A non-randomised pilot study of the Solutions for Medication Adherence Problems (S-MAP) intervention in community pharmacies to support older adults adhere to multiple medications.

BACKGROUND: Older patients prescribed multiple medications commonly experience difficulties with adherence. High-quality evidence on interventions targeting older patients is lacking. Theory is rarely used to tailor adherence solutions. This study aimed to pilot test a novel intervention, developed using the Theoretical Domains Framework, which guides community pharmacists in identifying adherence barriers and delivering tailored solutions (behaviour change techniques). Key study procedures (e.g. recruitment, data collection) for a future randomised controlled trial (cRCT) were also assessed. METHODS: Using purposive sampling, this non-randomised pilot study aimed to recruit 12 community pharmacies (six in Northern Ireland; six in London, England). Pharmacists were trained to deliver the intervention to non-adherent older patients (maximum 10 per pharmacy; target n = 60-120) aged ≥ 65 years (reduced to 50 years due to recruitment challenges) and prescribed ≥ 4 regular medicines. The intervention, guided by an iPad web-application, was delivered over 3-4 face-to-face or telephone sessions, tailored to specific barriers to adherence. We assessed the feasibility of collecting adherence data (primary outcome: self-report and dispensing records), health-related quality of life (HRQOL) and unplanned hospitalisations (secondary outcomes) at baseline and 6-months. The final decision on progressing to a cRCT, using pre-defined 'stop-amend-go' criteria, is presented. RESULTS: Fifteen pharmacists from 12 pharmacies were recruited and trained. One pharmacy subsequently dropped out. Sixty patients were recruited (meeting the 'Amend' progression criteria), with 56 receiving the intervention. Adherence barriers were identified for 55 patients (98%) and a wide range of behaviour change solutions delivered (median: 5 per patient). Self-report and dispensing adherence data were available for 37 (61.7%) and 44 (73.3%) patients, respectively. HRQOL data were available for 35 (58.3%) patients. GP-reported and self-reported hospitalisations data were available for 47 (78.3%) and 23 (38.3%) patients, respectively. All progression concepts were met (nine 'Go' and three 'Amend' criteria). CONCLUSION: This study demonstrates the feasibility of key study procedures (e.g. pharmacy recruitment) and delivery of a tailored adherence intervention in community pharmacies. However, modifications are required to enhance issues identified with patient recruitment, retention and missing data. A future definitive cRCT will explore the effectiveness of the intervention. TRIAL REGISTRATION: ISRCTN, ISRCTN73831533 , Registered 12 January 2018.

Prolonged hemiplegic episodes in children due to mutations in ATP1A2.

BACKGROUND: Familial hemiplegic migraine (FHM) is an unusual migraine syndrome characterised by recurrent transient attacks of unilateral weakness or paralysis as part of the migraine aura. Genetically and clinically heterogeneous, FHM1 is caused by mutations in CACNA1A and FHM2 by mutations in ATP1A2. AIM: Three children with prolonged hemiplegia were tested for mutations in CACNA1A or ATP1A2. METHODS: Mutations in CACNA1A and ATP1A2 were screened for by denaturing high performance liquid chromatography and confirmed by sequencing. Expression studies were performed to characterise the functional consequences of these mutations. RESULTS: No mutation was found in the FHM1 gene while three mutations were identified in the FHM2 gene. All three mutations were missense: two were novel and one was de novo; none was found in controls. Functional studies in HeLa cells showed complete loss of mutant pump function without interfering with the wild-type pump, consistent with haploinsufficiency. CONCLUSION: We identified novel disease causing mutations in the FHM2 gene. Genetic screening for FHM should be considered in a child with prolonged hemiplegia even if there is no prior history or family history of migraine or hemiplegic episodes.

Rapid Isolation of Staphylococcus aureus Pathogens from Infected Clinical Samples Using Magnetic Beads Coated with Fc-Mannose Binding Lectin.

Here we describe how Staphylococcus aureus bacteria can be rapidly isolated from clinical samples of articular fluid and synovial tissue using magnetic beads coated with the engineered chimeric human opsonin protein, Fc-mannose-binding lectin (FcMBL). The FcMBL-beads were used to capture and magnetically remove bacteria from purified cultures of 12 S. aureus strains, and from 8 articular fluid samples and 4 synovial tissue samples collected from patients with osteoarthritis or periprosthetic infections previously documented by positive S. aureus cultures. While the capture efficiency was high (85%) with purified S. aureus strains grown in vitro, direct FcMBL-bead capture from the clinical samples was initially disappointing (< 5% efficiency). Further analysis revealed that inhibition of FcMBL binding was due to coating of the bacteria by immunoglobulins and immune cells that masked FcMBL binding sites, and to the high viscosity of these complex biological samples. Importantly, capture of pathogens using the FcMBL-beads was increased to 76% efficiency by pretreating clinical specimens with hypotonic washes, hyaluronidase and a protease cocktail. Using this approach, S. aureus bacteria could be isolated from infected osteoarthritic tissues within 2 hours after sample collection. This FcMBL-enabled magnetic method for rapid capture and concentration of pathogens from clinical samples could be integrated upstream of current processes used in clinical microbiology laboratories to identify pathogens and perform antibiotic sensitivity testing when bacterial culture is not possible or before colonies can be detected.

Recombinant E1-deleted adenovirus-mediated gene therapy for cancer: efficacy studies with p53 tumor suppressor gene and liver histology in tumor xenograft models.

Type 5 adenoviral (Ad) vectors have been the "vector-of-choice" for preclinical studies on p53 tumor suppressor gene therapy of cancer. Previous studies have examined the in vivo efficacy of p53 Ad when given intratumorally. However published information does little to guide clinicians in the design of intraperitoneal (i.p.) dosing trials for i.p. tumors, e.g., ovarian, or clinical trials using regional organ perfusion, e.g., for lung tumors. Therefore, we examined several parameters with special significance for these routes of administration. Lung metastases from p53mut MDA-MB-231 mammary xenografts were treated with therapeutic levels of intravenous buffer, beta-galactosidase (beta-Gal) Ad, or p53 Ad. Treatment with intravenous p53 Ad significantly reduced the number of metastases per lung and there was a dramatic reduction in the surface area occupied by these tumors as compared to control groups. Two types of i.p. tumor xenografts were used for preclinical modeling of i.p. gene therapy, the p53null SK-OV-3 ovarian and the p53mut DU-145 prostate human cancers. In a study examining the effect of different vehicle volumes on the efficacy of a constant drug dose, all mice treated with p53 Ad had reduced tumor burden compared to controls. Dosing volumes between 0.2 and 1 ml were equally effective and all were more effective than a dosing volume of 0.1 ml. However, reduced efficacy was observed when a volume of 1.5 ml was used. When the effect of dosing frequency on antitumor efficacy was examined, fractionated doses of p53 Ad had somewhat greater efficacy than fewer, bolus injections. One of the significant elements in the emerging toxicology associated with recombinant adenoviruses is the hepatocyte pathology caused by high systemic concentrations of adenovirus. For recombinant Ad used in this study, there was a pronounced dose-dependence for the liver response, with very high, repeated doses causing significant hepatocellular insult. Expression of cytoplasmic beta-Gal protein coincided with areas of greatest damage in mice treated with high doses of beta-Gal Ad. Ultrastructural examination of hepatocyte intranuclear inclusions revealed moderately electron-dense, tightly packed granular material interspersed with more electron-dense nuclear material. Human tumor xenografts, but not mouse tissues, expressed viral hexon protein. In summary, hepatic toxicity caused by high concentrations of recombinant adenovirus was observed in murine cancer models. However, therapeutic levels of p53 Ad could be achieved which had dramatic efficacy without significant pathology.

Sulfated glucuronyl glycolipids and gangliosides in the optic nerve of humans.

Pathologically delayed visual evoked potentials may be present in patients with neuropathy associated with IgM M-proteinemia, which is directed against myelin-associated glycoprotein and sulfated glucuronyl glycolipids (SGGLs), but there are no reports of these antigens in the optic nerve. We recently examined human optic nerve and occipital lobe tissues for the occurrence of SGGLs using the technique of immunostaining on thin-layer chromatographic plates and found them in the optic nerve, but not the occipital lobe. SGGLs in the optic nerve may represent target antigens for CNS involvement by the M-protein in patients with neuropathy. We also studied the ganglioside composition of the optic nerve and found it different from that of the brain. Human optic nerve is characterized by an abundance of the b-series gangliosides, including GD1b, GT1b, and GQ1b. GD1a, which is usually a major component of brain gangliosides, is only a minor species of the optic nerve ganglioside fraction.

The human nerve growth factor gene: structure of the promoter region and expression in L929 fibroblasts.

We previously studied the transcriptional mechanisms involved in expression of the murine nerve growth factor (NGF) gene. To investigate the regulation of transcription of the human NGF gene, the promoter region was cloned. The nucleotide sequences of the human and mouse genes are greater than 90% similar near their promoters. The cloned human promoter was transcriptionally active in mouse L929 fibroblasts. 5' Deletion analyses indicated that the -85 to -45 region stimulates basal transcription 6-fold. This segment is greater than 80% identical in human and mouse genes except for an AP-1 consensus sequence found only in the human gene. A second AP-1 consensus sequence at +34, previously shown to function as a regulatory element in the mouse gene, is identical in both genes. Gel shift analyses of L929 cell extracts revealed binding of protein to oligonucleotide probes spanning each of the two AP-1 consensus sequences of the human gene. The gel shift patterns differed, suggesting interaction of different proteins with the two probes. Our results demonstrate that the human NGF gene promoter is transcriptionally active in mouse fibroblasts, and implicate an upstream region in basal transcription.

Correlation of asymmetric damage with asymmetric intraocular pressure in normal-tension glaucoma (low-tension glaucoma).

If intraocular pressure plays a role in producing visual field loss in normal-tension glaucoma, there may be a possible benefit from therapeutic efforts to lower the pressure. To see whether pressure plays a role in the production of damage, we studied 14 cases of normal-tension glaucoma with asymmetric intraocular pressure (1- to 6-mm Hg interocular difference in pressure). In 12 of these 14 cases, we found that glaucomatous cupping and field loss (damage) was greater in the eye with higher pressure. This statistically significant correspondence of the higher pressure with the greater visual damage suggests that the level of pressure is a factor in producing optic nerve damage. Other factors also must contribute to account for the few instances in which damage asymmetry did not reflect interocular pressure-difference and for the occurrence of injury at such low levels of pressure in the first place. Although benefit may be expected from therapeutic lowering of pressure in this condition, the degree of benefit, as well as the side effects from treatment required for successful lowering of pressure, remains to be documented by a future clinical trial.

Drill guide for hydroxyapatite implants.

A drill guide to facilitate the second drilling of hydroxyapatite orbital implants is presented. The drill guide is adaptable to various drill types. It is nontraumatic and provides excellent, one-handed fixation, eliminating the need for an assistant. It allows for consistent, straight drilling to a predetermined depth and, because it is encased, it protects the patient from injury. The drill guide has been used on 30 patients and is without untoward effects.

Immune-related disease and normal-tension glaucoma. A case-control study.

We reviewed the charts of 67 patients with the diagnosis of normal-tension glaucoma listed in the Bascom Palmer Eye Institute computer database. These patients were matched with respect to age, race, and sex with an equal number of patients having ocular hypertension. All medical diagnoses in the charts for both groups were tabulated and classified as either immune-related or non-immune-related. Twenty (30%) patients with normal-tension glaucoma had one or more immune-related disease(s) compared with five (8%) patients in the comparison group (P = .00134, McNemar statistic with continuity correction).

Expression of neurotrophin genes in human fibroblasts: differential regulation of the brain-derived neurotrophic factor gene.

Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) are structurally related survival and differentiation factors for distinct sets of peripheral and central neurons. We previously reported that BDNF and NGF gene expression are differentially regulated in mouse L929 fibroblasts. Here we examine expression of these three neurotrophins in human fibroblasts. Northern blots detected BDNF and NT-3 mRNAs in fibroblasts derived from lung (WI-38), calvarium and foreskin. WI-38 cells and foreskin fibroblasts expressed 1.6 kb as well as 4 kb BDNF mRNAs whereas only the smaller BDNF mRNA was detected in calvarium fibroblasts. NGF mRNA was present in foreskin and calvarium but not lung fibroblasts. In WI-38 cells serum treatment increased levels of BDNF mRNA within 2 hr. Cycloheximide did not inhibit the increase. Treatment with 12-O-tetradecanoyl phorbol-13-acetate (TPA) transiently suppressed BDNF mRNA. Treatment with both serum and TPA first stimulated and then transiently suppressed BDNF mRNA. TPA and/or serum did not significantly affect BDNF mRNA in calvarium fibroblasts. These results show that human fibroblasts derived from different tissues express and regulate neurotrophin genes differentially.

Measurements of upper eyelid and eyebrow dimensions in healthy white individuals.

Facial appearance is influenced by the anatomic relationship of the eyebrow and eyelid, and surgical procedures on these structures attempt to restore or preserve not only symmetry but also normal appearance. To provide useful benchmarks for such interventions, we measured the eyebrow height, upper eyelid crease height, and amount of visible pretarsal skin of 143 white subjects who had no facial abnormalities. An age effect was observed for all measures, indicating a direct relationship with age until the middle age range (41 to 60 years), when mean estimates leveled off or decreased somewhat relative to younger age groups. Within the 41- to 60-year age group, for example, the average (S.D.) values for pretarsal skin height, eyelid crease height, and eyebrow height were 1.4 mm (1.1 mm), 6.4 mm (1.2 mm), and 6.4 mm (1.8 mm), respectively. Eyebrow and pretarsal skin heights were greater in females than males, and eyelid crease height showed similar gender-related trends. With increasing age, variation around the mean estimates for eyelid and eyebrow measurement increased, which may be indicative of variability across individuals in the physiologic response to the aging process. As expected, a high degree of intereye correlation was observed (correlation coefficients of 0.87 to 0.96). These results emphasize the importance of providing a normal anatomic relationship that relates to the patient's age and gender, as well as an outcome that is symmetric, in corrective or cosmetic procedures on the eyelid and eyebrow.

Synovial cyst of a cervical facet joint: case report.

Intraspinal synovial cysts are rare. Those reported have occurred in the lumbar region. We report a case of an extradural true synovial cyst of the cervical spine causing spastic paraparesis. The cyst occurred after a cervical spine fracture and, hence, was probably related to trauma. Surgical therapy resulted in a satisfactory recovery.

Sporothrix schenckii endophthalmitis presenting as granulomatous uveitis.

Sporothrix schenckii occurs worldwide as a chronic subcutaneous mycotic infection, but can result in intraocular infection of cryptogenic origin without evident systemic infection. A case of S schenckii endophthalmitis is presented without a history of trauma or systemic infection originally diagnosed as granulomatous uveitis that resulted in scleral perforation.

Tension pneumocephalus associated with rupture of a middle fossa encephalocele. Case report.

Acquired nontraumatic (spontaneous) encephaloceles of the middle fossa are not common. Rupture of an encephalocele frequently leads to a cerebrospinal fluid fistula. Tension pneumocephalus consequent to rupture of an encephalocele has not been previously reported, but conceivably occurs by means of a ball-valve mechanism in the ensuing fistulous tract. An unusual case is presented of an elderly man who suffered acute life-threatening neurological symptoms from a tension pneumocephalus that likely developed from rupture of an acquired nontraumatic encephalocele of the left middle fossa. The symptoms correlated with the location of the intracranial abnormalities. The literature is reviewed and the pathophysiology of the lesion is discussed.

In vitro alteration of Schirmer's tear strip wetting by commonly instilled anesthetic agents.

The Schirmer's tear test is often performed with topical anesthesia to reduce reflex tearing. Fluress (Barnes-Hind, Sunnyvale, CA, U.S.A.) and Fluoracaine (Akorn, Abita Springs, LA, U.S.A.) are commonly used anesthetic-fluorescein preparations that contain viscous additives. Because the rate of Schirmer's strip wetting is dependent on capillary action, a property related to solution viscosity and surface tension, spurious results may be obtained if these agents are used for anesthesia. We report in vitro Schirmer's strip wetting rates for various concentrations of Fluress and Fluoracaine, as well as pure fluorescein solution using a tear substitute (Dacriose; IOLAB, Claremont, CA, U.S.A.) as a diluent. Results showed a direct concentration-dependent reduction of Schirmer's strip wetting with time for both Fluress and Fluoracaine dilutions compared with Dacriose alone (p < 0.001) or Dacriose-fluorescein solutions (p < 0.001). In addition, Schirmer's wetting with Dacriose-fluorescein solutions caused a separation of the Dacriose and fluorescein wetting fronts (p < 0.001) but did not affect the overall Dacriose wetting. These data have clinical implications concerning false-positive results when testing for dry eyes.

Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice.

A subpopulation of the CF-1 mouse strain contains a spontaneous mutation in the P-glycoprotein (Pgp) mdr1a gene, which leads to a lack of mdr1a expression in the placenta as well as brain and intestine. Individual CF-1 mice can be identified according to their Pgp status by a restriction fragment length polymorphism. Male and female mice selected on the basis of Pgp genotype were mated and the pregnant dams exposed during gestation to the known Pgp substrate, L-652,280, the 8,9 Z photoisomer of the naturally occurring avermectin Bla, which is known to produce cleft palate in mice. Fetal examination demonstrated that within individual litters, fetuses deficient in Pgp (-/-) were 100% susceptible to cleft palate, whereas their +/- heterozygote littermates were less sensitive. The homozygous +/+ fetuses with abundant Pgp were totally insensitive at the doses tested. The degree of chemical exposure of fetuses within each litter was inversely related to expression of placental Pgp, which was determined by the fetal genotype. These results demonstrate the importance of placental Pgp in protecting the fetus from potential teratogens and suggest that Pgp inhibitors should be carefully evaluated for their potential to increase susceptibility to chemical-induced teratogenesis.

Determination of simple and complex iodides with ferric chloride-an alternative to the andrews titration.

The iodide content of simple and complex iodides can be extracted as iodine after dissolution of the sample with acidified ferric chloride solution. Most iodides can thus be decomposed in 3M hydrochloric acid medium. A suitable extraction flask is described. Information on the cation oxidation state can be obtained by titrating the released ferrous ions in situ. A precision of 0.2% for 1-5 mmoles of iodide is attainable.

Dietary two-generation reproduction study of thiabendazole in Sprague-Dawley rats.

The potential reproductive toxicity of the fungicide and anthelmintic thiabendazole (TBZ) was assessed in Sprague-Dawley rats for two generations. Doses of 10, 30 or 90 mg/kg/day were administered by way of the diet beginning at 8 wk of age for the F0 generation and postnatal wk 4 for the F1 generation and continuing until the animals were killed. Concentrations of TBZ in the diet were adjusted weekly, except during the gestation and lactation intervals when concentrations were held constant. There were no TBZ-related deaths or adverse physical signs during the study. TBZ-related effects consisted of decreases in average body weight gains and food consumption in the middle and high dose groups. In both the F0 and F1 generations during the premating and post-cohabitation periods, the effects in the middle-dose group were observed only in males and were generally slight in magnitude (food consumption 3-5% below control, weight gain 7-18% below control), whereas the effects in the high dose group occurred in both sexes and were slight to moderate in magnitude (food consumption 9-13% below control, weight gain 13-46% below control). During gestation of the F0 females there were slight decreases in average weight gain and food consumption (8% and 4-16% below control, respectively); a similar effect on food consumption, but not weight gain, occurred in the F1 generation. There were no effects on F0 or F1 reproductive performance (including indices of mating, fecundity, fertility, length of gestation, litter size, birth weight, and post-implantation survival), nor were any histomorphological changes observed in the reproductive tissues of animals in the high dose group. There was no evidence of developmental toxicity in the TBZ-exposed F1 or F2 generations, except for slight decreases in average pup weights between postnatal days 4 and 21 in the high dose group (5-10% below control). The NOAEL (no-observed-adverse-effect level) for all developmental, growth, survival and reproductive performance parameters assessed in this study was 10 mg/kg/day.

Posterior fossa arachnoid cyst presenting with an isolated twelfth nerve paresis. Case report and review of the literature.

An unusual case of a posterior fossa arachnoid cyst containing atypical fluid is described in a patient presenting with an isolated ipsilateral twelfth nerve paresis. Despite the chronicity of symptoms, surgical decompression resulted in a satisfactory functional recovery.

Von Kossa's method for renal mineralization: application for multiple specimens using capillary gap technology.

Mineralization of renal tissue was investigated using Von Kossa's method and capillary gap technology. Combining these techniques allowed the simultaneous processing of 100 slides, reduced the volume of 5% silver nitrate required, and produced consistent dark brown to black silver deposits in positive control sections. A 25-fold savings in silver nitrate was achieved. By markedly reducing individual slide handling, technician time also was greatly reduced. Two or three slide sets, each containing approximately 100 slides, can be conveniently stained daily.