SULFISOMIDINE IN THE TREATMENT OF PERTUSSIS

Sulfisomidine and pertussis serum were used in the treatment of 21 patients with pertussis. Twenty of the patients were under six months of age and seven had bronchopneumonia.Therapeutic concentrations of the drug in the blood were obtained in 14 cases when it was given in dosage of 0.26 gm. per kilogram of body weight per 24 hours.The average stay in hospital was ten days. None of the patients died. Hematuria developed in one case but crystalluria was not concomitant and it abated promptly when fluid intake was increased.     

A Comparative Survey of Automated Parameter-Search Methods for Compartmental Neural Models

One of the most difficult and time-consuming aspects of building compartmental models of single neurons is assigning values to free parameters to make models match experimental data. Automated parameter-search methods potentially represent a more rapid and less labor-intensive alternative to choosing parameters manually. Here we compare the performance of four different parameter-search methods on several single-neuron models. The methods compared are conjugate-gradient descent, genetic algorithms, simulated annealing, and stochastic search. Each method has been tested on five different neuronal models ranging from simple models with between 3 and 15 parameters to a realistic pyramidal cell model with 23 parameters. The results demonstrate that genetic algorithms and simulated annealing are generally the most effective methods. Simulated annealing was overwhelmingly the most effective method for simple models with small numbers of parameters, but the genetic algorithm method was equally effective for more complex models with larger numbers of parameters. The discussion considers possible explanations for these results and makes several specific recommendations for the use of parameter searches on neuronal models.     

Isothiazolidinone inhibitors of PTP1B containing imidazoles and imidazolines

The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme.     

Setting standards based on patients' views on access and continuity: secondary analysis of data from the general practice assessment survey

ObjectivesTo examine patients'' views on access and continuity in general practice to derive quality standards.DesignSecondary analysis of data from general practice research studies and routine quality assessment activities undertaken by practices and primary care trusts.SettingGeneral practice.ParticipantsGeneral practice patients.ResultsSatisfactory standards of access were next day appointments with general practitioners and a 6-10 minute wait for consultations to begin. A satisfactory level of continuity was seeing the same general practitioner “a lot of the time.” Standards varied with the analytic method used and by sociodemographic group.ConclusionsStandards expected by patients in primary care can be derived from linked report-assessment pairs. Patients may have expectations of access that are in excess of government targets. Patients also have high expectations of continuity of care. It is unclear the degree to which such standards are reliable or valid, how conflicts between access and continuity should be resolved, or how these standards relate to other priorities of patients such as high quality interpersonal care.

What is already known on this topic

Standards are increasingly being set for the provision of health servicesSurveys and consultation exercises before the NHS plan helped set the standard for a maximum waiting time of 48 hours for appointments to see general practitionersThe optimal methods by which patients should be involved in setting standards and the utility of such standards are unclear

What this study adds

Satisfactory standards of access were next day appointments, a 6-10 minute wait for consultations to begin, and seeing the same general practitioner a lot of the timePatients may have expectations for access to primary care in excess of current government targets     

Walking the fine line between intracellular and membrane activities of antibacterial peptides

Analogs of pyrrhocoricin, a proline-rich antibacterial peptide with a potential therapeutic use, show multiple actions on bacterial cells. We used a dual-fluorochrome membrane viability assay to provide evidence that the lead drug candidate, Pip-pyrr-MeArg dimer derivative, kills bacteria better than the native peptide due to an improved activity on bacterial membranes. This assay was also instrumental in documenting that activity on bacterial membranes and toxicity to human cells can be correlated, and the predominant mode of action can be changed from intracellular DnaK inhibition to membrane disintegration. Similar analyses with an alanine-scan on pyrrhocoricin identified Lys3 as a crucial player to interaction with bacterial membranes, three prolines in mid-chain position as being responsible for maintaining structural integrity and Asp2, Tyr6, Leu7, and Arg9 as putative contact points to the D-E helix of the bacterial target protein DnaK.     

Proof-of-concept human laboratory study for protracted abstinence in alcohol dependence: effects of gabapentin

There is a need for safe medications that can effectively support recovery by treating symptoms of protracted abstinence that may precipitate relapse in alcoholics, e.g. craving and disturbances in sleep and mood. This proof-of-concept study reports on the effectiveness of gabapentin 1200 mg for attenuating these symptoms in a non-treatment-seeking sample of cue-reactive, alcohol-dependent individuals. Subjects were 33 paid volunteers with current Diagnostic and Statistical Manual of Mental Disorders-IV alcohol dependence and a strength of craving rating 1 SD or greater for alcohol than water cues. Subjects were randomly assigned to gabapentin or placebo for 1 week and then participated in a within-subjects trial where each was exposed to standardized sets of pleasant, neutral and unpleasant visual stimuli followed by alcohol or water cues. Gabapentin was associated with significantly greater reductions than placebo on several measures of subjective craving for alcohol as well as for affectively evoked craving. Gabapentin was also associated with significant improvement on several measures of sleep quality. Side effects were minimal, and gabapentin effects were not found to resemble any major classes of abused drugs. Results suggest that gabapentin may be effective for treating the protracted abstinence phase in alcohol dependence and that a randomized clinical trial would be an appropriate next step. The study also suggests the value of cue-reactivity studies as proof-of-concept screens for potential antirelapse drugs.     

SEPALLATA3: the 'glue' for MADS box transcription factor complex formation

Background  

Plant MADS box proteins play important roles in a plethora of developmental processes. In order to regulate specific sets of target genes, MADS box proteins dimerize and are thought to assemble into multimeric complexes. In this study a large-scale yeast three-hybrid screen is utilized to provide insight into the higher-order complex formation capacity of the Arabidopsis MADS box family. SEPALLATA3 (SEP3) has been shown to mediate complex formation and, therefore, special attention is paid to this factor in this study.     

Intrinsic resistance of neural stem cells to toxic metabolites may make them well suited for cell non-autonomous disorders: evidence from a mouse model of Krabbe leukodystrophy

While transplanted neural stem cells (NSCs) have been shown to hold promise for cell replacement in models of a number of neurological disorders, these examples have typically been under conditions where the host cells become dysfunctional due to a cell autonomous etiology, i.e. a 'sick' cell within a relatively supportive environment. It has long been held that cell replacement in a toxic milieu would not likely be possible; donor cells would succumb in much the same way as endogenous cells had. Many metabolic diseases are characterized by this situation, suggesting that they would be poor targets for cell replacement therapies. On the other hand, models of such diseases could prove ideal for testing the capacity for cell replacement under such challenging conditions. In the twitcher (twi ) mouse -- as in patients with Krabbe or globoid cell leukodystrophy (GLD), for which it serves as an authentic model -- loss of galactocerebrosidase (GalC) activity results in the accumulation of psychosine, a toxic glycolipid. Twi mice, like children with GLD, exhibit inexorable neurological deterioration presumably as a result of dysfunctional and ultimately degenerated oligodendrocytes with loss of myelin. It is believed that GLD pathophysiology is related to a psychosine-filled environment that kills not only host oligodendrocytes but theoretically any new cells placed into that milieu. Through the implantation of NSCs into the brains of both neonatal and juvenile/young adult twi mice, we have determined that widespread oligodendrocyte replacement and remyelination is feasible. NSCs appear to be intrinsically resistant to psychosine -- more so in their undifferentiated state than when directed ex vivo to become oligodendrocytes. This resistance can be enhanced by engineering the NSCs to over-express GalC. Some twi mice grafted with such engineered NSCs had thicker white tracts and lived 2-3 times longer than expected. While their brains had detectable levels of GalC, it was probably more significant that their psychosine levels were lower than in twi mice that died at a younger age. This concept of resistance based on differentiation state extended to human NSCs which could similarly survive within the twi brain. Taken together, these results suggest a number of points regarding cellular therapies against degenerative diseases with a prominent cell non-autonomous component: Cell replacement is possible if cells resistant to the toxic environment are employed. Furthermore, an important aspect of successful treatment will likely be not only cell replacement but also cross-correction of host cells to provide them with enzyme activity and hence resistance. While oligodendrocyte replacement alone was not a sufficient treatment for GLD (even when extensive), the replacement of both cells and molecules -- e.g. with NSCs that could both become oligodendrocytes and 'pumps' for GalC -- emerges as a promising basis for a multidisciplinary strategy. Most neurological disease are complex in this way and will likely require multifaceted approaches, perhaps with NSCs serving as the 'glue'.