Pharmacological profile of NOP receptors coupled with calcium signaling via the chimeric protein Gαqi5

In this study, the Gα_qi5 protein was used to force the human nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor to signal through the Ca²⁺ pathway in CHO cells. [Ca²⁺]_i levels were monitored using the fluorometer FlexStation II and the Ca²⁺ dye Fluo 4 AM. Concentration response curves were generated with a panel of full and partial agonists, while NOP antagonists were assessed in inhibition-response curves. The following rank order of potency of antagonists was measured: naloxone, which is superimposable to literature findings. The rank order of potency of full and partial agonists is also similar to that obtained in previous studies with the exception of a panel of ligands (UFP-112, Ro 64-6198, ZP120, UFP-113) whose potency was relatively low in the Gα_qi5–NOP receptor calcium assay. Interestingly, these NOP ligands are characterized by slow kinetic of interaction with the NOP receptor, as demonstrated by bioassay experiments. These results demonstrated that the FlexStation II–Gα_qi5–NOP receptor calcium assay represents an adequate and useful screening for NOP receptor ligands, particularly for antagonists.     

Conservative management of mechanical neck disorders: a systematic review

OBJECTIVE: To determine if conservative treatments (manual therapies, physical medicine methods, medication, and patient education) relieved pain or improved function/disability, patient satisfaction, and global perceived effect in adults with acute, subacute, and chronic mechanical neck disorders (MND) by updating 11 systematic reviews of randomized controlled trials (RCT). METHODS: Two independent authors selected studies, abstracted data, and assessed methodological quality from computerized databases. We calculated relative risks and standardized mean differences (SMD) when possible. In the absence of heterogeneity, we calculated pooled effect sizes. RESULTS: We studied 88 unique RCT. The mean methodological quality scores were acceptable in 59% of the trials. We noted strong evidence of benefit for maintained pain reduction [pooled SMD -0.85 (95% CI -1.20, -0.50)], improvement in function, and positive global perceived effect favoring exercise plus mobilization/manipulation versus control for subacute/chronic MND. We found moderate evidence of longterm benefit for improved function favoring direct neck strengthening and stretching for chronic MND, and for high global perceived effect favoring vertigo exercises. We noted moderate evidence of no benefit for botulinium-A injection [pooled SMD -0.39 (95% CI -01.25, 0.47)]. We found many treatments demonstrating short-term effects. CONCLUSION: Exercise combined with mobilization/manipulation, exercise alone, and intramuscular lidocaine for chronic MND; intravenous glucocorticoid for acute whiplash associated disorders; and low-level laser therapy demonstrated either intermediate or longterm benefits. Optimal dosage of effective techniques and prognostic indicators for responders to care should be explored in future research.     

Synaptic Plasma Membrane Na<Superscript>+</Superscript>, K<Superscript>+</Superscript>-ATPase Activity is Significantly Reduced by the α-Keto Acids Accumulating in Maple Syrup Urine Disease in Rat Cerebral Cortex

The objective of the present study was to investigate the in vitro effects of the branched-chain α-keto acids accumulating in maple syrup urine disease, namely L-2-ketoisocaproic acid, L-2-keto-3-methylvaleric acid and L-2-ketoisovaleric acid on Na⁺, K⁺-ATPase activity in synaptic plasma membranes from cerebral cortex of 35-day-old rats. All keto acids significantly inhibited Na⁺, K⁺-ATPase activity at concentrations similar (1 mM) or even lower (0.5 mM) than those found in blood and cerebrospinal fluid of maple syrup urine disease patients. We also tested the effects of alanine on this enzyme activity. Alanine per se did not alter Na⁺, K⁺-ATPase activity, but totally prevented the branched-chain α-keto acids-induced Na⁺, K⁺-ATPase inhibition, indicating that alanine and the keto acids may possibly bind to the same site on the enzyme. We also observed that the branched-chain amino acids leucine, isoleucine and valine also inhibited Na⁺ K⁺-ATPase activity to a similar degree as that of the branched-chain α-keto acids and that alanine was able to fully prevent these effects. Considering that Na⁺, K⁺-ATPase is a critical enzyme for normal brain development and functioning, it is presumed that these findings may be involved in the pathophysiology of the neurological dysfunction of maple syrup urine disease.     

Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis

Infantile neuronal ceroid lipofuscinosis (INCL) is caused by deficiency of the lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1). We have investigated the onset and progression of pathological changes in Ppt1 deficient mice (Ppt1-/-) and the development of their seizure phenotype. Surprisingly, cortical atrophy and neuron loss occurred only late in disease progression but were preceded by localized astrocytosis within individual thalamic nuclei and the progressive loss of thalamic neurons that relay different sensory modalities to the cortex. This thalamic neuron loss occurred first within the visual system and only subsequently in auditory and somatosensory relay nuclei or the inhibitory reticular thalamic nucleus. The loss of granule neurons and GABAergic interneurons followed in each corresponding cortical region, before the onset of seizure activity. These findings provide novel evidence for successive neuron loss within the thalamus and cortex in Ppt1-/- mice, revealing the thalamus as an important early focus of INCL pathogenesis.     

Periodontal surgery associated with odontoplasty in the esthetic functional rehabilitation of a fractured anterior tooth

Anterior dental fractures often require a multidisciplinary approach. This article presents a case in which an extensive fracture with palatal biological width invasion was treated successfully through clinical crown lengthening with odontoplasty. This procedure was a simple direct technique that restored the tooth without damaging the dental esthetics, the gingival contour, or the papillae.     

Combined bezafibrate and medroxyprogesterone acetate have efficacy without haematological toxicity in elderly and relapsed acute myeloid leukaemia (AML)

Acute myeloid leukaemia (AML) causes life‐threatening deficits of functional blood cells that require management using red cell and platelet transfusion and aggressive treatment of neutropenic infections. Current cytotoxic chemotherapy further worsens the problem of reduced haemopoiesis and two‐thirds of patients are too frail to tolerate intensive chemotherapy at all. Median survival amongst these patients remains at <3 months emphasizing the urgent need for anti‐AML therapies that do not suppress haemopoiesis. Our laboratory studies showed combined Bezafibrate and Medroxyprogesterone acetate (BaP) had activity against AML without toxicity to normal stem cells. Here we report the safety and efficacy of BaP in 20 patients (19 AML, 1 high‐risk myelodysplasia) for whom intensive chemotherapy was not an option. No patient exhibited haematological toxicity from BaP. Eleven patients took BaP alone for >4 weeks. One reverted from high risk myelodysplasia and remains transfusion independent after 201 weeks of therapy. Three AML patients gained major haematological improvements for 22–30 weeks; in one, marrow was available to document a partial AML response. Thus, this trial indicates that BaP therapy has potential for treatment of elderly and relapsed AML.     

Facilitators for practice change in Spanish community pharmacy

Objective To identify and prioritise facilitators for practice change in Spanish community pharmacy. Setting Spanish community pharmacies. Method Qualitative study. Thirty-three semi-structured interviews were conducted with community pharmacists (n = 15) and pharmacy strategists (n = 18), and the results were examined using the content analysis method. In addition, two nominal groups (seven community pharmacists and seven strategists) were formed to identify and prioritise facilitators. Results of both techniques were then triangulated. Main outcome measures Facilitators for practice change. Results Twelve facilitators were identified and grouped into four domains (D1: Pharmacist; D2: Pharmacy as an organisation; D3: Pharmaceutical profession; D4: Miscellaneous). Facilitators identified in D1 include: the need for more clinical education at both pre- and post-graduate levels; the need for clearer and unequivocal messages from professional leaders about the future of the professional practice; and the need for a change in pharmacists’ attitudes. Facilitators in D2 are: the need to change the reimbursement system to accommodate cognitive service delivery as well as dispensing; and the need to change the front office of pharmacies. Facilitators identified in D3 are: the need for the Spanish National Professional Association to take a leadership role in the implementation of cognitive services; the need to reduce administrative workload; and the need for universities to reduce the gap between education and research. Other facilitators identified in this study include: the need to increase patients’ demand for cognitive services at pharmacies; the need to improve pharmacist-physician relationships; the need for support from health care authorities; and the need for improved marketing of cognitive services and their benefits to society, including physicians and health care authorities. Conclusion Twelve facilitators were identified. Strategists considered clinical education and pharmacists’ attitude as the most important, and remuneration of little importance. Community pharmacists, in contrast, considered remuneration as the most important facilitator for practice change.