Focused parathyroidectomy without intra-operative parathormone monitoring: The value of PTH assay in preoperative ultrasound guided fine needle aspiration washout.
The accurate identification of hyperfunctioning parathyroid (HP) gland is the only issue for definitive surgical treatment in primary hyperparathyroidism (pHPT). Various imaging and operative techniques have been proposed to confirm the localization of the diseased gland. Nevertheless, none of these methods proved to be the gold standard. The presented study aimed to assess the value of parathyroid hormone assay in preoperative ultrasound guided fine needle aspiration (FNA)-PTH washout fluid to verify the correct localisation for focused parathyroidectomy without intra-operative PTH monitoring. The retrospective analysis of 57 patients with pHPT who underwent FNA-PTH was conducted from a prospective database. Biochemical assessment together with radiological (ultrasonography) and nuclear (MIBI scan) imaging was reviewed. Associations between FNA-PTH washout values and localization technics were evaluated and compared in terms of operative findings. Focused parathyroidectomy without intraoperative PTH monitoring was performed to 45 patients with high FNA-PTH values. The median largest diameter of the target parathyroid lesion identified by ultrasonography was 13 mm (range, 6 to 36). The median serum PTH level was 190 pg/mL (range, 78 to 1709; reference range, 15 to 65) whereas the median washout PTH was 2500 pg/mL (range, 480 to 3389). According to operative findings high FNA-PTH levels correctly identified parathyroid adenoma in 40 cases (89% of sensitivity and 100% of specificity and positive predictive value) whereas MIBI scan localized the lesion in 36 of these cases (80% of sensitivity). The higher level of PTH in preoperative ultrasound guided FNA washout is a considerable data to predict the correct localization of HP, particularly in circumstances of greater values than the serum PTH level. However, although its specificity is high, in cases of coexisting nodular thyroid disease, associated additional HP might be missed at focused parathyroidectomy without PTH monitoring, leading to recurrent disease.


Moringa oleifera polysaccharide regulates colonic microbiota and immune repertoire in C57BL/6 mice.
This study investigated the effects of Moringa oleifera polysaccharide (MOP) on serum immune indices, immune organ indices, colonic microflora and immune repertoire of mice. Forty male SPF C57BL/6 mice were randomly divided into four groups and subjected to gavage of 0, 20, 40 and 60 mg/kg MOP for 28 days. Mice were sacrificed on the last day of the experiment and their thymus, spleen, blood and colon contents were collected for further detection. Our findings suggested that MOP could significantly increase the thymus index (P < 0.01) and spleen index (P < 0.05), and significantly decrease the levels of interleukin-6 and tumour necrosis factor-α in mice (P < 0.05). And MOP could regulate the proportion of colonic microflora of mice, significantly increase the abundance of Muribaculaceae and significantly decrease the abundance values of Proteobacteria, Helicobacter, Stenotrophomonas, etc (P < 0.05). In addition, MOP could regulate the usage frequencies of TRBV15 (P = 0.06) and TRBV9 (P = 0.10) on the TCRα chain and 9 V-J pairs were found to have remarkable usage frequency changes. These results implied that MOP exerted positive effects on the immune performance and intestinal health of mice.


Microsatellite (GT)n polymorphism at 3'UTR of SLC11A1 influences the expression of brucella LPS induced MCP1 mRNA in buffalo peripheral blood mononuclear cells.
A (GT)n microsatellite polymorphism at 3'UTR of SLC11A1(solute carrier family 11A1) is associated with the natural resistance to bovine brucellosis. A pleiotropic effect of SLC11A1 on other candidate genes influencing the host resistance including monocyte chemotactic/chemoattractant protein 1 (MCP1) is also hypothesized. In the present study, we report the cloning and characterization of the complete coding sequence of bubaline (bu) MCP1 and its tissue distribution at the transcript level. The buMCP1 exhibited as high as 99% and >80% of sequence identities with the bovine and other domestic animal species homologues. The buMCP1 mRNA was abundant across the different tissues: most abundant in liver and mammary gland, moderate in ovary, skeletal muscle and testis, and least in uterus. Further, quantitative real-time PCR (RTqPCR) analysis revealed that PBMCs carrying so called resistant GT13 allele produced more MCP1 mRNA endogenously as well as when induced with brucella LPS suggesting the pleiotropic roles of SLC11A1 in conferring resistance against the intracellular pathogens particularly against brucellosis. However, the underlying molecular mechanisms by which 3'UTR SLC11A1 concomitantly increases the production of chemokines like MCP1 are yet to be investigated.


The binding of haloperidol to human blood platelets and interactions with 5-hydroxytryptamine and dopamine.
1 The binding of [3H]-5-hydroxytryptamine ([3H]-5-HT), [3H]-haloperidol and [3H]-dopamine to human blood platelets was investigated and the effects of unlabelled haloperidol on [3H]-5-HT binding and (+)- and (-)-butaclamol on [3H]-haloperidol were studied. 2 Scatchard analysis did not show any specific binding of [3H]-haloperidol or [3H]-dopamine to platelets, but two binding sites were identified for binding of [3H]-5-HT. 3 Unlabelled haloperidol reduced the binding of 5-HT in concentrations comparable to those inhibigint 5-HT-induced platelet aggregation; (+)- and (-)-butaclamol did not affect the binding of [3H]-haloperidol. 4 It is concluded that haloperidol binding represents saturation of the platelet membrane, and that the platelet is not a suitable model for investigation of dopamine-drug interactions.


Pharmacoepidemiology of medications omitted in New Zealand Residential Aged Care Homes.
To investigate the dispensing, administration and omission of medications in residential aged care (RAC) homes in New Zealand (NZ). Secondary data from a medication management database were analysed, to identify the most frequently omitted regular medications and commonly reported reasons for omissions in a sample of 11 015 residents across 374 RAC homes. Overall, 3.59 medication doses were omitted per 100 (±7.4) prescribed doses per resident (SD 7.43). Common regular medications omitted ranged from analgesics to psychotropic medications. Recording of justifications for medication omissions was inconsistent-only 48% of omissions had a recorded reason. A wide range of medications are regularly prescribed and administered to RAC home residents in NZ. Omitted doses are frequently recorded without a justification. Inconsistent recording of omissions can increase potential for error, particularly in relation to psychotropic medications. More consistent recording may help staff to maintain a high standard of quality care.


Inhibition of casein kinase 2 enhances the death ligand- and natural kiler cell-induced hepatocellular carcinoma cell death.
Recent studies have shown that the inhibition of casein kinase 2 (CK2) sensitizes many cancer cells to Fas ligand- and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. However, it has not been demonstrated directly whether CK2 inhibition can also enhance the cytotoxicity of natural killer (NK) cells, which actually use the death ligands to kill cancer cells in vivo. To address whether NK cell-mediated cancer cell death is affected by the inhibition of CK2, we first checked whether the death ligand-induced apoptosis of hepatocellular carcinoma cells (HCCs) and HeLa were affected by CK2 inhibition. We then investigated the effect of CK2 inhibition on NK cytotoxicity against HCCs and HeLa cells and its mechanistic features. Inhibition of CK2 by emodin increased the apoptotic cell death of HepG2, Hep3B and HeLa when the cancer cell lines were treated with a soluble form of recombinant TRAIL or an agonistic antibody of Fas. This phenomenon appeared to be correlated with the expression level of death receptors on the cancer cell surface. More interestingly, the inhibition of CK2 also greatly increased the NK cell-mediated cancer cell killing. The NK cytotoxicity against the cancer cells increased about twofold when the target cells were pretreated with a specific CK2 inhibitor, emodin or 4,5,6,7-tetrabromobenzotriazole. Furthermore, the increase of the NK cytotoxicity against cancer cells by CK2 inhibition was granule-independent and mediated possibly by the death ligands on the NK cell surface. This suggests that CK2 inhibitors could be used to enhance the cytotoxicity of NK cells and consequently increase host tumour immunity.


Population cycles caused by overcompensating density-dependence in an annual plant.
We analyse demographic data from a seven-year study of the annual crucifer Erophila verna which showed two-year cycles of abundance in the field. The unusual behaviour of this population is shown to be the consequence of overcompensating density-dependence. Very local differences in germination succes between plots can account for observed differences in their population dynamics over the long term.


Percutaneous nephrolithotomy to remove a cartridge detonating cap mimicking a renal pelvic stone 12 years after renal trauma.
Complications of gunshot injuries of the kidney usually present in the early postoperative period. We describe a case of a cartridge's plastic detonating cap retained in the renal pelvis of a young male patient for 12 years. Renal colic was the cause of admission. This missile's part was mimicking a renal stone on both an intravenous urogram and a CT scan. The nature of the "stone" was identified during a percutaneous nephrolithotomy procedure during which the foreign body was removed.


Fat depot-specific expression of adiponectin is impaired in Zucker fatty rats.
Adiposity, particularly increased intra-abdominal fat, is a predisposing factor for the development of insulin resistance in obesity and type 2 diabetes. Visceral fat seems to differ from subcutaneous adipose tissue in adipocytokine production. This fat depot-related difference has been viewed as an important mechanism by which adipose tissue exerts its paracrine/autocrine effects on peripheral tissue in modulating insulin sensitivity. We have studied the relative expression of adiponectin in visceral versus subcutaneous fat in Zucker fatty versus lean rats. Visceral fat, as opposed to subcutaneous fat, exhibited relatively higher levels of adiponectin production in lean animals. However, in Zucker fatty rats, adiponectin expression in visceral fat was suppressed to basal levels, which correlated with significantly reduced plasma adiponectin concentrations and increased insulin resistance. These results suggest that an impaired depot-specific expression of adiponectin is a contributing factor for the development of insulin resistance in Zucker fatty rats.


Pharmacological inhibition of epidermal growth factor receptor attenuates intracranial aneurysm formation by modulating the phenotype of vascular smooth muscle cells.
To study the effect of pharmacological inhibition of epidermal growth factor receptor (EGFR) on intracranial aneurysm (IA) initiation. Human IA samples were analyzed for the expression of p-EGFR and alpha smooth muscle actin (α-SMA) by immunofluorescence (IF). Rat models of IA were established to evaluate the ability of the EGFR inhibitor, erlotinib, to attenuate the incidence of IA. We analyzed anterior cerebral artery tissues by pathological and proteomic detection for the expression of p-EGFR and relevant proteins, and vessel casting was used to evaluate the incidence of aneurysms in each group. Rat vascular smooth muscle cells (VSMCs) and endothelial cells were extracted and used to establish an in vitro co-culture model in a flow chamber with or without erlotinib treatment. We determined p-EGFR and relevant protein expression in VSMCs by immunoblotting analysis. Epidermal growth factor receptor activation was found in human IA vessel walls and rat anterior cerebral artery walls. Treatment with erlotinib markedly attenuated the incidence of IA by inhibiting vascular remodeling and pro-inflammatory transformation of VSMC in rat IA vessel walls. Activation of EGFR in rat VSMCs and phenotypic modulation of rat VSMCs were correlated with the strength of shear stress in vitro, and treatment with erlotinib reduced phenotypic modulation of rat VSMCs. In vitro experiments also revealed that EGFR activation could be induced by TNF-α in human brain VSMCs. These results suggest that EGFR plays a critical role in the initiation of IA and that the EGFR inhibitor erlotinib protects rats from IA initiation by regulating phenotypic modulation of VSMCs.


Study of heavy metal concentration and partitioning in the Estrela River: implications for the pollution in Guanabara Bay – SE Brazil.
In this study, the geochemical analysis of ten sediment samples collected along the fluvial system of the Estrela River, which flows into the northern portion of Guanabara Bay, shows the presence of anthropogenic impacts in this area. Concentrations of Fe, Mn, Zn, Cu, Pb, Cr and Ni obtained were slightly higher, when compared with values found in natural environments. The particle size and organic matter content in most of the analyzed stations showed features not conducive to the accumulation of pollutants due to the low organic matter content and the strong presence of sand fraction. There was also the fractionation of heavy metals in sediments and it was found the prominence of residual and reducible phase, besides the significant occurrence of organic fractions in some analyzed stations. These factors, thus, highlight the potential risks of contamination, where the metals associated with the organic phase can become bioavailable in processes of dissolution, provided by physico-chemical changes that can occur in this aquatic environment.


Phosphodiesterase type 5 and high altitude pulmonary hypertension.
This study explored phosphodiesterase type 5 (PDE5) inhibition as a strategy for treating high altitude pulmonary arterial hypertension (HAPH). 689 subjects (313 men) of mean (SD) age 44 (0.6) years living above 2500 m were screened for HAPH by medical examination and electrocardiography, and 188 (27%) met the criteria for right ventricular hypertrophy. 44 underwent cardiac catheterisation and 29 (66%) had a resting mean pulmonary artery pressure (PAP) above 25 mmHg. 22 patients with a raised mean PAP were randomised to receive sildenafil (25 or 100 mg) or matching placebo taken 8 hourly for 12 weeks. At 3 months, patients on sildenafil 25 mg 8 hourly (n = 9) had a significantly (p = 0.018) lower mean PAP (-6.9 mmHg) at the end of the dosing interval than those on placebo (n = 8) (95% CI -12.4 to -1.3). The treatment effect for sildenafil 100 mg 8 hourly (n = 5) compared with placebo was -6.4 mm Hg (95% CI -12.9 to 0.1). Both doses improved 6 minute walk distance, the lower dose by 45.4 m (95% CI 11.5 to 79.4; p = 0.011) and the higher dose by 40.0 m (95% CI 0.2 to 79.8; p = 0.049). Sildenafil was well tolerated. Necroscopic lung specimens from three subjects with HAPH showed abundant PDE5 in the muscular coat of remodelled pulmonary arterioles. PDE5 is an attractive drug target for the treatment of HAPH and a larger study of the long term effects of PDE5 inhibition in HAPH is warranted.


Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM).
Mesenchymal stromal cells (MSCs) may offer a novel therapy for diabetic kidney disease (DKD), although clinical translation of this approach has been limited. The authors present findings from the first, lowest dose cohort of 16 adults with type 2 diabetes and progressive DKD participating in a randomized, placebo-controlled, dose-escalation phase 1b/2a trial of next-generation bone marrow-derived, anti-CD362 antibody-selected allogeneic MSCs (ORBCEL-M). A single intravenous (iv) infusion of 80×10 6 cells was safe and well-tolerated, with one quickly resolved infusion reaction in the placebo group and no subsequent treatment-related serious adverse events (SAEs). Compared with placebo, the median annual rate of decline in eGFR was significantly lower with ORBCEL-M, although mGFR did not differ. The results support further investigation of ORBCEL-M in this patient population in an appropriately sized phase 2b study. Systemic therapy with mesenchymal stromal cells may target maladaptive processes involved in diabetic kidney disease progression. However, clinical translation of this approach has been limited. The Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM) study, a randomized, placebo-controlled phase 1b/2a trial, assesses safety, tolerability, and preliminary efficacy of next-generation bone marrow-derived, anti-CD362-selected, allogeneic mesenchymal stromal cells (ORBCEL-M) in adults with type 2 diabetes and progressive diabetic kidney disease. This first, lowest dose cohort of 16 participants at three European sites was randomized (3:1) to receive intravenous infusion of ORBCEL-M (80×10 6 cells, n =12) or placebo ( n =4) and was followed for 18 months. At baseline, all participants were negative for anti-HLA antibodies and the measured GFR (mGFR) and estimated GFR were comparable between groups. The intervention was safe and well-tolerated. One placebo-treated participant had a quickly resolved infusion reaction (bronchospasm), with no subsequent treatment-related serious adverse events. Two ORBCEL-M recipients died during follow-up of causes deemed unrelated to the trial intervention; one recipient developed low-level anti-HLA antibodies. The median annual rate of kidney function decline after ORBCEL-M therapy compared with placebo did not differ by mGFR, but was significantly lower by eGFR estimated by the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Immunologic profiling provided evidence of preservation of circulating regulatory T cells, lower natural killer T cells, and stabilization of inflammatory monocyte subsets in those receiving the cell therapy compared with placebo. Findings indicate safety and tolerability of intravenous ORBCEL-M cell therapy in the trial's lowest dose cohort. The rate of decline in eGFR (but not mGFR) over 18 months was significantly lower among those receiving cell therapy compared with placebo. Further studies will be needed to determine the therapy's effect on CKD progression. ClinicalTrial.gov NCT02585622 .


Overproduced bone marrow neutrophils in collagen-induced arthritis are primed for NETosis: An ignored pathological cell involving inflammatory arthritis.
Bone marrow edema is a universal manifestation of rheumatoid arthritis (RA), and its pathological essence is a bone marrow lesion (BML) formed by various bone marrow (BM) immune cells. Neutrophils play an important role in inflammatory arthritis, but the role and mechanism of neutrophils in BML are not clear. Granulocyte colony-stimulating factor (G-CSF) -/- mice and wild type (WT) C57BL/6 mice were immunized for collagen-induced arthritis (CIA). Histological scores of arthritis were evaluated. Immunohistochemistry staining with anti-Ly6G was conducted. Neutrophil extracellular traps (NETs) in joint sections were determined by immunofluorescence staining. BM neutrophils were isolated for flow cytometry and NETosis induction in vitro. Histological study showed significant neutrophil infiltrations in BML of CIA mice. Inhibition of BM neutrophil production by G-CSF knock out can obstruct the induction of BML and CIA. In addition to abundant infiltrated NETs intra-articular, remarkable NETosis primed BM neutrophils were infiltrated in BML of CIA mice, which was positively related to bone erosion. Neutrophils derived from G-CSF-/- mice have diminished ability of NETs formation in vitro, while G-CSF induction can enhance its capacity of NETs formation. We propose for the first time that the overproduced BM neutrophils in CIA mice are primed for NETosis in a G-CSF dependent manner, and these pathogenic cells may have an important role in inflammatory arthritis. Blocking this pathological process could be a potential strategy for the treatment of RA.


Gender Bias in Diagnostic Radiology Resident Selection, Does it Exist?
To investigate whether there is a bias in the residency selection process that influences the proportion of females entering diagnostic radiology residencies. A total of 4117 applications to one diagnostic radiology residency program from 2008 to 2014 were analyzed. Invitations to interview were evaluated by each year, specifically looking at gender. Ranking of applicants, especially those placed in top 25% of the rank, was also assessed. Additional data analyzed included United States Medical Licensing Examination Step 1 board examination score (a proxy for academic performance), interview scores, and final position on rank list. Female applicants averaged 24% of the total applicant pool during the years studied, yet made up a disproportionately high percentage of applicants invited to interview (30%) and those ranked in top 25% (38%). It was found that female applicants had slightly higher mean interview scores and lower Step 1 scores than male applicants. Our findings suggest that program directors in one program want to increase gender diversity by making strides to keep the female candidate pool and the proportion of female residents in the program at least stable. The pipeline of female medical students pursuing a career in radiology appears to be a limiting factor rather than a bias against women in the resident selection process. Identifying such trends is important as it provides a better understanding of the etiology for an overall lack of gender diversity within the field. Furthermore, it may lead to closing the gender gap in radiology.


SCH23390 causes persistent antidopaminergic effects in vivo: evidence for longterm occupation of receptors.
SCH23390 has neurochemical properties characteristic of a specific D1 dopamine receptor antagonist. However, it is a potent inhibitor of dopamine-mediated behaviors which previously had been thought to be linked to D2 receptors. The metabolism of SCH23390 following parenteral administration to rats was much more rapid in the periphery than in brain, and SCH23390 had behavioral effects long after its circulating concentration had declined below detectable levels. Furthermore, the stimulation of adenylate cyclase by dopamine was attenuated in striatal homogenates taken from rats treated with SCH23390 as much as twelve hours before sacrifice. Pretreatment with cis-flupenthixol, a compound with equivalent D1 potency in vitro, failed to inhibit dopamine-stimulated adenylate cyclase activity one or four hours following injection, despite the fact that this dose produced significant behavioral effects. These data indicate that SCH23390 may act with unusual tenacity at certain sites in the central nervous system.


Efficacy and toxicity of CLAG combined with pegylated liposomal doxorubicin in the treatment of refractory or relapsed acute myeloid leukemia.
Refractory and relapsed acute myeloid leukemia (r/rAML) is associated with a difficult prognosis; clinical trials are typically suggested despite lack of a recognized standard of care. Combinatorial chemotherapy regimens utilized for r/rAML salvage play a crucial role in battling this invasive phase. Although it is characterized by a low response rate, CLAG is a traditional regimen used in r/rAML. We aimed to compare the efficacy and toxicity of CLAG+PLD to explore whether there was any improvement with the addition of pegylated liposomal doxorubicin (PLD) to CLAG METHODS: A total of 110 r/rAML patients were retrospectively analyzed from February 2017 to June 2020 at the Medical Center of Hematology, XinQiao Hospital, the 303rd Hospital of the Chinese People's Liberation Army, and Central Hospital of Chang Sha, Hunan Province. The response, overall survival (OS), disease-free survival (DFS), and side effects in 110 r/rAML patients were evaluated retrospectively. Of these, 55 patients were administered CLAG+PLD, while 55 patients received CLAG alone as salvage therapy. In the CLAG+PLD group, there were 27 (49.1%) cases of complete response (CR) with no measurable residual disease (MRD-), 12 (21.8%) cases of CR with positive MRD (MRD+), 5 (9.1%) cases of partial response (PR), 11 (20%) cases of no response (NR), and no cases of death during the cycles. The response rates in the CLAG group were lower: CR was reached in 24 (46.6%) patients with MRD-, 6 (10.9%) patients with MRD+, 10 (18.2%) patients with PR, 13 (23.6%) patients with NR, and 2 (3.6%) patients who passed away, one from infection and the other from cerebral hemorrhage. The median OS and DFS were not attained in the CLAG+PLD group during the 2-year OS and DFS follow-up, while both values were 10 months in the CLAG group (p = 0.023 and p = 0.045, respectively). The results of the Cox regression analysis for the CLAG+PLD group were strongly illustrative of the importance of hematopoietic stem cell transplantation (HSCT) following salvage therapy. No increased toxicity was observed in the CLAG+PLD group. CLAG+PLD is a potential salvage regimen for r/r AML that has a similar toxicity profile to CLAG and that improves response rates, 2-year OS, and DFS relative to CLAG.


Ultrasonography-assisted assessment of the influence of the volar prominence of the plate on the median nerve in distal radius fractures.
The study aimed to explore the effect of differing volar locking plate (VLP) prominence on the median nerve (MN) in distal radius fracture (DRF) with ultrasound assistance to guide clinical treatment. Forty-four patients who received VLP for DRF at our department were admitted and followed-up between January 2019 and May 2021. Different plate positions were graded using Soong classification; 13 were Grade 0, 18 were Grade 1, and 13 were Grade 2. The MN parameters at different wrist positions in patients with different Soong grades were measured with ultrasound assistance, including the median nerve cross-sectional area (MNCSA), diameter in the radial-ulnar direction (D1), and diameter in the dorsal-palmar direction (D2). The sensation in the affected finger and grip strength were collected at follow-up, scored using the Disabilities of the Arm, Shoulder, and Hand (DASH) scale to determine function, and statistically analysed. The MNCSA differed significantly across Soong grades. The MNCSA at the flexed, neutral, and extended wrist positions was smallest at Grade 0 and largest at Grade 2 (P < 0.05), and that at the neutral position was not significantly different between Grades 1 and 2 (P > 0.05). There was no significant interaction between the wrist positions and Soong grade (P > 0.05). The differences in D1 and D2 among different Soong grades were not statistically significant (P > 0.05). There were no statistical differences in grip strength, DASH, and sensation among different Soong grades (P > 0.05). Differing plate protrusions in DRF treatment did not cause clinical symptoms during follow-up; however, excessive plate protrusion (Soong Grade 2) increased the cross-sectional area of the MN. We recommend placing the plate as proximal as possible during VLP treatment of DRFs to avoid excessive bulges affecting the MN.


Immunologically discrete conformation isomers of I-A locus-equivalent class II molecules detected in Lewis rats.
Monoclonal antibodies MRC-OX6 and MRC-OX3 were used to define biosynthetically inter-related subsets of I-A-equivalent class II molecules from Lewis rat spleen cells. MRC-OX6 was shown to recognize specifically multiple forms of the class II molecule arising along its maturation pathway from the origin of polypeptide chain synthesis, the rough endoplasmatic reticulum, through the Golgi compartment to the plasma membrane. Three MRC-OX6-reactive polypeptide chain complexes were distinguished: (a) an early complex composed of immature components of the polymorphic alpha,beta heterodimer in noncovalent association with immature proteins of the invariant gamma-chain group p40, p33 (gamma), p28, p20; (b) a biosynthetic intermediate comprising the subunits alpha,beta and gamma all of them being extensively glycosylated and sialylated. The latter constituent is referred to as p36; (c) a cell surface structure consisting of the mature alpha,beta heterodimer devoid of the mature invariant chain p36. A two-dimensional (2D) separation pattern exhibited by an MRC-OX6-specific immunoprecipitate from spleen cells labeled for 4 h represents a superposition of these three MRC-OX6-reactive polypeptide chain complexes. In contrast, MRC-OX3 recognizes exclusively a fully mature alpha,beta heterodimer devoid of protein precursor forms and devoid of any invariant chains. Considering the previous observation that the respective alpha and beta subunits of MRC-OX6 and MRC-OX3-specific molecules comigrate on 2D O'Farrell gels combined with the data of this investigation, it is suggested that the mature MRC-OX6-specific alpha,beta heterodimer and the mature MRC-OX3-specific alpha,beta heterodimer originate from the same biosynthetic intermediate. We propose that before entering the plasma membrane an MRC-OX6-reactive molecule composed of fully glycosylated alpha, beta and p36 releases its post-translationally processed gamma chain (p36), giving rise to two conformation isomers, one alpha,beta heterodimer still being reactive with MRC-OX6 and one alpha,beta heterodimer which has lost the serologic MRC-OX6 and gained the MRC-OX3 specificity. Both alpha, beta heterodimers are expressed on the cell surface as two distinct subsets of I-A-equivalent class II molecules.


Potential antibacterial activity of berberine against multi drug resistant enterovirulent Escherichia coli isolated from yaks (Poephagus grunniens) with haemorrhagic diarrhoea.
To evaluate the antimicrobial efficacy of berberine, a plant alkaloid. Five multi-drug resistant (MDR) STEC/EPEC and five MDR ETEC isolates from yaks with haemorrhagic diarrhoea were selected for the study. Antibacterial activity of berberine was evaluated by broth dilution and disc diffusion methods. The binding kinetics of berberine to DNA and protein was also enumerated. For both categories of enterovirulent Escherichia coli (E. coli) isolates, berberine displayed the antibacterial effect in a dose dependent manner. The MIC(50) of berberine chloride for STEC/EPEC isolates varied from 2.07 μM to 3.6 μM with a mean of (2.95 ± 0.33) μM where as for ETEC strains it varied from 1.75 to 1.96 μM with a mean of (1.87 ± 0.03) μM. Berberine bind more tightly with double helix DNA with Bmax and Kd of (24.68±2.62) and (357.8±57.8), respectively. Berberine reacted with protein in comparatively loose manner with Bmax and Kd of (18.9±3.83) and (286.2±113.6), respectively. The results indicate clearly that berberine may serve as a good antibacterial against multi drug resistant E. coli.


To be or not to be a hamlet pair in sympatry.
Recent adaptive radiations, such as the fringillid finches on the Galapagos archipelago or the cichlid fishes in the East African Great Lakes, are invaluable model systems for evolutionary and ecological research. Puebla et al., in this issue of Molecular Ecology, have established a group of colorful coral reef fishes from the Caribbean sea for studying the early phases of species formation in a marine adaptive radiation. It appears that local evolutionary processes are important in this system, which might have even triggered in situ speciation.


Suppression of 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis by pre-initiation treatment of rats with beta-naphthoflavone coincides with decreased levels of the carcinogen-derived DNA adducts in the mammary gland.
Mechanisms underlying prevention by beta-naphthoflavone (beta-NF) of mammary carcinogenesis initiated with 7,12-dimethylbenz[a]anthracene (DMBA) in the rat were elucidated. Treatment of female Sprague-Dawley rats with beta-NF at 40 mg/kg b.wt. for 4 days by oral gavage in corn oil before a single oral dose of DMBA (112 mg/kg b.wt.) suppressed mammary gland carcinogenesis as shown by an increase in the median latent period from 10 to 24 weeks and a 60% decrease in the multiplicity of mammary adenocarcinomas. In contrast, a 20-day treatment with beta-NF starting 3 weeks after DMBA had no significant effects on mammary tumorigenesis. The activities of phase I and phase II enzymes were examined in the liver and mammary gland 24 h after treatment of rats with beta-NF, DMBA, or beta-NF followed by DMBA as in the first bioassay. Treatment with either beta-NF or DMBA increased the hepatic activities of cytochrome P450 (CYP)1A1, 1A2, and 2B1/2, and glutathione S-transferase, and the mammary activity of CYP1A1. The activity of mammary CYP2B1/2 induced by DMBA was decreased by beta-NF. In the liver, the increase of UDP-glucuronosyl transferase (GT) activity in rats treated with beta-NF and DMBA was 2.3-fold greater than in rats treated with DMBA alone. Thus, treatment with beta-NF likely increased the rate of glucuronidation of DMBA dihydrodiols leading to carcinogen detoxification. The levels of the DMBA adducts determined by 32P-postlabeling of the mammary gland DNA were decreased in the beta-NF-pretreated rats. The beta-NF-induced increase in the hepatic UDP-GT activity and decrease in the mammary DNA-DMBA adducts occurred under the same treatment regimen that led to suppression of DMBA-induced mammary carcinogenesis.


Pattern of left ventricular diastolic filling in chronic aortic regurgitation: a gated blood pool assessment.
Limited information exists regarding the pattern of left ventricular diastolic filling in moderate to severe chronic aortic regurgitation (AR). The left ventricular diastolic filling curve derived from gated blood pool scans was evaluated in 24 normal subjects and 29 patients with AR. The peak filling rate (PFR), mean filling rate (MFR), peak ejection rate (PER), PFR/MFR, PFR/PER, and the time of the rapid filling period divided by the diastolic time were determined. PFR, MFR and PER were calculated as end-diastolic volumes per second (EDV/s). PFR was lower in the AR group than in the normal subjects (2.24 +/- 0.70 vs 3.09 +/- 0.71 EDV/s, p less than 0.001). Similarly, MFR was lower in the AR group (1.31 +/- 0.40 vs 1.63 +/- 0.29 EDV/s, p less than 0.01). PER was also reduced in the AR group. Both PFR/MFR and PFR/PER were reduced, while the ratio of rapid filling period to diastolic time was longer in the AR group than in normal subjects. Clinical evidence of congestive heart failure occurred in 8 patients in the AR group. Diastolic filling variables were not significantly different from the asymptomatic subgroup of patients with AR, but were abnormal when compared with those of normal subjects. In patients with AR, an abnormal pattern of diastolic filling was noted, consisting of a reduced PFR, MFR and PFR/ with a more linear pattern of filling (reduced PFR/MFR) during a longer rapid filling period.


Strain-specific determinants on the major phosphoprotein of murine mammary tumor viruses.
The major phosphoprotein (p23) of murine mammary tumor virus (MuMTV) was purified for C3H virus, using a combination of alkyl agarose chromatography and gel filtration. Monospecific antiserum was raised against glutaraldehyde crosslinked polymers of purified p23, and the antiserum was then used with iodinated p23 to develop a competition radioimmunoassay. Phosphoprotein p23 was shown to contain both group- and type-specific antigenic determinants in assays using detergent-disrupted virions of MuMTV strains C3H, RIII, GR, and DBA/2 as competing antigens. Tryptic and chymotryptic peptide mapping analysis of p23 polypeptides isolated from MuMTV strains C3H, RIII, GR and DBA/2 showed that the p23s of each virus strain could be clearly distinguished from each other.


Sunlight-induced effective heterogeneous photocatalytic decomposition of aqueous organic pollutants to CO2 assisted by a CO2 sorbent, amine-containing mesoporous silica.
Photocatalytic mineralization of aqueous formic acid and phenol on pure TiO(2) under sunlight irradiation was substantially accelerated to give a reliable photocatalytic efficiency by conducting the reactions in the presence of a CO(2) sorbent, amine-containing SBA-15, placed in the gas phase of the reactor.


Hemiclamshell incision in the treatment of mediastinal goiter.
The thyroid disease can appear in 0.16-3.3% of cases as mediastinal goiter. The treatment is difficult and requires a mediastinal approach. We have analyzed our experience from September 1995 to September 2007 among 2,439 thyroidectomies conducted for thyroid disease; 16 cases required a sternotomy, in seven patients conducted as hemiclamshell approach (median sternotomy associated to a fourth intercostals space incision). Preoperative evaluation included otorhinolaryngology evaluation and computed tomography. All the cases were followed up to 12 months. For seven cases treated trough hemiclamshell, the mean age was 57.8 years; hospital stay is 5.2 days. All the patients were discharged after respiratory evaluation; two patients required a pneumological admittance to physio-kinesi-respiratory. There were no cases of hemorrhage, nerve injury, permanent hypocalcemia, and chylothorax. There was no mortality at 30 days. The hemiclamshell is a safe procedure to treat mediastinal goiter and permit a good exposure of subclavian vessels and mediastinal nodes.


Completing the human genome: the progress and challenge of satellite DNA assembly.
Genomic studies rely on accurate chromosome assemblies to explore sequence-based models of cell biology, evolution and biomedical disease. However, even the extensively studied human genome has not yet reached a complete, 'telomere-to-telomere', chromosome assembly. The largest assembly gaps remain in centromeric regions and acrocentric short arms, sites known to contain megabase-sized arrays of tandem repeats, or satellite DNAs. This review aims to briefly address the progress and challenges of generating correct assemblies of satellite DNA arrays. Although the focus is placed on the human genome, many concepts presented here are applicable to other genomes.


Serum level of IL-1β in patients with inflammatory demyelinating disease: Marked upregulation in the early acute phase of MOG antibody associated disease (MOGAD).
To evaluate the serum cytokine profiles in patients with myelin oligodendrocyte glycoproteins antibody associated disease (MOGAD), compared to those in neuromyelitis optica spectrum disorder with aquaporin-4 immunoglobulin G (APQ4-IgG+ NMOSD), multiple sclerosis (MS), and other inflammatory demyelinating diseases (IDDs). The level of interleukin (IL)-1β, IL-5, IL-6, IL-10, IL-12p70, IL-17A, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in sera from 21 patients with MOGAD, 32 APQ4-IgG+ NMOSD, 24 MS, and 16 other IDDs were assessed. In MOGAD patients, the levels of IL-1β and IL-12p70 were elevated compared to APQ4-IgG+ NMOSD. The level of IL-10 and the ratio of T helper (Th)-1/Th2-related cytokines were elevated in MOGAD patients compared to MS or other IDDs. In an intragroup analysis, the IL-1β was increased in acute stage of MOGAD, APQ4-IgG+ NMOSD, and also MS compared to their chronic stage counterpart. It was inversely correlated with time from acute attack to sampling in MOGAD (p < 0.001) and AQP4-IgG+ NMOSD (p = 0.001), but not in MS. Moreover, the IL-1β was most markedly upregulated in MOGAD sera sampled within 1 week from acute attack compared to those sampled after (p = 0.002). The serum IL-1β can be elevated in the acute stage of patients with diverse IDDs including, MOGAD, APQ4-IgG+ NMOSD, and MS. This upregulation of serum IL-1β can be most markedly observed in the early acute stage of MOGAD patients. Further studies seem to be needed to determine the proper mechanism for the upregulation of serum IL-1β and also the role of IL-1β inhibition especially at the early acute stage of MOGAD.


Ambulatory detoxification of heroin addicts: a follow-up study.
The present study was devised to investigate whether or not 18 psychosocial characteristics of 141 male and 43 female heroin addicts who entered a 21-day ambulatory detoxification program were correlated with (1) length of stay, (2) completing the full course of detoxification, (3) being successfully transferred to aftercare treatment, and (4) being locatable for follow-up one month later. The study also described the status of the patients who were locatable one month after receiving their last dose of methadone in the detoxification program. Only 74 persons were contacted one month after receiving their last dose of methadone, and they were all in treatment. Eighty-three addicts were transferred to other programs before leaving the detoxification program. There were only two significant relationships between the 18 psychosocial characteristics and the four dependent variables. Number of arrests was inversely related to length of stay, and whites were more likely to be transferred to an aftercare program than blacks. The implications of the results for evaluating other ambulatory detoxification programs and for improving retention rates were discussed.


Data assimilation in dynamical cognitive science.
Dynamical models make specific assumptions about cognitive processes that generate human behavior. In data assimilation, these models are tested against time-ordered data. Recent progress on Bayesian data assimilation demonstrates that this approach combines the strengths of statistical modeling of individual differences with the those of dynamical cognitive models.


Na(+)-dependent HCO3- transport and Na+/H+ exchange regulate pHi in human ciliary muscle cells.
We investigated intracellular pH (pHi) regulation in cultured human ciliary muscle cells by means of the pH-sensitive absorbance of 5(and 6)-carboxy-4',5'-dimethylfluorescein (CDMF). The steady-state pHi was 7.09 +/- 0.04 (n = 12) in CO2/HCO3(-)-buffered and 6.86 +/- 0.03 (n = 12) in HEPES-buffered solution. Removal of extracellular sodium for 6 min acidified the cells by 1.11 +/- 0.06 pH units (n = 12) in the presence of CO2/HCO3- and by 0.91 +/- 0.05 pH units (n = 8) in its absence. Readdition of external sodium resulted in a rapid pHi recovery, which was almost completely amiloride-sensitive in the absence of CO2/HCO3- but only slightly influenced by amiloride in its presence. Application of DIDS under steady-state conditions significantly acidified the ciliary muscle cells by 0.25 +/- 0.02 (n = 4) in 6 min, while amiloride had no effect. The pHi recovery after an intracellular acid load was completely dependent on extracellular sodium. In HEPES-buffered solution the pHi recovery was almost completely mediated by Na+/H+ exchange, since it was blocked by amiloride (1 mmol/liter). In contrast, a marked amiloride-insensitive pHi recovery was observed in CO2/HCO3(-)-buffered solution which was mediated by chloride-independent and chloride-dependent Na+ HCO3- cotransport. This recovery, inhibited by DIDS (0.2 mmol/liter), was also observed if the cells were preincubated in chloride-free solution for 4 hr. Analysis of the sodium dependence of the pHi recovery after NH4Cl prepulse revealed Vmax = 0.57 pH units/min, Km = 39.7 mmol/liter extracellular sodium for the amiloride-sensitive component and Vmax = 0.19 pH units/min, Km = 14.3 mmol/liter extracellular sodium for the amiloride-insensitive component. We conclude that Na+/H+ exchange and chloride-independent and chloride-dependent Na(+)-HCO3- cotransport are involved in the pHi regulation of cultured human ciliary muscle cells.


Biological activity in the repopulating rat spermatocyte after the withdrawal of gossypol treatment: II. The activity for the synthesis of cellular and nuclear basic proteins.
The synthesis of cellular and nuclear basic proteins in the first generation of the repopulated pachytene spermatocyte (RPS) and the control pachytene spermatocyte (CPS) was studied by the incorporation of 3H-arginine into proteins. After pretreatment with gossypol for various lengths of time, the synthetic activity for cellular protein in the RPS was slightly inhibited. In comparison to CPS, on the other hand, the inhibition ranged from 12% to 26% (for gossypol pretreatment from 3 to 12 weeks, respectively). However, the synthetic activity for nuclear basic protein in the RPS was drastically reduced in comparison to that of the CPS. The reduction ranged from 46% to 61% in RPS after receiving gossypol pretreatment for 3 to 12 weeks, respectively. Gel electrophoretic separation of the basic protein extracted from the pachytene cell indicated that the major basic proteins are nucleosomal linker and core proteins, i.e., histone H1, H2A,B, H3, and H4, and with a lesser amount of sperm-specific BP and X1 proteins. After gossypol treatment in the RPS, the synthesis of sperm-specific proteins (BP and X1) and core histones (H2A and H4) became drastically reduced. Finally, the effect of gossypol on the ratio of nuclear basic protein to DNA in RPS and the direct correlation of this ratio to nucleosomal spacing and chromatin structure are discussed.


[Effect of suo quan pill for reducing clozapine induced salivation].
40 Schizophrenic inpatients with clozapine induced salivation were divided into two groups randomly. They were treated with Suo Quan pill and a control study of the placebo (neutral pill) for reducing clozapine induced salivation. These cases were also classified by TCM Syndrome Differentiation and laboratory examinations were performed. There was a significant difference in effect on salivation between the therapeutic group (21 cases) and the controlled group (19 cases), P < 0.01. According to their TCM subtypes two subtypes (Stagnation of Phlegm-Dampness and Yin Deficiency) showed the best results. No correlation between the peripheral clozapine level and salivation was found. No side effect was recorded.


Association between the rs12255372 variant of the TCF7L2 gene and obesity in a Cameroonian population.
The transcription factor 7-like 2 (TCF7L2) is one of the genes that have been identified as possible determinants of diabetes which is associated with obesity. Data on the genetic causes of obesity in sub-Saharan African populations are very scares. The aim of this study was to assess the association between the transcription factor 7-like 2 (TCF7L2) gene polymorphism (rs12255372 G/T) and obesity and weight-related traits in a Cameroonian population. A case-control study was conducted on 35 obese and 30 non-obese Cameroonian adults. TCF7L2 rs12255372 genotypes were determined using PCR-RFLP and correlated with BMI and weight-related traits. No significant association was observed between the rs12255372 T allele (χ(2) = 0.0684, p = 0.79) or the TT genotype (χ(2) = 0.372, p = 0.54) of the TCF7L2 gene and obesity in the Cameroonian population. However, amongst the weight-related traits, triglycerides were significantly associated with the T risk allele of the TCF7L2 gene (p = 0.012). This study on Cameroonian subjects replicates the absence of association between the TCF7L2 rs12255372 variant and obesity as observed in European and American populations.


Experience affects cortical but not subcortical polyamines.
The effect of brief periods of experience in an enriched environment (7 hours per day for 3 days), and of inhibition of polyamine synthesis was studied in four brain regions: occipital cortex, remaining cortex, subcortex and cerebellum plus medulla. Polyamine synthesis was inhibited by alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. DFMO caused a 30-50% decrease in putrescine content in all brain areas, irrespective of the environmental treatment. Spermidine was decreased by the inhibitor in subcortex and in cerebellum plus medulla, while spermine was increased in remaining cortex. The regional differences in inhibitor effect suggest that the regulation of polyamine metabolism varies among the four brain areas. Experience increased the weight and spermidine content of remaining cortex and decreased putrescine content of occipital cortex. Noncortical areas were not affected. The effects of experience on polyamine levels were somewhat increased by DFMO. Therefore, experience did not have a generalized effect on polyamine levels; rather, each polyamine responded in a specific manner. In addition, polyamine levels were affected only in those brain areas which are known from previous studies to respond to environmental stimulation with weight increase. These facts suggest that polyamines might have a role in the regulation of experience-induced plasticity.


Alpl prevents bone ageing sensitivity by specifically regulating senescence and differentiation in mesenchymal stem cells.
Mutations in the liver/bone/kidney alkaline phosphatase (Alpl) gene cause hypophosphatasia (HPP) and early-onset bone dysplasia, suggesting that this gene is a key factor in human bone development. However, how and where Alpl acts in bone ageing is largely unknown. Here, we determined that ablation of Alpl induces prototypical premature bone ageing characteristics, including bone mass loss and marrow fat gain coupled with elevated expression of p16INK4A (p16) and p53 due to senescence and impaired differentiation in mesenchymal stem cells (MSCs). Mechanistically, Alpl deficiency in MSCs enhances ATP release and reduces ATP hydrolysis. Then, the excessive extracellular ATP is, in turn, internalized by MSCs and causes an elevation in the intracellular ATP level, which consequently inactivates the AMPKα pathway and contributes to the cell fate switch of MSCs. Reactivating AMPKα by metformin treatment successfully prevents premature bone ageing in Alpl+/- mice by improving the function of endogenous MSCs. These results identify a previously unknown role of Alpl in the regulation of ATP-mediated AMPKα alterations that maintain MSC stemness and prevent bone ageing and show that metformin offers a potential therapeutic option.


Crime and punishment in Saudi Arabia: Lashing, imprisonment, and other unusual punishments.
In this paper, we examine the antecedents of the sanctions of lashing and imprisonment for juveniles in Saudi Arabia. The current study examined 437 court cases and files across several court systems in Saudi Arabia to determine the extent to which justice-involved youth are punished. The data were drawn from hundreds of court files and records received from several court systems in Saudi Arabia spanning 2010 to 2015. We tested several predictor variables on sentence type, number of lashes, and prison length. We employed binary logistic regression to examine sentence type, while we employed negative binomial analysis to examine the second and third dependent variables, number of lashes and length of prison sentence, respectively. We found that juveniles processed in juvenile court were more likely to receive more lenient sentences than juveniles tried in the general court system. In addition, older juveniles received harsher sentences (flogging and imprisonment) than younger juveniles (flogging or imprisonment), those who committed multiple offenses received more lashes than those who committed a single offense, and those who had both juvenile and adult criminal associates received more lashes than those who had only juvenile criminal associates. Moreover, the number of presiding judges influenced the severity of punishment: justice-involved youth who were tried by a single judge received fewer lashes than justice-involved youth who were tried by three or more judges. Lastly, justice-involved youth tried by a lone judge were less likely to be sentenced to a longer prison term than those tried by three or more judges. However, justice-involved youth tried by two judges received an even longer prison term than those tried by three or more judges. About one-half of all rulings examined in the current study were presided over by a lone judge. While punishments imposed by lone judges were not as severe as those imposed by two judges or three or more judges, Saudi judges wield tremendous power over their fellow citizens, more so because there are no jury trials in the Kingdom. We therefore recommend that judicial training emphasize a "do no harm" principle in sentencing. Because a two-judge panel generally imposes a harsher sentence than a panel with three or more judges, we recommend an extensive examination of the country's prior judicial rulings presided over by two judges to understand why they are more likely to issue harsher sentences than lone judges or three- or four-judge panels. The findings would lead to the development of sentencing guidelines to curb arbitrary sentencing and reverse the generally unpredictable sentence lengths imposed on justice-involved youth.


Interprofessional Clinical Assignments: A Project in Nursing Education.
Education involving interprofessional activities helps to improve learning and the ability to work in an effective collaborative environment. In this project, 16 baccalaureate nursing students were given the opportunity to work with other members of the health care team to develop an understanding of the roles and responsibilities of each group of professionals and the communication skills needed to provide quality and safe care to patients and to positively impact their motivation to work with members of other health professions. All the students in the group documented the successful completion of these objectives in their journals.


Increased skin barrier disruption by sodium lauryl sulfate in mice expressing a constitutively active STAT6 in T cells.
Atopic dermatitis (AD) is a pruritic, chronic inflammatory skin disease that affects 10-20% of children and 1-3% of adults worldwide. Recent studies have indicated that the ability of Th2 cytokines, such as interleukin-4 (IL-4) to regulate skin barrier function may be a predisposing factor for AD development. The present studies examined the ability of increased Th2 activity to affect cutaneous barrier function in vivo and epidermal thickening. Mice that express a constitutively active Signal Transducer and Activator of Transcription 6 (STAT6VT) have increased Th2 cells and a predisposition to allergic inflammation were used in these studies, they demonstrate that topical treatment with the irritant sodium lauryl sulfate (SLS) caused increased transepidermal water loss and epidermal thickening in STAT6VT mice over similarly treated wild-type mice. The proliferation marker Ki-67 was increased in the epidermis of STAT6VT compared to the wild-type mice. However, these differences do not appear to be linked to the addition of an irritant as control-treated STAT6VT skin also exhibited elevated Ki-67 levels, suggesting that the increased epidermal thickness in SLS-treated STAT6VT mice is primarily driven by epidermal cell hypertrophy rather than an increase in cellular proliferation. Our results suggest that an environment with increased Th2 cytokines results in abnormal responses to topical irritants.


Developers and evaluation of interactive health communication applications. The Science Panel on Interactive Communications and Health.
Developers of Interactive Health Communication (IHC) are capable of providing great benefit by creating interactive programs that serve to protect and improve health. Conducting proper evaluation of these programs will ensure that they achieve these goals more successfully. This article seeks to inform developers of IHC about which types of evaluation are most important to include as a part of the development process and to examine the ways in which such evaluation can be implemented to benefit the producers--and ultimately, the consumers--of IHC.


Temporary suppression of pulsatile LH release following a single injection of a GnRH agonist (deslorelin) in ovariectomised Holstein dairy cows.
The objective of the experiment was to investigate the potential for using a single injection of the GnRH agonist [D-Trp(6), Pro(9)-des-Gly(10)-NH(2)] GnRH-ethylamide (deslorelin) to suppress LH secretion in ovariectomised Holstein cows. Each dose of 10, 100 and 1000 microg deslorelin was injected intravenously into each of four ovariectomised cows on day 0. Blood samples were collected hourly on day 0 to profile the induced LH release. Frequent serial blood samples were collected at 10min intervals over 4h on days -3, -1, +2, +4 and +6. The injection of deslorelin induced a surge-like release of LH that begun within 1h in all cows. There was no difference between deslorelin doses in terms of maximum LH concentration, area under the LH curve (AUC) or log(10)(AUC). The average interval from injection to maximum LH concentration was longer for cows receiving 1000 microg than in those receiving 10 microg (3.5 versus 1.5h; P<0.01), though no different to 100 microg (2.8h; P>0.1). This relationship was described by a logarithmic function of deslorelin dose in micrograms (R(2)=73.3%, P<0.01). Pre-treatment smoothed mean LH concentration was significantly correlated with peak LH concentration of the induced surge: max_LH=5.37+9.57 x pre-amplitude (R(2)=33.2%, P=0.05). Similarly, LH pulse amplitude pre-deslorelin was also correlated with peak LH of the induced surge max_LH=0.07+12.9 x pre-amplitude (R(2)=53.7%, P=0.07). Pulsatile release of LH was suppressed only with the 1000 microg dose on day +2. Suppression was characterised by a reduction in mean LH, smoothed mean LH and LH pulse amplitude. By day +4, LH parameters were no different to pre-treatment ones. Pulse frequency was not affected by the treatment, although a small non-significant reduction at day +2 for 1000 microg dose was observed (3.9 versus 2.8, P=0.14). In conclusion, temporary suppression of LH output for at least 48h occurred following a single intravenous injection of 1000 microg of deslorelin, even though there were similar peak LH concentrations were for the three doses.


Cochlear Nucleus Transcriptome of a Fragile X Mouse Model Reveals Candidate Genes for Hyperacusis.
Fragile X Syndrome (FXS) is a hereditary form of autism spectrum disorder. It is caused by a trinucleotide repeat expansion in the Fmr1 gene, leading to a loss of Fragile X Protein (FMRP) expression. The loss of FMRP causes auditory hypersensitivity: FXS patients display hyperacusis and the Fmr1- knock-out (KO) mouse model for FXS exhibits auditory seizures. FMRP is strongly expressed in the cochlear nucleus and other auditory brainstem nuclei. We hypothesize that the Fmr1-KO mouse has altered gene expression in the cochlear nucleus that may contribute to auditory hypersensitivity. RNA was isolated from cochlear nuclei of Fmr1-KO and WT mice. Using next-generation sequencing (RNA-seq), the transcriptomes of Fmr1-KO mice and WT mice (n = 3 each) were compared and analyzed using gene ontology programs. We identified 270 unique, differentially expressed genes between Fmr1-KO and WT cochlear nuclei. Upregulated genes (67%) are enriched in those encoding secreted molecules. Downregulated genes (33%) are enriched in neuronal function, including synaptic pathways, some of which are ideal candidate genes that may contribute to hyperacusis. The loss of FMRP can affect the expression of genes in the cochlear nucleus that are important for neuronal signaling. One of these, Kcnab2, which encodes a subunit of the Shaker voltage-gated potassium channel, is expressed at an abnormally low level in the Fmr1-KO cochlear nucleus. Kcnab2 and other differentially expressed genes may represent pathways for the development of hyperacusis. Future studies will be aimed at investigating the effects of these altered genes on hyperacusis. Level N/A Laryngoscope, 2023.


Evolution of international collaborative research efforts to develop non-Cochrane systematic reviews.
This research-on-research study describes efforts to develop non-Cochrane systematic reviews (SRs) by analyzing demographical and time-course collaborations between international institutions using protocols registered in the International Prospective Register of Systematic Reviews (PROSPERO) or published in scientific journals. We have published an a priori protocol to develop this study. Protocols published in scientific journals were searched using the MEDLINE and Embase databases; the query terms "Systematic review" [Title] AND "protocol" [Title] were searched from February 2011 to December 2017. Protocols registered at PROSPERO during the same period were obtained by web scraping all non-Cochrane records with a Python script. After excluding protocols that had a fulfillment or duplication rate of less than 90%, they were classified as published "only in PROSPERO", "only in journals", or in "journals and PROSPERO". Results of data and metadata extraction using text mining processes were curated by two reviewers. These Datasets and R scripts are freely available to facilitate reproducibility. We obtained 20,814 protocols of non-Cochrane SRs. While "unique protocols" by reviewers' institutions from 60 countries were the most frequent, a median of 6 (2-150) institutions from 130 different countries were involved in the preparation of "collaborative protocols". The highest Ranked countries involved in overall protocol production were the UK, the U.S., Australia, Brazil, China, Canada, the Netherlands, Germany, and Italy. Most protocols were registered only in PROSPERO. However, the number of protocols published in scientific journals (924) or in both PROSPERO and journals (807) has increased over the last three years. Syst Rev and BMJ Open published more than half of the total protocols. While the more productive countries were involved in "unique" and "collaborative protocols", less productive countries only participated in "collaborative protocols" that were mainly published in PROSPERO. Our results suggest that, although most countries were involved in solitary production of protocols for non-Cochrane SRs during the study period, it would be useful to develop new strategies to promote international collaborations, especially with less productive countries.


Neurodevelopmental outcomes after open heart operations before 3 months of age.
The purpose of this study was to monitor developmental progress and identify predictors of developmental outcomes at 2 years after operation in infants who underwent a surgical procedure with cardiopulmonary bypass (CPB) at less than 3 months of age. Patients (N=131 enrolled; N=106 assessed) less than 3 months of age at the time of cardiac operation were prospectively enrolled (years 1999-2003) and assessed at 8, 12, and 24 months after operation. Patients with preexisting conditions independently associated with poor neurodevelopmental outcomes were excluded. Fine and gross motor development was formally assessed at all 3 visits, and parent ratings of development across several domains were obtained. Neurodevelopment was formally assessed at 24 months of age using the Bayley Scales of Infant Development, 2nd edition (BSID-II) Mental Development Index score (MDI). Significant gross motor difficulties were identified at 8 months of age (p<0.001) and, although improved by the 24-month assessment, remained lower than average. Fine motor skills showed a significant decrease from 8 to 24 months of age (p=0.001). Factors associated with poorer neurodevelopmental outcome (BSID-II MDI) at 24 months after operation included a diagnosis of univentricular anatomy or complex coarctation of the aorta, higher complexity of the surgical procedure, longer duration of hospital stay, and presence of complications in the postoperative period. Children undergoing repair of congenital heart disease (CHD) still have impaired development 2 years after the operation. Observed patterns of development were specific to the skill being assessed and related to both anatomic complexity and increased complexity of care received.


(S)-4-Phenyl-2-(1,2,3,4-tetra-hydro-isoquinolin-3-yl)-1,3-thia-zole.
In the title compound, C(18)H(16)N(2)S, the N-containing ring adopts a half-chair configuration. The crystal packing features C-H⋯N contacts. There is no π-π stacking within the crystal structure.


The Mediterranean diet: rationale and evidence for its benefit.
There is now a consensus about recommending the Mediterranean diet pattern for the prevention of coronary heart disease (CHD) and cancer. The most important aspect of this treatment decision, in contrast with the pharmacologic prevention of CHD (including cholesterol lowering), is that the Mediterranean diet has a striking effect on survival. The main explanation for this is that the Mediterranean diet is protective not only against CHD and cancers but also against other various chronic diseases. Furthermore, the Mediterranean diet appears to be effective at reducing atherosclerosis and the risk of fatal complications (ie, sudden cardiac death and heart failure) of atherosclerosis. Finally, unlike drug therapies, no harmful side effect has been reported following the adoption of this dietary pattern. Many micro- and macronutrients characteristic of the Mediterranean diet interact in a synergistic way to induce states of resistance to chronic diseases. More research is required to understand these complex interplays.


Metabolism of 4-chlorophenol by Azotobacter sp. GP1: structure of the meta cleavage product of 4-chlorocatechol.
A mutant strain of Azotobacter sp. GP1 converted 4-chlorophenol to 4-chlorocatechol under cometabolic conditions. Under the same conditions the wild-type strain accumulated a yellow compound, which by chemical and spectroscopic methods was identified as 5-chloro-2-hydroxy-6-oxohexadienoic acid (5-chloro-2-hydroxy-muconic semialdehyde). The structure of this compound indicates a meta-proximal cleavage of 4-chlorocatechol.


Late Middle Pleistocene hominin teeth from Panxian Dadong, South China.
The hominin teeth and evidence of hominin activities recovered from 1991 to 2005 at the Panxian Dadong site in South China are dated to the late Middle Pleistocene (MIS 8-6 or ca. 130-300 ka), a period for which very little is known about the morphology of Asian populations. The present study provides the first detailed morphometric description and comparisons of four hominin teeth (I(1), C1, P(3) and P3) from this site. Our study shows that the Panxian Dadong teeth combine archaic and derived features that align them with Middle and Upper Pleistocene fossils from East and West Asia and Europe. These teeth do not display any typical Neanderthal features and they are generally more derived than other contemporaneous populations from Asia and Africa. However, the derived traits are not diagnostic enough to specifically link the Panxian Dadong teeth to Homo sapiens, a common problem when analyzing the Middle Pleistocene dental record from Africa and Asia. These findings are contextualized in the discussion of the evolutionary course of Asian Middle Pleistocene hominins, and they highlight the necessity of incorporating the Asian fossil record in the still open debate about the origin of H. sapiens.


LYATK1 potently inhibits LPS-mediated pro-inflammatory response.
Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-β-activated kinase1 (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAK1 inhibited LPS-induced mRNA expression and production of several pro-inflammatory cytokines [interleukin 1β (IL-1β), tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro-inflammatory cytokine production was again attenuated with LYTAK1 co-treatment. Molecularly, LYTAK1 dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAK1 inhibited LPS-induced activation of TAK1-NFκB-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings.


Lung damage following bone marrow transplantation: I. The contribution of irradiation.
High dose whole body irradiation is commonly included in conditioning regimens for bone marrow transplantation for treatment of patients with hematological malignancies. Interstitial pneumonitis is a major complication after BMT. About one-fourth of all BMT patients die from IP. In about half of these cases, an infectious agent, particularly cytomegalovirus, is involved. When no infectious cause is found, it is classified as idiopathic IP (IIP). Total body irradiation is often associated with the induction of IIP; however, extrapolation of animal data from the experiments presented indicates that this is not the only factor contributing to IIP in man. Brown Norway (BN/Bi) rats were bilaterally irradiated to the lungs with 300 kV X rays at a high dose rate (HDR; 0.8 Gy/min) and at a low dose rate (LDR; 0.05 Gy/min). The dose-response curves found were very steep. In the LDR group, lung function studies were performed. There was a strong correlation between the increase in ventilation rate and the death pattern. The LD50 at 180 days was 13.3 Gy for HDR and 22.7 Gy for LDR. The ratios of LD50/180 at 0.05 Gy/min to that at 0.8 Gy/min is 1.7, which indicates a great repair capacity of the lungs. Extrapolation of animal data to patient data leads to an estimated dose of about 15-16 Gy at a 50% radiation pneumonitis induction for low dose rate TBI. As the absorbed dose in the lungs of BMT patients rarely exceeds 10 Gy, additional factors such as remission-induction chemotherapy, cyclophosphamide, methotrexate, cyclosporin A, graft-versus-host disease, etc., might be involved in the high incidence of IIP in man after BMT.


Successful fluconazole treatment of catheter-related candidemia caused by Candida haemulonii: report of 2 neonatal cases.
Candida haemulonii forms part of the non-albicans Candida species. The candidemia caused by C. haemulonii is extremely rare but fatal in neonates. We reported the first two neonates with C. haemulonii candidemia in China which were treated with fluconazole and reviewed two papers previously reported. Our report adds further awareness on C. haemulonii candidemia in critical neonates and points out the importance of an early diagnosis and treatment of this fatal infection.


Effect of restricted emissions during COVID-19 on atmospheric aerosol chemistry in a Greater Cairo suburb: Characterization and enhancement of secondary inorganic aerosol production.
To prevent the rapid spreading of the COVID-19 pandemic, the Egyptian government had imposed partial lockdown restrictions which led emissions reduction. This served as ideal conditions for a natural experiment, for study the effect of partial lockdown on the atmospheric aerosol chemistry and the enhanced secondary inorganic aerosol production in a semi-desert climate area like Egypt. To achieve this objective, SO2, NO2, and PM2.5 and their chemical compositions were measured during the pre-COVID, COVID partial lockdown, and post-COVID periods in 2020 in a suburb of Greater Cairo, Egypt. Our results show that the SO2, NO2, PM2.5 and anthropogenic elements concentrations follow the pattern pre-COVID > post-COVID > COVID partial lockdown. SO2 and NO2 reductions were high compared with their secondary products during the COVID partial lockdown compared with pre-COVID. Although, PM2.5, anthropogenic elements, NO2, SO2, SO4 2-, NO3 -, and NH4 + decreased by 39%, 38-55%, 38%, 32.9%. 9%, 14%, and 4.3%, respectively, during the COVID partial lockdown compared with pre-COVID, with the secondary inorganic ions (SO4 2-, NO3 -, and NH4 +) being the dominant components in PM2.5 during the COVID partial lockdown. Moreover, the enhancement of NO3 - and SO4 2- formation during the COVID partial lockdown was high compared with pre-COVID. SO4 2- and NO3 - formation enhancements were significantly positive correlated with PM2.5 concentration. Chemical forms of SO4 2- and NO3 - were identified in PM2.5 based on their NH4 +/SO4 2- molar ratio and correlation between NH4 + and both NO3 - and SO4 2-. The particles during the COVID partial lockdown were more acidic than those in pre-COVID.


Occupational contact allergy to cocamidopropyl betaine and its impurities.
Contact allergy to cocamidopropyl betaine has been attributed to its impurities dimethylaminopropylamine and cocamidopropyl dimethylamine. To describe patients with positive patch test reactions to cocamidopropyl betaine-related compounds in an occupational dermatology clinic. We reviewed the 2002-2009 patch test records at the Finnish Institute of Occupational Health for allergic reactions to cocamidopropyl betaine, dimethylaminopropylamine, cocamidopropyl dimethylamine, and oleamidopropyl dimethylamine. Results. Irritant reactions to at least one of the test substances were seen in 39% of the 1092 patients tested. Fifteen (1.3%) patients showed allergic reactions: 13 to cocamidopropyl dimethylamine, 11 to dimethylaminopropylamine, 8 to oleamidopropyl dimethylamine, and 2 to cocamidopropyl betaine. Concomitant reactions to cocamidopropyl dimethylamine, dimethylaminopropylamine and oleamidopropyl dimethylamine were common. Ten of the 15 patients were diagnosed with occupational allergic contact dermatitis caused by cocamidopropyl betaine-related compounds. The sources of occupational exposure included hair care products, hair colours, perm wave solutions, and liquid soaps. Multiple contact allergies and exposure to several irritant factors were common, and all patients had hand eczema. Patch test reactions to cocamidopropyl betaine-related compounds are difficult to interpret, owing to extremely common irritant reactions. Cocamidopropyl betaine itself is probably not an allergen. Occupational allergic contact dermatitis caused by cocamidopropyl betaine-related compounds is relatively rare and, unlike non-occupational cocamidopropyl betaine-related allergy, typically manifests as hand dermatitis.


Fibroblast Growth Factor 2 as an Antifibrotic: Antagonism of Myofibroblast Differentiation and Suppression of Pro-Fibrotic Gene Expression.
Fibrosis is a pathological condition that is characterized by the replacement of dead or damaged tissue with a nonfunctional, mechanically aberrant scar, and fibrotic pathologies account for nearly half of all deaths worldwide. The causes of fibrosis differ somewhat from tissue to tissue and pathology to pathology, but in general some of the cellular and molecular mechanisms remain constant regardless of the specific pathology in question. One of the common mechanisms underlying fibroses is the paradigm of the activated fibroblast, termed the "myofibroblast," a differentiated mesenchymal cell with demonstrated contractile activity and a high rate of collagen deposition. Fibroblast growth factor 2 (FGF2), one of the members of the mammalian fibroblast growth factor family, is a cytokine with demonstrated antifibrotic activity in non-human animal, human, and in vitro models. FGF2 is highly pleiotropic and its receptors are present on many different cell types throughout the body, lending a great deal of variety to the potential mechanisms of FGF2 effects on fibrosis. However, recent reports demonstrate that a substantial contribution to the antifibrotic effects of FGF2 comes from the inhibitory effects of FGF2 on connective tissue fibroblasts, activated myofibroblasts, and myofibroblast progenitors. FGF2 demonstrates effects antagonistic towards fibroblast activation and towards mesenchymal transition of potential myofibroblast-forming cells, as well as promotes a gene expression paradigm more reminiscent of regenerative healing, such as that which occurs in the fetal wound healing response, than fibrotic resolution. With a better understanding of the mechanisms by which FGF2 alters the wound healing cascade and results in a shift away from scar formation and towards functional tissue regeneration, we may be able to further address the critical need of therapy for varied fibrotic pathologies across myriad tissue types.


Comparison of diafiltration and tangential flow filtration for purification of nanoparticle suspensions.
The study reports evaluation of different purification processes for removing surplus surfactant and formulating stable nanoparticle dispersions. Nanoparticle formulations prepared from poly(D,L-lactide-co-glycolide) and polyvinyl alcohol (PVA) were purified by a diafiltration centrifugal device (DCD), using 300K and 100K molecular weight cut-off (MWCO) membranes and a tangential flow filtration (TFF) system with a 300K MWCO membrane. The effects of process parameters including MWCO, transmembrane pressure (TMP), and mode of TFF on nanoparticle purification were evaluated, and two purification techniques were compared to the commonly used ultracentrifugation technique. Both DCD and TFF systems (concentration mode at TMP of 10 psi) with 300K MWCO membrane removed maximal percent PVA from nanoparticle dispersions (89.0 and 90.7%, respectively). T90, the time taken to remove 90% of PVA in 200-ml sample, however, was considerably different (9.6 and 2.8 h, respectively). Purified nanoparticle dispersions were stable and free of aggregation at ambient conditions over 3 days. This is in contrast to the ultracentrifugation technique, which, although it can yield a highly purified sample, suffers from drawbacks of a level of irreversible nanoparticle aggregation and loss of fine particles in the supernatant during centrifugation. The TFF, in concentration mode at TMP of 10 psi, is a relatively quick, efficient, and cost-effective technique for purification and concentration of a large nanoparticle batch (>or=200 ml). The DCD technique can be an alternative purification method for nanoparticle dispersions of small volumes.


Perception mirrors production in 14- and 18-month-olds: the case of coda consonants.
In a word learning experiment, 14- and 18-month-old infants are tested on their perceptual sensitivity to coda-consonant omissions. The results indicate that 14-month-olds are not sensitive to coda consonant omissions, showing a parallel with the omission of target coda consonants in early child language productions. At 18 months, infants are sensitive to coda-omission. The study strengthens the hypothesis that phonological wellformedness constraints influence infants' speech processing in general, and might restrict what is stored in their initial lexical representations. A lexical representation lacking information on the target coda consonant is, in turn, a likely source for coda-omissions in production.


(15)N CSA tensors and (15)N-(1)H dipolar couplings of protein hydrophobic core residues investigated by static solid-state NMR.
In this work, we assess the usefulness of static (15)N NMR techniques for the determination of the (15)N chemical shift anisotropy (CSA) tensor parameters and (15)N-(1)H dipolar splittings in powder protein samples. By using five single labeled samples of the villin headpiece subdomain protein in a hydrated lyophilized powder state, we determine the backbone (15)N CSA tensors at two temperatures, 22 and -35 °C, in order to get a snapshot of the variability across the residues and as a function of temperature. All sites probed belonged to the hydrophobic core and most of them were part of α-helical regions. The values of the anisotropy (which include the effect of the dynamics) varied between 130 and 156 ppm at 22 °C, while the values of the asymmetry were in the 0.32-0.082 range. The Leu-75 and Leu-61 backbone sites exhibited high mobility based on the values of their temperature-dependent anisotropy parameters. Under the assumption that most differences stem from dynamics, we obtained the values of the motional order parameters for the (15)N backbone sites. While a simple one-dimensional line shape experiment was used for the determination of the (15)N CSA parameters, a more advanced approach based on the "magic sandwich" SAMMY pulse sequence (Nevzorov and Opella, 2003) was employed for the determination of the (15)N-(1)H dipolar patterns, which yielded estimates of the dipolar couplings. Accordingly, the motional order parameters for the dipolar interaction were obtained. It was found that the order parameters from the CSA and dipolar measurements are highly correlated, validating that the variability between the residues is governed by the differences in dynamics. The values of the parameters obtained in this work can serve as reference values for developing more advanced magic-angle spinning recoupling techniques for multiple labeled samples.


Intraperitoneal Administration of a Novel TAT-BDNF Peptide Ameliorates Cognitive Impairments via Modulating Multiple Pathways in Two Alzheimer's Rodent Models.
Although Alzheimer's disease (AD) has been reported for more than 100 years, there is still a lack of effective cures for this devastating disorder. Among the various obstacles that hold back drug development, the blood-brain barrier (BBB) is one of them. Here, we constructed a novel fusion peptide by linking the active domain of brain-derived neurotrophic factor (BDNF) with an HIV-encoded transactivator of transcription (TAT) that has a strong membrane-penetrating property. After intraperitoneal injection, the eGFP-TAT could be robustly detected in different brain regions. By using scopolamine-induced rats and APPswe mice representing AD-like cholinergic deficits and amyloidosis, respectively, we found that intraperitoneal administration of the peptide significantly improved spatial memory with activation of the TrkB/ERK1/2/Akt pathway and restoration of several memory-associated proteins in both models. Administration of the peptide also modulated β-amyloid and tau pathologies in APPswe mice, and it increased the amount of M receptor with modulation of acetylcholinesterase in scopolamine-induced rats. We conclude that intraperitoneal administration of our TAT-BDNF peptide could efficiently target multiple molecular pathways in the brain and improve the cognitive functions in AD-like rodent models.


Onycholysis of the fingernails: evaluation and management.
Onycholysis (ONY) of the fingernails is a common disorder that is diagnosed with ease but often managed with great difficulty. The full spectrum of causes is broad and not always readily apparent. In this review, an approach to the evaluation and management of ONY is offered.


High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of DBCG 82 b&c.
International consensus reports recommend postmastectomy radiotherapy only to patients at high risk of a local recurrence (LR). The present analysis included 1000 out of 3083 high-risk breast cancer patients randomly assigned to postmastectomy radiotherapy in the DBCG82 b&c trials. Tissue microarrays had been constructed and sections stained for estrogen, progesterone and HER2 receptors. Median potential follow-up time was 17 years. Endpoints were LR as isolated first event, breast cancer mortality and overall mortality. Among patients randomly assigned to not receive radiotherapy, three prognostic subgroups of LR risk were found. "The good" defined by at least four out of five favorable criteria (3 positive nodes, tumor size <2cm, Grade 1 malignancy, estrogen or progesterone receptor positive, HER2 negative), "the Poor" defined by at least two out of three un-favorable criteria (>3 positive nodes, tumor size >5cm, Grade 3 malignancy) and finally "the Intermediate" the group in between. The smallest absolute reduction in 5-year LR probability (11%) after radiotherapy was seen for the good prognosis group. A similar absolute reduction in 15-year breast cancer mortality after radiotherapy (11%) was seen. The largest absolute reduction in 5-year LR probability after radiotherapy was seen for the poor prognosis group (36%). However, this large LR reduction did not translate into any reduction in 15-year breast cancer mortality (0%). Translation of LR reduction into breast cancer mortality reduction after postmastectomy radiotherapy to high-risk breast cancer patients seems to be heterogeneous, with the largest translation occurring within the good prognosis group.


A Rapid and Sensitive UPLC-MS/MS Method for Determination of Docetaxel in Rabbit Plasma: Pharmacokinetic Study of New Lung-Targeting Docetaxel Liposome at Low Dose.
In this study, a more rapid and more sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method is developed and validated for the pharmacokinetic study of a new lung-targeting docetaxel liposome (DTX-LP) at low dose (1 mg/kg) in rabbits. The method is reliable and reproducible with intra-day precision below 5.75 %, inter-day precision below 7.57 %, and mean extraction recovery of 84.1-91.7 %. At low dose, the validated method is successfully applied to the comparative pharmacokinetic study of docetaxel (DTX) in rabbit plasma after intravenous administration of DTX-LP and DTX injection, respectively. The results indicate that the pharmacokinetic profile of DTX is completely changed when loaded in the new type of liposome, which can make DTX quicker distribution from the circulation to the target organ and slower eliminated from the body.


Cytotoxicity of activated rat macrophages against syngeneic islet cells is arginine-dependent, correlates with citrulline and nitrite concentrations and is identical to lysis by the nitric oxide donor nitroprusside.
Lysis of rat islet cells by syngeneic activated macrophages in vitro can be completely inhibited by the nitric oxide-synthase-inhibitor NG-methyl-L-arginine. This inhibition can be reversed by an excess of L-arginine. Time-dependent lysis of islet cells by activated macrophages is accompanied by increasing concentrations of nitrite and citrulline in the culture medium both of which are measures of nitric oxide formation derived from L-arginine. Lysis of isolated islet cells and disintegration of isolated whole islets is also obtained within 15 h by culture in the presence of the nitric oxide generating vasodilator sodium nitroprusside. We thus conclude that nitric oxide is extremely toxic for islet cells and that nitric oxide alone and in the absence of other macrophage-generated potentially toxic products can rapidly and completely kill islet cells.


Radiofrequency ablation in osteoid osteoma of the finger.
The occurrence of osteoid osteomas of the hand is rare and their treatment usually is surgical. A 26-year-old man with an osteoid osteoma in the proximal phalanx of the right middle finger was treated with percutaneous radiofrequency ablation. Two years later he remains free of pain and finger function is normal.


Gut microbiota in muscular atrophy development, progression, and treatment: New therapeutic targets and opportunities.
Skeletal muscle atrophy is a debilitating condition that significantly affects quality of life and often lacks effective treatment options. Muscle atrophy can have various causes, including myogenic, neurogenic, and other factors. Recent investigation has underscored a compelling link between the gut microbiota and skeletal muscle. Discerning the potential differences in the gut microbiota associated with muscle atrophy-related diseases, understanding their influence on disease development, and recognizing their potential as intervention targets are of paramount importance. This review aims to provide a comprehensive overview of the role of the gut microbiota in muscle atrophy-related diseases. We summarize clinical and pre-clinical studies that investigate the potential for gut microbiota modulation to enhance muscle performance and promote disease recovery. Furthermore, we delve into the intricate interplay between the gut microbiota and muscle atrophy-related diseases, drawing from an array of studies. Emerging evidence suggests significant differences in gut microbiota composition in individuals with muscle atrophy-related diseases compared with healthy individuals. It is conceivable that these alterations in the microbiota contribute to the pathogenesis of these disorders through bacterium-related metabolites or inflammatory signals. Additionally, interventions targeting the gut microbiota have demonstrated promising results for mitigating disease progression in animal models, underscoring the therapeutic potential of modulating the gut microbiota in these conditions. By analyzing the available literature, this review sheds light on the involvement of the gut microbiota in muscle atrophy-related diseases. The findings contribute to our understanding of the underlying mechanisms and open avenues for development of novel therapeutic strategies targeting the gut-muscle axis.


Profiling ethanol-targeted transcription factors in human carcinoma cell-derived embryoid bodies.
Fetal alcohol spectrum disorder is a collective term that represents fetal abnormalities associated with maternal alcohol consumption. Prenatal alcohol exposure and related anomalies are well characterized, but the molecular mechanism behind this phenomenon is not yet understood. Few insights have been gained from genetic and epigenetic studies of fetal alcohol spectrum disorder. Our aim was to profile the important molecular regulators of ethanol-related alterations of the genome. For this purpose, we have analyzed the gene expression pattern of human carcinoma cell-derived embryoid bodies in the absence or presence of ethanol. A cDNA microarray analysis was used to profile mRNA expression in embryoid bodies at day 7 with or without ethanol treatment. A total of 493 differentially expressed genes were identified in response to 50 mM ethanol exposure. Of these, 111 genes were up-regulated, and 382 were down-regulated. Gene ontology term enrichment analysis revealed that these genes are involved in important biological processes: neurological system processes, cognition, behavior, sensory perception of smell, taste and chemical stimuli and synaptic transmission. Similarly, the enrichment of disease-related genes included relevant categories such as neurological diseases, developmental disorders, skeletal and muscular disorders, and connective tissue disorders. Furthermore, we have identified a group of 26 genes that encode transcription factors. We validated the relative gene expression of several transcription factors using quantitative real time PCR. We hope that our study substantially contributes to the understanding of the molecular mechanisms underlying the pathology of alcohol-mediated anomalies and facilitates further research.


PBMC and exosome-derived Hotair is a critical regulator and potent marker for rheumatoid arthritis.
Despite growing importance of long non-coding RNAs (lncRNAs) in normal physiological and disease conditions, our knowledge of RA-related lncRNAs remains limited. Therefore, we aimed to identify lncRNA signatures that have prognostic values in RA. There was a notably high expression level of Hotair in blood mononuclear cells and serum exosome of rheumatoid arthritis (RA) patients, leading the migration of active macrophage. In contrast, markedly lower level of Hotair was detected in differentiated osteoclasts and rheumatoid synoviocytes and enforced expression of Hotair led to significantly decreased levels of MMP-2 and MMP-13. This exploratory study provides novel empirical evidence that Hotair could be one of potential biomarkers for diagnosing RA.


Phosphorylated walnut protein isolate as a nanocarrier for enhanced water solubility and stability of curcumin.
The low solubility and poor dispersion of alkaline-extracted walnut protein isolate (AWPI) limit its application as a protein-based carrier for the delivery of poorly soluble nutraceuticals, including curcumin. This work investigated the physicochemical characteristics of phosphorylated walnut protein isolate (PWPI) extracted using sodium tripolyphosphate (STP) and evaluated its encapsulation ability. The results of phosphorus determination, X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared (FTIR) spectroscopy confirmed the phosphorylation of the extracted PWPI. Circular dichroism (CD) analysis indicated that PWPI contained higher α-helix and lower β-sheet contents than AWPI. The PWPI prepared at pH 9.0 and 11.0 showed significantly improved solubility, similar surface hydrophobicity, and increased surface charges compared to the AWPI. Fluorescence quenching experiments indicated that the binding affinity of curcumin to PWPI was significantly higher than that of AWPI. When bound to PWPI, the solubility of curcumin in aqueous solution was greatly enhanced, with an 8700-fold increase at a nanocomplex concentration of 10 mg mL-1 . The complexation of curcumin with PWPI significantly improved the storage stability of curcumin. Additionally, the PWPI-curcumin nanocomplexes showed significantly increased antioxidant capacity. Phosphorylated walnut protein isolate showed greatly improved solubility and strong encapsulation ability, making it a promising nanocarrier for curcumin. © 2022 Society of Chemical Industry.


Bioactive compounds and mechanism of Xianglian pill in the treatment of gastric cancer: Network pharmacology analysis and experimental validation.
Gastric cancer (GC) affects people's quality of life because of its high incidence rate and mortality. The Xianglian Pill (XLP) is a traditional Chinese medicine (TCM) prescription used to treat gastrointestinal (GI) diseases. Its anti-tumor effect has been found in recent years, but it's bioactive compounds and mechanism of action in treating GC are remain unknown. This study reveals the bioactive compounds and mechanisms of XLP in the treatment of GC through network pharmacology analysis and experimental verification. The main compounds in XLP were searched and the active compounds with anti-GC activity were selected. Compounds targets and GC- related targets were predicted, and common targets were obtained. Subsequently, a protein-protein interaction (PPI) network of common targets is constructed, while GO and KEGG enrichment analyses were performed on common targets. Finally, the anti-GC effects of active compounds in XLP were verified in GC cell lines MGC-803 and HGC-27 by wound healing assay, cell cycle assay, cell apoptosis assay and western blotting (WB) assay. A total of 33 active compounds of XLP were obtained. MTT assay showed that dehydrocostus lactone (DHL) and berberrubine (BRB) had lower IC50 value in GC cells HGC-27 and MGC-803, and has a less inhibitory effect on normal gastric epithelial cells. Further, 73 common targets were obtained after the total target of DHL and BRB intersected with GC. Among them, CASP3, AKT1, SRC, STAT3,and CASP9 were the most associated genes in the PPI network. GO and KEGG enrichment analyses indicated that apoptosis played a major role in the biological processes and signaling pathways involved. Moreover, the in vitro experiment revealed that DHL and BRB inhibited GC cell viability via inducing cell cycle arrest at G2/M phase, and promoting cell apoptosis by up-regulating the caspase3 expression and down-regulating the expression of Bcl2/Bax. DHL and BRB are the two main anti-GC active compounds in XLP, and their mechanism is mainly to inhibit cell cycle and promote cell apoptosis.


Random forests for genomic data analysis.
Random forests (RF) is a popular tree-based ensemble machine learning tool that is highly data adaptive, applies to "large p, small n" problems, and is able to account for correlation as well as interactions among features. This makes RF particularly appealing for high-dimensional genomic data analysis. In this article, we systematically review the applications and recent progresses of RF for genomic data, including prediction and classification, variable selection, pathway analysis, genetic association and epistasis detection, and unsupervised learning.


Chiropractic Management of a 67-Year-Old Veteran With Chronic Low Back Pain Utilizing Low-Velocity Flexion-Distraction: A Case Report.
The purpose of this case report was to describe the treatment of an older veteran with chronic low back pain, utilizing flexion-distraction as a primary intervention for management. A 67-year-old man with chronic low back pain for several decades presented to the chiropractic clinic for evaluation. He reported low back pain that extended into the right lower extremity intermittently. The patient's imaging demonstrated significant degenerative changes in the lumber spinal anatomy. He had never experienced chiropractic interventions or management for his condition. A trial of conservative care with flexion-distraction was applied as a primary intervention for the management of chronic low back pain. Instrument-assisted soft-tissue mobilization and moist heat were also applied for interventions. Despite having no changes in outcome assessments, the patient reported an improvement in his condition, reduced use of pain medication, and increased mobility after 4 sessions over a 4-week period. Flexion-distraction was a beneficial chiropractic approach to the management of an older veteran with chronic low back pain and intermittent lower extremity pain for several decades.


Free radical damage produced by carbon tetrachloride in the lipids of various rat tissues.
Alterations produced by carbon tetrachloride in the lipids of extrahepatic tissues were studied. Consistent incorporation (about one-half of that occurring in the liver) of 14C from 14CCl4 was found in the phospholipids of the intestinal mucosa; kidney, adrenal and lung phospholipids were labeled to a lower extent, while spleen, testis, brain, heart and skeletal muscle lipids showed minor levels of radioactivity. The analysis of fatty acid methyl esters derived from phospholipids by gas-liquid chromatography (GLC) with an electron capture detector (ECD), showed ECD response similar to that observed with the liver, in the case of the intestinal mucosa and the kidney; on the contary no ECD response was seen with the organs, such as skeletal muscle, heart and testis in which the incorporation is almost negligible. Unlike liver phospholipids, the phospholipids of the intestinal mucosa and the kidney did not show diene conjugation absorption. Also, no evidence of lipid peroxidation was found in the thin-layer chromatographic analysis of fatty acid methyl esters prepared from the phospholipids of these organs. Possible meanings of these results are discussed.