Maxillary sinusitis in adults: an evaluation of placebo-controlled double-blind trials

BACKGROUND: In general practice, acute sinusitis is frequently diagnosed and treated with antibiotics. OBJECTIVE: This study aimed to determine the evidence for the effectiveness of antibiotic treatment in acute maxillary sinusitis in adults by assessing the methodological quality of placebo-controlled double-blind randomized trials. METHOD: An evaluation by four raters through a 35-item scoring-scale for internal and external validity of all placebo-controlled double-blind randomized trials on acute sinusitis found between January 1966 and July 1996. RESULTS: Eighty-five trials were excluded because they were not placebo-controlled, double-blind, randomized, or were carried out in patients with chronic sinusitis or in children. The three remaining trials were performed in different populations (one in general practice) between 1973 and 1978. Only one study claimed superiority of antibiotic treatment. Different inclusion criteria and major outcome measures were used by the authors. The reliability of major outcome events was reported poorly or not at all and in two studies outcome measures were clinically inappropriate. The studies scored 30-62% of the maximum attainable score for internal validity and 10-20% for external validity. CONCLUSION: The effectiveness of antibiotic treatment in acute maxillary sinusitis in a general practice population is not based sufficiently on evidence.      

Convergence of occipital nerve and superior sagittal sinus input in the cervical spinal cord of the cat

Co-existence of facial and occipital pain may occur in occipital neuralgia, migraine and cluster headache; suggesting convergence of trigeminal and cervical afferents. Such convergence has been shown in humans and other animals, but the site and extent of this are uncertain. In anaesthetized adult cats, the superior sagittal sinus and occipital nerve were stimulated electrically, and extracellular recordings made in the dorsolateral area of the upper cervical cord using glass-coated tungsten electrodes. Of 49 units in 10 cats, 33 (67%) had input from the superior sagittal sinus and the occipital nerve. Thirteen (27%) had superior sagittal sinus input and 3 (6%) had occipital nerve input. Convergent receptive fields were identified mechanically in 7 units. These experiments in cats show convergent input from occipital nerve and superior sagittal sinus on dorsolateral area units in two-thirds of cases studied. This experimental site of trigeminocervical convergence may relate to referral of pain in occipital neuralgia and other headaches.     

Nonsteroidal anti-inflammatory drugs (NSAIDs) and the kidney

In patients with PG-dependent renal function, NSAID administration constantly reduces GFR and RBF in a dose-dependent fashion. In this situation, the risk of overt acute renal failure is high and should be taken into proper account. In contrast, the incidence of NSAID-related renal structural alterations appears to be very low, yet the absolute number of patients may be significant considering the wide use of such drugs. Concerning the antiproteinuric effect of NSAIDs, the unfavourable ratio risk/benefit does not seem to support their indication in proteinuric nephropathies. The development of PGHS-2 selective inhibitors is promising, and may open new therapeutical strategies in the treatment of the progression of renal disease.      

New Potent Azomethine Prodrugs of the Histamine H3-Receptor Agonist (R)-α-Methylhistamine Containing a Heteroarylphenyl Partial Structure

The therapeutic value of histamine H₃-receptor ligands is under current investigation. On the basis of recently described diaryl imine prodrugs of the histamine H₃-receptor agonist (R)-α-methyl-histamine ( 1 ) a series of new azomethine prodrugs containing five- and six-membered heterocycles were synthesized and tested for their in vitro hydrolysis rates and in vitro activity after oral application. It was found that electron-deficient six-membered heterocycles drastically destabilized the imine double bond so that these prodrugs decomposed unsuitably fast. On the contrary, prodrugs containing five-membered heterocycles appeared to be highly effective for the CNS delivery of 1 , and a remarkable correlation between chemical structure and pharmacokinetic profile was observed. Particularly (R)-4-fluoro-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino](1H-pyrrol-2-yl)methyl]phenol ( 8c ), the 2-furanyl analogue 8d , and its 3-furanyl isomer 8e proved to be equipotent to the most potent of recently described halogenated diaryl imine prodrugs of 1. However, in contrast to any other azomethine prodrug, 8c exhibited an incomparably long lasting delivery of 1 in the CNS and can thus be regarded as a ‘retard’ prodrug. Assuming that a therapeutic indication of histamine H₃-receptor agonists will soon be established, these highly potent heteroarylphenyl azomethine prodrugs, which already serve as valuable pharmacological tools, may also become potential drugs in clinical use.     

CAG repeat length in RAI1 is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2)

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder caused by the expansion of a polymorphic (CAG)(n) tract, which is translated into an expanded polyglutamine tract in the ataxin-2 protein. Although repeat length and age at disease onset are inversely related, approximately 50% of the age at onset variance in SCA2 remains unexplained. Other familial factors have been proposed to account for at least part of this remaining variance in the polyglutamine dis-orders. The ability of polyglutamine tracts to interact with each other, as well as the presence of intra-nuclear inclusions in other polyglutamine disorders, led us to hypothesize that other CAG-containing proteins may interact with expanded ataxin-2 and affect the rate of protein accumulation, and thus influence age at onset. To test this hypothesis, we used step-wise multiple linear regression to examine 10 CAG-containing genes for possible influences on SCA2 age at onset. One locus, RAI1, contributed an additional 4.1% of the variance in SCA2 age at onset after accounting for the effect of the SCA2 expanded repeat. This locus was further studied in SCA3/Machado-Joseph disease (MJD), but did not have an effect on SCA3/MJD age at onset. This result implicates RAI1 as a possible contributor to SCA2 neurodegeneration and raises the possibility that other CAG-containing proteins may play a role in the pathogenesis of other polyglutamine disorders.     

Endothelin receptor expression in human decidua

The endothelins are signalling peptides that act via two receptors, ET(A) and ET(B). In the human endometrium, endothelin receptors have been demonstrated in glands and stroma and have been shown to vary during the course of the menstrual cycle. The present study was undertaken to determine whether or not expression of endothelin receptors changes during pregnancy or after administration of exogenous progestagens. The expression of the receptors was correlated with the appearance of basement membrane components during decidualization of the endometrial stroma. Decidual specimens (n = 15) were obtained during the first trimester of pregnancy and 10 at term. Sixteen pairs of endometrial biopsies were obtained from women with menorrhagia before and after exposure to exogenous progestagens. A total of 15 hysterectomy specimens were used as controls for the expression of stromal basement membrane proteins in the absence of decidualization. Autoradiography was carried out with selective ligands for ET(A) ([125I]-PD 151242) and ET(B) ([125I]-BQ3020). The distribution of ligand binding was then compared with the distribution of laminin alpha2 light chain and collagen IV. ET(A), ET(B), laminin alpha2 light chain, and collagen IV were expressed in stromal decidual cells in the first trimester of pregnancy. ET(B) was also found on endometrial glandular epithelium. Quantitative macro-autoradiography and multiple regression analysis demonstrated a highly significant positive correlation (P < 0.001) between expression of ET(B) and laminin alpha2 light chain. In the third trimester qualitative examination suggested a reduction of ET(A) in the stroma. Progestagen-induced decidua exhibited a similar pattern to that found in first trimester decidua. This study has demonstrated up-regulation of ET(B) during the progesterone- dependent process of decidualization and suggests a paracrine or autocrine role for endothelins in the decidua.      

A New Care Model Reduces Polypharmacy and Potentially Inappropriate Medications in Long-Term Care

ObjectivesAssess the impact of a new pharmaceutical care model on (1) polypharmacy and (2) potentially inappropriate medication (PIM) use in long-term care facilities (LTCFs).DesignPragmatic quasi-experimental study with a control group. This multifaceted model enables pharmacists and nurses to increase their professional autonomy by enforcing laws designed to expand their scope of practice. It also involves a strategic reorganization of care, interdisciplinary training, and systematic medication reviews.Setting and ParticipantsTwo LTCFs exposed to the model (409 residents) were compared to 2 control LTCFs (282 residents) in Quebec, Canada. All individuals were aged 65 years or older and residing in included LTCFs.MeasuresPolypharmacy (≥10 medications) and PIM (2015 Beers criteria) were analyzed throughout 12 months between March 2017 and June 2018. Groups were compared before and after implementation using repeated measures mixed Poisson or logistic regression models, adjusting for potential confounding variables.ResultsOver 12 months, for regular medications, polypharmacy decreased from 42% to 20% (exposed group) and from 50% to 41% (control group) [difference in differences (DID): 13%, P < .001]. Mean number of PIMs also decreased from 0.79 to 0.56 (exposed group) and from 1.08 to 0.90 (control group) (DID: 0.05, P = .002).Conclusions and ImplicationsCompared with usual care, this multifaceted model reduced the probability of receiving ≥10 medications and the mean number of PIMs. Greater professional autonomy, reorganization of care, training, and medication review can optimize pharmaceutical care. As the role of pharmacists is expanding in many countries, this model shows what could be achieved with increased professional autonomy of pharmacists and nurses in LTCFs.