Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure

Heart Failure Reviews - The nitric oxide (NO)–guanylate cyclase (GC)–cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal...     

Natural Variant of Collagen-Like Protein A in Serotype M3 Group A Streptococcus Increases Adherence and Decreases Invasive Potential

Group A Streptococcus (GAS) predominantly exists as a colonizer of the human oropharynx that occasionally breaches epithelial barriers to cause invasive diseases. Despite the frequency of GAS carriage, few investigations into the contributory molecular mechanisms exist. To this end, we identified a naturally occurring polymorphism in the gene encoding the streptococcal collagen-like protein A (SclA) in GAS carrier strains. All previously sequenced invasive serotype M3 GAS possess a premature stop codon in the sclA gene truncating the protein. The carrier polymorphism is predicted to restore SclA function and was infrequently identified by targeted DNA sequencing in invasive strains of the same serotype. We demonstrate that a strain with the carrier sclA allele expressed a full-length SclA protein, while the strain with the invasive sclA allele expressed a truncated variant. An isoallelic mutant invasive strain with the carrier sclA allele exhibited decreased virulence in a mouse model of invasive disease and decreased multiplication in human blood. Further, the isoallelic invasive strain with the carrier sclA allele persisted in the mouse nasopharynx and had increased adherence to cultured epithelial cells. Repair of the premature stop codon in the invasive sclA allele restored the ability to bind the extracellular matrix proteins laminin and cellular fibronectin. These data demonstrate that a mutation in GAS carrier strains increases adherence and decreases virulence and suggest selection against increased adherence in GAS invasive isolates.     

Development of metabolic alkalosis after massive transfusion during orthotopic liver transplantation

Five patients undergoing orthotopic liver transplantation were investigated for changes in acid-base homeostasis secondary to large volume transfusions. All patients developed a transient acidemia during the operative period, followed by alkalemia which persisted into the early postoperative period. The patients received an estimated mean of 750 mEq of citrate, which appeared to cause metabolic alkalosis. The biochemical basis underlying the regulation of citrate metabolism that may have led to the timing, extent, and duration of the subsequent metabolic alkalosis is presented. Finally, the time course for the development of metabolic alkalosis may be a potentially sensitive indicator of early allograft function.     

Role of Multiple Scouting Biopsies before Mohs Micrographic Surgery for Extramammary Paget's Disease

Background. Extramammary Paget's disease (EMPD) frequently extends subclinically, resulting in high recurrence rates after surgical excision. Mohs micrographic surgery (MMS) improves cure rates but may require time-consuming reexcision of subclinical extension. A mechanism to estimate the location and extent of subclinical extension would be helpful.
Objective. To describe and evaluate a technique for multiple scouting biopsies before MMS for EMPD.
Method. A retrospective review of patients at Mayo Clinic who had multiple scouting biopsies before MMS for EMPD without dermal invasion.
Technique. The clinical extent of EMPD is identified. The scouting biopsy sites are determined and documented with photographs. The scouting biopsy specimens are sent for permanent sections. The results of the scouting biopsies help guide the extent of the initial Mohs layer. The tumor is cleared with MMS. An additional 1 mm peripheral margin of tissue is usually submitted for permanent sections.
Results. Multiple scouting biopsies were done in five patients. Four of the five patients had at least one true-positive result. At least one true-negative result was obtained in all five patients. Two patients had at least one false-negative result.
Conclusion. Multiple scouting biopsies before MMS for EMPD without dermal invasion can be a beneficial adjuvant technique.
DAVID L. APPERT, MD, CLARK C. OTLEY, MD, P. KIM PHILLIPS, MD, AND RANDALL K. ROENIGK, MD, HAVE INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS.     

Graduating medical students' ratings of stresses, pleasures, and coping strategies

The authors' objective in the study reported here was to gather data on the stress and coping of medical students in order to design a health promotion and wellness program. A retrospective questionnaire was completed by 71 of 157 graduating seniors. Examinations, classwork, and financial responsibilities were considered the three most stressful aspects of medical education. The most uplifting items (that is, pleasant, happy, or satisfying experiences) were recreation and social interaction, although good examination performance was rated second highest. Planful problem-solving (that is, deliberate problem-focused efforts to alter a situation) was the most frequently used form of coping, although four of the eight forms of coping assessed were used at least moderately often and all eight were used to some extent.     

An alternative mechanism of actions for neuroleptic and antidepressant drugs

It has earlier been proposed by the author that the aetiology of schizophrenic symptomatology may be due to the presence of abnormally connected interhemispheric fibres which link specialised functions in the brains of schizophrenics that are not connected in normal subjects, and that the neuroleptic drugs may produce their action through a local anaesthetic-like effect in suppression of conduction in these fibres. This line of thought has been extended here to consider the possible mechanism of action of the neuroleptic drugs in more detail, as well as that of the tricyclic antidepressant drugs which are derivatives of the phenothiazine group. Pharmacological similarities with the local anaesthetics both structurally and functionally have been considered, as well as the effects that these drug groups may have in common with the lithium salts. It has been suggested that these drugs all produce their primary effect on cell membranes, though not necessarily at the synapse, that the time course of their clinical effect may correlate with their incorporation into various cell membranes within the CNS, and that they may thus bring about a fundamental alteration in cell membrane microstructure. The possible role of electroconvulsive therapy has also been considered. The corollary of this argument is that the affective disorders may be genetically determined diseases of cell membrane microstructure.