Protein kinase C gamma mutations in spinocerebellar ataxia 14 increase kinase activity and alter membrane targeting.

The protein kinase C gamma (PKCgamma) gene is mutated in spinocerebellar ataxia type 14 (SCA14). In this study, we investigated the effects of two SCA14 missense mutations, G118D and C150F, on PKCgamma function. We found that these mutations increase the intrinsic activity of PKCgamma. Direct visualization of labelled PKCgamma in living cells demonstrates that the mutant protein translocates more rapidly to selected regions of the plasma membrane in response to Ca2+ influx. These results point to specific alterations in mutant PKCgamma function that could lead to the selective neuronal degeneration of SCA14.

A new autosomal dominant pure cerebellar ataxia.

A kindred is described with a dominantly inherited "pure" cerebellar ataxia in which the currently known spinocerebellar ataxias have been excluded. In the eight subjects studied, a notable clinical feature is slow progression, with the three least affected having only a mild degree of gait ataxia after three or more decades of disease duration. Pending an actual chromosomal locus discovery, the name spinocerebellar ataxia (SCA)15 is expectantly applied.

Synthesis of potent cyclic hexapeptide NK-1 antagonists. Use of a minilibrary in transforming a peptidal somatostatin receptor ligand into an NK-1 receptor ligand via a polyvalent peptidomimetic.

The endogenous peptides somatostatin (SRIF) and substance P comprise very different structures. Although both bind G-protein-coupled receptors, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta-turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substance P. Conversely the NK-1 receptor binds substance P but not the above ligands. In contrast, the beta-D-glucosides 1 and 2, designed to mimic the beta-turn of 6a, bind both receptors. This observation led us to attempt the conversion of 6a into the first potent, selective cyclic hexapeptide ligand for the NK-1 receptor. To this end, we combined design with a minilibrary approach. The goal was accomplished with surprising ease, leading to the NK-1 receptor antagonist 9 (IC50 2.0 +/- 0.4 nM). This demonstrates that peptidomimetics, incorporating in this case the promiscuous beta-D-glucose scaffold, can provide valuable clues about receptor similarities not revealed by their endogenous ligands. In addition, this work suggests that the use of libraries and rational design need not be mutually exclusive approaches to lead discovery.

Modulation of receptor and receptor subtype affinities using diastereomeric and enantiomeric monosaccharide scaffolds as a means to structural and biological diversity. A new route to ether synthesis.

We show that carbohydrates constitute an attractive source of readily available, stereochemically defined scaffolds for the facile attachment of side chains contained in genetically encoded and other amino acids. beta-D- and beta-L-glucose, L-mannose, and the 6-deoxy-6-N-analogue of beta-D-glucose have been employed to synthesize peptidomimetics that bind the SRIF receptors on AtT-20 mouse pituitary cells, five cloned human receptor subtypes (hSSTRs), and the NK-1 receptor. The affinity profile of various sugar-based ligands at the hSSTRs is compared with that of SRIF. Compound 19 bound hSSTR4 with a Ki of 100 nM. Subtle structural changes affect affinities. Evidence is presented that suggests that one compound (8) binds both the AtT-20 cell receptors and the five hSSTRs via a unique mode. The SARs of the glycosides at SRIF receptors differ markedly from those at the NK-1 receptor. For example a 4-benzyl substituent is important for SRIF receptor binding, but the 4-desbenzyl analogue 27 was highly potent (IC50 of 27 nM) at the NK-1 receptor. A new, nonbasic method for the synthesis of base-sensitive ethers from primary and secondary alcohols is also described.

Monoclonal antibody LICR-LON-E36 recognizes gonadotrophs in female rat pituitaries.

The distribution of the antigen localized by monoclonal antibody LICR-LON-E36 has been studied by means of light and electron microscopical immunocytochemical procedures on resin-embedded pituitaries from male and female rats. Using both immunoperoxidase and immunogold labeling techniques, the localization of LICR-LON-E36 has been compared with that obtained with antibodies against the beta subunit of rat luteinizing hormone (beta LH) and human follicle stimulating hormone (beta FSH), porcine adrenocroticotropic hormone (ACTH) and rat S-100. LICR-LON-E36 is localized in a portion of beta LH-containing cells in female rat pituitaries and where present both antigens are localized within the same storage granules. LICR-LON-E36 is rarely detectable within beta LH-containing cells of male rat pituitaries that also stain positively with anti-beta FSH antibodies. ACTH and S-100 were localized within different cell populations.

Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene.

Mutations in the presenilin 1 (PS1) gene are responsible for approximately 50% of early onset autosomal-dominant Alzheimer's disease cases. A PCR based mutation detection method, chemical cleavage of mismatch, was used to detect a novel PS1 mutation in the coding sequence of the PS1 gene. Sequencing confirmed a T to C transition altering a leucine to proline at codon 219 of the PS1 gene. This is a novel mutation in exon 7 of the PS1 gene occurring outside the transmembrane regions of IV and V.

Should doctors be more proactive as advocates for victims of violence?

Currently the management of adult victims of violence by general practitioners and accident and emergency departments is reactive, concerned almost exclusively with the management of physical injuries. Professor Jonathan Shepherd outlines some ideas for a more proactive approach on the part of doctors to improve the protection and support of vulnerable people; to deal with psychological sequelae; to take the responsibility of making an official complaint to the police away from seriously injured people, who are unable to give or withhold consent to disclosure; and to prevent assailants inflicting further injuries. We asked a sociologist, a psychiatrist, a moral philosopher, and a police surgeon for their comments.

Video-assisted cycling alters perception of effort and increases self-selected exercise intensity.

Two studies were conducted to assess whether indoor video-assisted cycling influenced a person's quality of exercise (subjectively and quantitatively), compared to indoor cycling alone. In the first study 12 recreationally active subjects completed an initial test of VO2max, and three randomized trials of cycling at 70% VO2max (35 min.) watching a commercial cycling tape (cycle video), a test pattern displayed on the ergometer screen (blank video), or no video. Subjects' ratings of perceived exertion (RPE) and Affect were recorded, and heart rate and oxygen consumption (VO2) were measured during testing. The second study required 12 different subjects first to complete an assessment of VO2max and then two randomized trials (cycle video and no video) on a cycle ergometer where they freely set the intensity of their own exercise. Measurements of VO2, heart rate, blood lactate, power output, RPE, and Affect were recorded during testing. Results of Exp. 1 indicated that subjects' perceived effort equally between the two conditions, yet reported significantly (p < .05) higher affect at 25 and 35 min. of cycling during the cycle video condition than no video condition. Results of Exp. 2 indicated that despite similar levels of blood lactate, subjects exercised at a significantly higher intensity during the cycle video condition compared to no video condition, with a higher VO2 and heart rate. The data support the use of indoor exercise videos to improve the exercise experience and also to increase the physiological demands of indoor exercise.

Needleless i.v. therapy: comparing three systems for safety.

Three needleless systems were compared for general usability and cost. A closed, one-piece, nonmechanical unit was chosen as it proved safe in both peripheral and central lines, required minimal inservicing and yielded significant cost savings.

Quality indicators for partial hospitalization.

Partial hospitalization and other services along the continuum of ambulatory mental healthcare are rapidly gaining acceptance as attractive alternatives to inpatient treatment. To assure continued development of high caliber programs, leaders of the partial hospital field have been working to develop quality indicators and outcomes measures specifically tailored to the unique aspects of ambulatory care. The quality domains and indicators outlined below are based upon the principles of effectiveness, efficiency, satisfaction and viability that provide foundations for this treatment modality.

Development of a system dynamics model for financially sustainable management of municipal watermain networks.

This paper develops causal loop diagrams and a system dynamics model for financially sustainable management of urban water distribution networks. The developed causal loop diagrams are a novel contribution in that it illustrates the unique characteristics and feedback loops for financially self-sustaining water distribution networks. The system dynamics model is a mathematical realization of the developed interactions among system variables over time and is comprised of three sectors namely watermains network, consumer, and finance. This is the first known development of a water distribution network system dynamics model. The watermains network sector accounts for the unique characteristics of watermain pipes such as service life, deterioration progression, pipe breaks, and water leakage. The finance sector allows for cash reserving by the utility in addition to the pay-as-you-go and borrowing strategies. The consumer sector includes controls to model water fee growth as a function of service performance and a household's financial burden due to water fees. A series of policy levers are provided that allow the impact of various financing strategies to be evaluated in terms of financial sustainability and household affordability. The model also allows for examination of the impact of different management strategies on the water fee in terms of consistency and stability over time. The paper concludes with a discussion on how the developed system dynamics water model can be used by water utilities to achieve a variety of utility short and long-term objectives and to establish realistic and defensible water utility policies. It also discusses how the model can be used by regulatory bodies, government agencies, the financial industry, and researchers.

Application of system dynamics for developing financially self-sustaining management policies for water and wastewater systems.

Recently enacted regulations in Canada and elsewhere require water utilities to be financially self-sustaining over the long-term. This implies full cost recovery for providing water and wastewater services to users. This study proposes a new approach to help water utilities plan to meet the requirements of the new regulations. A causal loop diagram is developed for a financially self-sustaining water utility which frames water and wastewater network management as a complex system with multiple interconnections and feedback loops. The novel System Dynamics approach is used to develop a demonstration model for water and wastewater network management. This is the first known application of System Dynamics to water and wastewater network management. The network simulated is that of a typical Canadian water utility that has under invested in maintenance. Model results show that with no proactive rehabilitation strategy the utility will need to substantially increase its user fees to achieve financial sustainability. This increase is further exacerbated when price elasticity of water demand is considered. When the utility pursues proactive rehabilitation, financial sustainability is achieved with lower user fees. Having demonstrated the significance of feedback loops for financial management of water and wastewater networks, the paper makes the case for a more complete utility model that considers the complexity of the system by incorporating all feedback loops.

Spinocerebellar ataxia type 14: study of a family with an exon 5 mutation in the PRKCG gene.

We report our observations in an Australian family with spinocerebellar ataxia type 14 (SCA 14). We describe a novel mutation in exon 5 of the PRKCG gene, altering a highly conserved cysteine to a phenylalanine at codon 150, and record the detailed clinical observations in six affected family members.

Social work practice in rural mental health systems.

A precise understanding of the role of the social worker in rural mental health services is necessary to ensure the adequate training of workers destined for this setting. The authors have conducted a survey of mental health staff in one rural area, examining the interrelationships among such factors as education, perceived levels of knowledge, and clinical functions.

Decompression sickness in women divers.

The comparative incidence of DCS in women has been debated for years. Diving log data from the Naval Diving and Salvage Training Center (NDSTC), Panama City, FL, demonstrate that there is no increased risk of DCS among Navy female divers compared to their male counterparts. Twenty-eight female students were compared to their 487 male classmates on 878 air and helium-oxygen dives between 4.64 and 10.10 ATA (120 to 300 fsw). None of the women experienced DCS while 8 men developed DCS symptoms. The total duration of the dives ranged from 8 min to 2 h and 6 min; bottom times were less than 20 min. Theoretical inert gas supersaturation on these profiles are commensurate with those experienced on 40- to 60-min sport scuba dives.