Paradoxical cellular Ca2+ signaling in severe but compensated canine left ventricular hypertrophy

In conscious dogs with severe left ventricular (LV) hypertrophy (H) (doubling of LV/body weight), which developed gradually over 1 to 2 years after aortic banding, baseline LV function was well compensated. The LV was able to generate twice the LV systolic pressure without an increase in LV end-diastolic pressure, or decrease in LV dP/dt or LV wall thickening. However, LV myocytes isolated from LVH dogs exhibited impaired contraction at baseline and in response to Ca2+. There was no change in L-type Ca2+ channel current (ICa) density but the ability of ICa to trigger Ca2+ release from the sarcoplasmic reticulum (SR) was reduced. Immunoblot analysis revealed a 68% decrease in SERCA2a, and a 35% decrease in the number of ryanodine receptors (RyR2), with no changes in protein level of calsequestrin, Na+/Ca2+ exchanger or phospholamban (PLB), but with both RyR2 and PLB hyperphosphorylated. Spontaneous Ca2+ sparks in LVH cells were found to have prolonged duration but similar intensities despite the reduced SR Ca2+ load. A higher Ca2+ spark rate was observed in LVH cells, but this is inconsistent with the reduced SR Ca2+ content. However, Ca2+ waves were found to be less frequent, slower and were more likely to be aborted in Ca2+-challenged LVH cells. These paradoxical observations could be accounted for by a nonuniform SR Ca2+ distribution, RyR2 hyperphosphorylation in the presence of decreased global SR Ca2+ load. We conclude that severe LVH with compensation masks cellular and subcellular Ca2+ defects that remain likely contributors to the limited contractile reserve of LVH.     

Monocanalicular versus bicanalicular silicone intubation for nasolacrimal duct stenosis in adults

PURPOSE: To compare the success rate of monocanalicular versus bicanalicular silicone intubation of incomplete nasolacrimal duct obstruction (nasolacrimal duct stenosis) in adults. METHODS: In a retrospective, nonrandomized comparative case series, 48 eyes of 44 adult patients with nasolacrimal duct stenosis underwent endoscopic probing and either bicanalicular (BCI; n=22 eyes) or monocanalicular (MCI; n=26 eyes) nasolacrimal duct intubation under general anesthesia. "Complete success" was defined as complete disappearance of the symptoms, "partial success" as improvement with some residual symptoms, and "failure" as absence of improvement or worsening of symptoms at last follow-up. The last follow-up examination included diagnostic probing and irrigation if there was not complete success. RESULTS: Patient ages ranged from 31 to 90 years (mean, 69; SD, 11.5). Forty-five tubes were removed 6 to 17 weeks (mean, 9.1; SD, 3) after surgery. Premature tube dislocation and removal occurred in one eye with BCI and in two eyes with MCI. Follow-up ranged from 6 to 52 months (mean, 14.9; SD, 8.4). The complete success rate was nearly the same in eyes with MCI (16/26, 61.53%) and BCI (13/22, 59.09%). Partial success (MCI: 8/26, 30.76%; BCI: 1/22, 4.54%) and failure (MCI: 2/26, 7.69%; BCI: 8/22, 36.36%) were, however, significantly different (p=0.010). Complications included 3 slit puncta with BCI and 4 temporary superficial punctuate keratopathy after MCI. CONCLUSIONS: MCI had virtually the same complete success rate as BCI, a higher partial success rate than BCI, and a lower failure rate than BCI in treatment of nasolacrimal duct stenosis in adults.     

Interaction between gamma-aminobutyric acid GABAB and cannabinoid CB1 receptors in spinal pain pathways in rat

Antinociceptive effects of cannabinoids are mediated, in part, at the spinal level. Cannabinoid CB1 receptors are co-localized with dorsal horn interneurons containing gamma-aminobutyric acid (GABA). In this study, we investigated the interaction between intrathecally administered cannabinoid and GABA(B) receptor agonists and antagonists in the modulation of formalin-induced pain at the spinal level. Intrathecal pretreatment of rats with a cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide] (SR141716A, 30 microg) decreased the analgesic effect of the intrathecal administration of the GABA(B) receptor agonist, baclofen (0.125 microg and 0.25 microg). Intrathecal administration of the GABA(B) receptor antagonist, saclofen (30 microg), 10 min before administration of the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexano (CP55940), did not affect the analgesia produced by the cannabinoid receptor agonist. Our results confirm that intrathecal administration of cannabinoid and GABA(B) receptor agonists have analgesic effects and that spinal antinociceptive effects of GABA(B) receptor agonists are likely through endocannabinoid modulation.     

Clozapine: New research on efficacy and mechanism of action

Summary Clozapine can produce greater clinical improvement in both positive and negative symptoms than typical antipsychotic drugs in neuroleptic-resistant schizophrenic patients. The clinical response may occur rapidly in some patients but is delayed in others. Clozapine has also been reported to produce fewer parkinsonian symptoms, to involve a lower risk of producing tardive dyskinesia, and to produce no serum prolactin elevations in man. It seems likely that these effects are the result of a common biological mechanism or related mechanisms, rather than unrelated effects. Other atypical antipsychotic drugs, such as melperone and fluperlapine, share at least some of these properties. A relatively low affinity for the D-2 dopamine (DA) receptor and high affinity for the 5-HT₂ receptor, producing a high 5-HT₂/D-2 ratio, best distinguishes atypical antipsychotics like clozapine from typical antipsychotic drugs. Through its weak antagonist action on D-2 DA receptors and a potent inhibitory effect on 5-HT₂ receptors, as well as its abiltiy to increase DA and 5-HT release, clozapine may be able to permit more normal dopaminergic function in the anterior pituitary, the mesostriatal, mesolimbic and mesocortical regions. The numerous advantages of clozapine over typical neuroleptics are consistent with the primary importance of DA to the pathophysiology of schizophrenia. The secondary but still significant role of 5-HT in the action of clozapine may either be direct or via the effect of 5-HT on dopaminergic mechanisms. Some aspects of schizophrenia could be due to a dysregulation of the interaction between serotonergic and dopaminergic neurotransmission.Parts of this article were presented on the occasion of the inauguration ceremony of the Department of Psychiatry of the University of Mainz on April 2 and 3, 1987     

Different chromotropic behaviour of DNA and RNA and of poly(adenylic acid) and poly(uridylic acid) with the dye pinacyanol chloride

The cyanine dye pinacyanol chloride (PCYN) distinguishes various polyanions by exhibiting two distinct types of absorption spectra of the dye-polyanion system. This dye can also differentiate between the biopolymers DNA and RNA, as well as between poly(adenylic acid) (poly-A) and poly(uridylic acid) (poly-U). The dye-RNA spectra are independent of polymer/dye (P / D) ratio and show a sharp peak at 490 nm and a very broad band around 560 nm indicating not well organized aggregation of dye cations bound to the polymer. The spectra of the dye-DNA system are similar only at low P / D, but with increase in DNA concentration a sharp band appears at 560 nm with disappearance of the peak at 490 nm. The poly-U/PCYN system resembles the RNA-PCYN system and the poly-A/PCYN system resembles the DNA-PCYN system. These differences are interpreted to arise from the preferential binding of the dye to purine bases rather than to pyrimidine bases, and from the partial intercalation of the dye within the DNA helix at high P / D. The sharp band at 560 nm of DNA-PCYN at high P / D is due to dimerization of PCYN — the major, if not the only, state of aggregation of the dye induced by DNA at high P / D.     

Not all polyanions induce a J-band in the dye pseudoisocyanine

N,N′-diethylpseudoisocyanine chloride (PIC) forms compounds with various vinyl poly+ and DNA, but the shapes of the spectra of the dye-polyanion compounds depend on the nature of the polyanions. PIC forms compounds with 1:1 polyanion/dye stoichiometries with DNA (native and denatured), polymethacrylate and poly(styrenesulfonate); and the spectra of these compounds do not show any pronounced metachromasia or red-shifted J-band. Polyacrylate and poly(vinyl sulfate) form compounds with polyanion/dye stoichiometry of 2:1, and give spectra with extremely sharp and red-shifted J-band. This is the first report on the relation between the polyanion/PIC stoichiometry and the depiction of the J-band of the resulting compound.     

Transverse myelitis

Transverse myelitis is a known complication of radiation treatment for carcinoma of the head and neck. Otolaryngologists treat patients who receive radiotherapy and should be familiar with this complication. During the past ten years there has been little or no mention made of this problem in the ENT literature. In a five year period, 1970 to 1975, 120 patients with head and neck cancer received radiation as part of their treatment in this hospital. A review of the records of these patients showed only two cases of myelitis, an incidence of about 2%. This paper reviews the clinical syndrome; treatment and preventive measures are discussed and a survey of the literature is presented.     

Basal Cell Carcinoma Following Chronic Otitis Media

Abstract: A 36-year-old white woman presented with a gradually enlarging lesion in the right preauricular area of 15 years duration. The patient had a 25-year history of chronic otitis media of the right ear; in spite of multiple courses of systemic antibiotics, she frequently noted a slight discharge from the affected ear, draining across the right preauricular area, causing a mild pruritic eruption. She recalled having had approximately 30 roentgenographs of mastoids, but denied any history of fluoroscopic examination. The patient denied a history of excessive sun exposure or exposure to arsenic or other carcinogenic factors. There was no family history of skin cancer.