Design and in vitro evaluation of formulations with pH and transit time controlled sigmoidal release profile for colon-specific delivery

The primary objective of the study was to develop a pH and transit time controlled sigmoidal release polymeric matrix for colon-specific delivery of indomethacin. Tablet matrices were prepared using a combination of hydrophilic polymers (polycarbophil or carbopol) having pH sensitive swelling properties with hydrophobic polymer ethyl cellulose. The prepared matrices were characterized for physical properties and in vitro release kinetics. The presence of ethyl cellulose in a hydrophilic polymer matrix resulted in a sigmoidal in vitro drug release pattern with negligible to very low drug release in the initial phase (0–6?h) followed by controlled release for 14–16?h. The retardation in initial release can be attributed to the presence of ethyl cellulose that reduced swelling of hydrophilic polymer(s) while in the later portion, polymer relaxation at alkaline pH due to the ionization of acrylic acid units on carbopol and polycarbophil resulted in enhanced drug release. Thus, a sigmoidal release pattern was obtained that could be ideal for colonic delivery of indomethacin in the potential treatment of colon cancer.     

Does post septoplasty nasal packing reduce complications?

The main issues in nasal surgery are to stabilize the nose in the good position after surgery and preserve the cartilages and bones in the favorable situation and reduce the risk of deviation recurrence. Also it is necessary to avoid the synechia formation, nasal valve narrowing, hematoma and bleeding. Due to the above mentioned problems and in order to solve and minimize them nasal packing, nasal splint and nasal mold have been advised. Patients for whom the nasal packing used may faced to some problems like naso-pulmonary reflex, intractable pain, sleep disorder, post operation infection and very dangerous complication like toxic shock syndrome. We have two groups of patients and three surgeons (one of the surgeons used post operative nasal packing in his patients and the two others surgeons did not).Complications and morbidities were compared in these two groups. Comparing the two groups showed that the rate of complication and morbidities between these two groups were same and the differences were not valuable, except the pain and discomfort post operatively and at the time of its removal. Nasal packing has several risks for the patients while its effects are not studied. Septoplasty can be safely performed without postoperative nasal packing. Nasal packing had no main findings that compensated its usage. Septal suture is one of the procedures that can be used as alternative method to nasal packing. Therefore the nasal packing after septoplasty should be reserved for the patients with increased risk of bleeding.     

Transitions between the stages of smoking in Iranian adolescents

Objective

This study examined the prevalence of smoking, the rates of transitions, and predictors of transition through the three stages of smoking.

Methods

A total of 1785 high school students in Tabriz (northwest of Iran) were assessed at 2 time points with a 12-month interval in 2005 and 2006, regarding changes in smoking stages. The predictor variables were measured when the students were in the 10th grade. Logistic regression was employed to predict the different smoking stages at grade 11.

Results

The results showed that 14.3% (95% confidence interval, 12.3%-16.4%) and 2.8% (2.0%-4.0%) of the never smokers became experimenters and regular smokers, respectively, whereas 16.5% (12.4%-21.7%) of the experimenters became regular smokers. Among never smokers, participation in groups with at least one smoker (odds ratio, 1.24 (95% confidence interval, 1.05-1.47)), having smoker friends (1.85 (1.21-2.83)), and a positive attitude toward smoking (1.22 (1.02-1.46)) predicted smoking experience. Among the experimenters, those who had general risk behaviors (2.56 (1.12-5.87)) and participated in groups with at least one smoker (2.58 (1.26-5.31)) significantly progressed to becoming a regular smoker at the follow-up.

Conclusion

Prevention of smoking in adolescence should begin by focusing on the predictors of transition through smoking stages, especially participating in smoker groups.     

Modulation of afferent-evoked neurotransmission by 5-HT3 receptors in young rat dorsal horn neurones in vitro: a putative mechanism of 5-HT3 induced anti-nociception.

1. The in vitro hemisected spinal cord from young rat was used to investigate the mechanism of serotoninergic modulation of primary afferent-mediated synaptic transmission in the dorsal horn through activation of the 5-HT3 receptor. 2. Dorsal root-evoked excitatory post-synaptic potentials (DR-EPSPs) were recorded intracellularly from dorsal horn neurones. Extracellular recordings of the population primary afferent depolarization (PAD) and the dorsal root-evoked dorsal root reflex (DR-DRR) were made from segmental dorsal roots. 3. 5-Hydroxytryptamine (5-HT) and the selective 5-HT3 receptor agonist 1-(m-chloro-phenyl)-biguanide hydrochloride (m-ChPB) (10 and 50 microM) induced statistically significant reductions of the DR-EPSP amplitude (P<0.001) and duration (P<0.001) in the majority of dorsal horn neurones. The 5-HT3 receptor selective antagonists 3-Tropanyl-indole-3-carboxylate hydrochloride (Tropisetron, 10 microM) and N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazine-8-carboxamide (Y-25130, 10 microM) abolished m-ChPB-induced DR-EPSP attenuation and partially blocked the 5-HT effect. 4. m-ChPB (50 microM)-induced DR-EPSP amplitude and duration attenuation was retained in the presence of the GABA(A) receptor antagonist bicuculline (30 microM), the GABA(B) receptor antagonist saclofen (50 microM) and the opioid receptor antagonist naloxone (50 microM). 5. Both 5-HT and m-ChPB (10 and 50 microM) induced a PAD but the mean peak amplitude of 5-HT-induced PAD was significantly greater than PAD to m-ChPB (98.6+/-12 microV compared to 51.8+/-10 V for 50 microM of agonist, respectively). Tropisetron partially reduced 5-HT-induced PAD and abolished m-ChPB-induced PAD. 5-HT, but not m-ChPB, significantly (P<0.001) reduced the peak amplitude of the DR-DRR and this action of 5-HT was unaffected by Tropisetron or Y-25130. 6. These data provide experimental evidence for a putative cellular mechanism at the level of the dorsal horn for anti-nociceptive effects of 5-HT3 receptor activation. This 5-HT3-mediated modulation of sensory afferent transmission was evidently independent of inhibitory GABA- or opioid-dependent interneuronal pathways. The extent to which the 5-HT3 receptor could be involved in the operation of endogenous analgesia and sensory modulation by descending monoamine bulbo-spinal pathways is discussed.     

Lack of association between endometriosis and the CYP17 MspA1 polymorphism in UK and Japanese populations.

Endometriosis is a complex trait, which means that multiple susceptibility genes interact with one another and the environment to produce the phenotype. One of the genes previously implicated in the disease is CYP17; this encodes the enzyme P450c17alpha, which plays a vital role in steroid biosynthesis in the ovary. The presence of a single nucleotide polymorphism (T-->C) in the 5'-promoter region of the gene creates a new recognition site for the restriction enzyme MspA1 producing a mutant allele (A2), which affects circulating estrogen levels. In this study, we compared the frequency of the CYP17 MspA1 polymorphism in two different ethnic populations. DNA was obtained from (1) 94 women with revised American Fertility Society (rAFS) stage III-IV endometriosis and 97 male blood donors in the UK, and (2) 130 women with rAFS stage III-IV endometriosis and 179 female newborn infants in Japan. No significant differences in allele or genotype frequencies were seen in either population. The genotype distribution in the UK population was 33/94 [35.1%] (cases) and 39/97 [40.2%] (controls) for A1A1 (homozygous wild-type); 43/94 [45.7%] (cases) and 44/97 [45.4%] (controls) for A1A2; and 18/94 [19.1%] (cases) and 14/97 [14.4%] (controls) for A2A2. The genotype distribution in the Japanese population was 31/130 [23.9%] (cases) and 57/179 [31.8%] (controls) for A1A1; 73/130 [56.2%] (cases) and 89/179 [49.7%] (controls) for A1A2; and 26/130 [20.0%] (cases) and 33/179 [18.4%] (controls) for A2A2. The CYP17 MspA1 polymorphism is probably not associated with endometriosis in either the UK or the Japanese population.     

The anticonvulsant remacemide and its metabolite AR‐R12495AA attenuate spinal synaptic transmission and carrageenan‐induced inflammation in the young rat

The effects of the anticonvulsants remacemide [(±)‐2‐amino‐N‐(1‐methyl‐1,2‐diphenylethyl)‐acetamide hydrochloride] and its des ‐glycinated metabolite AR‐R12495AA [(±)‐1‐methyl‐1,2‐diphenylethylamine‐ monohydrochloride] on primary afferent‐induced synaptic transmission and frequency‐dependent summation of synaptic potentials were assessed in the young rat spinal cord in vitro. Behavioural studies in the rat determined the effects of these anticonvulsant compounds in the carrageenan model of inflammation. Recordings of the extracellular dorsal root‐evoked ventral root potential (DR‐VRP) revealed a significant reduction of the duration and t1/2 decay of the long latency, slow DR‐VRP by remacemide (50 and 100 μM) and AR‐R12495AA (25, 50 and 100 mM). The short‐latency, fast monosynaptic DR‐VRP peak was reduced by only the highest concentration of AR‐R12495AA (100 μM). In intracellular dorsal root‐evoked excitatory postsynaptic potentials (DR‐EPSPs) of single ventral horn neurons, AR‐R12495AA (100 μM) attenuated the time course of the long‐latency (slow) EPSP. Frequency‐dependent (0.5–2.0 Hz) summation of dorsal root‐evoked synaptic events (recorded extracellularly as the cumulative ventral root depolarization (CVRD), and intracellularly as wind‐up) was attenuated by remacemide (100 μM) and AR‐R12495AA (50 and 100 μM). Pre‐treatment with intra‐peritoneal injection of 75 mg/kg of remacemide or AR‐R12495AA caused a significant reduction of carrageenan‐induced mechanical hyperalgesia and oedema. These electrophysiological and behavioural data provide evidence that remacemide and AR‐R12495AA may also possess analgesic and anti‐inflammatory activity. Copyright 2000 European Federation of Chapters of the International Association for the Study of Pain     

Engineering Analysis of Tricuspid Annular Dynamics in the Beating Ovine Heart

Functional tricuspid regurgitation is a significant source of morbidity and mortality in the US. Furthermore, treatment of functional tricuspid regurgitation is suboptimal with significant recurrence rates, which may, at least in part, be due to our limited knowledge of the relationship between valvular shape and function. Here we study the dynamics of the healthy in vivo ovine tricuspid annulus to improve our understanding of normal annular deformations throughout the cardiac cycle. To this end, we determine both clinical as well as engineering metrics of in vivo annular dynamics based on sonomicrometry crystals surgically attached to the annulus. We confirm that the tricuspid annulus undergoes large dynamic changes in area, perimeter, height, and eccentricity throughout the cardiac cycle. This deformation may be described as asymmetric in-plane motion of the annulus with minor out-of-plane motion. In addition, we employ strain and curvature to provide mechanistic insight into the origin of this deformation. Specifically, we find that strain and curvature vary considerable across the annulus with highly localized minima and maxima resulting in aforementioned configurational changes throughout the cardiac cycle. It is our hope that these data provide valuable information for clinicians and engineers alike and ultimately help us improve treatment of functional tricuspid regurgitation.     

SDH-deficient renal cell carcinoma – clinical,pathologic and genetic correlates: a case report

Background

Succinate dehydrogenase (SDH)- deficient renal cell carcinoma (RCC) is a newly identified rare subtype of RCC, having only gained acceptance from the World Health Organization in 2016. To the best of our knowledge, there are only 55 reported cases worldwide. Here, we report a new case of SDH-deficient RCC.

Case presentation

A 49-year-old male patient was incidentally found to have a large right renal mass. He had no personal or family history of paragangliomas (PGL), pheochromocytomas (PC), or gastrointestinal stromal tumors (GIST). The neoplasm was unilateral and unifocal. He underwent an open partial nephrectomy. Detailed pathological analysis was conducted to confirm the diagnosis. Genetic testing revealed a pathogenic mutation in the SDHB gene. He has been followed for 24?months now and has remained well without any evidence of local or distant recurrence. In this report we describe our experience with this diagnosis and review the relevant clinical, pathological, and genetic features.

Conclusions

Without the identification of SDHB deficiency, this patient’s personal and familial predisposition to PC, PGL, GIST and metachronous RCCs may have gone undetected despite his RCC diagnosis. When faced with an eosinophilic RCC, pathologists should routinely search for vacuoles or flocculent cytoplasmic inclusions. When these are present, or in cases of difficult eosinophilic renal tumors, staining for SDHB is recommended. For tumours without adverse pathologic features (i.e. high nuclear grade, coagulative necrosis, or sarcomatoid differentiation) excision alone may be a reasonable option, with the addition of regular surveillance for PC and PGLs in those found to harbor germline SDH mutations.