Effects of pill splitting training on drug physiochemical properties, compliance, and clinical outcomes in the elderly population: a randomised trial.

INTRODUCTION: This study aimed to provide information about the clinical and physiochemical effects of pill splitting training in elderly cardiac patients in Hong Kong. METHODS: A parallel study design was adopted. Patients taking lisinopril, amlodipine, simvastatin, metformin, or perindopril who needed to split pills were recruited from the Prince of Wales Hospital. Patients were divided into two groups at their first visit. Patients in group A split drugs using their own technique, whereas patients in group B used pill cutters after relevant training until their next follow-up visit. The primary outcome was the change in drug content between before and after the pill splitting training. Assays were performed to determine the drug content. Secondary outcomes were the changes in clinical outcomes, patients' attitudes and acceptance towards pill splitting, and patients' knowledge about pill splitting. RESULTS: A total of 193 patients were recruited, and 101 returned for the follow-up visit. The percentage of split tablets falling within the assay limits increased from 39.13% to 47.82% (P=0.523) in group A and from 48.94% to 51.06% (P=1.000) in group B. The changes did not reach statistical significance. As for clinical outcomes, the mean triglyceride level decreased from 1.62±1.05 to 1.36±0.80 (P=0.049), whereas the mean heart rate increased significantly from 73.97±11.01 to 77.92±12.72 (P=0.026). Changes in other parameters were not significant. CONCLUSION: This study highlights the high variability of drug content after pill splitting. Pills with dosages that do not require splitting would be preferable, considering patients' preference. Patients should be educated to use pill cutters properly if pill splitting is unavoidable.

Branded versus generic drug use in chronic disease management in Hong Kong-perspectives of health care professionals and the general public.

INTRODUCTION: The aim of the present study was to evaluate the understanding of generic substitution among health care professionals and members of the general public ("general public") in Hong Kong. METHODS: This cross-sectional descriptive study was performed by using a self-completed anonymous questionnaire from March 2015 to May 2017. The questionnaire included demographic data, knowledge of generic drugs, experiences of generic substitution, and views on policy. RESULTS: A total of 2106 general public, 73 doctors, 22 nurses, and 50 pharmacists responded the questionnaire. In all, 41.2% of the general public was aware that generic drugs have the same active ingredients. Although a majority of the health care professionals knew that generic drugs have the same active ingredients (doctors: 79.5%; nurses: 86.4%; pharmacists: 98.0%), many were unaware of bioequivalence (doctors: 37.0%; nurses: 18.2%; pharmacists: 50.0%). "Efficacy" was ranked as the primary concern among all groups; a substantial portion of respondents reported experiencing adverse drug reactions upon generic substitution (general public: 26.6%; doctors: 23.3%; nurses: 9.1%; pharmacists: 42.0%). At least half of the general public, nurses, and pharmacists considered that patients should be given a choice for generic substitution. However, fewer than one-fifth of doctors and nurses and approximately one-third of pharmacists considered that patient consent was needed prior to generic substitution, compared with approximately two-thirds of the general public. CONCLUSION: The knowledge and perception of generic substitution remains low, both in the general public and among health care professionals. This knowledge deficit could potentially lead to different perspectives among stakeholders regarding generic substitution.

A metagenomic study of the preventive effect of Lactobacillus rhamnosus GG on intestinal polyp formation in ApcMin/+ mice.

AIMS: To investigate the in vivo effects of Lactobacillus rhamnosus GG (LGG) on intestinal polyp development and the interaction between this single-organism probiotic and the gut microbiota therein. METHODS AND RESULTS: The ApcMin/+ mouse model was used to study the potential preventive effect of LGG on intestinal polyposis, while shotgun metagenomic sequencing was employed to characterize both taxonomic and functional changes within the gut microbial community. We found that the progression of intestinal polyps in the control group altered the community functional profile remarkably despite small variation in the taxonomic diversity. In comparison, the consumption of LGG helped maintain the overall functional potential and taxonomic profile in the resident microbes, thereby leading to a 25% decrease of total polyp counts. Furthermore, we found that LGG enriched those microbes or microbial activities related to short-chain fatty acid production (e.g. Roseburia and Coprococcus), as well as suppressed the ones that can lead to inflammation (e.g. Bilophila wadsworthia). CONCLUSIONS: Our study using shotgun metagenomics highlights how single probiotic LGG may exert its beneficial effects and decrease polyp formation in mice by maintaining gut microbial functionality. SIGNIFICANCE AND IMPACT OF THE STUDY: This probiotic intervention targeting microbiota may be used in conjugation with other dietary supplements or drugs as part of prevention strategies for early-stage colon cancer, after further clinical validations in human.

Development of maternal and neonatal composite outcomes for trials evaluating management of late-onset pre-eclampsia.

OBJECTIVE: Pre-eclampsia is associated with significant maternal and neonatal complications, and delivery is often expedited to minimise complications. For randomised trials evaluating interventions in women with late-onset (>34 weeks) mild to moderate pre-eclampsia, no single outcome has been identified to be the most clinically important. Existing composite outcomes with more than one clinically relevant endpoint to evaluate interventions in pre-eclampsia provide limited justification for selection of the components. Our objective was to develop robust, valid composite maternal and neonatal outcome measures for clinical trials evaluating interventions in women with late-onset mild and moderate pre-eclampsia. STUDY DESIGN: A two-generational Delphi method was used to identify these clinically important maternal and neonatal outcomes. Composite outcomes were developed based on biological plausibility, independence from each other, frequency of occurrence and level of importance. RESULTS: The final maternal composite outcome included maternal death, eclampsia, stroke or reversible ischaemic neurological deficit, pulmonary oedema, major obstetric haemorrhage, need for positive inotropic support, haemolysis, elevated liver enzymes and low platelets syndrome and placental abruption; and the neonatal composite outcome included neonatal death, respiratory distress syndrome needing ventilator support and neurological outcomes as cystic periventricular leukomalacia and grade III/IV intraventricular haemorrhage. CONCLUSION: The composite outcomes developed will enable clinical trials to provide robust estimates on the effectiveness of the interventions in women with mild to moderate late onset pre-eclampsia to inform clinical practice. Caution is needed in the interpretation of composite outcomes due to variation in the importance of individual components.

Recessive oligodontia linked to a homozygous loss-of-function mutation in the SMOC2 gene.

OBJECTIVE: Recently, several genes have been reported with mutations or variants that underlie a number of syndromic and non-syndromic forms of oligodontia including MSX1, PAX9, AXIN2, EDA and WNT10A. This study aimed to identify the causal mutations in a consanguineous Pakistan family with oligodontia and microdontia. DESIGN: Exome sequencing was performed in two of affected members of the Pakistan family. RESULTS: The exome sequencing data revealed that the affected individuals were homozygous with a novel mutation in exon 8 of the SMOC2 gene, c.681T>A (p.C227X). CONCLUSIONS: This is the second report describing SMOC2 mutations with oligodontia and microdontia underlining the key role for this signalling molecule in tooth development.

Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ.

The pathological hallmark of Alzheimer disease is the senile plaque principally composed of tightly aggregated amyloid-beta fibrils (fAbeta), which are thought to be resistant to degradation and clearance. In this study, we explored whether proteases capable of degrading soluble Abeta (sAbeta) could degrade fAbeta as well. We demonstrate that matrix metalloproteinase-9 (MMP-9) can degrade fAbeta and that this ability is not shared by other sAbeta-degrading enzymes examined, including endothelin-converting enzyme, insulin-degrading enzyme, and neprilysin. fAbeta was decreased in samples incubated with MMP-9 compared with other proteases, assessed using thioflavin-T. Furthermore, fAbeta breakdown with MMP-9 but not with other proteases was demonstrated by transmission electron microscopy. Proteolytic digests of purified fAbeta were analyzed with matrix-assisted laser desorption ionization time-of-flight mass spectrometry to identify sites of Abeta that are cleaved during its degradation. Only MMP-9 digests contained fragments (Abeta(1-20) and Abeta(1-30)) from fAbeta(1-42) substrate; the corresponding cleavage sites are thought to be important for beta-pleated sheet formation. To determine whether MMP-9 can degrade plaques formed in vivo, fresh brain slices from aged APP/PS1 mice were incubated with proteases. MMP-9 digestion resulted in a decrease in thioflavin-S (ThS) staining. Consistent with a role for endogenous MMP-9 in this process in vivo, MMP-9 immunoreactivity was detected in astrocytes surrounding amyloid plaques in the brains of aged APP/PS1 and APPsw mice, and increased MMP activity was selectively observed in compact ThS-positive plaques. These findings suggest that MMP-9 can degrade fAbeta and may contribute to ongoing clearance of plaques from amyloid-laden brains.

Radiation disasters and emergency department preparedness.

There are few radiation disasters that have occurred worldwide. These events, however, give some insight as to the potential for theoretical radiation disaster events of the future. Some of our current fears, such as terrorist uses of radiation, currently have no historical basis for planning guidance. Hospital facilities should assess the potential for radiation accidents and potential radiation disaster scenarios when in the process of disaster planning. Preparation and training will lead to confidence and improved emergency management of potentially chaotic events.

Heteroduplex analysis detects frameshift and point mutations in patients with acute intermittent porphyria.

We used heteroduplex analysis to screen for mutations in the porphobilinogen deaminase gene in 21 patients with acute intermittent porphyria (AIP). Unique banding patterns were investigated by direct sequencing of polymerase chain reaction products and, when indicated, sequencing of cloned DNA containing the exon of interest. Two frameshift mutations were found, a 2-bp deletion in exon 5 and a 1-bp insertion in exon 7. Both mutations generate a premature stop codon. Two point mutations, in exons 10 and 14, were also observed. The C-->T mutation in exon 10 codes for an Arg173 to Trp substitution, while a G-->A mutation in exon 14 changes Trp283 into a premature stop codon. This study extends the spectrum of mutations that cause AIP and demonstrates the utility of heteroduplex analysis as a screening technique.

Helicobacter pylori infection and gastric metaplasia in the duodenum in China.

Biopsy specimens from antral and duodenal mucosa were obtained from 64 patients with active duodenal ulcer and from 78 with nonulcer dyspepsia. Gastric metaplasia in the duodenal bulb was more frequent in patients with duodenal ulcer (82.5%) than in patients with dyspepsia and duodenitis (53.1%) or in patients with dyspepsia without duodenitis (34.5%). Helicobacter pylori infection in the duodenal bulb was found more often in patients with moderate to severe gastric metaplasia (62.3%) than in patients with mild gastric metaplasia (20%). Therefore, patients from a developing country, China, showed the same relationship between duodenitis, gastric metaplasia, duodenal colonization with H. pylori, and duodenal ulcer previously demonstrated in developed countries.

[Pacemaker implantation in a patient with persistent left superior vena cava and atresia of the right superior vena cava]. / Implantação de pacemaker em doente com persistência da veia cava superior esquerda e atrésia da veia cava superior direita.

Persistent left superior vena cava with absence or atresia of right superior vena cava is a congenital abnormality of systemic venous return to the heart which may complicate the insertion of a pacemaker electrode. We present a case report of a patient with conduction system disturbances in whom this abnormality was diagnosed during pacemaker implantation, with the possibility of using a transvenous electrode without active fixation system.

Molecular diagnosis of acute intermittent porphyria by analysis of DNA extracted from hair roots.

Analysis for mutations in the porphobilinogen deaminase gene offers a more definitive diagnosis of acute intermittent porphyria (AIP) than do conventional biochemical tests. We used single-strand conformation polymorphism analysis followed by direct sequencing to identify a new G-->A mutation at the last position of intron 7 in a patient with AIP. The mutation disrupts the invariant AG dinucleotide at the 3' splice acceptor site and therefore interferes with mRNA processing. To identify other individuals who inherited this mutation, we analyzed five hairs with intact roots collected by each participating family member and sent to us by mail. DNA was extracted from the hair roots and amplified by the polymerase chain reaction. The amplified products were digested with the restriction enzyme BsaJI to confirm the presence or absence of the mutation. All six family members who were known to have AIP tested positive, as did three members who had not been previously diagnosed. Hair roots provide a convenient, accessible, and economical alternative to blood as a source of DNA for molecular diagnostic testing.

Causal link between nucleotide pyrophosphohydrolase overactivity and increased intracellular inorganic pyrophosphate generation demonstrated by transfection of cultured fibroblasts and osteoblasts with plasma cell membrane glycoprotein-1. Relevance to calcium pyrophosphate dihydrate deposition disease.

OBJECTIVE: In subjects with idiopathic calcium pyrophosphate dihydrate (CPPD) deposition disease, cartilage chondrocytes elaborate increased amounts of PPi. The mechanism of the intracellular PPi elevation is not known. Plasma membrane 5'-nucleotide phosphodiesterase I/nucleotide pyrophosphohydrolase (NTPPPH) activity also is elevated in chondrocytes and dermal fibroblasts of patients with idiopathic CPPD deposition disease. NTPPPH, as an ecto-enzyme, could act within certain intracellular compartments. Thus, we hypothesized a potential causal link between increased NTPPPH activity and increased intracellular PPi. METHODS: Transformed simian fibroblasts (COS cells) and human osteoblasts (U2OS cells) were transfected with the 5'-nucleotide phosphodiesterase I ecto-enzyme plasma cell membrane glycoprotein-1 (PC-1), recently shown to be expressed in cartilage, osteoblasts, and fibroblasts. RESULTS: Transfection with PC-1 markedly up-regulated 5'-nucleotode phosphodiesterase I activity and increased intracellular PPi concentrations by increasing the capacity of cells to generate PPi. Importantly, this did not require supplementation with exogenous nucleotides. CONCLUSION: Cellular overexpression of PC-1 produces NTPPPH overactivity and increased intracellular PPi generation in vitro. These findings support the potential importance of NTPPPH overactivity in PPi generation, both inside and outside the cell, in some subjects with CPPD deposition disease.

Frameshift mutations in exons 9 and 10 of the porphobilinogen deaminase gene produce a crossreacting immunological material (CRIM)-negative form of acute intermittent porphyria.

Single-strand conformation polymorphism analysis was used to screen all 15 exons of the porphobilinogen deaminase gene from 13 patients with acute intermittent porphyria. Unique banding patterns in two amplified gene fragments, one containing exon 9 and another containing exon 10, were further investigated. Sequence analysis of cloned genomic DNA revealed a single base pair insertion in the middle of exon 9 in one patient and a single base pair deletion near the 3' end of exon 10 in two related patients. Both mutations change the reading frame of the mRNA transcript and predict proteins that are normal at their NH2-terminal ends but contain novel, unrelated sequences at their COOH-terminal ends and are prematurely terminated. Frameshift mutations in the porphobilinogen deaminase gene are uncommon; this is the first report of an insertion mutation causing acute intermittent porphyria.

Beneficial acute effects of selective modulation of renal dopamine system by gamma-L-glutamyl-L-dopa in rabbits with congestive heart failure.

gamma-L-Glutamyl-L-dopa (gludopa) is a dopamine (DA) prodrug with a high degree of renal selectivity. We compared the acute renal effects of gludopa in conscious control rabbits (n = 6) and rabbits with doxorubicin-induced congestive heart failure (CHF, n = 5). Normal saline and gludopa 25 and 100 micrograms/kg/min were infused intravenously (i.v.), each for 60 min. One week later, the same protocol was followed except that the DA-1 antagonist SCH 23390 was given i.v. in a dose of 0.3 mg/kg 10 min before gludopa infusion. An additional control group (n = 6) received the DA-1 antagonist alone and saline vehicle infusion throughout the study period. In both control and CHF groups, gludopa elicited significant and similar increases in urine flow (70, 62%), sodium excretion (127, 98%), and renal blood flow (RBF) (33, 27%), and decreased renal vascular resistance (RVR) (-23, -38%). All these changes were abolished by previous DA-1 antagonism with SCH 23390. Blood pressure (BP), heart rate (HR), and hindlimb blood flow (HBF) remained unchanged during gludopa infusion in both groups. In the control group, but not in the CHF group, plasma renin activity (PRA) increased during gludopa infusion; this was not influenced by DA-1 antagonism. In normal rabbits (n = 6), treatment with SCH 23390 alone had no significant effect on renal excretory function or haemodynamics. During gludopa administration, plasma DA concentration was not significantly altered, whereas urine DA excretion and renal DA content were markedly increased. Intrarenal conversion of gludopa to DA was significantly less in CHF rabbits as compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth response of loblolly pine (Pinus taeda L.) seedlings to ozone fumigation.

Twenty-two week-old Pinus taeda L. (loblolly pine) seedlings of 30 open-pollinated and five full-sib families, representing a wide range in geographic origin, were grown in charcoal-filtered (CF) air or CF-air supplemented with 160 or 320 nl liter(-1) ozone for 8 h day(-1), 4 days week(-1), for 9 weeks. Visible foliar injury (banded chlorosis, tip burn and premature senescence) was apparent in many families after 3 weeks in 320 nl liter(-1) and 6 weeks in 160 nl liter(-1) ozone. Decreases in relative height and root collar diameter growth rates, total dry weight, root dry weight, shoot dry weight, and root/shoot ratios were evident after 9 weeks of treatment with both 160 and 320 nl liter(-1) ozone. For relative height growth rates, family differences in response to ozone were observed. By the study's end, net photosynthesis rates were 15% less for the 320 nl liter(-1) ozone treatment as compared to the CF-air treatment. Total soluble sugar and total starch content of roots were not changed after 9 weeks of ozone exposure.

Abscisic Acid Regulation of DC8, A Carrot Embryonic Gene.

DC8 encodes a hydrophylic 66 kilodalton protein located in the cytoplasm and cell walls of carrot (Daucus carota) embryo and endosperm. During somatic embryogenesis, the levels of DC8 mRNA and protein begin to increase 5 days after removal of auxin. To study the role of abscisic acid (ABA) in the regulation of DC8 gene, fluridone, 1-methyl-3-phenyl,-5(3-trifluoro-methyl-phenyl)-4(1H)-pyridinone, was used to inhibit the endogenous ABA content of the embryos. Fluridone, 50 micrograms per milliliter, effectively inhibits the accumulation of ABA in globular-tage enbryos. Western and Northern analysis show that when fluridone is added to the culture medium DC8 protein and mRNA decrease to very low levels. ABA added to fluridone supplemented culture media restores the DC8 protein and mRNA to control levels. Globular-stage embryos contain 0.9 to 1.4 x 10(-7) molar ABA while 10(-6) molar exogenously supplied ABA is the optimal concentration for restoration of DC8 protein accumulation in fluridone-treated embryos. The mRNA level is increased after 15 minutes of ABA addition and reaches maximal levels by 60 minutes. Evidence is presented that, unlike other ABA-regulated genes, DC8 is not induced in nonembryonic tissues via desiccation nor addition of ABA.

Abscisic Acid ELISA: Organic Acid Interference.

Consideration must be exercised in determination of buffers and solutions used when carrying out enzyme-linked immunosorbent assays (ELISAs). A commercial monoclonal antibody kit for abscisic acid (Idetek, Inc.) gives significant false-positives with tricarboxylic acid cycle intermediates. The organic acids or contaminants interfered with ELISA assays for ABA as indicated by deviations in the slopes of standard curves of ABA in the organic acids. The interference, in the case of alpha-ketoglutarate, was caused by a contaminant. Of the organic buffers tested-Tris, Tricine, and Hepes-only Hepes showed false-positive ABA. In addition, we present data indicating the presence of ABA in commercial mannitol and provide a simple procedure for removal of the ABA.