Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology.

N-methyl-D-aspartate receptors (NMDARs) are a subtype of ionotropic glutamate receptors critical for synaptic transmission and plasticity, and for the development of neural circuits. Rare or de-novo variants in GRIN genes encoding NMDAR subunits have been associated with neurodevelopmental disorders characterized by intellectual disability, developmental delay, autism, schizophrenia, or epilepsy. In recent years, some disease-associated variants in GRIN genes have been characterized using recombinant receptors expressed in non-neuronal cells, and a few variants have also been studied in neuronal preparations or animal models. Here we review the current literature on the functional evaluation of human disease-associated variants in GRIN1, GRIN2A and GRIN2B genes at all levels of analysis. Focusing on the impact of different patient variants at the level of receptor function, we discuss effects on receptor agonist and co-agonist affinity, channel open probability, and receptor cell surface expression. We consider how such receptor-level functional information may be used to classify variants as gain-of-function or loss-of-function, and discuss the limitations of this classification at the synaptic, cellular, or system level. Together this work by many laboratories worldwide yields valuable insights into NMDAR structure and function, and represents significant progress in the effort to understand and treat GRIN disorders. Keywords: NMDA receptor , GRIN genes, Genetic variants, Electrophysiology, Synapse, Animal models.

Evaluating the Efficacy of Chemical Disinfectants on Contaminated Dental Materials Contaminated by An Airborne Disease Tuberculosis Similar to COVID-19.

BACKGROUND: Tuberculosis (TB) is a communicable disease as well as an airborne disease. Mycobacterium tuberculosis (MTB) could survive on dental materials shipped to dental laboratories. AIMS: The aim of this study was to determine the number of bacilli held on the prosthetic material and the effect of chemical disinfection agents on various prosthetic materials that were shipped to dental laboratory of TB patient. MATERIALS AND METHODS: The study consisted of three study groups, and a control group. 10 mm x 2 mm disc-shaped (n = 18 for each group, n = 72 in total) nickel-chromium alloy (Ni-Cr), polymethylmethacrylate (PMMA), and dental ceramic (DC) samples were prepared. After exposure to MTB 24 hours in a 37°C incubator, six samples for each group (PMMA), Ni-Cr alloy and a control group DC samples) were exposed to three disinfectants; 10 minutes into 2% glutaraldehyde, 10 minutes into 5% sodium hypochlorite, and 1 minute into alcohol-based disinfectant after vortexed in distilled water. Colony forming units (CFU/ml) were calculated per milliliters. Two-way ANOVA statistical analysis method was used, and a P value less than 0.05 was considered as significant. RESULTS: The bacteria count for six Ni-Cr alloy disc-shaped specimens were recorded as 40, 10, 8, 6, 5, and 4 CFU/ml, respectively. Intensity of the colonies were found to be lower in other groups. 5 CFU/ml were detected on a single PMMA sample in the control group, and 40 CFU/ml were detected on one of the dental ceramic sample. No MTB uptake was observed on any sample in the 2% glutaraldehyde and 5% NaOCl disinfectant study groups. In alcohol-based disinfectant group, 1 CFU/ml was observed on Ni-Cr alloy sample. The effect of prosthetic materials used in this experimental study were not statistically significant on the CFU (p = 0.293). However, the disinfectants use was statistically significant on the number of colonies (p = 0.004). CONCLUSION: NaOCl and glutaraldehyde appeared to be more effective than alcohol-based disinfectant in removing MTB from Ni-Cr alloy, PMMA and dental ceramic surfaces.

Effect of goal-directed haemodynamic therapy on postoperative complications in low-moderate risk surgical patients: a multicentre randomised controlled trial (FEDORA trial).

BACKGROUND: The aim of this study was to evaluate postoperative complications in patients having major elective surgery using oesophageal Doppler monitor-guided goal-directed haemodynamic therapy (GDHT), in which administration of fluids, inotropes, and vasopressors was guided by stroke volume, mean arterial pressure, and cardiac index. METHODS: The FEDORA trial was a prospective, multicentre, randomised, parallel-group, controlled patient- and observer-blind trial conducted in adults scheduled for major elective surgery. Randomization and allocation were carried out by a central computer system. In the control group, intraoperative fluids were given based on traditional principles. In the GDHT group, the intraoperative goals were to maintain a maximal stroke volume, with mean arterial pressure >70 mm Hg, and cardiac index ≥2.5 litres min-1 m-2. The primary outcome was percentage of patients with moderate or severe postoperative complications during the first 180 days after surgery. RESULTS: In total, 450 patients were randomized to the GDHT group (n=224) or control group (n=226). Data from 420 subjects were analysed. There were significantly fewer with complications in the GDHT group (8.6% vs 16.6%, P=0.018). There were also fewer complications (acute kidney disease, pulmonary oedema, respiratory distress syndrome, wound infections, etc.), and length of hospital stay was shorter in the GDHT group. There was no significant difference in mortality between groups. CONCLUSIONS: Oesophageal Doppler monitor-guided GDHT reduced postoperative complications and hospital length of stay in low-moderate risk patients undergoing intermediate risk surgery, with no difference in mortality at 180 days. CLINICAL TRIAL REGISTRATION: ISRCTN93543537.

Bilateral inguinal hernia with an uncommon content : A case report.

Here we present a sixty-two year old man with bilateral swellings palpated in inguinal areas on physical examination. Ultrasonography and abdominal multi-detector computed tomography revealed a bladder herniation through the right inguinal canal and a sigmoid colon herniation through the left inguinal canal. Radiologic imaging methods are important and can guide clinicians for preemptive or emergent surgery. (Acta gastroenterol. belg., 2016, 79, 495-496).

Expression profiling of SCN8A and NDUFC2 genes in colorectal carcinoma.

AIM: The expression differences of SCN8A (which encodes type VIII alpha subunit of voltage gated sodium channel) and NDUFC2 (which encodes C2 subunit of Complex I enzyme in oxidative phosphorylation) genes were evaluated in paired colorectal cancer (CRC) tissues which was relied on our partial transcriptome analysis data in cancer cell lines. MATERIALS AND METHODS: A total of 62 paired tissues of CRC patients (34 male, 28 female) were included in the study. The mRNA levels of SCN8A and NDUFC2 genes were determined by using real-time PCR (qRT-PCR and semiquantitative PCR). RESULTS: SCN8A gene expression level was significantly lower in tumor tissues (p = 0.0128) and in the patients with the age below 45 years (p = 0.0049). There were also meaningful relationships between the gender, grade of CRC, tumor location, histopathological classification, and SCN8A expression. There was no NDUFC2 differential expression. However, the tumors taken from right colon had significantly lower NDUFC2 expression. CONCLUSION: Although the voltage gated sodium channels (VGSCs) and Complex I (CI) were associated to a number of diseases including different types of cancers, the different subunits of CI and individual members of VGSCs seem to be cancer type-specific in varying proportions.

Structure, function, and pharmacology of NMDA receptor channels.

NMDA receptors have received much attention over the last few decades, due to their role in many types of neural plasticity on the one hand, and their involvement in excitotoxicity on the other hand. There is great interest in developing clinically relevant NMDA receptor antagonists that would block excitotoxic NMDA receptor activation, without interfering with NMDA receptor function needed for normal synaptic transmission and plasticity. This review summarizes current understanding of the structure of NMDA receptors and the mechanisms of NMDA receptor activation and modulation, with special attention given to data describing the properties of various types of NMDA receptor inhibition. Our recent analyses point to certain neurosteroids as NMDA receptor inhibitors with desirable properties. Specifically, these compounds show use-dependent but voltage-independent block, that is predicted to preferentially target excessive tonic NMDA receptor activation. Importantly, neurosteroids are also characterized by use-independent unblock, compatible with minimal disruption of normal synaptic transmission. Thus, neurosteroids are a promising class of NMDA receptor modulators that may lead to the development of neuroprotective drugs with optimal therapeutic profiles.

GnRH-I and GnRH-II-induced calcium signaling and hormone secretion in neonatal rat gonadotrophs.

Two forms of gonadotropin-releasing hormone (GnRH), GnRH-I and GnRH-II, are commonly present in mammals. The main hormone controlling reproduction is GnRH-I acting through its receptor (GnRHR-I), whereas the function of GnRH-II is unknown. In primates, it has been suggested that GnRH-II is a specific agonist for the structurally distinct GnRHR-II. Here we compared effects of GnRH-I and GnRH-II on intracellular calcium and gonadotropin hormone release in neonatal rat gonadotrophs in vitro and the dependence of agonist actions on cyclic nucleotide levels. Both agonists elevated intracellular calcium and stimulated gonadotropin secretion in a concentration-dependent manner, with comparable peak amplitudes, but GnRH-I was three times more potent than GnRH-II. Antide, a specific GnRHR-I antagonist, completely blocked the action of both agonists on gonadotropin release. Inhibition of adenylyl cyclase activity by melatonin and MDL significantly attenuated GnRH-I- and GnRH-II-induced calcium signaling and gonadotropin release, whereas inhibition of soluble guanylyl cyclase activity was ineffective. GnRH-II also generated calcium oscillations in a fraction of gonadotrophs not expressing melatonin receptors. These results indicate that GnRH-I and GnRH-II act on the same GnRHR to stimulate gonadotropin release through intracellular calcium and cyclic nucleotide signaling, and that GnRH-II is less potent agonist for this receptor in neonatal rat gonadotrophs.

Photoperiod regulates genes encoding melanocortin 3 and serotonin receptors and secretogranins in the dorsomedial posterior arcuate of the Siberian hamster.

The mechanism(s) involved in the regulation of the seasonal-appropriate body weight of the Siberian hamster are currently unknown. We have identified photoperiodically regulated genes including VGF in a sub-region of the arcuate nucleus termed the dorsomedial posterior arcuate (dmpARC). Gene expression changes in this nucleus so far account for a significant number of those reported as photoperiodically regulated and are therefore likely to contribute to seasonal physiological responses of the hamsters. The present study aimed to identify additional genes expressed in the dmpARC regulated by photoperiod that could be involved in regulating the activity of this nucleus with respect to seasonal physiology of the Siberian hamster. Using laser capture microdissection coupled with a microarray analysis and a candidate gene approach, we have identified several photoperiodically regulated genes in the dmpARC that are known to have roles in secretory and intracellular signalling pathways. These include secretogranin (sg) III and SgVI (secretory pathway), melanocortin 3 receptor (MC3-R) and serotonin (5-HT) receptors 2A and 7 (signalling pathway), all of which increase in expression under a short photoperiod. The spatial relationship between receptor signalling and potential secretory pathways was investigated by dual in situ hybridisation, which revealed that 5-HT2A and 5-HT7 receptors are expressed in neurones expressing VGF mRNA and that a sub-population (approximately 40%) of these neurones express MC3-R. These gene expression changes in dmpARC neurones may reflect the functional requirement of these neurones for seasonal physiological responses of the hamster.

Molecular structure of purinergic P2X receptors and their expression in the hypothalamus and pituitary.

Purinergic P2X receptors represent a novel structural type of ligand-gated ion channels activated by extracellular ATP. So far, seven P2X receptor subunits have been found in excitable as well as non-excitable tissues. Little is known about their structure, mechanism of channel opening, localization, and role in the central nervous system. The aim of this work is to summarize recent investigations and describe our contribution to elucidating the structure of the ATP binding site and transmembrane domains of the P2X receptor, we also discuss the expression and physiological roles played by the ATP and P2X receptors in the anterior pituitary and hypothalamus.

Spontaneous rupture of the spleen in secondary amyloidosis: a patient with rheumatoid arthritis.

A 63-year-old man who had had a history of rheumatoid arthritis presented with shock and hemoperitoneum, without a history of trauma. An emergency laparatomy revealed hemoperitoneum and splenic rupture with massive bleeding. Splenectomy was performed. Histopathological examination of the spleen revealed amyloid deposition in the wall of the vessels. Rectal biopsy revealed amyloid deposition in mucosa that indicating amyloidosis was systemic. Histochemical studies showed that amyloid was secondary or AA.

Intussusception in adults.

To review clinical, radiological and histopathological findings of adult intussusception and its management, 18 adult patients who had been treated surgically because of intussusception were reviewed. Of the patients, 5 (27.8%) had idiopathic intussusceptions, while the other 13 (72.2%) had a definable intraluminal pathology. The site of the intussusception was more common in the small bowel (83.3%) than the colon (16.7%). Ultrasonography and computed tomography were successful in demonstrating "target lesion" in 80% and 75% respectively. Patients with idiopathic intussusception were treated with simple reduction, while the others underwent segmental resection because of the possibility of malignant tumour. In contrast to intussusception in childhood, intussusception in adults usually has a definable lead point and resection of the involved bowel, rather than simple reduction, is indicated.

Hypothalamic energy balance gene responses in the Sprague-Dawley rat to supplementation of high-energy diet with liquid ensure and subsequent transfer to chow.

Energy dense, high fat, high sugar, foods and beverages in our diet are a major contributor to the escalating global obesity problem. Here, we examine the physiological and neuroendocrine effects of feeding rats a solid high-energy (HE) diet with or without a liquid supplement (Ensure) and the consequence of subsequently transferring animals back to chow (C). Outbred Sprague-Dawley rats were fed C until 49-56 days of age, and then transferred a HE diet for 3 weeks before allocation to one of two weight-matched groups. Over the next 10 weeks, one group remained on HE diet, whereas the other had access to the liquid diet, chocolate Ensure (EN), in addition to HE diet (HE + EN). Half the rats from each group were then killed, and the remainder were returned to C for 3 weeks. Supplementation of the HE diet with EN accelerated weight gain and increased daily energy intake, adipose tissue mass, and circulating leptin levels. Transferring animals back to C caused a decrease in bodyweight in the HE + EN group, whereas HE animals were weight stable. Both groups also exhibited voluntary hypophagia, although the magnitude and duration of this response was greater in HE + EN animals. The only effect of Ensure on the hypothalamic genes studied was on tyrosine kinase B expression in the ventromedial hypothalamic nucleus (VMH), which was increased in rats given the supplement. Withdrawal of the obesogenic diets decreased gene expression for cocaine-and-amphetamine regulated transcript (CART) and dynorphin (DYN) in the arcuate nucleus (ARC), and DYN and brain-derived neurotrophic factor (BDNF) in the VMH, whereas neuropeptide Y (NPY) gene expression in the ARC was increased. These changes were independent of previous dietary history. EN supplementation generates distinct physiological responses, yet has a minimal effect on hypothalamic neuropeptide or receptor gene expression, possibly due to the development of leptin resistance. Withdrawal of obesogenic diets induces changes in the gene expression consistent with NPY, CART and BDNF attempting to oppose weight gain on either HE or HE + EN.

Late complications of incisional hernias following prosthetic mesh repair.

BACKGROUND: Incisional hernias still continue to be a serious problem for surgeons. In this study, we aimed to investigate the effects of polypropylene mesh and mersilene mesh, which are frequently employed in incisional hernias, as well as the effects of their application techniques on late complications. METHODS: Two-hundred-sixty-four open abdominal hernia repairs were performed between 1986--2000, using prosthetic materials: polypropylene mesh and mersilene mesh were used in hernia repair. Mesh was placed as onlay, underlay and sandwich techniques. Follow-up data were obtained from medical records. RESULTS: Comparisons were made with respect to surgical techniques and to late complications such as recurrence, enterocutaneous fistula, intestinal obstruction, and infections. Enterocutaneous fistulas developed in two patients. Recurrence occurred in 6.4 per cent. Chronic infection and wound sinus formation occurred in 5 per cent. The causes of recurrence included smoking, cellulitis, chronic infection/sinus tract, upper abdominal localization, and obstruction. Fistula formation occurred in patients with no peritoneal prevention, which was statistically significant (p=0.012). Chronic infection/sinus tract was high in patients for whom mersilene mesh was used, and enterocutaneous fistula occurred in 2 patients. CONCLUSION: To prevent late complications, it is necessary to avoid the contact of mesh with bowel.

Melatonin action in neonatal gonadotrophs.

Neonatal pituitary cells express MT1 and MT2 subtype of melatonin receptors that are coupled to pertussis toxin-sensitive G proteins. Their activation by melatonin leads to a decrease in cAMP production and activity of protein kinase A, and attenuation of gonadotropin-releasing hormone (GnRH)-induced gonadotropin secretion. Single cell calcium and electrophysiological recordings have revealed that a reduction in gonadotropin release results from melatonin-induced inhibition of GnRH-stimulated calcium signaling. Melatonin inhibits both calcium influx through voltage-dependent calcium channels and calcium mobilization from intracellular stores. Inhibition of calcium influx, probably in a cAMP/protein kinase C-dependent manner, and the accompanying calcium-induced calcium release from ryanodine-sensitive intracellular pools by melatonin results in a delay of GnRH-induced calcium signaling. Melatonin-induced attenuation of GnRH-induced and inositol (1,4,5)-trisphosphate-mediated calcium release from intracellular pools attenuates the amplitude of calcium signal. The potent inhibition of GnRH-induced calcium signaling and gonadotropin secretion by melatonin provides an effective mechanism to protect premature initiation of pubertal changes that are dependent on plasma gonadotropin levels. During the development, such tonic inhibitory effects of melatonin on GnRH action gradually decline due to a decrease in expression of functional melatonin receptors. In adult animals, melatonin does not have obvious direct effects on pituitary functions, whereas the connections between melatonin release and hypothalamic functions, including GnRH release, are preserved, and are critically important in synchronizing the external photoperiods and reproductive functions through still not well characterized mechanisms.

Hydatid cysts of the adrenal gland: review of nine patients.

Adrenal cysts are very rare lesions, especially with parasitic origin. But with the wider application of ultrasonography (US) and computed tomography (CT) more adrenal cysts are detected incidentally. To gain more insight into this entity, the records of nine patients with hydatid cysts of adrenal gland seen at our department from January 1980 till January 2002 are reviewed. There were four men and five women, and their ages ranged from 15 to 80 years (median: 41 years). All of the patients had unilateral cysts. Seven cysts were located on the right and two on the left side. Five of the cysts were primary and four were secondary. In three patients the cysts were found incidentally. The most common presenting symptom was pain, which was present in six patients. An indirect hemagglutination (IHA) test was positive in six cases. In all patients, US and CT successfully imaged all cysts, but the definitive diagnosis was made by macroscopic and microscopic examination of the cyst's content. The patients were treated surgically. In all patients adrenal glands with the cystic masses were removed. The median follow-up period was 16 months (range: 6-64 months). No evidence of recurrence was found in any patient. It should not be forgotten that cystic masses of the upper abdomen might also originate from the adrenal gland. The etiology and nature of the cyst should be well researched, and appropriate treatment should be given as soon as possible. Surgical excision of the gland, including the cyst is the treatment of choice.

Intrabiliary rupture in liver hydatid cysts: results of 20 years' experience.

To assess the diagnostic tools and results of treatment of biliary rupture observed in liver cyst hydatids, clinical findings of 562 patients with hepatic hydatid disease were reviewed. Imaging techniques were not very effective to determine intrabiliary ruptures. Rates of rupture sizes determined in the patients were as follows; 22 (%24.7) large, 38 (%42.7) small, and 29 (%32.6) occult. Most frequently utilized procedures for patients with intrabiliary rupture were Roux-en-y cystojejunostomy, tube drainage + omentoplasty, sutured fistula + omentoplasty, and sutured fistula + tube drainage. Of the total 25 external biliary fistulas, 21 closed spontaneously. Of the four fistulas that did not close, one was managed by internal drainage and three by endoscopic sphincterotomy. Preoperative diagnosis of biliary rupture in liver hydatid cyst allows early planning of operation and helps the surgeon design the operative strategy. In the treatment of cases with large rupture, internal drainage may be proposed.

Anal canal amputation and necrosis of the anal sphinchter due to electric current injury.

The pathophysiology of electrical burns differs from thermal and chemical burns and electrical injuries which are associated with significant morbidity and mortality. We report on a patient who suffered anal canal amputation and necrosis of the anal sphinchter as a result an electric current injury.

Importance of psychiatric intervention in intolerances in endoscopic procedures.

Despite the fact that pre-medication, in a number of different drug combinations, has been used for a long time in endoscopy units, and has been subject to extended clinical studies, it is still not possible to claim that it has attained an ideal state with regard to patient tolerance to endoscopy procedures. In this clinical study, we have investigated the effects of psychological intervention in addition to medication, which we used on patients with intolerance to endoscopy. Intolerance was very high in all endoscopic procedures (15.8% total). It was observed that average midazolam doses were significantly higher in intolerant than in tolerant patients. It was found that in patients who had received psychiatric intervention, the decrease in midazolam dose was statistically significant in a subsequent endoscopy procedure.

Percutaneous drainage of hydatid cyst of the liver: long-term results.

BACKGROUND: Previously surgical operation was the only accepted treatment for hydatid liver cysts. Recently percutaneous management has become more preferable because of its low morbidity rate and lower cost. PATIENTS AND METHODS: In all, 101 patients harbouring 120 hydatid cysts of the liver were treated by percutaneous drainage between October 1994 and December 1997. Of these cysts, 89 were in the right liver and 31 in the left liver.Thirty-one patients had had previous operations for hydatid disease. All cysts had an anechoic or hypoechoic unilocular appearance on ultrasound scan. The mean dimension of the cysts was 7.5+/-2.9 cm (range 3-10.4 cm). All patients received oral albendazole 10 mg/kg perioperatively. After aspiration under sonographic guidance, cysts were irrigated with 95% ethanol. RESULTS: The amount of cyst fluid aspirated was 220+/-75 ml and the amount of irrigation solution used was 175+/-42 ml. Four patients developed mild fever and three had urticaria. Mean length of hospital stay was 2.1+/-0.7 (range 1-4) days, and patients were followed up for 43-62 months (mean 54+/-5.4 months). Maximal cyst diameter decreased from 7.5+/-2.9 cm to 3.2+/-15 cm (p<0.001). Sonographic examinations revealed high-level heterogeneous echoes in the cyst cavity (heterogeneous echo pattern), while the cyst cavity was completely obliterated by echogenic material (pseudotumour echo pattern). DISCUSSION: Most hydatid cysts of the liver can be managed successfully by a combination of drug therapy and percutaneous drainage.