Sustained in vivo release from imprinted therapeutic contact lenses.

In this paper, we demonstrate the successful in vivo extended release of a small molecular weight therapeutic, ketotifen fumarate (MW=425), from molecularly imprinted, therapeutic contact lenses. This is the first time that a steady, effective concentration of drug is maintained in the tear film from a contact lens for an extended period of time for the entire duration of lens wear. Poly(HEMA-co-AA-co-AM-co-NVP-co-PEG200DMA) soft contact lenses were prepared (100±5 µm thickness, diameter 11.8 mm, power zero), and a constant tear film concentration of 170±30 µg/mL was measured for up to 26 hrs in a New Zealand white rabbit model. The results showed a dramatic increase in ketotifen mean residence time (MRT) and bioavailability compared to topical drop therapy and drug soaked lenses. The MRT for imprinted lenses was 12.47±3.99 hrs, ~4 and 50 fold greater than non-imprinted lenses and 0.035% eye drops (Zaditor®), respectively. Furthermore, AUC(0-26 hrs) was 9 and 94 fold greater for imprinted lenses than non-imprinted lenses and eye drops, respectively. The results indicate that molecular imprinting provides an exciting rational engineering strategy for sustained release. It is clear that imprinted lenses are very promising combination devices and are much more effective and efficient delivery devices than eye drops.

Shoot development--genetic interactions in the meristem.

Development of the plant shoot is dependent on the shoot apical meristem. Interactions between KNOX homeodomain transcription factors and the myb domain transcription factor AS1 (ASYMMETRIC LEAVES1) regulate both meristem function as well as leaf patterning. This review summarizes these interactions.

Asymmetric leaves1 mediates leaf patterning and stem cell function in Arabidopsis.

Meristem function in plants requires both the maintenance of stem cells and the specification of founder cells from which lateral organs arise. Lateral organs are patterned along proximodistal, dorsoventral and mediolateral axes. Here we show that the Arabidopsis mutant asymmetric leaves1 (as1) disrupts this process. AS1 encodes a myb domain protein, closely related to PHANTASTICA in Antirrhinum and ROUGH SHEATH2 in maize, both of which negatively regulate knotted-class homeobox genes. AS1 negatively regulates the homeobox genes KNAT1 and KNAT2 and is, in turn, negatively regulated by the meristematic homeobox gene SHOOT MERISTEMLESS. This genetic pathway defines a mechanism for differentiating between stem cells and organ founder cells within the shoot apical meristem and demonstrates that genes expressed in organ primordia interact with meristematic genes to regulate shoot morphogenesis.

Directors' duty of care to monitor information systems in HMOs: some lessons from the Oxford Health Plan.

This paper examines the legal and strategic issues raised by the use of information systems in health maintenance organizations (HMOs) and other managed care organizations. Given the critical nature of information systems to an HMO's business success and regulatory compliance, the large financial investment HMOs make in their systems, and the widely publicized concerns over the year 2000 "millennium bug" problem, information systems are appropriately a matter of concern to an HMO's board of directors. The recent experience of Oxford Health Plans, Inc. offers a case study in the apparent failure of the directors to monitor adequately the in-house development of an information system. The systems disaster which this corporation suffered in 1997 led to a dramatic drop in stock price, from which the company has yet to recover, as well as intense scrutiny by state and federal regulators and countless shareholder derivative actions against the directors. Corporate directors are subject to the fiduciary duty of care. Despite statutes in some states requiring directors to act prudently, state courts almost always apply the standard of gross negligence. As a result, even when directors act without due deliberation in their decision, it is rare that a court will find them to have failed in their duty of care. The business and regulatory community may find otherwise, however, when directors fail to evaluate information systems options carefully and the business suffers as a result.

Pragmatic language behaviors of adults diagnosed with chronic schizophrenia.

35 adults diagnosed with schizophrenia provided samples of narrative and conversational discourse and completed a criterion-referenced test of pragmatic language ability. There was a significant relationship between performance on pragmatic language tasks and perceived over-all functioning of schizophrenic subjects as measured by psychological assessment. Subjects who were perceived as functioning at low levels on the Global Assessment of Functioning Scale from the Diagnostic and 1994 Statistical Manual of Mental Disorders had low self-disclosure in conversation, produced less information in narratives, and produced more nonscorable items on a criterion-referenced test of pragmatic language. Appropriateness of speech suprasegmentals was also related to patients' perceived effectiveness as communicators as well as to their perceived over-all functioning as measured by the Global Assessment of Functioning Scale.

A retrospective molecular analysis of gentamicin resistance in Staphylococcus aureus strains from UK hospitals.

The composite transposon Tn4001 and a related chromosomal Tn4001-like element, encode resistance to the aminoglycosides gentamicin, tobramycin and kanamycin (GmTmKmr) in Australian strains of Staphylococcus aureus. Southern hybridisation analysis of GmTmKmr S. aureus strains isolated from various hospitals in the UK between 1975 and 1985 indicated that they predominantly encoded chromosomal copies of Tn4001 or a Tn4001-like element. However, a strain isolated in 1985 was found to carry Tn4001 on a plasmid related to pSK1, the prototypical multiresistance plasmid commonly detected in S. aureus strains from Australian hospitals.

Metalinguistic and pragmatic abilities of participants in adult literacy programs.

The relationship between oral and written language skills was explored in this study involving 97 participants enrolled in an adult literacy program. Pragmatic language skills were assessed in videotaped conversational dyads which were later analyzed for level of conversational assertiveness and responsiveness and for the status of basic interactional skills. Those behaviors which were judged as being most likely to detract from communicative effectiveness were body movement, eye gaze, and facial expression. Metalinguistic/ semantic language skills were assessed with the Test of Word Knowledge (TOWK) (Wiig & Secord, 1991). A significant relationship was found between total scores on the TOWK and reading levels of subjects as they entered the program. Post-testing was conducted approximately 6 to 8 months after the initial testing. These results were available for 22 of the subjects and indicated that, even for adults, some aspects of oral language improve as reading levels increase.

Possible role of insertion sequence IS257 in dissemination and expression of high- and low-level trimethoprim resistance in staphylococci.

The transposon-like structure Tn4003 and related elements were found to encode high- and low-level trimethoprim resistance (Tpr) in Staphylococcus aureus and coagulase-negative staphylococci. By using transcriptional fusions in Escherichia coli, the variation in resistance levels was found to correlate with the transcriptional activity of the region presumed to carry the promoter for the operon containing the Tpr dihydrofolate reductase gene, dfrA, encoded by these elements. The reduced transcriptional activities exhibited by elements encoding low-level Tpr appear to be a consequence of deletions adjacent to the copy of IS257 which normally encodes the -35 sequences of these promoters. The data obtained not only support the involvement of IS257 in the transcription of the proposed thyE-dfrA-orf-140 operon of Tn4003 but may also implicate this insertion sequence in the mechanisms resulting in the variation in Tpr levels observed in staphylococci.

Analysis of a transfer region from the staphylococcal conjugative plasmid pSK41.

The nucleotide sequence of a 14.4-kb region (tra) associated with DNA transfer of the staphylococcal conjugative plasmid, pSK41, has been determined. Analysis of the sequence revealed the presence of 15 genes potentially involved in the conjugative process. Polypeptide products likely to correspond to ten of these genes have been identified, of which one was found to be a lipoprotein. Comparison of the deduced tra products to the protein databases revealed several interesting similarities, one of which suggests an evolutionary link between this Gram+ bacterial conjugation system and DNA transfer systems of Gram- bacteria, such as Escherichia coli and Agrobacterium tumefaciens. The nt sequence also provided an insight into the transcriptional organisation and regulation of the region.

The nurse clinician: role conflict in research.

In a recent pilot study focusing on stroke rehabilitation, four clinical nurse specialists (CNSs) experienced role conflict when assuming the nurse researcher-interviewer role. Presenting an overview of the pilot study and the experiences that occurred, the authors question the reliability of the interviews. They propose that outcomes of research can be biased by role conflict when CNSs serve as interviewers and collect data. The authors suggest that interviewing training specifically address role conflict.

Symptomatic choroid plexus xanthogranuloma of the lateral ventricle. Case report and brief critical review of xanthogranulomatous lesions of the brain.

Xanthogranulomas of the choroid plexus are found relatively frequently at autopsy; however only 8 cases of symptomatic choroid plexus xanthogranuloma of the lateral ventricle have been reported. We describe an additional case in a 63-year-old man who presented with headache. A well circumscribed mass located in the trigone of the right lateral ventricle and extending into the periventricular white matter was detected on imaging studies. The clinical impression was metastasis. The resected material had the typical histological appearance of a xanthogranuloma of the choroid plexus. The clinical and histopathologic features of these lesions are reviewed and other xanthogranulomatous processes involving the brain are briefly discussed.

4',4'' adenyltransferase activity on conjugative plasmids isolated from Staphylococcus aureus is encoded on an integrated copy of pUB110.

In staphylococci, linked resistance to the aminoglycosides kanamycin, neomycin, paromomycin, and tobramycin (KmNmPmTmr) is generally mediated by an aadD determinant which encodes production of an adenyltransferase aminoglycoside modifying enzyme, AAD(4',4''). The aadD resistance determinant is located on small multicopy plasmids such as pUB110, and has also been found on large multiresistance plasmids and on the chromosome in some strains. Examination of two conjugative plasmids from strains of Staphylococcus aureus isolated in North America indicated that the aadD determinant on these plasmids is located on an integrated copy of pUB110. The integrated pUB110 is flanked by direct repeats of the staphylococcal insertion sequence IS257. Analysis of the conjugative plasmid pSK41 showed an 8-bp duplication of the pUB110 sequence immediately adjacent to flanking IS257 elements, suggesting that integration of pUB110 was mediated by IS257.

Molecular analysis of a gentamicin resistance transposonlike element on plasmids isolated from North American Staphylococcus aureus strains.

Plasmid-encoded resistance to the aminoglycosides gentamicin (Gm), tobramycin (Tm), and kanamycin (Km) (GmTmKmr) in strains of Staphylococcus aureus isolated in Australia and North America appears to be mediated by one resistance determinant. In Australian isolates, this determinant is flanked by inverted copies of a 1.3-kb insertion sequence, IS256, thereby forming a composite transposon, Tn4001. Analysis of two conjugative plasmids and a related nonconjugative plasmid from strains of S. aureus isolated in North America showed that the GmTmKmr determinant on these plasmids is also flanked by inverted repeats. In the nonconjugative plasmid, these repeats include only 425 bp of IS256 immediately adjacent to the GmTmKmr region and identical to that on Tn4001. This truncated Tn4001 element is flanked by copies of the insertion element IS257, and together these elements form a truncated Tn4001-IS257 hybrid transposonlike structure. A third copy of IS257 was located 418 bp from the hybrid structure. The truncated Tn4001 and three repeats of IS257 were present at a conserved site on the plasmids studied. Four additional copies of IS257 were identified on the two conjugative plasmids. These elements flank determinants for resistance to the aminoglycosides neomycin and paromomycin and to ethidium bromide and quaternary ammonium compounds, as well as the region involved in conjugative plasmid transfer.

Wound healing. Oral and topical activity of Aloe vera.

The influence of Aloe vera, orally and topically, on wound healing was studied. Wounds were induced on both sides of the vertebral column of ICR mice using a biopsy punch. For the oral study, experimental animals received A. vera in their drinking water for 2 months, whereas the control animals received only water. In the topical study, experimental animals were given 25% A. vera in Eucerin cream topically. The control animals received cream only. A 62.5% reduction in wound diameter was noted in mice receiving 100 mg/kg/day oral A. vera and a 50.8% reduction was recorded in animals receiving topical 25% A. vera. These data suggest that A. vera is effective by both oral and topical routes of administration.

Nucleotide sequence analysis of IS256 from the Staphylococcus aureus gentamicin-tobramycin-kanamycin-resistance transposon Tn4001.

Resistance to the aminoglycosides gentamicin, tobramycin and kanamycin (GmTmKmR) in Australian clinical strains of Staphylococcus aureus is commonly carried on the composite transposon Tn4001. The resistance gene aacA-aphD of Tn4001, which encodes a bifunctional AAC(6')-APH(2") modifying enzyme, is flanked by two 1324-bp inverted repeats, IS256L and IS256R, that are identical in sequence. Analysis of the IS256 sequence revealed structural features characteristic of IS elements including 26-bp imperfect terminal inverted repeats and a single open reading frame with coding capacity for a 45.6 kDa protein. The nucleotide sequence of IS256 described here, together with the sequence of the aacA-aphD gene reported previously [Rouch et al., J. Gen. Microbiol. 133 (1987) 3039-3052], completes the entire sequence of Tn4001, which totals 4566 bp.

Anti-inflammatory activity of Aloe vera against a spectrum of irritants.

The authors have evaluated the spectrum of anti-inflammatory activity of A. vera in a number of models of inflammation in the hind paw of the experimental rat induced by kaolin, carrageenan, albumin, dextran, gelatin, and mustard. Croton oil was used in a topical model of inflammation to determine the oral activity and time-dependent dosing of A. vera. The authors found that A. vera was active in all models of inflammation. Of the various irritants tested, A. vera was especially active against gelatin-induced and kaolin-induced edema and, in contrast, had minimal activity when tested against dextran-induced edema. Oral activity of A. vera was demonstrated to be dependent on the presence of anthraquinones. The various irritant-induced edema models provided a broad spectrum of anti-inflammatory activity for A. vera.

Rural health, family practice, and area health education centers: a national study.

The National Area Health Education Center (AHEC) Program and the family practice specialty were both created around 1970, in part to help meet the health care needs of medically underserved populations. Because these two entities share the common goal of alleviating physician shortages in rural areas, a study was conducted to determine the nature and extent of their interaction. Questionnaires were mailed to all AHEC projects and all nonmilitary family practice residency programs. Response rates were 100% and 79%, respectively. Elective rural rotations (usually preceptorships) are offered by 135 (49%) residencies, but only 84 (31%) require them. Fourteen (64%) AHEC projects interact with family practice residencies; however, only 9% (15/167) of the programs in those states utilize AHEC resources. The authors conclude that additional rural rotations could be offered to family practice residents by taking advantage of under-utilized resources of the National AHEC Program.

Multiresistant Staphylococcus aureus: genetics and evolution of epidemic Australian strains.

Molecular and genetic analysis of multiresistant isolates of Staphylococcus aureus from widely separated hospitals in Australia has demonstrated that these are clearly related, and that the predominant strains possess up to three different plasmids, which fall into the following classes: (i) small 1.6 kb plasmids, such as pSK3, which are phenotypically cryptic, (ii) 4.5 kb chloramphenicol resistance plasmids, such as pSK2, and (iii) the pSK1 family of multiresistance plasmids, which range in size from 20 to 42 kb and variously encode resistance to antiseptics and disinfectants, trimethoprim (Tpr), penicillin (Pcr) and the aminoglycosides gentamicin, tobramycin and kanamycin (Gmr Tmr Kmr). Gmr Tmr Kmr is encoded on the pSK1 family plasmids by transposon Tn4001, which was also detected on the chromosomes of some clinical isolates. Tn4001 is composed of inverted repeats of the insertion sequence IS256; these repeats flank a Gmr Tmr Kmr sequence encoding for a 57,000 dalton bifunctional protein with aminoglycoside acetyltransferase [AAC(6')] and phosphotransferase [APH(2")] activities. A Tn4001-like structure, which is defective in transposition but encodes for a Gmr Tmr Kmr determinant homologous with that on Tn4001, occurs on conjugative plasmids from strains isolated in North America. Physical studies indicate that Pcr, via a beta-lactamase, and Tpr, via a trimethoprim-insensitive dihydrofolate reductase (DHFR), are also encoded on the pSK1 family by transposons; these transposons have been designated Tn4002 and Tn4003, respectively. Tn4003 is flanked by direct repeats of the insertion sequence IS257. The evolution of the pSK1 family of multiresistance plasmids is traced through the transposition and genetic rearrangement of resistance determinants. Transposition and genetic rearrangement have also contributed to the evolution of a multiresistant chromosome in Staph. aureus. In the majority of contemporary multiply resistant Staph. aureus strains the determinants for resistance to erythromycin (Emr), fusidic acid, methicillin (Mcr), minocycline, rifampicin, spectinomycin, streptomycin, sulphonamides, tetracycline (Tcr), cadmium (Cdr), and mercury (Hgr) are chromosomally encoded; these strains also possess chromosomally encoded Pcr, via a beta-lactamase. Evidence indicates that some of these determinants, Pcr, Cdr, Hgr, and Tcr, were plasmid encoded in isolates collected from Australian hospitals prior to 1970. Through transposition and site-specific integration, they have since been acquired by the chromosome in more recent Staph. aureus strains.(ABSTRACT TRUNCATED AT 400 WORDS)