of mast cells from various strains of mice.
A comparison has been made of the in vitro histamine releasing capacity of peritoneal mast cells from BALB/c, C3H/A, C57BL/6J and CFW mouse strains in response to immunological and non-immunological stimuli namely anti-mouse IgE, Concanavalin A (Con A), ionophore A23187 and sodium fluoride. Anti-IgE-induced histamine secretion was highest in mast cells of CFW mice, intermediate in the cells of C57BL/6J and C3H/A mice and lowest in the cells of BALB/c mice. Similar, although less pronounced, strain-dependent differences were observed in Con A-induced release. Mast cells of C57BL/6J and CFW mice were significantly more sensitive to the action of ionophore A23187 compared to the two other strains, although the cells of each strain responded in different manner. Sodium fluoride-induced histamine release occurred in two ways: from mast cells of BALB/c and C57BL/6J it was dose-dependent at NaF concentrations of 1-15 mM, whereas cells of the two other strains were insensitive to the action of NaF at concentrations of 1-5 mM but at a concentration of 7.5 mM, a very strong potentiation of release was observed. Our results suggest functional heterogeneity of mast cells from various strains of mice, a point to be considered in further studies of mast cell function.


Interprovincial migration of physicians in Canada: What are the determinants?
This paper analyzes factors contributing to interprovincial migration of physicians in Canada. It (1) compares the migration patterns of the general practitioners and specialists (medical and surgical); (2) analyzes the changing patterns of out-migration over time via the interactions between the province of residence and time period; (3) analyzes the effect of language as a determinant of migration out of predominantly French speaking Quebec. A logistic formulation of discrete-time hazard model was employed to estimate the probability of moving from the current province of residence. Sets of physician's individual characteristics variables along with dummy variables to reflect the provincial characteristics and various time-periods were included in the model. The model was extended to allow for interaction effects between the province of residence and time-period, and also between language and Quebec (the only province in Canada which is predominantly French speaking) as province of residence. The results suggest that physician's age, specialty, province of residence have significant impact on interprovincial migration of physicians. The probability of moving differs significantly across province of residences in various time-periods.


The Clinical and Pathological Features of IgG(4)-Related Disease.
The rapidly emerging disorder now known as IgG(4)-related disease (IgG(4)-RD) includes a variety of clinical entities once regarded as being entirely separate diseases. Manifestations of IgG(4)-RD have now been reported in essentially all organ systems. Regardless of which organ is involved, tissue biopsies reveal striking histopathological similarities. The hallmark pathology findings are diffuse lymphoplasmacytic infiltrates, abundant IgG(4)-positive plasma cells, modest tissue eosinophilia, and extensive fibrosis. Tumorous swelling and obliterative phlebitis are other frequently observed features. Polyclonal elevations of serum IgG(4) are found in approximately 70% of patients. Many questions pertaining to the etiology, pathophysiology, epidemiology, clinical features, therapy, disease monitoring, and long-term outcomes remain to be addressed. This paper focuses on the clinical and pathological features of IgG(4)-RD.


Sox9 is required for prostate development.
The mammalian prostate arises from the urogenital sinus and few factors have been identified to be important in the early stages of prostate development. In this study we show that the transcription factor Sox9 is expressed in the epithelia of all mouse prostatic lobes from the initial stages of their development. We used a conditional approach with mice expressing Cre recombinase under the control of Nkx3.1 regulatory sequences to delete Sox9 from the developing prostate. Mice with a prostate specific deletion of Sox9 showed a lack of ventral prostate development and abnormal anterior prostate differentiation. Analysis of these mutant animals revealed an early loss of expression of genes specific to the prostate epithelia such as Nkx3.1 and Shh and a marked reduction in proliferation in the ventral prostate but not in other lobes. Fgf signalling, through the MAPK pathway, has been shown to be important in prostate development and a lobe specific phenotype was reported for a prostate specific Fgfr2 mutant mouse model. Here we show that the levels of Fgfr2 and Sprouty2, a downstream target of Fgf signalling, were severely reduced in the ventral prostate of Sox9 mutant animals but not in other lobes. Prostate organ culture studies with a Mek inhibitor, U0126, and a Fgf receptor inhibitor, SU5402, indicate that the timing of expression of Cre in the mutant animals could account for the lobe specific phenotype in the Sox9 and Fgfr2 mutants. These studies imply that Sox9 is required for the early differentiation of the prostate bud epithelia.


Atomic force microscopy study of the interaction of Fusarium solani pisi cutinase with lipid surfaces.
We present an atomic force microscopy (AFM) study of a supported triacylglyceride multilayer phase and its interaction with lipolytic enzyme cutinase from Fusarium solani pisi. The multilayer triacylglyceride phase of coconut oil showed a rippled surface structure in the AFM images. Upon enzymatic degradation of the triacylglyceride phase, the ripple structure vanished rapidly. The apparent catalytic rate constants could be estimated based on the AFM image information. Interestingly, in one sample we observed what we interpret as a recurrent structural collapse of the cavity dug out by the protein. We interpret the cavities seen in the AFM images as molten surfaces or surface holes filled with liquidified phase containing product molecules, which appear transparent during the image recording.


Axon elimination in the developing corticospinal tract of the rat.
Quantitative ultrastructural analysis of the corticospinal tract (CST) at the mid-thoracic spinal level in a series of early postnatal and young adult rats reveals that the tract is initially composed primarily of morphologically immature axon shafts, growth cones, and pale neuroglial processes. The total number of axons in the tract rises quickly to a peak level up to 90% greater than that present in the adult tract; it then declines, contemporaneously with the restriction of the areal extent of the set of spinally projecting cells in the cerebral cortex. During the time of axon elimination, axons remain small and morphologically immature, and small numbers of growth cones persist. Glial cells take on more mature forms within the tract several days before axon outgrowth ceases and myelination begins at the end of the second postnatal week. The fully mature CST retains a large complement of small, unmyelinated axons.


Purification and characterization of an extracellular alpha-amylase produced by Lactobacillus manihotivorans LMG 18010(T), an amylolytic lactic acid bacterium.
This work presents the purification and characterization of an extracellular alpha-amylase (1,4-alpha-D-glucan glucanohydrolase, EC 188.8.131.52) produced by a new lactic acid bacterium: Lactobacillus manihotivorans able to produce L(+) lactic acid from starch. The molecular weight was found to be 135 kDa. The temperature and pH optimum were 55 degrees C and 5.5, respectively, and pI was 3.8. The alpha-amylase had good stability at pH range from 5 to 6 and the enzyme was sensitive to temperature, losing activity within 1 h of incubation at 55 degrees C. Higher thermal stability was observed when the enzyme was incubated in presence of soluble starch. K(m) value and activation energy were 3.44 mg/ml and 32.55 kJ/mol, respectively. Amylose was found to be a better substrate than soluble starch and amylopectin. Al(3+), Fe(3+), and Hg(2+) (10 mM) almost completely inhibited the alpha-amylase.


HCV prevalence in methadone maintenance: self-report versus serum test.
To assess hepatitis C virus (HCV) serostatus, risk factors, and desire for education about HCV among methadone maintenance treatment (MMT) patients. We surveyed 200 MMT patients and reviewed charts for 276 patients. The self-report HCV seroprevalence was 34%, adjusted to 52%. The chart review HCV seroprevalence was 70%. Most participants had risk factors for contracting or spreading HCV. There is discrepancy in HCV seroprevalence by self-report versus serum test results among MMT patients. Some HCV+ MMT patients engage in high-risk behaviors for HCV transmission and may not disclose HCV+ status. MMT patients want HCV education.


Preeclampsia as a risk factor for diabetes: a population-based cohort study.
Women with preeclampsia (PEC) and gestational hypertension (GH) exhibit insulin resistance during pregnancy, independent of obesity and glucose intolerance. Our aim was to determine whether women with PEC or GH during pregnancy have an increased risk of developing diabetes after pregnancy, and whether the presence of PEC/GH in addition to gestational diabetes (GDM) increases the risk of future (postpartum) diabetes. We performed a population-based, retrospective cohort study for 1,010,068 pregnant women who delivered in Ontario, Canada between April 1994 and March 2008. Women were categorized as having PEC alone (n=22,933), GH alone (n=27,605), GDM alone (n=30,852), GDM+PEC (n=1,476), GDM+GH (n=2,100), or none of these conditions (n=925,102). Our main outcome was a new diagnosis of diabetes postpartum in the following years, up until March 2011, based on new records in the Ontario Diabetes Database. The incidence rate of diabetes per 1,000 person-years was 6.47 for women with PEC and 5.26 for GH compared with 2.81 in women with neither of these conditions. In the multivariable analysis, both PEC alone (hazard ratio [HR]=2.08; 95% CI 1.97-2.19) and GH alone (HR=1.95; 95% CI 1.83-2.07) were risk factors for subsequent diabetes. Women with GDM alone were at elevated risk of developing diabetes postpartum (HR=12.77; 95% CI 12.44-13.10); however, the co-presence of PEC or GH in addition to GDM further elevated this risk (HR=15.75; 95% CI 14.52-17.07, and HR=18.49; 95% CI 17.12-19.96, respectively). Data on obesity were not available. Women with PEC/GH have a 2-fold increased risk of developing diabetes when followed up to 16.5 years after pregnancy, even in the absence of GDM. The presence of PEC/GH in the setting of GDM also raised the risk of diabetes significantly beyond that seen with GDM alone. A history of PEC/GH during pregnancy should alert clinicians to the need for preventative counseling and more vigilant screening for diabetes. Please see later in the article for the Editors' Summary.


Factors of increase in serum triglyceride-rich lipoproteins in uremic rats.
The possible mechanisms of the increase in serum triglycerides (TG) and TG-rich lipoproteins were studied in chronically uremic (U) rats by comparison with either ad-lib fed control (C) rats or diet-restricted (DR), sham-operated pair-fed control rats. A first series of animals was studied in the fed state and a second series after a 16-hr fast. In U animals the concentration of serum TG and TG-rich particles was lower than that of C rats in the fed state but significantly higher than that of C and DR rats after a 16-hr fast. Serum glucose and lactate concentrations in the fed or fasted state were unchanged by uremia. Serum insulin concentration was significantly decreased in U rats as compared to C and DR rats in both series. The fast did not increase the concentration of serum nonesterified fatty acids (NEFA) in U or DR animals to the same extent as in C rats, whereas the serum concentration of beta-hydroxybutyrate (BOB), which was higher than that of C rats in the fed state, was significantly lower after a 16-hr fast. In U animals, as compared to control rats of either series, a significant decrease of epididymal lipoprotein lipase (LPL) activity was observed during both nutritional states when expressing the enzymic activity per number of cells. In conclusion, our data provide evidence against hepatic over-production of TG-rich lipoproteins in rats with chronic renal failure and strongly point to an LPL-mediated defect of their peripheral catabolism, probably related to the insulin deficiency state.


Soil properties and plant species can predict population size and potential introduction sites of the endangered orchid Cypripedium calceolus.
To counteract the ongoing worldwide biodiversity loss, conservation actions are required to re-establish populations of threatened species. Two key factors predominantly involved in finding the most suitable habitats for endangered plant species are the surrounding plant community composition and the physicochemical parameters of the soil rooting zone. However, such factors are likely to be context- and species-dependent, so it remains unclear to what extent they influence the performance of target species. We studied large and small Swiss populations of the endangered orchid Cypripedium calceolus. We measured functional traits related to C. calceolus plant and population performance (clonal patch area, plant height, number, of leaf, stems, flowers and fruits), realized vegetation surveys, soil profile analyses, and tested for relationships between plant traits and the surrounding vegetation structure or soil physicochemical parameters. Large populations contained bigger patches with more stems and leaves, and produced more flower per individual than small populations. Neither vegetation alliances nor soil classes per se could predict C. calceolus functional traits and population size. However, functional traits explaining population performance and size were related to specific soil parameters (soil organic matter content, pH and phosphorus), in addition to a combination of presence-absence of plant indicator species, relating to ecotones between forests and clearings. We show that even for species that can grow across a wide range of vegetation groups both indicator species and specific soil parameters can be used to assess the most favourable sites to implement (re)-introduction actions. The online version contains supplementary material available at 10.1007/s11104-023-05945-4.


Long-term variations and potency of neutralizing antibodies against Omicron subvariants after CoronaVac-inactivated booster: A 7-month follow-up study.
The long-term protective efficacy of neutralizing antibodies (Nabs) against Omicron subvariants after inactivated booster vaccines remains elusive. During the follow-up study, 54 healthy volunteers aged 20-31 years received inactivated CoronaVac booster vaccinations and were monitored for 221 days. The dynamic efficacy and durability of Nab against Omicron subvariants BA.1, BA.2, BA.2.12.2, and BA4/5 were assessed using a pseudotyped virus neutralization assay at up to nine time points post immunization. The antibody response against Omicron subvariants was substantially weaker than D614G, with BA.4/5 being the least responsive. The geometric mean titer (GMT) of Nab against Omicron subvariants BA.1, BA.2, BA.2.12.1, and BA.4/5 was 2.2-, 1.7-, 1.8-, and 2.2-fold lower than that against D614G (ps < 0.0001). The gap in Nab response between Omicron subvariants was pronounced during the 2 weeks-2 months following booster vaccination (ps < 0.05). Seven months post booster, the antibody potency against D614G was maintained at 100% (50% for Nab titers ≥ 100 50% inhibitory dilution [EC50 ]), whereas at 77.3% for BA.1, 90.9% for BA.2, 86.4% for BA.2.12.1, and 86.4% for BA.4/5 (almost 20% for Nab titers ≥ 100 EC50 ). Despite the inevitable immune escape, Omicron subvariants maintained sustained and measurable antibody potency post-booster vaccination during long-term monitoring, which could help optimize immunization strategies.


Effects of various doses of thyroxine and triiodothyronine on the metamorphosis of flounder (Paralichthys olivaceus).
Two experiments were carried out to clarify the effects of thyroxine (T4) and triiodothyronine (T3) on flounder metamorphosis. In the first experiment, three doses of T4 were administered to premetamorphic flounder larvae together with thiourea (TU). Thiourea treatment (30 ppm in ambient seawater) alone caused metamorphic stasis in the fish, although the beginning of the right eye migration was not completely inhibited. T4 at 100 and 10 ppb in ambient seawater induced metamorphosis in the thiourea-treated larvae. The fish of these groups completed translocation of the right eye to the left side and resorption of elongated dorsal fin rays. However, 1 ppb T4 failed to induce metamorphic climax. The elongated dorsal fin rays continued to grow until the end of the experiment in the group treated with TU alone and in combination with 1 ppb T4. In the second experiment, premetamorphic flounder larvae were treated with two doses of T4 and three doses of T3. The T3 treatment was several times more potent than T4 treatment in the induction of metamorphosis. The results of the present study suggest that the metamorphic events of flounder larvae are dependent on the thyroid hormone concentration, and the relative biological potency of T4 and T3 on flounder metamorphosis is similar to that observed in mammals and amphibia.


Effect of age on levels of diazepam in plasma and brain of rats.
The pharmacokinetics and distribution in brain and cerebellum of diazepam after a single dose were studied in middle aged (6 months) and old (18 months) rats. Following the single intravenous bolus of 5 mg/kg diazepam was eliminated more slowly in old rats (T 1/2 (beta) = 3.1 H) than in middle aged rats (1.4H). This was due to an increase in the apparent volume of distribution Vd beta from 11.0 l/kg (control rats) to 29.5 l/kg. Concentrations of diazepam in brain and cerebellum were in the same range (0.5-1.1 ng/mg) in both groups after this dose. We conclude that the distribution of diazepam is age-dependent which might be due to an altered body composition.


Defeating the Hidden Foe: Antibiotic Therapy and Clinical Outcomes of Cutibacterium acnes Spinal Implant Infections.
Cutibacterium acnes can cause spinal implant infections. However, little is known about the optimal medical management and outcomes of C. acnes spinal implant infections (CSII). Our study aims to describe the management of patients with CSII and evaluate the clinical outcomes. We performed a retrospective cohort study of patients aged 18 years or older who underwent spinal fusion surgery with instrumentation between January 1, 2011, and December 31, 2020, and whose intraoperative cultures were positive for C. acnes. The primary outcome was treatment failure based on subsequent recurrence, infection with another organism, or unplanned surgery secondary to infection. There were 55 patients with a median follow-up (interquartile range) of 2 (1.2-2.0) years. Overall, there were 6 treatment failures over 85.8 total person-years, for an annual rate of 7.0% (95% CI, 2.6%-15.2%). Systemic antibiotic treatment was given to 74.5% (n = 41) of patients for a median duration of 352 days. In the subgroup treated with systemic antibiotics, there were 4 treatment failures (annual rate, 6.3%; 95% CI, 1.7%-16.2%), all of which occurred while on antibiotic therapy. Two failures occurred in the subgroup without antibiotic treatment (annual rate, 8.8%; 95% CI, 1.1%-31.8%). Our study found that the estimated annual treatment failure rate was slightly higher among patients who did not receive antibiotics. Of the 6 failures observed, 4 had recurrence of C. acnes either on initial or subsequent treatment failures. More studies are warranted to determine the optimal duration of therapy for CSII.


Antiamoebin can function as a carrier or as a pore-forming peptaibol.
Antiamoebin is a 16-residue polypeptide whose crystal structure and lytic activity in membrane vesicles have recently been reported. It is a bent helical molecule and a member of the peptaibol family of antibiotics. Under conditions which produce voltage-dependent conductance activity by other members of the family, no single-channel conductance was detected for antiamoebin, and a carrier-like mechanism was put forward to account for its mode of action. We now present evidence for pore formation that is largely voltage-insensitive, with large amplitude single-channel events on top of a background conductance that may account for the previously proposed carrier-like activity. Thus, antiamoebin may be the first instance of a peptide which can function both as an ion carrier and a pore former.


Small cytoplasmic RNAs from rat liver mRNP particles. Studies on their structure and function.
Free cytoplasmic 40S mRNP particles from rat liver were treated with EDTA and separated into two populations of RNP particles with sedimentation maxima of 20S and 35S, respectively. A characteristic set of distinct scRNAs is found for 20S and 35S RNP particles. The sequences of two of the most abundant scRNAs from 20S RNP particles with chain lengths of 104 (alpha 1-RNA) and 124 (beta 1-RNA) nucleotides, respectively, are presented. alpha 1-RNA shows a high sequence homology to the 3'-end of 18S rRNA. Since alpha 1-RNA carries a cap, it cannot be a degradation product of 18S rRNA. The beta 1-RNA is strongly post-transcriptionally modified, but uncapped. When the individual scRNAs of 20S and 35S RNP particles isolated from preparative polyacrylamide gels were assayed for their capability to inhibit in vitro protein synthesis, several potent translational inhibitory RNAs were detected. Particularly, the scRNAs of 147,203 and 263 nucleotide length associated with the 35S RNP particles turned out to be strong inhibitors of protein synthesis.


"… because I'm so drunk at the time, the last thing I'm going to think about is calories": Strengthening the argument for Drunkorexia as a food and alcohol disturbance, evidence from a qualitative study.
Drunkorexia are inappropriate compensatory behaviours in response to alcohol consumption (restricting food intake, excessive exercise, and purging). Past (predominantly quantitative) research shows that Drunkorexia is prevalent in 18-26-year-olds, and has significant negative health-related consequences. There is a debate whether Drunkorexia constitutes an eating or substance disorder, or a Food and Alcohol Disturbance (FAD). To further explore this, and understand underlying motivators, this study utilized qualitative methods. Qualitative interviews with ten participants (aged 18-26). Interviews were analysed with Thematic Analysis. Three themes were developed: (1) Appearance concerns as motivators, (2) Drunkorexia behaviours to get value for money, and (3) "It's just a pattern… something I've always done": Drunkorexia as a routine. Results show that Drunkorexia is driven by appearance-related concerns, such as, wanting to look better/slimmer, engaged in, in relation to an event, such as going out drinking, and carried out despite negative health-related consequences. However, disregard for compensatory behaviours once drunk was also described, culminating in the consumption of high-calorie food. This suggests that Drunkorexia is not a persistent pattern of maladaptive behaviour as found in eating or substance use disorders. Wanting value for money (i.e., feeling the maximum intoxication) was described as another reason for Drunkorexia engagement; thus showing that participants consider compensatory behaviours part of their routine of going out drinking. These result support the view of Drunkorexia as a FAD, rather than an eating or substance use disorder, and show that 18-26-year-olds are an at-risk group for Drunkorexia and its negative health-related consequences.


Ectomesenchymoma. A malignant tumor of migratory neural crest (ectomesenchyme) remnants showing ganglionic, schwannian, melanocytic and rhabdomyoblastic differentiation.
A case is reported in which a tumor containing elements of mature and immature ganglioneuroma, Schwannoma, clusters of apparently benign melanocytes and embryonal rhabdomyosarcoma presented as a right-sided facial mass in a six-month-old child. Different elements of the tumor were intimately intermingled without distinct borders. Embryogenesis of the tumor, which is thought to arise from remnants of migratory neural crest cells (ectomesenchyme), showing multidirectional phenotypic expression is discussed. It was felt that the lesion contributed additional evidence in support of pluripotentiality of the migratory, neural crest derivatives, and their susceptibility to mutagenic and oncogenic influences.


Matching-Adjusted Indirect Comparisons of Diroximel Fumarate, Ponesimod, and Teriflunomide for Relapsing Multiple Sclerosis.
Diroximel fumarate (DRF), ponesimod (PON), and teriflunomide (TERI) are oral disease-modifying therapies approved for the treatment of relapsing multiple sclerosis. No randomized trials have compared DRF versus PON or TERI. The objectives of this analysis were to compare DRF versus PON and DRF versus TERI for clinical and radiological outcomes. We used individual patient data from EVOLVE-MS-1, a 2-year, open-label, single-arm, phase III trial of DRF (n = 1057), and aggregated data from OPTIMUM, a 2-year, double-blind, phase III trial comparing PON (n = 567) and TERI (n = 566). To account for cross-trial differences, EVOLVE-MS-1 data were weighted to match OPTIMUM's average baseline characteristics using an unanchored matching-adjusted indirect comparison. We examined the outcomes of annualized relapse rate (ARR), 12-week confirmed disability progression (CDP), 24-week CDP, absence of gadolinium-enhancing (Gd+) T1 lesions, and absence of new/newly enlarging T2 lesions. After weighting, we did not observe strong evidence of differences between DRF and PON for ARR [DRF versus PON incidence rate difference (IRD) -0.02; 95% confidence interval (CI) -0.08, 0.04; incidence rate ratio (IRR) 0.92; 95% CI 0.61, 1.2], 12-week CDP [risk difference (RD) -2.5%; 95% CI -6.3, 1.2; risk ratio (RR) 0.76; 95% CI 0.38, 1.1], 24-week CDP (RD -2.7%; 95% CI -6.0, 0.63; RR 0.68; 95% CI 0.28, 1.0), and absence of new/newly enlarging T2 lesions (RD -2.5%; 95% CI -13, 7.4; RR 0.94; 95% CI 0.70, 1.2). However, a higher proportion of DRF-treated patients were free of Gd+ T1 lesions than PON-treated patients (RD 11%; 95% CI 6.0, 16; RR 1.1; 95% CI 1.06, 1.2). Compared with TERI, DRF showed improved ARR (IRD -0.08; 95% CI -0.15, -0.01; IRR 0.74; 95% CI 0.50, 0.94), 12-week CDP (RD -4.2%; 95% CI -7.9, -0.48; RR 0.67; 95% CI 0.38, 0.90), 24-week CDP (RD -4.3%; 95% CI -7.7, -1.1; RR 0.57; 95% CI 0.26, 0.81), and absence of Gd+ T1 lesions (RD 25%; 95% CI 19, 30; RR 1.4; 95% CI 1.3, 1.5). However, DRF and TERI did not appear to differ significantly with respect to absence of new/newly enlarging T2 lesions when based on comparisons using the overall EVOLVE-MS-1 sample (RD 8.5%; 95% CI -0.93, 18; RR 1.3; 95% CI 0.94, 1.6), or in a sensitivity analysis restricted to newly enrolled EVOLVE-MS-1 patients (RD 2.7%; 95% CI -9.1, 14; RR 1.1; 95% CI 0.68, 1.5). We did not observe differences between DRF and PON for ARR, CDP, and absence of new/newly enlarging T2 lesions, but there was a higher proportion of patients free of Gd+ T1 lesions among DRF-treated patients than PON-treated patients. DRF had improved efficacy versus TERI for all clinical and radiological outcomes, except for absence of new/newly enlarging T2 lesions. EVOLVE-MS-1 (ClinicalTrials.gov identifier: NCT02634307); OPTIMUM (ClinicalTrials.gov identifier: NCT02425644).


Neurological manifestations as the initial presentation of acute myelogenous leukemia.
This case report illustrates neurological deficits as an unusual presentation of acute myelogenous leukemia. Neurological deficits are rare early in this disease. Our patient presented with anorexia, malaise, headache, and multiple cranial nerve palsies. A high WBC count and abnormal peripheral smear led to the diagnosis of leukemia. This report demonstrates that, although rare, CNS symptoms may be the initial manifestation of leukemia. Blood dyscrasias should not be overlooked in patients with the acute onset of neurological symptoms. A complete blood count and differential should be obtained under those circumstances.


DNA methylation as a triage marker for colposcopy referral in HPV-based cervical cancer screening: a systematic review and meta-analysis.
Screening plays a key role in secondary prevention of cervical cancer. High-risk human papillomavirus (hrHPV) testing, a highly sensitive test but with limited specificity, has become the gold standard frontline for screening programs. Thus, the importance of effective triage strategies, including DNA methylation markers, has been emphasized. Despite the potential reported in individual studies, methylation markers still require validation before being recommended for clinical practice. This systematic review and meta-analysis aimed to evaluate the performance of DNA methylation-based biomarkers for detecting high-grade intraepithelial lesions (HSIL) in hrHPV-positive women. Hence, PubMed, Scopus, and Cochrane databases were searched for studies that assessed methylation in hrHPV-positive women in cervical scrapes. Histologically confirmed HSIL was used as endpoint and QUADAS-2 tool enabled assessment of study quality. A bivariate random-effect model was employed to pool the estimated sensitivity and specificity as well as positive (PPV) and negative (NPV) predictive values. Twenty-three studies were included in this meta-analysis, from which cohort and referral population-based studies corresponded to nearly 65%. Most of the women analyzed were Dutch, and CADM1, FAM19A4, MAL, and miR124-2 were the most studied genes. Pooled sensitivity and specificity were 0.68 (CI 95% 0.63-0.72) and 0.75 (CI 95% 0.71-0.80) for cervical intraepithelial neoplasia (CIN) 2+ detection, respectively. For CIN3+ detection, pooled sensitivity and specificity were 0.78 (CI 95% 0.74-0.82) and 0.74 (CI 95% 0.69-0.78), respectively. For pooled prevalence, PPV for CIN2+ and CIN3+ detection were 0.514 and 0.392, respectively. Furthermore, NPV for CIN2+ and CIN3+ detection were 0.857 and 0.938, respectively. This meta-analysis confirmed the great potential of DNA methylation-based biomarkers as triage tool for hrHPV-positive women in cervical cancer screening. Standardization and improved validation are, however, required. Nevertheless, these markers might represent an excellent alternative to cytology and genotyping for colposcopy referral of hrHPV-positive women, allowing for more cost-effective screening programs.


Interdomain side-chain interactions in human gammaD crystallin influencing folding and stability.
Human gammaD crystallin (HgammaD-Crys) is a two domain, beta-sheet eye lens protein that must remain soluble throughout life for lens transparency. Single amino acid substitutions of HgammaD-Crys are associated with juvenile-onset cataracts. Features of the interface between the two domains conserved among gamma-crystallins are a central six-residue hydrophobic cluster, and two pairs of interacting residues flanking the cluster. In HgammaD-Crys these pairs are Gln54/Gln143 and Arg79/Met147. We previously reported contributions of the hydrophobic cluster residues to protein stability. In this study alanine substitutions of the flanking residue pairs were constructed and analyzed. Equilibrium unfolding/refolding experiments at 37 degrees C revealed a plateau in the unfolding/refolding transitions, suggesting population of a partially folded intermediate with a folded C-terminal domain (C-td) and unfolded N-terminal domain (N-td). The N-td was destabilized by substituting residues from both domains. In contrast, the C-td was not significantly affected by substitutions of either domain. Refolding rates of the N-td were significantly decreased for mutants of either domain. In contrast, refolding rates of the C-td were similar to wild type for mutants of either domain. Therefore, domain interface residues of the folded C-td probably nucleate refolding of the N-td. We suggest that these residues stabilize the native state by shielding the central hydrophobic cluster from solvent. Glutamine and methionine side chains are among the residues covalently damaged in aged and cataractous lenses. Such damage may generate partially unfolded, aggregation- prone conformations of HgammaD-Crys that could be significant in cataract.


Prevalence and Seasonality of the Amphibian Chytrid Fungus Batrachochytrium dendrobatidis Along Widely Separated Longitudes Across the United States.
The chytrid fungus Batrachochytrium dendrobatidis (Bd) has been implicated in amphibian declines on almost all continents. We report on prevalence and intensity of Bd in the United States amphibian populations across three longitudinally separated north-to-south transects conducted at 15 Department of Defense installations during two sampling periods (late-spring/early summer and mid to late summer). Such a standardized approach minimizes the effects of sampling and analytical bias, as well as human disturbance (by sampling restricted military bases), and therefore permits a cleaner interpretation of environmental variables known to affect chytrid dynamics such as season, temperature, rainfall, latitude, and longitude. Our prevalence of positive samples was 20.4% (137/670), and our mean intensity was 3.21 zoospore equivalents (SE = 1.03; range 0.001-103.59). Of the 28 amphibian species sampled, 15 tested positive. Three sites had no evidence of Bd infection; across the remaining 12 Bd-positive sites, neither infection prevalence nor intensity varied systematically. We found a more complicated pattern of Bd prevalence than anticipated. Early season samples showed no trend associated with increasing temperature and precipitation and decreasing (more southerly) latitudes; while in late season samples, the proportion of infected individuals decreased with increasing temperature and precipitation and decreasing latitudes. A similar pattern held for the east-west gradient, with the highest prevalence associated with more easterly/recently warmer sites in the early season then shifting to more westerly/recently cooler sites in the later season. Bd intensity across bases and sampling periods was comparatively low. Some of the trends in our data have been seen in previous studies, and our results offer further continental-level Bd sampling over which more concentrated local sampling efforts can be overlaid.


Development of the thyroid.
The fetal hypothalamic-pituitary-thyroid axis develops autonomously of maternal influence. System ontogenesis begins with the appearance and histological development of the thyroid and pituitary glands followed by development of the hypothalamus and the pituitary portal vascular system. Hypothalamic-pituitary control of thyroid function matures during the last half of human fetal development. Thyroid hormones undergo several types of biochemical transformations in tissues, including deiodination, side-chain metabolism, and conjugation with sulphate or glucuronide. Enzyme-mediated monodeiodination is the most important pathway. The first step in T4 metabolism is either outer-ring monodeiodination to active T3 or innerring monodeiodination to inactive rT3. Most T4 is metabolized to rT3 in fetal tissues and/or placenta and rT3 is the major circulating T4 metabolite in the fetus. Selective tissues, such as brain, can monodeiodinate T4 to T3, and this T3 is available for local action. Nuclear thyroid hormone receptors mature at different times in different tissues. Receptors appear earlier in brain than in liver and local T3 production and action may be important in fetal brain development. Most thyroid hormone actions, however, appear in the perinatal period, and infants with thyroid agenesis appear normal at birth and develop normally with prompt neonatal diagnosis and treatment. Premature infants, particularly those less than 30-32 weeks' gestational age, have an immature thyroid system and manifest a state of transient hypothalamic-pituitary TSH deficiency. This does not require treatment. Infants with primary hypothyroidism, either due to thyroid dysgenesis or to thyroid dyshormonogenesis, by contrast, require prompt diagnosis and treatment. Rarely an infant is born with permanent TSH deficiency with or without other pituitary hormone deficiencies. These infants also require prompt treatment. Mothers with thyroid disease or a history of thyroid disease and with IgG autoantibodies to thyroid gland TSH receptors may deliver infants with hypothyroidism or hyperthyroidism due to transplacental passage of the receptor-blocking or receptor-stimulating autoantibodies. These infants also require careful evaluation and management.


Building a Health Care Legal Partnership Learning Collaborative.
Many Americans need both health care and legal interventions to maximize their opportunities for health. Medical-legal partnerships (MLPs), also known as health care legal partnerships (HLPs), bring the power of law to health care to reduce barriers and negative social determinants of health. The two terms--HLP and MLP--are used interchangeably in this article. Growing research shows that these partnerships can improve care, improve health, enhance interprofessional collaboration, and improve the financial status of patients and providers. HLPs take many forms, depending on their settings and resources. A health care legal partnership learning collaborative that brings leaders of diverse HLPs together to share experiences and best practices can help expand this effective model and enhance its potential for collective impact in improving population health.


Metabonomic study of biochemical changes in the rat urine induced by Pinellia ternata (Thunb.) Berit.
We adopted an ultra performance liquid chromatography coupled with quadrupole time-of-fight mass spectrometry (UPLC Q-TOF/MS) metabonomics approach to study metabonomic features of rats induced by orally administered Pinellia ternata (Thunb.) Berit. (BX). The integrated urinary MS data were analyzed via principal component analysis (PCA) and partial least squares-discriminant analysis (OPLS-DA) to identify the differential metabolites. Ten potential biomarkers were identified within complex sample matrix of urine. The identified biomarkers indicated the perturbations of tryptophan, phenylacetylglycine and pantothenic acid metabolism in BX-induced rats. The biomarkers that were found to be changed with the passage of time were explained tentatively based on previous study.


Culture-negative sepsis after pediatric cardiac surgery: Incidence and outcomes.
Significant proportion of congenital heart surgery (CHS) children exhibit sepsis, but have negative blood culture and defined "culture negative sepsis (CNS)." Retrospective analysis of CNS patients undergoing CHS. 437 consecutive CHS children grouped as controls (antibiotic prophylaxis), CNS, and culture positive sepsis (CPS). Incidences of CNS and CPS were 16% and 7%. Median mechanical ventilation (MV) in hours among CPS, CNS, and control was 116 (45-271), 63 (23-112), and 18 (6-28) (P < 0.001), respectively. Multivariable linear regression identified CPS (median ratio: 3.1 [2.3-4.1], P < 0.001), CNS (median ratio: 5.6 [3.7-8.4], P < 0.001), and weight (kg) (median ratio: 0.98 [0.96-0.99], P = 0.009) as associations of MV. Intensive care unit (ICU) stay (hours) was 192 (120-288) in CNS, 288 (156-444) in CPS, and 72 (48-120) in controls (P < 0.0001). Multivariable linear regression showed CNS (median ratio: 2.4 [2.0-2.9], P< 0.001) CPS (median ratio: 3.3 [2.5-4.4], P < 0.001), and weight (median ratio: 0.98 [0.97-0.99], P ≤ 0.001) prolonging ICU stay. Mortality was 10.7%, 2.9% and 1.2% in CPS, CNS, and control (P = 0.03). Multivariable regression identified CPS an independent predictor of mortality with odds ratio 8.6 (1.7-44.9; P = 0.010). 11.26% patients in CNS and 79.3% in CPS received antibiotics for more than 10 days. Incidence of CNS was 16%; duration of MV and ICU stay and mortality was significantly less in CNS than CPS patients.


Comparative Studies of the (Anti) Mutagenicity of Baccharis dracunculifolia and Artepillin C by the Bacterial Reverse Mutation Test.
Baccharis dracunculifolia is a plant native from Brazil, commonly known as 'Alecrim-do-campo' and 'Vassoura' and used in alternative medicine for the treatment of inflammation, hepatic disorders and stomach ulcers. Previous studies reported that artepillin C (ArtC, 3-{4-hydroxy-3,5-di(3-methyl-2-butenyl)phenyl}-2(E)-propenoic acid), is the main compound of interest in the leaves. This study was undertaken to assess the mutagenic effect of the ethyl acetate extract of B. dracunculifolia leaves (Bd-EAE: 11.4-182.8 µg/plate) and ArtC (0.69-10.99 µg/plate) by the Ames test using Salmonella typhimurium strains TA98, TA97a, TA100 and TA102, and to compare the protective effects of Bd-EAE and ArtC against the mutagenicity of a variety of direct and indirect acting mutagens such as 4-nitro-O-phenylenediamine, sodium azide, mitomycin C, benzo[a]pyrene, aflatoxin B1, 2-aminoanthracene and 2-aminofluorene.The mutagenicity test showed that Bd-EAE and ArtC did not induce an increase in the number of revertant colonies indicating absence of mutagenic activity. ArtC showed a similar antimutagenic effect to that of Bd-EAE in some strains of S. typhimurium, demonstrating that the antimutagenic activity of Bd-EAE can be partially attributed to ArtC. The present results showed that the protective effect of whole plant extracts is due to the combined and synergistic effects of a complex mixture of phytochemicals, the total activity of which may result in health benefits.


TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury.
In normal kidney, TNFR1 is expressed in glomerular and peritubular capillary EC, and some tubular cells, and colocalizes with inactive apoptosis signal-regulating kinase-1 (ASK1) phosphorylated at serine 967. Biopsies of rejecting or ischemic renal allografts, which show both tubular cell injury and proliferation, display down-regulation of TNFR1 and activation of ASK1 as well as up-regulation of TNFR2 on tubular cells, where it colocalizes with phosphorylated endothelial/epithelial tyrosine kinase (Etk). We have exploited receptor-selective muteins and evaluated phosphorylation of receptor-specific kinases to study TNF responses in situ. In organ culture, a TNFR1-specific mutein changes phosphorylation of ASK1 to threonine 845, indicative of kinase activation. A TNFR2-specific mutein down-regulates TNFR1 in glomerular EC, up-regulates TNFR2 and Etk in tubular cells, and induces phosphorylation of Etk. Wild-type TNF induces TNFR2 and Etk and activates both ASK1 and Etk but does not down-regulate TNFR1. Wild-type TNF and TNFR1-specific mutein trigger tubular cell apoptosis whereas wild-type TNF and TNFR2-specific mutein induce tubular cells to express proliferating cell nuclear antigen. Differential activation of ASK1 and Etk by regulated TNFRs in patient-derived materials provides an explanation for diverse and opposing responses to TNF at distinct sites, and an in situ bioassay of TNFR signaling.


Outcomes following minimally invasive plate osteosynthesis (MIPO) application in tibial pilon fractures - A systematic review.
This systematic review evaluates postoperative complications and functional outcomes of minimally invasive plate osteosynthesis (MIPO) for distal tibial pilon fractures. This paper aims to fill a key literature gap, as no previous reviews have specifically addressed MIPO for tibial pilon fractures or fractures other than those involving the humeral shaft. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic literature search was done using PubMed, Embase, Web of Science, and Scopus databases from 2000 to 2022. Inclusion criteria were MIPO treatment in skeletally mature patients, while exclusion criteria were non-English papers, conference abstracts, papers with multiple treatment modalities that didn't analyze MIPO outcomes separately, skeletally immature patients, case reports, and cohorts smaller than five patients. Unpublished papers were also searched using Clinical Trials. Data extraction included general study information, injury specification, outcome measures, and complications. Finally, a risk of bias assessment (RoB) was performed. A total of 1732 studies were identified, of which 23 were included in this review, with 673 patients and 678 fractures analyzed. The mean follow-up ranged from 6 to 62.53 months, with most studies representing intermediate to long-term follow-up. Primary outcome measures showed that 87.33% achieved 'excellent to good' results, 8.67% achieved 'fair' results, and 4% achieved 'poor' results. Stratified by fracture type, 76.47%, 80.05%, and 76.92% of AO/OTA type A, B, and C fractures, respectively, achieved 'excellent to good' results. 35.06% of cases reported complications (236 in total). These included one case of deep infection (0.148%), 28 superficial wound infections (4.16%), 4 nonunion cases (0.59%), and 22 malunion instances (3.27%). RoB assessment showed that 52.17% had a moderate overall risk of bias, 39.13% had a serious overall risk of bias, and 8.7% had a critical overall risk of bias. MIPO technique for pilon fractures showed good functional outcomes and reliability, with low complication rates and should be considered in cases where proper indirect reduction is possible. However, while the evidence is promising, further high-quality studies with larger sample sizes, longer-term follow-up, and comparison to other techniques are needed to evaluate the efficacy and safety of this technique. IV.


Diagnosis of coronary stenosis by two-dimensional echographic study of dysfunction of ventricular segments during and immediately after pacing.
The adequacy of two-dimensional echocardiography during right atrial pacing for the detection and characterization of coronary artery stenosis was examined in 10 closed chest dogs. Pacing at successively higher rates up to 210 beats/min was carried out in the control state and again during a 70% left anterior descending coronary artery stenosis-induced with intracoronary plugs. Left ventricular short-axis echographic cross sections were obtained at several levels of the left ventricle. After computer-aided standardized subdivision, contractile function of the global section and its subsegments was characterized by computed systolic fractional area change percent and wall thickening percent. Ventricular segments supplied from the site of the 70% coronary stenosis were delineated in a low papillary level cross section by a myocardial contrast echographic technique, and these segments demonstrated significant dysfunction during pacing at 150 to 210 beats/min. Echographic observation of the involved segments immediately after pacing revealed a maximal depression of function 5 seconds after pacing, equivalent to dysfunction at peak pacing, with function returning to control levels within about 2 minutes. Both maximal pacing and early postpacing studies facilitated satisfactory discrimination of ischemic from normally perfused myocardial segments. These experiments show that right atrial pacing study with quantitative two-dimensional echocardiography may serve to detect and assess a coronary stenosis associated with minor or no cardiac dysfunction in the rest state.


Citric acid crosslinked β-cyclodextrin/carboxymethylcellulose hydrogel films for controlled delivery of poorly soluble drugs.
Citric acid crosslinked β-cyclodextrin-carboxymethylcellulose (βCD-CMC) hydrogel films were prepared by esterification-crosslinking method for the controlled release of ketoconazole (model drug). The hydrogel films were evaluated for active βCD content, carboxyl content, swelling ratio, drug loading and release, and hemolytic activity. The structural characterization was carried out using solid state 13C NMR, ATR-FTIR, TGA and DSC analysis. The βCD-CMC hydrogel films showed increase in active βCD content swelling ratio and drug loading with increase in the concentration of βCD in the feed. The βCD helped to minimize the burst effect and retarded the release of ketoconazole. The hydrogel films were found to be biocompatible and capable of controlling the release of ketoconazole for long duration.


Antifungal and antimycobacterial activity of 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives.
1-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives were synthesized and tested for their in vitro antifungal and antimycobacterial activities. These imidazole derivatives showed an excellent antifungal activity against a clinical strain of Candida albicans and an interesting antitubercular activity against Mycobacterium tuberculosis H(37)Rv reference strain.


Brain-scale cortico-cortical functional connectivity in the delta-theta band is a robust signature of conscious states: an intracranial and scalp EEG study.
Long-range cortico-cortical functional connectivity has long been theorized to be necessary for conscious states. In the present work, we estimate long-range cortical connectivity in a series of intracranial and scalp EEG recordings experiments. In the two first experiments intracranial-EEG (iEEG) was recorded during four distinct states within the same individuals: conscious wakefulness (CW), rapid-eye-movement sleep (REM), stable periods of slow-wave sleep (SWS) and deep propofol anaesthesia (PA). We estimated functional connectivity using the following two methods: weighted Symbolic-Mutual-Information (wSMI) and phase-locked value (PLV). Our results showed that long-range functional connectivity in the delta-theta frequency band specifically discriminated CW and REM from SWS and PA. In the third experiment, we generalized this original finding on a large cohort of brain-injured patients. FC in the delta-theta band was significantly higher in patients being in a minimally conscious state (MCS) than in those being in a vegetative state (or unresponsive wakefulness syndrome). Taken together the present results suggest that FC of cortical activity in this slow frequency band is a new and robust signature of conscious states.


Early events in ischemic renal failure in the rat: effects of antioxidant therapy.
Renal ischemia followed by two hours of reperfusion produces a complex form of acute renal failure characterized by a reduction in nephron filtration rate (SNGFR) and moderate proximal tubular damage. We have examined glomerular hemodynamics, SNGFR and histologic changes after renal ischemia and two hours of reperfusion in untreated (I) rats and rats pretreated with the antioxidant, probucol (IP). SNGFR decreased significantly by 47% in I rats. Reduction in SNGFR was primarily the result of a major decrease in the glomerular capillary hydrostatic pressure gradient, delta P, and a decrease in nephron plasma flow (SNPF). The glomerular ultrafiltration coefficient remained equal to control valves. In IP rats SNGFR was improved to values 89% of control rats due to higher values of delta P and SNPF. Histologic evidence of modest damage to cells of the proximal tubule was equal in both untreated and probucol treated ischemic animals. These studies demonstrate that: (a) primary reductions in nephron filtration rate at the glomerulus result from decreases in delta P and nephron plasma flow; b) pretreatment with the antioxidant, probucol, increases nephron plasma flow and SNGFR, and maintains more normal values for delta P; and c) tubular damage was equivalent in I and IP rats in spite of differences in SNGFR.


Forty-Year Follow-Up After Great Toe-to-Thumb Transfer: A Literature Review.
The thumb is a crucial part of the hand, and traumatic thumb amputation is a devastating injury that significantly diminishes hand function. In situations in which replantation is not possible, great toe-to-thumb transfer is a well-established option for reconstruction. Although most studies describe excellent functional outcomes and patient satisfaction, there is a paucity of literature presenting long-term follow-up to determine whether these outcomes are maintained. In this case report, we present a case of great toe-to-thumb transfer performed 40 years ago and evaluate outcomes using validated questionnaires and standardized examination maneuvers. Our results highlight sustained patient satisfaction and excellent functional outcomes decades after the initial reconstruction.


Affinity of osteogenin, an extracellular bone matrix associated protein initiating bone differentiation, for concanavalin A.
Subcutaneous implantation of demineralized bone matrix results in bone differentiation. The bone inductive protein, osteogenin, was isolated recently by heparin affinity chromatography. The affinity of osteogenin for various lectins was examined to attain further purification and characterization. Osteogenin extracted from bovine bone matrix binds to concanavalin A (Con A) but not to wheat germ agglutinin or soybean lectin. The present data indicate that the bone inductive protein, osteogenin, is a glycoprotein. The use of a Con A Sepharose affinity column followed by preparative gel electrophoresis resulted in a greater than 250,000 fold purification of osteogenin.


Effect of environmental and clinical factors on lung function and respiratory symptoms in adolescents with alpha1-antitrypsin deficiency.
Individuals identified in the Swedish neonatal alpha1-antitrypsin (AAT) screening study were followed prospectively from their first to their eighteenth year of life. The aim of this study was to analyse the effect of environmental factors, i.e. active and passive smoking, and of clinical factors on lung function and the occurrence of respiratory symptoms in AAT-deficient adolescents. The study group consisted of 88 protease inhibitor (Pi)ZZ and 40 PiSZ adolescents. Medical history including respiratory symptoms, and active and passive smoking were recorded at each follow-up up to the age of 18 y. Lung function tests were performed at the present check-up. At the age of 18 y, both forced expiratory volume in one second (FEV ) and FEV1/vital capacity (VC) were significantly lower in the smoking than in the non-smoking subgroup, and significantly more smokers than non-smokers reported the presence of phlegm. The mean FEV1/VC ratio was lower for those presently exposed to parental smoking. Multiple linear regression analysis indicated that clinical liver disease in early life, active smoking and parental smoking were independent determinants of FEV1/VC. The results suggest that marginal deviations in lung function and the symptom of phlegm among AAT-deficient adolescents occur characteristically early in the subgroup of smokers. Parental smoking may contribute to decreased lung function.


Electrophoretic and isoelectrophoretic characteristics of hemoglobins of Italian Ictalurids.
Electrophoretic and isoelectrophoretic behaviour of the hemoglobins of Italian freshwater Ictalurids was analysed. Multiple and polymorphic hemoglobin patterns were found in Ictalurus sp. (I. nebulosus nebulosus?, I. melas?); multiple and monomorphic patterns in I. n. marmoratus and I. punctatus. Hypotheses are advanced for further investigation of the question.


Optical Coherence Tomography- Versus Angiography-Guided Magnesium Bioresorbable Scaffold Implantation in NSTEMI Patients.
The purpose of a bioresorbable scaffold (BRS) is to provide radial support during coronary healing. In this study, coronary artery healing after optical coherence tomography (OCT)- versus angiography-guided magnesium BRS (MBRS) implantation in patients with non-ST-segment-elevation myocardial infarction (NSTEMI) is compared. 75 patients were randomized 1:1 to OCT- or angiography-guided implantation of a MBRS with protocolled pre- and post-dilation. In the OCT-guided group, prespecified criteria indicating additional intervention were (1) scaffold under-expansion, (2) strut malapposition, (3) edge dissection, and (4) residual stenosis at distal or proximal reference segments. The primary endpoint was OCT-derived healing stage at 6 months. At 6 months, there was no difference in average healing stage between OCT- and angiography-guided intervention (4.6 [interquartile range (IQR): 4.5-4.7] versus 4.5 [IQR: 4.3-4.7]; p = 0.54). The MBRSs were completely resolved in 77.0% [IQR: 68.5-85.5] versus 76.5% [IQR: 67.9-85.5]; (p = 0.97). Minimal lumen area (MLA) was reduced at 6 months in both the OCT- (32.3%; p < 0.01) and the angiography-guided group (21.3%; p < 0.01), however OCT-guided implantation was associated with a greater reduction of total lumen volume (-27.1 ± 32.5 mm3 versus -5.0 ± 32.9 mm3; p < 0.01) and MLA (-2.3 ± 1.6 mm2 vs. -1.4 ± 1.4 mm2; p = 0.02). In NSTEMI patients, OCT-guidance with protocolled pre- and post-dilation of MBRS implantation showed similar healing pattern at 6 months compared to angiography-guidance alone. The Coronary Artery Healing Process after Optical Coherence Tomography Guided Percutaneous Coronary Intervention with Magmaris Bioresorbable Scaffold in Patients with Non-ST-Segment-Elevation Myocardial Infarction: (HONEST) trial is registered with ClinicalTrials.gov, NCT03016624.


Mononuclear phagocyte adherence in the presence of laminin. A possible marker of cellular differentiation.
The effect of laminin on the vitro adhesive behavior of mononuclear phagocytes was investigated. Laminin significantly inhibited the adhesion of guinea pig, mouse, and rat alveolar or peritoneal macrophages and of human peripheral blood monocytes. Adhesion of these cells was unaffected by similar concentrations of fibronectin. Experiments performed with monocytes maintained in culture showed that the degree of laminin-mediated inhibition of adherence was dependent on the state of differentiation of the cells: the less mature the monocytes, the greater the degree of inhibition. Laminin also reduced the attachment capacity of polymorphonuclear leukocytes isolated from human peripheral blood. These results suggest a possible role for laminin in the regulation of the passage of cells across the basement membrane during inflammation.


Selective retina therapy (SRT) in patients with therapy refractory persistent acute central serous chorioretinopathy (CSC): 3 months functional and morphological results.
Central serous chorioretinopathy (CSC) is a disease presenting with detachment of the neurosensory retina and characteristic focal leakage on fluorescein angiography. The spontaneous remission rate is 84% within 6 months. In this study, the efficacy of selective retina therapy (SRT) was examined in patients with therapy refractory persistent acute CSC defined by symptoms for at least 6 months and persistent subretinal fluid (SRF) despite eplerenone therapy. This is a prospective, monocentric observational study in 17 eyes (16 patients, mean age 42 years, 2 female). SRT was performed with the approved R:GEN laser (Lutronic, South Korea), a micropulsed 527-nm Nd:YLF laser device, with a train of 30 pulses of 1.7 μs at 100-Hz repetition rate at the point of focal leakage determined by fluorescein angiography (FA) at baseline (BSL). Visits on BSL, week 4 (wk4), and week 12 (wk12) included best corrected visual acuity (BCVA, logMar), central retinal thickness (CRT) on spectral domain optical coherence tomography (SD-OCT), and FA. Statistical analysis was performed by pair-by-pair comparisons of multiple observations in each case with Bonferroni correction for multiple testing. (IBM SPSS Statistics 25®). Mean CRT at BSL was 387.69 ± 110.4 μm. CRT significantly decreased by 106.31 μm in wk4 (95%-KI: 21.42-191.2; p = 0.01), by 133.63 μm in wk12 (95%-KI: 50.22-217.03; p = 0.001) and by 133.81 μm (95%-KI: 48.88-218.75; p = 0.001) compared to BSL. Treatment success defined as complete resolution of SRF occurred at wk4 in 7/17 eyes (35.3%) and at wk12 in 10/17 eyes (58.8%). Re-SRT was performed in 7/17 eyes (41.2%) after an average of 107.14 ± 96.59 days. Treatment success after Re-SRT was observed in 4/6 eyes (66.6%, 12 weeks after Re-SRT). Mean BCVA did not change significantly from BSL to any later timepoint after adjusting for multiple testing. Notably, eyes with treatment success showed better BCVA at all timepoints and gained more letters compared to failures. Single or repetitive SRT may be an effective and safe treatment in 2 of 3 patients suffering from acute persistent CSC after 6 months of symptoms or more. We observed complete resolution of SRF in around 60% of eyes 12 weeks after first SRT treatment and also 12 weeks after Re-SRT treatment in eyes with persistent or recurrent SRF. Results on the long-term course after SRT are still pending.


Switching statin therapy using a pharmacist-managed therapeutic conversion program versus usual care conversion among indigent patients.
STUDY OBJECTIVE. To evaluate the effectiveness of switching statin therapy using a therapeutic conversion program versus usual care conversion among patients enrolled in the Colorado Indigent Care Program when atorvastatin was removed from the formulary. Prospective cohort study. Family medicine center and other ambulatory care clinics of a university-based health care system. One hundred seventeen ambulatory care patients with dyslipidemia who were treated with atorvastatin. Clinical pharmacists in the family medicine center implemented a therapeutic conversion program (30 patients), switching atorvastatin to a new formulary regimen of simvastatin, rosuvastatin, or ezetimibe-simvastatin, using an algorithm designed to achieve patient-specific goals for low-density lipoprotein cholesterol (LDL). Usual care occurred in the other ambulatory care clinics without clinical pharmacists (87 patients), where medical providers switched atorvastatin to a formulary regimen based on a suggested (but optional) equipotency conversion algorithm. Primary end points were LDL concentration and LDL goal attainment before and after conversion. Before and after conversion, respectively, mean LDL concentrations were 86.7 and 82.3 mg/dl in the therapeutic conversion group (p=0.44) versus 78.3 and 85.2 mg/dl in the usual care group (p=0.01). Percentages of patients attaining LDL goal were 80% before and 97% after conversion in the therapeutic conversion group (p=0.04) compared with 90% before and 75% after conversion in the usual care group (p=0.01). Use of a prospective, therapeutic statin conversion program was associated with increased control of dyslipidemia, whereas usual care statin conversion was associated with decreased control. These data suggest that proactive involvement of clinical pharmacists in converting lipid-lowering drugs results in superior patient care outcomes compared with a less aggressive approach.


Isolated limb fractures - the underestimated injury in the Israeli Defence Forces (IDF).
Musculoskeletal injuries dominate warfare-related trauma and differ from civilian settings in higher hospitalization costs, morbidity, and mortality. Partly due to introduction of personal protective equipment in the Israel Defence Force (IDF) to minimize head and torso injuries while the extremities remained unprotected. This study describes military extremity injury patterns, prehospital treatment and injury sequela regarding return-to-duty and disability compensation. This retrospective study examined cases of battle and non-battle trauma casualties treated by the IDF Medical Corps from 2013 to 2020. Data from the IDF Trauma Registry (IDF-TR) was merged with The Israeli National Trauma Registry (INTR). Cases with high morbidity discharged from military service were compared with lower morbidity patients who returned to active duty service. Out of 1360 injured soldiers, 280 (20.6%) were found to have isolated limb fractures (ILFs). High morbidity casualties had more open fractures (63% vs. 42%) and higher involvement of lower extremities (79% vs. 58%) (p < 0.001), higher rates of tourniquets use (28% compared to 9%, p < 0.001), external fixation (34% vs. 19%, p < 0.001) and amputations (9% vs. 1%, p = 0.003), required more rehabilitation (34% vs. 7%, p < 0.001), and had 46% medical disabilities compared to 24% with low morbidity (p < 0.001). ILFs are associated with significant morbidity and disability. High morbidity is associated with high energy, scar-producing, lower-extremity open fractured limbs treated by tourniquets. Future studies should evaluate whether junctional or extremity protective gear is combat feasible and whether introducing Clinical Practice Guidelines to manage suspected limb fractures can decrease morbidity rates and improve return to duty.


Neural disorganization in the superior cerebellar peduncle and cognitive abnormality in patients with schizophrenia: A diffusion tensor imaging study.
Disconnection in the frontal-thalamic-cerebellar circuit is thought to be associated with cognitive abnormality in patients with schizophrenia. The superior cerebellar peduncle is involved in neural connectivity in the circuit. Because diffusion tensor imaging (DTI) can detect neural disconnection, we investigated whether there was neural disruption in the superior cerebellar peduncle in patients with schizophrenia. DTI was performed in 21 schizophrenic subjects and 21 age- and sex-matched healthy subjects. Cognitive cluster scores were attained by using the Positive and Negative Syndrome Scale (PANSS). Schizophrenic subjects had significantly lower fractional anisotropy (FA) in the right and left superior cerebellar peduncles than healthy subjects. Higher FA in the left superior cerebellar peduncle was associated with worse cognitive function in patients with schizophrenia. These findings suggest that there is neural disruption in the superior cerebellar peduncle in patients with schizophrenia, which may be involved in the cognitive abnormalities found in schizophrenia.


Acute portal vein thrombosis secondary to COVID-19: a case report.
COVID-19 pneumonia exhibits several extra-pulmonary complications. A 23-year old, asthmatic male with coronavirus pneumonia developed with generalized, acute abdominal pain. Further evaluations revealed a mild ascites and portal vein thrombosis although the patient received proper anticoagulation therapy. Routine lab data regarding the secondary causes of portal vein thrombosis were normal. We speculated that the underlying cause of portal vein thrombosis in our case was coronaviruses. Therefore, clinicians should always consider thrombosis and other hypercoagulable diseases in patients with COVID-19.


Muscarinic supersensitivity: a possible model for the sleep disturbance of primary depression?
The sleep changes induced in normal volunteers following the administration of scopolamine on 3 consecutive mornings resemble many of the abnormalities observed in the sleep of patients with primary depression: increased sleep latency and reduced rapid eye movement (REM) latency, total sleep time, and sleep efficiency. Furthermore, in a multivariate discriminant analysis--previously shown to distinguish the sleep records of depresed patients from those of normal controls and insomniac patients--the records from baseline nights were selected as normal and those after scopolamine as predominately depressed. Those observations suggest to us that muscarinic supersensitivity in normals may function as a pharmacological model for the sleep disturbances of depression.


A validated 1H NMR method for the determination of the degree of deacetylation of chitosan.
A method for the determination of the degree of deacetylation (DDA) of chitosan by 1H NMR spectroscopy has been formally validated. Chitosans with DDA ranging from 48 to 100% have been used for the validation. The method is found to be simple, rapid and more precise than other known techniques like IR or titration for %DDA measurements. The precision, ruggedness, robustness, specificity, stability and accuracy of the technique are discussed in this paper.


Risk assessment in adult acute lymphoblastic leukaemia before early haemopoietic stem cell transplantation with a geno-identical donor: an easy clinical prognostic score to identify patients who benefit most from allogeneic haemopoietic stem cell transplantation.
In 1402 patients allografted in Europe during the period 1990-2000 with an HLA-identical sibling in first remission (CR1), the median interval from CR1 to allotransplant (96 days) was a major prognostic factor, patients transplanted earlier having a worse outcome. We studied in depth the 414 fully evaluable patients transplanted less than 96 days after achieving CR1; in these patients, only three factors predicted for the outcome by multivariate analysis: patient age, CR1 achievement with one or more induction courses and the recipient/donor sex combination. These three factors overcame the information from cytogenetics and source of stem cells. Three prognostic groups could be identified in relation to the outcome, using a prognostic score affecting 1 to each poor risk factor (total from 0 to 3): Group 1 (good prognosis) includes patients <35 years old, achieving CR1 with one induction course and to be transplanted with any other sex combination than female to male (score 0); group 2 (intermediate) with one adverse factor (score 1); and group 3 (bad prognosis) with two or three adverse criteria (scores 2 and 3). In these three groups, the 3-year leukaemia-free survival was 56+/-5%, 48+/-4% and 29+/-4% and the overall survival was 65+/-5, 53+/-4 and 29+/-5%, respectively. Therefore, adult patients with ALL and a score of 0 or 1 are good candidates for an early transplant if they have an identical sibling donor. Patient age, response to induction and the sex of the HLA-identical family donor (if existing) are the strongest easy predictors of the outcome for an early transplant in an adult patient with ALL. No additional information is mandatory.


IL-36γ signaling controls the induced regulatory T cell-Th9 cell balance via NFκB activation and STAT transcription factors.
Regulatory and effector T helper (Th) cells are abundant at mucosal surfaces, especially in the intestine, where they control the critical balance between tolerance and inflammation. However, the key factors that reciprocally dictate differentiation along these specific lineages remain incompletely understood. Here we report that the interleukin-1 (IL-1) family member IL-36γ signals through IL-36 receptor, myeloid differentiation primary response gene 88, and nuclear factor-κBp50 in CD4+ T cells to potently inhibit Foxp3-expressing induced regulatory T cell (Treg) development, while concomitantly promoting the differentiation of Th9 cells via a IL-2-STAT5- (signal transducer and activator of transcription factor 5) and IL-4-STAT6-dependent pathway. Consistent with these findings, mice deficient in IL-36γ were protected from Th cell-driven intestinal inflammation and exhibited increased colonic Treg cells and diminished Th9 cells. Our findings thus reveal a fundamental contribution for the IL-36/IL-36R axis in regulating the Treg-Th9 cell balance with broad implications for Th cell-mediated disorders, such as inflammatory bowel diseases and particularly ulcerative colitis.


Voice Analysis in Patients with Essential Tremor.
The objective of this study was to reveal the phonetic characteristics of patients with or without voice tremor in patients with essential tremor (ET), determine whether these phonetic features are ET specific, and test the influence of ET on vocal tremor. The study included a total of 30 patients with ET and 29 healthy volunteers. The severity of ET was evaluated using the Washington Heights Inwood Genetic Study of Essential Tremor (WHIGET) tremor rating scale. Patients with major tremor complaints for at least 3years, WHIGET scoring scores below 15, and patients newly diagnosed in our clinic and for whom drug therapy has not yet been started were selected. A total of 59 participants (n = 34 with ET and n = 25 as control) were included in the study. The ages of the participants ranged from 20 to 82years, with a mean age of 54.50 ± 15.04years. The gender distribution was 57.6% male and 42.4% female, and there was no statistically significant difference between the two groups in terms of age and gender. The study found that individuals with ET had significantly higher jitter, shimmer, S/Z, Pataka, frequency tremor intensity index, amplitude tremor intensity index, and frequency tremor power index values than the control group. However, there was no statistically significant difference between the two groups in terms of MPT, frequency tremor cyclicality, amplitude tremor cyclicality, frequency tremor frequency, and amplitude tremor frequency values. Our study shows that, even in the absence of essential voice tremor, there is an effect of ET on voice quality. These findings contribute to the understanding of the nonmotor symptoms of ET and may aid in the diagnosis and management of this condition. Further research is needed to explore the potential use of acoustic analysis parameters in the diagnosis and monitoring of ET.


Pathophysiological aspects of brain edema.
Two mayor types of brain edema, related to two different pathomechanisms, can be recognized: 1) cytotoxic type-where the main feature is the swelling of cellular elements of brain parenchyma and 2) vasogenic type-where an increased vascular permeability leading to accumulation of edema fluid in the extracellular spaces plays the principal role. In this type of edema, there is a close interrelationship between extravasation of serum proteins and retention of water in the brain tissue. In the ischemic brain edema both cytotoxic and vasogenic mechanisms are involved. A biphasic opening of the blood-brain barrier, associated with vasogenic edema, is observed following release of major cerebral artery occlusion. The first opening of the barrier is related to a reactive hyperemia which follows promptly recirculation. The second opening, recognizable after a delay, is associated with a severe ischemic brain tissue injury.


Lack of association of APOE and tau polymorphisms with dementia in Parkinson's disease.
Some APOE or tau gene polymorphisms have been associated with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and Parkinson's disease (PD). The reports of a possible association between the APOE 4 allele and dementia in PD are controversial, and some studies suggest that the tau H1/H1 genotype may increase the risk of dementia in PD. Here we analysed these APOE and tau polymorphisms in 86 clinically diagnosed PD patients with dementia (PDD), in 138 clinically diagnosed non-demented PD (PDND) patients, and in 91 healthy controls. Genomic DNA isolated from blood was used for PCR and subsequent RFLP analysis. We examined the possible genetic association of these polymorphisms with dementia in PD, but found no differences in genotypic distributions between the PDND, PDD, and control groups. The effects of tau and APOE polymorphisms on the age at dementia onset were studied using Kaplan-Meier survival analysis but no significant association were found. The lack of association between the APOE 4 allele and PDD suggests that the pathological process involved in the development of dementia in PD is different from the one that occurs in AD.


Subclinical course of cholesterol ester storage disease (CESD) diagnosed in adulthood. Report on two cases with remarks on the nature of the liver storage process.
An extremely benign variant of cholesterol ester storage disease (CESD) was diagnosed in two female patients aged 43 and 56 years. In one of them the course was entirely subclinical until a stroke at the age of 47, most probably a complication of secondary hyperlipoproteinaemia. The diagnosis was made accidentally in vivo during extensive examination for concomitant monoclonal gammapathy. The other patient (aged 56), still displays a fairly stable course with minor dyspeptic symptoms. The clinical findings in both patients were confined to moderate well tolerated hepatomegaly, hyperlipoproteinaemia of IIb type and xanthelasmata. Acid lipase activity was markedly deficient in peripheral leukocytes and cultured fibroblasts. These cases represent a rare adult variant the existence of which should be borne in mind in the differential diagnosis of chronic liver disease in advanced age and of hyperlipoproteinaemic states. The diagnostic criteria for the routine clinicopathological steps are summarized with emphasis on a special lipopigment deposition pattern, encompassing inhibition and modification of lipofuscin generation in hepatocytes and an excess of ceroid production in both portal and intralobular histiocytes. The varied ultrastructural appearance of the lysosomal limiting membrane complex is described.


Influence of external defibrillator electrode polarity on cardiac resuscitation.
Eight hundred forty-seven consecutive patients discovered in cardiac arrest by first responding firefighters received initial defibrillation attempts using automatic external defibrillators. The effect of electrode polarity on defibrillation and resuscitation was determined in the subset of 289 (34%) with ventricular fibrillation in a prospective, randomized trial. The ECG was recorded in 205 consecutive patients whose initial rhythm was ventricular fibrillation. Eighty-seven of 114 patients (76%) in whom the apex chest electrode was positive were defibrillated with the first 200-joule shock, compared to 70 of 91 patients (77%) in whom the apex electrode was negative. There was no difference in the type of rhythm established, e.g., organized versus brady-asystole following defibrillation with either electrode polarity. Resuscitation was possible in 56% of patients in whom the apex electrode was positive and 60% of those in whom the apex electrode was of negative polarity. Hospital survival rates (26% vs 27%) were also similar for both treatment groups. Unlike results during experimental external defibrillation of animals or those obtained using implantable defibrillators, this randomized trial of external defibrillation conducted during attempted out-of-hospital resuscitation showed no difference in outcomes related to electrode polarity.


Cyanide-Free Cyanation of sp2 and sp-Carbon Atoms by an Oxazole-Based Masked CN Source Using Flow Microreactors.
This work reports a cyanide-free continuous-flow process for cyanation of sp2 and sp carbons to synthesize aryl, vinyl and acetylenic nitriles from (5-methyl-2-phenyloxazol-4-yl) boronic acid [OxBA] reagent as a sole source of carbon-bound masked -CN source. Non-toxic and stable OxBA reagent is generated by lithiation-borylation of bromo-oxazole, and the consecutive Suzuki-Miyaura cross-coupling with aryl, vinyl, or acetylenic halides and demasking [4+2]/retro-[4+2] sequence were successfully accomplished to give the desired cyano compounds with reasonably good yields in a four-step flow manner. A unique feature of this cyanation protocol in flow enables to cyanate a variety of sp2 and sp carbons to produce a broad spectrum of aryl acetonitrile. It is envisaged that the OxBA based cyanation would replace existing unstable and toxic approaches as well as non-toxic cyanation using two different sources of "C" and "N" to incorporate the -CN group.


Relative Surface Velocity of the Tibiofemoral Joint and Its Relation to the Development of Osteoarthritis After Joint Injury.
The relative velocity of the tibiofemoral surfaces during gait before and after partial-ACL and full MCL transection (p-ACL/MCL Tx) was examined in an ovine model (N = 5) and the relation between the variation in the relative sliding velocity component and gross morphological damage was investigated. We defined the in vivo kinematics of the tibiofemoral joints by using an instrumented spatial linkage and then determining the relative velocity components on the reconstructed femoral condyle surfaces. One major finding was that the magnitude of the relative velocity components was relatively high during the initial stance period of the gait and oscillated with a decaying envelope. Interestingly, for most subjects, the highest value of relative sliding velocity occurred during the stance phase, and not swing. The magnitude of the relative velocity components was increased in 3/5 subjects during stance after an injury. For the lateral compartment, there was a significant correlation (p value = 0.005) between the joint gross morphological damage and the increase in the maximum relative sliding velocity during stance. For the medial compartment, there was a trend (p value < 0.1) between the joint gross morphological score and the increase in the maximum relative sliding velocity during stance, 20 weeks after injury. In conclusion, a connection between an increase in the relative surface velocity and gross morphological damage might be due to an increase in the normal stress and the plowing friction between the surfaces.


Overcoming organic and nitrogen overload in thermophilic anaerobic digestion of pig slurry by coupling a microbial electrolysis cell.
The combination of the anaerobic digestion (AD) process with a microbial electrolysis cell (MEC) coupled to an ammonia stripping unit as a post-treatment was assessed both in series operation, to improve the quality of the effluent, and in loop configuration recirculating the effluent, to increase the AD robustness. The MEC allowed maintaining the chemical oxygen demand removal of the whole system of 46±5% despite the AD destabilization after doubling the organic and nitrogen loads, while recovering 40±3% of ammonia. The AD-MEC system, in loop configuration, helped to recover the AD (55% increase in methane productivity) and attained a more stable and robust operation. The microbial population assessment revealed an enhancement of AD methanogenic archaea numbers and a shift in eubacterial population. The AD-MEC combined system is a promising strategy for stabilizing AD against organic and nitrogen overloads, while improving the quality of the effluent and recovering nutrients for their reutilization.


The NPR/Hal family of protein kinases in yeasts: biological role, phylogeny and regulation under environmental challenges.
Protein phosphorylation is the most common and versatile post-translational modification occurring in eukaryotes. In yeast, protein phosphorylation is fundamental for maintaining cell growth and adapting to sudden changes in environmental conditions by regulating cellular processes and activating signal transduction pathways. Protein kinases catalyze the reversible addition of phosphate groups to target proteins, thereby regulating their activity. In Saccharomyces cerevisiae, kinases are classified into six major groups based on structural and functional similarities. The NPR/Hal family of kinases comprises nine fungal-specific kinases that, due to lack of similarity with the remaining kinases, were classified to the "Other" group. These kinases are primarily implicated in regulating fundamental cellular processes such as maintaining ion homeostasis and controlling nutrient transporters' concentration at the plasma membrane. Despite their biological relevance, these kinases remain poorly characterized and explored. This review provides an overview of the information available regarding each of the kinases from the NPR/Hal family, including their known biological functions, mechanisms of regulation, and integration in signaling pathways in S. cerevisiae. Information gathered for non-Saccharomyces species of biotechnological or clinical relevance is also included.


Comparison of Evaluations for Heart Transplant Before Durable Left Ventricular Assist Device and Subsequent Receipt of Transplant at Transplant vs Nontransplant Centers.
In 2020, the Centers for Medicare & Medicaid Services revised its national coverage determination, removing the requirement to obtain review from a Medicare-approved heart transplant center to implant a durable left ventricular assist device (LVAD) for bridge-to-transplant (BTT) intent at an LVAD-only center. The association between center-level transplant availability and access to heart transplant, the gold-standard therapy for advanced heart failure (HF), is unknown. To investigate the association of center transplant availability with LVAD implant strategies and subsequent heart transplant following LVAD implant before the Centers for Medicare & Medicaid Services policy change. A retrospective cohort study of the Society of Thoracic Surgeons Intermacs multicenter US registry database was conducted from April 1, 2012, to June 30, 2020. The population included patients with HF receiving a primary durable LVAD. LVAD center transplant availability (LVAD/transplant vs LVAD only). The primary outcomes were implant strategy as BTT and subsequent transplant by 2 years. Covariates that might affect listing strategy and outcomes were included (eg, patient demographic characteristics, comorbidities) in multivariable models. Parameters for BTT listing were estimated using logistic regression with center-level random effects and for receipt of a transplant using a Cox proportional hazards regression model with death as a competing event. The sample included 22 221 LVAD recipients with a median age of 59.0 (IQR, 50.0-67.0) years, of whom 17 420 (78.4%) were male and 3156 (14.2%) received implants at LVAD-only centers. Receiving an LVAD at an LVAD/transplant center was associated with a 79% increased adjusted odds of BTT LVAD designation (odds ratio, 1.79; 95% CI, 1.35-2.38; P < .001). The 2-year transplant rate following LVAD implant was 25.6% at LVAD/transplant centers and 11.9% at LVAD-only centers. There was an associated 33% increased rate of transplant at LVAD/transplant centers compared with LVAD-only centers (adjusted hazard ratio, 1.33; 95% CI, 1.17-1.51) with a similar hazard for death at 2 years (adjusted hazard ratio, 0.99; 95% CI, 0.90-1.08). Receiving an LVAD at an LVAD-transplant center was associated with increased odds of BTT intent at implant and subsequent transplant receipt for patients at 2 years. The findings of this study suggest that Centers for Medicare & Medicaid Services policy change may have the unintended consequence of further increasing inequities in access to transplant among patients at LVAD-only centers.


Viral morphogenesis and morphological changes in human neuronal cells following Tioman and Menangle virus infection.
Tioman virus (TioPV) and Menangle virus (MenPV) are two antigenically and genetically related paramyxoviruses (genus: Rubulavirus, family: Paramyxoviridae) isolated from Peninsular Malaysia (2001) and Australia (1997), respectively. Both viruses are potential zoonotic agents. In the present study, the infectivity, growth kinetics, morphology and morphogenesis of these two paramyxoviruses in a human neuronal cell (SK-N-SH) line were investigated. Sub-confluent SK-N-SH cells were infected with TioPV and MenPV at similar multiplicity of infection. These cells were examined by conventional and immunoelectron microscopy, and virus titres in the supernatants were assayed. Syncytia were observed for both infections in SK-N-SH cells and were more pronounced during the early stages of TioPV infection. The TioPV titre increased consistently (10(1)) every 12 h after infection. In MenPV-infected cells, cellular material was frequently observed within budding virions, and microfilaments and microtubules were abundant. Viral budding was common, and extracellular MenPVs tended to be more pleomorphic compared to TioPVs, which appeared to be more spherical in appearance. The MenPV cytoplasmic viral inclusion appeared to be comparatively smaller, loose and interspersed with randomly scattered circle-like particles, whereas huge tubule-like cytoplasmic inclusions were observed in TioPV-infected cells. Both viruses also displayed different cellular pathology in the SK-N-SH cells. The intracellular ultrastructural characteristics of these two viruses in infected neuronal cells may allow them to be differentiated by electron microscopy.


Transcatheter aortic valve implantation for patients with heyde syndrome: A literature review of case reports.
A systematic review of international case reports of patients with Heyde syndrome (HS) treated by transcatheter aortic valve implantation (TAVI) was conducted to explore the clinical characteristics of this group of patients and sirgical success. Methods: Electronic databases, including PubMed, Embase and CNKI, were searched with combinations of the search terms, Heyde syndrome, gastrointestinal bleeding, aortic stenosis, angiodysplasia and transcatheter aortic valve replacement. All case reports were screened according to inclusion criteria, and HS patient data was summarized. A total of 31 case reports concerned patients with a history of aortic stenosis and repeated gastrointestinal bleeding. Ultrasonic cardiograms (UCG) were recorded for 27 cases, including those with critical aortic stenosis (n = 26). Gastrointestinal sequelae were reported in 22 cases with duodenal and jejunal being the most common (n = 9). High-molecular-weight multimers of von Willebrand Factor (vWF-HMWM) were measured in 17 cases with the majority being lower (n = 15) and the minority normal (n = 2). All patients experienced recurrent bleeding after medication and endoscopic therapy and symptoms improved after TAVI (31/31). vWF was at normal levels in 11/12 cases post-TAVI. Twenty-five patients were followed up and 22 had no recurrence of symptoms giving an efficacy rate of 88% for TAVI in HS patients. HS is characterized by angiodysplasia, aortic stenosis and von Willebrand disease with frequent recurrence of bleeding after drug and endoscopic treatment. TAVI is an effective therapy with an 88% resolution rate.


Intravitreal Anti-Vascular Endothelial Growth Factor Therapies for Retinal Disorders.
Vascular endothelial growth factors (VEGFs) are key mediator of retinal and choroidal neovascularization as well as retinal vascular leakage leading to macular edema. As such, VEGF plays an important role in mediating visually significant complications associated with common retinal disorders such as diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration. Various drugs that inhibit vascular endothelial growth factors (anti-VEGF therapies) have been developed to minimize vision loss associated with these disorders. These drugs are injected into the vitreous cavity in a clinic setting at regular intervals. This article provides an overview of the various anti-VEGF drugs used in ophthalmology and the common retinal conditions that benefit from this therapy.


Inhibition of zebrafish epidermal growth factor receptor activity results in cardiovascular defects.
The physiological role of any of the epidermal growth factor (EGF) receptor tyrosine kinases has yet to be determined in zebrafish. We isolated a zebrafish homologue of EGFR (egfr) that shows a 63% amino acid overall identity to human EGFR but with 90% amino acid identity in the kinase domain. Whole mount in situ hybridization showed ubiquitous distribution of egfr transcripts during gastrulation, somitogenesis and later stages. When expressed in Chinese hamster ovary cells, zebrafish Egfr was a functional receptor that responded to EGF by receptor tyrosine phosphorylation and activation of MAP kinase. The function of zebrafish Egfr in vivo was determined by inhibiting its activity using EGFR kinase inhibitors and antisense morpholinos (MO), which inhibited Egfr kinase activity and translation of egfr messenger RNA into protein, respectively. The zebrafish is a particularly excellent model for studying cardiovascular development because zebrafish are transparent allowing direct visualization of the heart and circulation in the blood vessels. Inhibition of zebrafish Egfr activity in vivo impeded blood flow via the outflow tract into the aorta and impeded circulation in the axial and intersegmental vessels by 80 h post-fertilization. Analysis of the heart showed that the heart chambers and pericardial sacs were dilated and the outflow tracts were narrowed. Together these results suggested that zebrafish Egfr has a cardiovascular function in the developing zebrafish that is required for normal circulation.


Extracellular vesicles from hydroxycamptothecin primed umbilical cord stem cells enhance anti-adhesion potential for treatment of tendon injury.
Peritendinous fibrosis represents a fibrotic healing process that usually occurs after tendon injury or surgery. This worldwide challenge hampers the functional rehabilitation and the mobility of extremities. However, effective treatment is still lacking at present. The aim of our study was to explore the effect of extracellular vesicles derived from hydroxycamptothecin primed human umbilical cord stem cells (HCPT-EVs) on post-traumatic tendon adhesion. Extracellular vesicles derived from unprimed human umbilical cord mesenchymal stem cells (Unprimed EVs) or HCPT-EVs were isolated and characterized. A rat model of Achilles tendon injury was used to confirm the anti-adhesion effect of HCPT-EVs and compared with that of Unprimed EVs in vivo. In vitro, the inhibitory effects of HCPT-EVs on fibroblast proliferation, viability, and myofibroblast differentiation upon TGF-β1 stimulation were compared with the effects of Unprimed EVs. For mechanistic analysis, the expression of endoplasmic reticulum stress (ERS)-associated proteins was examined among the effector cargos of HCPT-EVs and Unprimed EVs. The ERS antagonist salubrinal was used to determine the ERS dependence of the anti-adhesion effects of HCPT-EVs. There were no obvious differences between Unprimed EVs and HCPT-EVs in terms of morphology, particle size, characteristic protein expression, and cellular uptake. HCPT-EVs exhibited a fortified anti-adhesion effect after Achilles tendon injury compared with Unprimed EVs. Fibroblast proliferation and viability and myofibroblast differentiation were all inhibited by HCPT-EVs. These properties were superior for HCPT-EVs relative to Unprimed EVs. Mechanistically, HCPT-EVs contained more ERS-associated protein than Unprimed EVs and activated the ERS pathway in fibroblast to counteract myofibroblast differentiation. This study demonstrates that HCPT-EVs show high anti-adhesion potential for the treatment of tendon injury by provoking ERS in fibroblasts. HCPT-EVs represent a promising strategy for clinical use in treating adhesion-related diseases.


The localization and properties of membrane adenosine triphosphatases in the guinea-pig placenta.
The distribution and properties of cytochemically demonstrable phosphatases in the near-term guinea-pig placenta were examined using a strontium capture technique for sodium- and potassium-dependent adenosine triphosphatase (Na+, K+-ATPase) and a lead capture technique for magnesium-dependent adenosine triphosphatase (Mg2+-ATPase). Localizations with the strontium technique in the presence of an alkaline phosphatase inhibitor were mainly on the syncytiotrophoblast plasma membranes; the reaction was potassium-dependent and ouabain-sensitive. Reaction product using the lead capture method was found on both trophoblast and endothelial cell plasma membranes and was independent of magnesium and insensitive to p-hydroxymercuribenzoate (POHMB), an inhibitor of membrane ATPases. However, a very large proportion of this reaction could be blocked by an alkaline phosphatase inhibitor. It is concluded that the strontium capture technique gave a reliable localization for Na+, K+-ATPase. However, the lead capture method mainly demonstrated alkaline phosphatase, and does not offer a useful approach to specific ATPase studies in this particular system.