Lack of apparent receptor reserve at postsynaptic 5-hydroxytryptamine1A receptors negatively coupled to adenylyl cyclase activity in rat hippocampal membranes.

Previous studies have demonstrated the existence of a large receptor reserve for agonists at somatodendritic 5-hydroxytryptamine1A (5-HT1A) serotonin receptors in the raphe nuclei of the rat. 5-HT1A agonists with anxiolytic properties (e.g., buspirone, gepirone, and ipsapirone) display full intrinsic activity at these receptors but are partial agonists at postsynaptic 5-HT1A receptors, which suggests that the latter sites may be devoid of a receptor reserve. In the present studies, this was directly determined by examining the relationship between receptor occupancy and response at postsynaptic 5-HT1A receptors, in rat hippocampus, mediating the inhibition of forskolin-stimulated adenylyl cyclase activity, using the method of partial irreversible receptor inactivation. Rats were treated with vehicle or the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), and 24 hr later hippocampi were removed for saturation analysis of [3H]8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) binding to 5-HT1A receptors or for adenylyl cyclase assays. EEDQ (1 and 6 mg/kg) dose-dependently reduced the maximal number of [3H]8-OH-DPAT binding sites by 68.5 and 80%, respectively, without altering the Kd. Concentration-response curves were generated for inhibition of forskolin-stimulated adenylyl cyclase activity by 5-HT and the selective 5-HT1A agonist N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT). EEDQ treatment dose-dependently reduced the maximal inhibitory effect of 5-HT [percentage of inhibition: control, 23.6; EEDQ (1 mg/kg), 13.4; EEDQ (6 mg/kg), 8.9], without altering either the slope factor (1.01) or the EC50 (96.4 nM). Analogous results were obtained with DP-5-CT [percentage of maximal inhibition: control, 24.1; EEDQ (1 mg/kg), 15.2; EEDQ (6 mg/kg), 10.7), again without changes in slope factor (0.89) or EC50 (9.9 nM). Analysis of double-reciprocal plots of equieffective concentrations of agonist, followed by calculation of fractional receptor occupancy, revealed a linear relationship between receptor occupancy and response for both 5-HT and DP-5-CT (i.e., an absence of receptor reserve). The receptor specificity of the effect of EEDQ was demonstrated in two ways. First, it was shown that pretreatment of rats with the selective 5-HT1A partial agonist BMY 7378 (10 mg/kg) before EEDQ afforded substantial protection (about 75%) against loss of the inhibitory effect of DP-5-CT on forskolin-stimulated adenylyl cyclase activity. Second, EEDQ did not alter the inhibition of forskolin-stimulated adenylyl cyclase activity induced by the adenosine A1 receptor agonist phenylisopropyladenosine (PIA).(ABSTRACT TRUNCATED AT 400 WORDS)     

Renal cancer in adults. Review of 68 cases

The authors report a series of 68 cases of renal cancer observed over a 9-year period. Patients consisted of 33 women (49%) and 35 men (51%), with a mean age of 53 years (range: 23-85 years). The clinical features were polymorphic, dominated by loin pain (44%), haematuria (37%), a lumbar mass (19%), alteration of the general state (7%). The diagnosis was established by ultrasonography in 59 patients and CT-scan in 63 patients. The mean tumour diameter was 11 cm (4-22 cm) and two cases presented bilateral tumours. The time to diagnosis ranged from 1 month to 7 years. Staging reflected the advanced stage of the cancer. Treatment was surgical for 58 patients (58%). A lumbar incision was performed, in 40% of cases. Radical nephrectomy was performed in 82%, and partial nephrectomy was performed in 3% of patients. Histological examination of the specimen showed renal cell carcinoma in 75% of cases. The lymph nodes removed were invaded in 20% of cases. The mean follow-up was 29 months (6 to 84 months), normal at one year for 44 patients (86%) and at 5 years for 16 patients (31%). Tumour recurrence in the renal compartment was observed in 2 patients (4%). Asynchronous metastases occurred in 11 patients (21.5%) after 21 months. (range: 12-48 months). The overall 5-year survival was 100% T1, 69% T2 and 50% T3.     

The Effect of Preoperative Intra-Articular Methylprednisolone on Pain After TKA: A Randomized Double-Blinded Placebo Controlled Trial in Patients With High-Pain Knee Osteoarthritis and Sensitization

In a randomized, double-blind, placebo controlled trial, we investigated the postoperative analgesic effect of a single intra-articular injection of 40?mg methylprednisolone acetate (MP) administered 1 week before total knee arthroplasty (TKA). Forty-eight patients with high pain osteoarthritis (≥5 on a numeric rating scale during walk) and sensitization (pressure pain threshold?<250?kPa), aged 50 to 80 years and scheduled for primary unilateral TKA under spinal anaesthesia were included. The primary outcome was the proportion of patients with moderate/severe pain during a 5-m walk test 24 hours postoperatively. Secondary outcomes included pain at 48 hours, during the first 14 days, sensitization (quantitative sensory testing with pressure pain threshold and wind-up from temporal summation), and inflammatory changes (systemic C-reactive protein, intra-articular interleukin [IL]-6). No difference in the proportion of patients with moderate/severe pain was found between MP/placebo groups at 24 hours (67% and 74%, χ²?=?.2, P?=?.63, odds ratio = .7, 95% confidence interval = .2–2.8) or at 48 hours (57% and 68%, χ²?=?.5, P?=?.46, odds ratio = .6, 95% confidence interval = .2–2.3), and no difference between groups in postoperative sensitization was found (P?>?.4) despite reduced preoperative intra-articular inflammation (IL-6) in the MP group versus placebo (median change in IL-6 = ?70?pg/mL, interquartile range = ?466 to 0 vs. 32?pg/mL, interquartile range = ?26 to 75, P = .029). Alternative central or peripheral analgesic interventions in this high-risk group are required.

Gastrointestinal transit times and motility in patients with cystic fibrosis

Abstract Objective. Patients with cystic fibrosis (CF) often suffer from gastrointestinal (GI) dysfunction including obstructive symptoms, malabsorption and pain, but the underlying pathophysiology remains obscure. Aim. To compare GI motility and transit times in CF patients and healthy controls. Material and methods. Ten CF patients (five women, median age 23) with pancreatic insufficiency were studied. Total gastrointestinal transit time (GITT) and segmental colonic transit times (SCTT) were assessed by radiopaque markers. Gastric emptying and small intestinal transit were evaluated using the magnet-based motility tracking system (MTS-1). With each method patients were compared with 16 healthy controls. Results. Basic contraction frequencies of the stomach and small intestine were normal, but the pill reached the cecum after 7 h in only 20% of CF patients while in 88% of controls (p = 0.001). Paradoxically, velocity of the magnetic pill through the upper small intestine tended to be faster in CF patients (median 1.1 cm/min, range 0.7-1.7) compared with controls (median 1.0 cm/min, range 0.6-1.7) (p = 0.09). No statistically significant differences were found in median gastric emptying time (CF: 58 min, range 6-107 vs. healthy: 41 min, range 4-125 (p = 0.24)), GITT (CF: 2 days, range 0.5-3.3 vs. healthy: 1.5 days, range 0.7-2.5 (p = 0.10)), right SCTT (CF: 0.5 day, range 0-1.1 vs. healthy: 0.4 day, range 0-1.0 (p = 0.85)), or left SCTT (CF: 1.0 day, range 0-2.2 vs. healthy 0.6 day, range 0.2-1.2 (p = 0.10)). Conclusions. In spite of normal contraction patterns, overall passage through the small intestine is significantly delayed in CF patients while upper small intestinal transit may be abnormally fast.     

In the Search of Marine Pestiviruses: First Case of Phocoena Pestivirus in a Belt Sea Harbour Porpoise

Pestiviruses are widespread pathogens causing severe acute and chronic diseases among terrestrial mammals. Recently, Phocoena pestivirus (PhoPeV) was described in harbour porpoises (Phocoena phocoena) of the North Sea, expanding the host range to marine mammals. While the role of the virus is unknown, intrauterine infections with the most closely related pestiviruses— Bungowannah pestivirus (BuPV) and Linda virus (LindaV)—can cause increased rates of abortions and deaths in young piglets. Such diseases could severely impact already vulnerable harbour porpoise populations. Here, we investigated the presence of PhoPeV in 77 harbour porpoises, 277 harbour seals (Phoca vitulina), grey seals (Halichoerus grypus) and ringed seals (Pusa hispida) collected in the Baltic Sea region between 2002 and 2019. The full genome sequence of a pestivirus was obtained from a juvenile female porpoise collected along the coast of Zealand in Denmark in 2011. The comparative Bayesian phylogenetic analyses revealed a close relationship between the new PhoPeV sequence and previously published North Sea sequences with a recent divergence from genotype 1 sequences between 2005 and 2009. Our findings provide further insight into the circulation of PhoPeV and expand the distribution from the North Sea to the Baltic Sea region with possible implications for the vulnerable Belt Sea and endangered Baltic Proper harbour porpoise populations.     

Light sheet fluorescence microscopy of optically cleared brains for studying the glymphatic system

Fluid transport in the perivascular space by the glia-lymphatic (glymphatic) system is important for the removal of solutes from the brain parenchyma, including peptides such as amyloid-beta which are implicated in the pathogenesis of Alzheimer’s disease. The glymphatic system is highly active in the sleep state and under the influence of certain of anaesthetics, while it is suppressed in the awake state and by other anaesthetics. Here we investigated whether light sheet fluorescence microscopy of whole optically cleared murine brains was capable of detecting glymphatic differences in sleep- and awake-mimicking anaesthesia, respectively. Using light-sheet imaging of whole brains, we found anaesthetic-dependent cerebrospinal fluid (CSF) influx differences, including reduced tracer influx along tertiary branches of the middle cerebral artery and reduced influx along dorsal and anterior penetrating arterioles, in the awake-mimicking anaesthesia. This study establishes that light sheet microscopy of optically cleared brains is feasible for quantitative analyses and can provide images of the entire glymphatic system in whole brains.     

The bacteriology of hidradenitis suppurativa: a systematic review

Hidradenitis suppurativa (HS) is a chronic inflammatory disabling skin disease consisting of recurrent nodules, sinuses, fistulas and scarring involving the intertriginous regions. HS is often a therapeutic challenge and most treatments are off‐label. A better understanding of aetiology and pathogenesis of HS may facilitate the development of effective treatment. Although the clinical presentation is strongly reminiscent of bacterial infection, the role of bacteria remains controversial. Studies have isolated an array of different bacteria specimens. Consistent findings of Gram‐positive cocci and Gram‐positive rods including Staphylococus aureus, coagulase‐negative staphylococci (CoNS) and Corynebacterium species in deep tissue samples have been demonstrated in HS and may constitute a central target for the immune system. Efficacy of antibiotics, that is rifampicin, clindamycin or tetracycline, supports a microbial role in disease pathogenesis. However, these antibiotics also work as immunomodulators of especially T cells, and the underlying mechanisms may therefore be more complex. We performed a systematic review of previous studies investigating the bacterial flora in hidradenitis suppurativa. We searched PubMed, EMBASE, Royal Danish Library and Cochrane library (search date 11 December 2014). A total of 66 papers were identified and nine papers published between 1988 and 2014 matched our inclusion criteria, yielding bacteriological data of a total of 324 patients with HS (mean age 36.8 years and female/male ratio 215/109). This overview of the bacteriology may aid researchers and physicians exploring the potential role of bacteria in HS. Furthermore, to stimulate a broader debate, we also present different viewpoints on the possible role of bacteria in HS.     

Smoking Is a Risk Factor for Recurrence of Groin Hernia

Studies of connective tissue from patients with inguinal hernia have shown that smoking may be associated with hernia formation due to a defective connective tissue metabolism. Whether smoking is a risk factor for recurrence, too, was examined in this study. From December 1990 through December 1995, 649 patients underwent hernia repair as open sutured repair (Cooper ligament or abdominal ring repair) or as open mesh repair. Five hundred forty-four eligible patients were evaluated for recurrence 2 years postoperatively. Association between recurrence and 17 patient-, disease-, and intraoperative variables were analyzed by multiple logistic regression. The results showed that smoking was significantly and independently associated with recurrence compared to nonsmoking [odds ratio (OR = 2.22; 95% confidence interval (95% CI) = 1.19–4.15)]. Open sutured repair compared to open mesh repair was the most significant predictor for recurrence (OR = 7.23; 95% CI = 3.01–17.37). Surprisingly, local anesthesia was associated with a higher risk of recurrence compared to general anesthesia (OR = 2.44; 95% CI = 1.19–5.09). Potential confounders and other risk factors for hernia recurrence such as age, alcohol consumption, previous surgery, and anatomical characteristics of the hernia were adjusted for in the analysis. In conclusion, smoking is an important risk factor for recurrence of groin hernia, presumably due to an abnormal connective tissue metabolism in smokers.     

Self-reported and technician-measured waist circumferences differ in middle-aged men and women

We investigated the agreement between 1) self-reported and technician-measured waist circumference at the level of the umbilicus, 2) circumference measured at the level of the umbilicus and halfway between the lower rib and the iliac crest (the natural waist), and 3) self-reported circumference at the level of the umbilicus and technician-measured circumference at the natural waist. At follow-up in the Danish "Diet, Cancer and Health" study, we recruited 176 men and 240 women for a validation study. Bland-Altman plots were used to evaluate agreement among measurement sites. Multiple regression was used to identify variables explaining the difference between measurements. The participants underestimated their waist circumference; the mean differences were -1.6 cm (95% CI: -2.4 cm, -0.8 cm) in men and -3.0 cm (95% CI: -3.8 cm, -2.3 cm) in women. Limits of agreement were from -11.9 to +8.7 cm among men and -14.9 to +8.9 cm among women. High BMI and large baseline waist circumference were associated with a larger degree of underreporting. Waist circumference measured at the level of the umbilicus was larger than at the natural waist; the mean differences were +0.7 cm (95% CI: +0.4 cm, +1.1 cm) in men and +5.0 cm (95% CI: +4.4 cm, +5.6 cm) in women. The self-reported waist circumference at the level of the umbilicus was correlated with the technician-measured circumference at the natural waist. The circumference at the natural waist was overestimated for women, depending on baseline waist circumference, and slightly underestimated for men, depending on baseline BMI.