Simultaneous totally robotic rectal resection and partial nephrectomy: case report and review of literature.

INTRODUCTION: The incidence of synchronous RCC and colorectal cancer is heterogeneous ranging from 0.03 to 4.85%. Instead, only one case of huge colon carcinoma and renal angiomyolipoma was reported. The treatment of synchronous kidney and colorectal neoplasm is, preferably, synchronous resection. Currently, laparoscopic approach has shown to be feasible and safe, and it has become the gold standard of synchronous resection due to advantages of minimally invasive surgery. We presented a case synchronous renal neoplasm and colorectal cancer undergone simultaneous totally robotic renal enucleation and rectal resection with primary intracorporeal anastomosis. As our knowledge, this is the first case in literature of simultaneous robotic surgery for renal and colorectal tumor. CASE PRESENTATION: A 53-year-old woman was affected by recto-sigmoid junction cancer and a solid 5 cm left renal mass. We performed a simultaneous robotic low anterior rectal resection and renal enucleation. Total operative time was 260 min with robotic time of 220 min; estimated blood loss was 150 ml; time to flatus was 72 h, and oral diet was administered 4 days after surgery. The patient was discharged on the eighth post-operative day without peri- and post-operative complication. The definitive histological examination showed a neuroendocrine tumor pT2N1 G2, with negative circumferential and distal resection margins. Renal tumor was angiomyolipoma. At 23 months follow-up, the patient is recurrence free. DISCUSSION AND CONCLUSION: As our knowledge, we described the first case in literature of simultaneous robotic anterior rectal resection and partial nephrectomy for treatment of colorectal tumor and renal mass. Robotic rectal resection with intracorporeal anastomosis surgery seems to be feasible and safe even when it is associated with simultaneous partial nephrectomy. Many features of robotic technology could be useful in combined surgery. This strategy is recommended only when patients' medical conditions allow for longer anesthesia exposure. The advantages are to avoid a delay treatment of second tumor, to reduce the time to start the post-operative adjuvant chemotherapy, to avoid a second anesthetic procedure, and to reduce the patient discomfort. However, further studies are needed to evaluate robotic approach as standard surgical strategy for simultaneous treatment of colorectal and renal neoplasm.

DNA-damage response gene polymorphisms and therapeutic outcomes in ovarian cancer.

Epithelial ovarian cancer has a poor prognosis owing to late diagnosis and frequent relapse after first-line therapy. Analysis of individual genetic variability could aid in the identification of markers, which could help in stratifying patients with the aim of optimizing individual therapy. In this study we assessed polymorphisms in three genes important in drugs' response in 97 early and 235 late-stage ovarian cancer patients. The Asp1104His polymorphism in xpg, a gene important for removal of platinum adducts, was associated with progression-free survival in early- and late-stage ovarian cancer. Our data indicate that a simple diagnostic analysis such as xpg genotyping can help in predicting response, and extension to other possibly relevant genotypes could be useful in selecting patients with epithelial ovarian cancer for optimal therapy and hence increase the chance of response.

Selective melanocortin MC4 receptor agonists reverse haemorrhagic shock and prevent multiple organ damage.

BACKGROUND AND PURPOSE: In circulatory shock, melanocortins have life-saving effects likely to be mediated by MC4 receptors. To gain direct insight into the role of melanocortin MC4 receptors in haemorrhagic shock, we investigated the effects of two novel selective MC4 receptor agonists. EXPERIMENTAL APPROACH: Severe haemorrhagic shock was produced in rats under general anaesthesia. Rats were then treated with either the non-selective agonist [Nle4, D-Phe7]-melanocyte-stimulating hormone (NDP--MSH) or with the selective MC4 agonists RO27-3225 and PG-931. Cardiovascular and respiratory functions were continuously monitored for 2 h; survival rate was recorded up to 24 h. Free radicals in blood were measured using electron spin resonance spectrometry; tissue damage was evaluated histologically 25 min or 24 h after treatment. KEY RESULTS: All shocked rats treated with saline died within 30-35 min. Treatment with NDP--MSH, RO27-3225 and PG-931 produced a dose-dependent (13-108 nmol kg-1 i.v.) restoration of cardiovascular and respiratory functions, and improved survival. The three melanocortin agonists also markedly reduced circulating free radicals relative to saline-treated shocked rats. All these effects were prevented by i.p. pretreatment with the selective MC4 receptor antagonist HS024. Moreover, treatment with RO27-3225 prevented morphological and immunocytochemical changes in heart, lung, liver, and kidney, at both early (25 min) and late (24 h) intervals. CONCLUSIONS AND IMPLICATIONS: Stimulation of MC4 receptors reversed haemorrhagic shock, reduced multiple organ damage and improved survival. Our findings suggest that selective MC4 receptor agonists could have a protective role against multiple organ failure following circulatory shock.

Reactive oxygen species, dietary restriction and neurotrophic factors in age-related loss of myenteric neurons.

We have studied the mechanisms underlying nonpathological age-related neuronal cell death. Fifty per cent of neurons in the rat enteric nervous system are lost between 12 and 18 months of age in ad libitum (AL) fed rats. Caloric restriction (CR) protects almost entirely against this neuron loss. Using the ROS-sensitive dyes, dihydrorhodamine (DHR) and 2-[6-(4'-hydroxy)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid (HPF) in vitro, we show that the onset of cell death is linked with elevated intraneuronal levels of reactive oxygen species (ROS). Treatment with the neurotrophic factors NT3 and GDNF enhances neuronal antioxidant defence in CR rats at 12-15 months and 24 months but not in adult or aged AL-fed animals. To examine the link between elevated ROS and neuronal cell death, we assessed apoptotic cell death following in vitro treatment with the redox-cycling drug, menadione. Menadione fails to increase apoptosis in 6-month neurons. However, in 12-15mAL fed rats, when age-related cell death begins, menadione induces a 7- to 15-fold increase in the proportion of apoptotic neurons. CR protects age-matched neurons against ROS-induced apoptosis. Treatment with neurotrophic factors, in particular GDNF, rescues neurons from menadione-induced cell death, but only in 12-15mCR animals. We hypothesize that CR enhances antioxidant defence through neurotrophic factor signalling, thereby reducing age-related increases in neuronal ROS levels and in ROS-induced cell death.

[Laparoscopic appendectomy]. / L'appendicectomia laparoscopica.

Most laparoscopic procedures are performed on an elective basis. However, as general surgeons have gained more experience with laparoscopy, they are employing this procedure also for the evaluation and treatment of acute abdominal conditions such acute appendicitis, acute cholecystitis, perforated gastroduodenal ulcer and abdominal trauma, acute pancreatitis and intestinal obstruction. Although its advantages are still under debate, the laparoscopic approach has already been adopted by many centers in the emergency setting.

A defunctioning stoma in the treatment of lower third rectal carcinoma.

INTRODUCTION: Total mesorectal excision (TME) is the accepted standard for rectal cancer treatment. However, there is an increased risk of symptomatic anastomotic leakage associated with TME as TME potentially endangers the blood supply of the remaining rectum. On top of this, many patients will receive neo-adjuvant radio-chemotherapy. A defunctioning stoma helps in avoiding severe complications of anastomotic failure. MATERIAL AND METHODS: We prospectively collected data of all patients with a rectal carcinoma within reach of the palpating finger, operated on in our department between December 2000 and January 2005. There were 70 patients (42 men and 28 women, median age 70 (range 32-95)). RESULTS: In 40 patients (40/70 = 57%) a sphincter-saving procedure was performed. Eleven patients were diagnosed with anastomotic leakage or failure. Seven patients had neo-adjuvant radio-chemotherapy, 4 had no neo-adjuvant therapy. In 4 patients signs of anastomotic leakage were seen on the barium-enema that is routinely performed before closing the defunctioning stoma. Seven patients (7/40 = 17,5%) had clinical signs of anastomotic leakage. Three of them could be treated conservatively with antibiotics and parenteral nutrition. Two of these patients did not have a defunctioning stoma. Four patients needed re-intervention and were treated in intensive care for several days. Three of these patients did not have a defunctioning stoma. CONCLUSION: Neo-adjuvant radio-chemotherapy and TME resection are two factors in the treatment of rectal cancer that might interfere with anastomotic healing in the case of a sphincter-saving procedure. The construction of a defunctioning stoma helps in limiting the complications of anastomotic leakage or failure.

Frozen section in thyroid surgery.

OBJECTIVE: We studied the use of frozen section in the detection of malignancy in thyroid surgery in a large teaching hospital. MATERIALS AND METHODS: We reviewed all case notes of patients operated on for thyroid disease between January 1st 1997 and December 31st 2004. We identified 420 operations in 408 patients. Data were available for 417 operations. RESULTS: In patients with a solitary thyroid nodule, a frozen section is sometimes performed. Frozen section was done in 128 of 417 operations. The specificity for malignancy was 98.16%. The positive predictive value was 81.81% and the negative predictive value 93.85%. However the sensitivity was 56.25%. Frozen section is a time-consuming investigation. With follicular lesions it is very difficult to distinguish between benign disease and malignancy since the diagnosis of malignancy depends on capsular and/or blood vessel invasion. Also it costs about 100 Euro (approximately 125 dollars). CONCLUSION: This study confirms that adequate histopathologic diagnosis of thyroid disease is based on extensive subsampling of the specimen which is not possible during a peroperatory frozen section procedure.

[Chilaiditi's syndrome: a rare cause of abdominal pain in the differential diagnosis of the abdominal perforation. Case report]. / Sindrome di Chilaiditi: una causa rara di dolore addominale nella diagnosi differenziale della sindrome perforativa addominale. Case report.

A case of a 92-years-old patient with abdominal pain and constipation is presented. He reported a recent traumatic fracture of the upper limb. Traditional diagnostic work-up for patient with abdominal pain was started up. He was submitted to abdominal film that demonstrated air underneath the diaphragm suggestive for perforation. This hallmark is opposed to clinical condition of patient, so differential diagnosis for rare Chilaiditi's syndrome was considered, because this syndrome is frequent in old patient. Diagnostic work-up was completed with upper abdominal CT that excluded intestinal perforation and confirmed the diagnosis of Chilaiditi's syndrome showing hepatodiaphragmatic interposition of the dilated colon. Therefore it was decided in favour of medical therapy. In the our case, in spite of negative clinical examination, the uncertain radiological hallmark obliged us to exclude diagnosis of abdominal perforative syndrome that needs emergency operation. Although the Chilaiditi's syndrome is rare, it must be considerated in differential diagnosis of perforative abdominal syndrome, when there are doubts about the subdiaphragmatic air in abdominal film.

Involvement of the histaminergic system in the resuscitating effect of centrally acting leptin in haemorrhagic shock in rats.

Leptin, acting centrally as a neuromodulator, induces the activation of the sympathetic nervous system, which may lead to a pressor action in normotensive animals. In haemorrhagic shock, leptin administered intracerebroventricularly (icv.) evokes the resuscitating effect, with long-lasting rises in mean arterial pressure (MAP) and heart rate (HR), subsequent increase in peripheral blood flows, and a 100% survival at 2 h. Since leptin is able to activate histaminergic neurons, and centrally acting histamine also induces the resuscitating effect with the activation of the sympathetic nervous system, in the present study, we investigated an involvement of the histaminergic system in leptin-evoked cardiovascular effects in haemorrhagic shock. The model of irreversible haemorrhagic shock, with MAP decreased to and stabilised at 20 - 25 mmHg, has been used. Leptin (20 µg) given icv. at 5 min of critical hypotension evoked 181.5% increase in extracellular hypothalamic histamine concentration during the first 10 min after injection. Rises in MAP, HR and renal, mesenteric and hindquarters blood flows induced by leptin were inhibited by icv. pre-treatment with histamine H1 receptor antagonist chlorpheniramine (50 nmol). In contrast, there was no effect of H2, H3 and H4 receptor antagonists ranitidine (25 nmol), VUF 5681 (25 nmol) and JNJ 10191584 (25 nmol), respectively. In conclusion, the histaminergic system is involved in centrally-acting leptin-induced resuscitating effect in haemorrhagic shock in rats.

Involvement of dopamine D2 receptors in the effect of cocaine on sexual behaviour and stretching-yawning of male rats.

The effect of cocaine (7.5, 15 and 30 mg/kg) administered in acute or subchronic mode, on the mating behaviour of sexually active male rats varied in a dose- and mode-dependent manner. Regardless of mode of treatment, 30 mg/kg markedly impaired the rats copulatory ability and impairment continued for a week after suspension of subchronic treatment. An acute dose of 15 mg/kg reduced intromission frequency, while in subchronic mode it also reduced ejaculation latency. Mount frequency was increased by 7.5 and 15 mg/kg, but only on first injection. In the case of sexually-naive male rats, acute administration of cocaine (3-30 mg/kg) stimulated penile erections at 7.5 mg/kg and motor hyperactivity at all doses. (-) Eticlopride (0.025 and 0.05 mg/kg), a DA D2 antagonist, counteracted cocaine-induced motor hyperactivity but not penile erection, which it enhanced. (-) Eticlopride at the same doses also antagonized cocaine potentiation of lisuride (0.2 mg/kg)-induced behavioural effects. When male rats treated with subchronic cocaine (15 mg/kg) were injected with the DA D2 agonist SND 919 (0.1 mg/kg), they displayed a more marked stretching-yawning behaviour than control animals receiving SND 919 at the same dose. The involvement of DA D2 receptors in cocaine-induced effects is suggested.

Behavioral effects induced by the dopamine D3 agonist 7-OH-DPAT in sexually-active and -inactive male rats.

The present study investigates the effects induced by the putative DA D3 agonist 7-OH-DPAT (0.1 and 1 mg/kg, s.c.) on: (1) the sexual behavior of male rats, categorized on the basis of seven consecutive mating pre-tests as sexually-active (SA) and sexually-inactive (SI); and (2) stretching-yawning, penile erection, sedation and stereotyped behavior of the same animals. The data obtained show that 7-OH-DPAT at both doses modifies the copulatory pattern of SA rats, facilitating ejaculation mechanisms, but fails to increase the sexual drive of the animals as is evident from the ineffectiveness in SI rats. The second major finding is that the two groups of rats, which are markedly different as regards sexual typology, exhibit different behavioral responses to 7-OH-DPAT.

Influence of sildenafil on copulatory behaviour in sluggish or normal ejaculator male rats: a central dopamine mediated effect?

The present study investigates the effects induced by sildenafil (1 mg/kg, p.o.) and the dopamine agonist, SND 919 (0.1 mg/kg, i.p.) on copulatory behaviour of male rats, categorized, on the basis of seven consecutive mating pre-tests, as sluggish and normal ejaculators (SE and NE, respectively). The data obtained show that sildenafil modifies both sexual arousal and ejaculatory mechanisms of copulation. It appears that, although it induced a facilitatory effect on ejaculation of all rats, similarly to SND 919, the lowering of ejaculatory threshold was achieved by means of a reduction of mount frequency and intromission frequency in SE and NE groups, respectively. Differently from SND 919, sildenafil increased sexual arousal, diminishing post ejaculatory interval in SE animals and inter-intromission interval in both SE and NE rats. As the dopamine antagonist, (-)eticlopride (0.02 mg/kg, s.c.), significantly inhibited sildenafil-induced enhancement of sexual arousal in SE rats, it is suggested that the drug acts both peripherally and centrally.

Synthesis, resolution, and preliminary evaluation of trans-2-amino-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes and related derivatives as dopamine receptors ligands.

The present work reports the synthesis of enantiomeric pairs of the trans-2-amino-6-hydroxy-1-phenyl-2,3-dihydro-1H-indene [(+)-14a, (-)-14a] and trans-2-amino-5-hydroxy-1-phenyl-2,3-dihydro-1 H-indene [(+)-14b, (-)-14b] and their N,N-di-n-propyl [(+)-and (-)-15a,b], N-methyl-N-allyl [(+)-and (-)-16a,b], and N-methyl-N-n-propyl [(+) and (-)-17a,b] derivatives obtained by a combination of stereospecific reactions and optical resolution. The new compounds were evaluated for their affinity at the dopamine D1 and D2 receptors. The amines (+)- and (-)-14a, incorporating the D1 pharmacophore 2-phenyl-2-(3-hydroxyphenyl)ethylamine in a trans extended conformation, and their derivatives displayed D1 and D2 affinity in the nanomolar range. On the other hand, the enantiomers (+)- and (-)-14b, (+)- and (-)-15b displayed high affinity and selectivity for the D1 receptor. In a preliminary behavioral study on rats (+)-14b, and to a greater extent (+)-15b, promoted episodes of intense grooming, thus indicating that they act as central D1 agonists. The trans-2-amino-5-hydroxy-1-phenyl-2,3-dihydro-1H-indenes (+)-14b and (+)-15b represent selective D1 agonists lacking a catechol group, which should meet the prerequisites for a central nervous system penetration.

Effects of ketamine anesthesia on central nociceptive processing in the rat: a 2-deoxyglucose study.

Ketamine is a dissociative anesthetic with complex actions on the CNS. We investigated here the effects of ketamine anesthesia on somatosensory processing in the rat spinal cord, thalamus, and cerebral cortex, using the quantitative 2-deoxyglucose mapping technique. Unanesthetized or ketamine-anesthetized male Sprague-Dawley rats received a s.c. injection of a dilute formaldehyde solution (5%, 0.08 ml) into a forepaw, inducing prolonged noxious afferent input, or an equal volume of isotonic saline as a control stimulus. The 2-deoxyglucose experiments started 30 min after the injection. In the cervical enlargement of the spinal cord, ketamine had no significant effect on glucose metabolic rates in saline-injected animals, whereas it prevented the metabolic increases elicited by prolonged noxious stimulation in unanesthetized animals. At the thalamic level, ketamine increased glucose uptake in both saline- and formalin-injected rats in the lateral posterior, lateral dorsal, medial dorsal, gelatinosus, antero-ventral and antero-medial thalamic nuclei, whereas it decreased metabolic activity in the ventro-basal complex. At the cortical level, the drug increased metabolic activity in both control and formalin groups in the lacunosus-molecularis layer of the dorsal hippocampus, posterior parietal, retrosplenial, cingulate and frontal cortex; significant metabolic decreases were found in the CA1 region of the dorsal hippocampus and in the parietal 1 and 2 cortical areas. In the investigated brain regions, ketamine did not abolish noxious-evoked increases in glucose uptake, which were in fact enhanced in the forelimb cortex and in the lacunosus-molecularis layer of the hippocampus. The dissociation between the spinal and supraspinal effects of ketamine suggests a specific antinociceptive action on spinal circuits, in parallel with complex changes of the activity of brain circuits involved in somatosensory processing. More generally, this study shows that functional imaging techniques are able to quantitatively assess the effects of anesthetic drugs on nociceptive processing at different levels of the neuraxis.

A rapid method for estimating mean platelet survival time.

Platelet survival studies were performed in 27 consecutive subjects, and mean platelet life span was derived by computerized calculations of radioactivity in blood samples obtained daily for 9-11 days. These computer derived estimates were then correlated with the raw whole blood radioactivity data obtained for the first 3 days of each study. Data from the 48-hr point correlates with the computer estimates so that platelet survival data can now be reported in 2 days with 93% precision of the long method and without visual curve fitting. Thus, one may take a "quick look" at the probable platelet lifespan, under steady state conditions, in order to evaluate therapy while avoiding problems of patient compliance.

Biological dosimetry of bone marrow for incorporated yttrium-90.

UNLABELLED: The biological response of bone marrow to incorporated radionuclides depends on several factors such as absorbed dose, dose rate, proliferation and marrow reserve. The determination of the dose rate and absorbed dose to bone marrow from incorporated radionuclides is complex. This research used survival of granulocyte-macrophage colony-forming cells (GM-CFCs) as a biological dosimeter to determine experimentally the dose rate and dose to bone marrow after administration of 90Y-citrate. METHODS: The radiochemical 90Y-citrate was administered intravenously to Swiss Webster mice. Biokinetics studies indicated that the injected 90Y quickly localized in the femurs (0.8% ID/femur) and cleared with an effective half-time of 62 hr. Subsequently, GM-CFC survival was determined as a function of femur uptake and injected activity. Finally, to calibrate GM-CFC survival as a biological dosimeter, mice were irradiated with external 137Cs gamma rays at dose rates that decreased exponentially with a half-time of 62 hr. RESULTS: Femur uptake was linearly proportional to injected activity. The survival of GM-CFCs was exponentially dependent on both the initial 90Y femur activity and the initial dose rate from external 137Cs gamma rays with 5.1 kBq/femur and 1.9 cGy/hr, respectively, required to achieve 37% survival. Thus, 90Y-citrate delivers a dose rate of 0.37 cGy/hr to the femoral marrow per kBq of femur activity and the dose rate decreased with an effective half-time of 62 hr. CONCLUSION: Survival of GM-CFCs can serve as a biological dosimeter to experimentally determine the dose rate kinetics in bone marrow.

Differential behavioral response to dopamine D2 agonists by sexually naive, sexually active, and sexually inactive male rats.

This study was performed with male rats categorized as sexually naive (SN), sexually active (SA), or sexually inactive (SI). In a first experiment the effects of dopamine (DA) D2 agonist SND 919 (0.05, 1, and 10 mg/kg) on the copulatory behavior of SN, SA and SI rats were assessed. In a second experiment the DA D2 agonist B-HT 920 (0.2 mg/kg) was used, and examination was limited to SN and SA rats. The effects exerted on stretching-yawning, penile erection, and sedation by the same compounds at the same doses in these three rat categories were also investigated. The main findings were that SND 919 and B-HT 920 facilitated ejaculation in SA rats, and that the rats that were different as regards level of sexual activity exhibited different behavioral responses to the two DA agonists.

Behavioural evidence that different neurochemical mechanisms underly stretching-yawning and penile erection induced in male rats by SND 919, a new selective D2 dopamine receptor agonist.

The behavioural effects induced in male Wistar rats by SND 919, a new drug reputed to have selective agonistic activity at D2 dopamine (DA) receptors, were studied. The following aspects of behaviour were considered: motor activity, stretching-yawning (SY), penile erection (PE) and stereotyped behaviour (SB). Intraperitoneal injection (IP) of the drug (0.01-20 mg/kg) induced an SY syndrome in the form of a bell-shaped dose-response curve, the effect being maximal at the dose of 0.1 mg/kg and disappearing completely at 10 mg/kg. SND 919 also potently elicited PE; this latter effect, however, was not coincident with SY induction, being maximal at 1 mg/kg and persisting at 10 and 20 mg/kg. SND 919-induced SY was potently antagonized by pretreatment not only with the D2 antagonist, L-sulpiride (20 mg/kg), but also with the alpha 2 antagonist, yohimbine (1, 3 mg/kg), and the more selective alpha 2 antagonist, idazoxan (1, 2 and 5 mg/kg). While sulpiride also decreased SND 919-induced PE, idazoxan at all doses and yohimbine at 1 mg/kg did not affect this behaviour. Inhibition of motor activity was induced by the D2 agonist at low doses (0.05, 0.1 mg/kg), while at high doses (1, 10 and 20 mg/kg), it was actually replaced by a form of SB characterized by downward sniffing and licking. When, for comparison, the D2 agonist, RU 24213 (0.1-20 mg/kg IP), was tested for PE, SY, motor activity and SB, it displayed a behavioural pattern very similar to that obtained with SND 919. Idazoxan (2 mg/kg), administered before RU 24213 (10 mg/kg), significantly antagonized the drug-induced SY, but not PE.(ABSTRACT TRUNCATED AT 250 WORDS)

NPY-induced inhibition of male copulatory activity is a direct behavioural effect.

In adult, sexually-experienced male rats, the intracerebroventricular injection of NPY caused a dose-related inhibition of copulatory behaviour, all parameters (mount, intromission and ejaculation latencies, mount and intromission frequencies, mean inter-intromission interval, post-ejaculatory interval) being significantly worsened at the dose of 8 micrograms/rat. Since rats were deprived of food during the behavioural test, it is concluded that inhibition of sexual behaviour is a 'true', direct behavioural effect of NPY, not due to a shift towards increased feeding.

Influence of idazoxan on the dopamine D2 receptor agonist-induced behavioural effects in rats.

The behavioural effects in rats of the dopamine D2 receptor agonists, lisuride, B-HT 920 and SND 919, were variously influenced by pre-treatment with the selective alpha 2-adrenoceptor antagonist, idazoxan (2 mg/kg), depending on the nature of the effect in question and the doses of agonist employed. The influence of idazoxan on drug-induced stretching-yawning, penile erection, sedation, stereotyped behaviour, aggressiveness and mounting is described and tentatively interpreted in neurochemical terms, account being taken of the activity of respective alpha 2-adrenoceptor antagonist and dopamine receptor agonists used, at alpha 2-adrenoceptors and at different dopamine D2 receptor subtypes, pre- and postsynaptically located.