Amplification of Olfactory Signals by Anoctamin 9 is Essential for Mammalian Olfaction: a Risk Factor for the Covid-19-associated Anosmia

Sensing smells of foods, prey, or predators determines animal survival. Olfactory sensory neurons in the olfactory epithelium (OE) detect odorants, where cAMP and Ca2+ play a significant role in transducing odorant inputs to electrical activity. Here we show Anoctamin 9, a cation channel activated by cAMP/PKA pathway, is expressed in the OE and amplifies olfactory signals. Ano9- deficient mice had reduced olfactory behavioral sensitivity, electro-olfactogram signals, and neural activity in the olfactory bulb. In line with the difference in olfaction between birds and other vertebrates, chick ANO9 failed to respond to odorants, whereas chick CNGA2, a major transduction channel, showed greater responses to cAMP. Importantly, single-cell transcriptome data from Covid-19 patients revealed that Ano9 transcripts were markedly suppressed among genes in the olfactory signal pathway. The signal amplification by ANO9 is essential for mammalian olfactory transduction, whose downregulation may be a risk factor for the olfactory dysfunction in Covid-19 patients.

Selective serotonin reuptake inhibitor escitalopram inhibits 5-HT₃ receptor currents in NCB-20 cells

Escitalopram is one of selective serotonin reuptake inhibitor antidepressants. As an S-enantiomer of citalopram, it shows better therapeutic outcome in depression and anxiety disorder treatment because it has higher selectivity for serotonin reuptake transporter than citalopram. The objective of this study was to determine the direct inhibitory effect of escitalopram on 5-hydroxytryptamine type 3 (5-HT₃) receptor currents and study its blocking mechanism to explore additional pharmacological effects of escitalopram through 5-HT₃ receptors. Using a whole-cell voltage clamp method, we recorded currents of 5-HT₃ receptors when 5-HT was applied alone or co-applied with escitalopram in cultured NCB-20 neuroblastoma cells known to express 5-HT₃ receptors. 5-HT induced currents were inhibited by escitalopram in a concentration-dependent manner. EC50 of 5-HT on 5-HT₃ receptor currents was increased by escitalopram while the maximal peak amplitude was reduced by escitalopram. The inhibitory effect of escitalopram was voltage independent. Escitalopram worked more effectively when it was co-applied with 5-HT than pre-application of escitalopram. Moreover, escitalopram showed fast association and dissociation to the open state of 5-HT₃ receptor channel with accelerating receptor desensitization. Although escitalopram accelerated 5-HT₃ receptor desensitization, it did not change the time course of desensitization recovery. These results suggest that escitalopram can inhibit 5-HT₃ receptor currents in a non-competitive manner with the mechanism of open channel blocking.

Gastroprokinetic agent, mosapride inhibits 5-HT₃ receptor currents in NCB-20 cells

Mosapride accelerates gastric emptying by acting on 5-hydroxytryptamine type 4 (5-HT₄) receptor and is frequently used in the treatment of gastrointestinal (GI) disorders requiring gastroprokinetic efficacy. We tested the effect of mosapride on 5-hydroxytryptamine type 3 (5-HT₃) receptor currents because the 5-HT₃ receptors are also known to be expressed in the GI system and have an important role in the regulation of GI functions. Using the whole-cell voltage clamp method, we compared the currents of the 5-HT₃ receptors when 5-HT was applied alone or was co-applied with mosapride in cultured NCB-20 cells known to express 5-HT₃ receptors. The 5-HT₃ receptor current amplitudes were inhibited by mosapride in a concentration-dependent manner. Mosapride blocked the peak currents evoked by the application of 5-HT in a competitive manner because the EC₅₀ shifted to the right without changing the maximal effect. The rise slopes of 5-HT₃ receptor currents were decreased by mosapride. Pre-application of mosapride before co-application, augmented the inhibitory effect of mosapride, which suggests a closed channel blocking mechanism. Mosapride also blocked the opened 5-HT₃ receptor because it inhibited the 5-HT₃ receptor current in the middle of the application of 5-HT. It accelerated desensitization of the 5-HT₃ receptor but did not change the recovery process from the receptor desensitization. There were no voltage-, or use-dependency in its blocking effects. These results suggest that mosapride inhibited the 5-HT₃ receptor through a competitive blocking mechanism probably by binding to the receptor in closed state, which could be involved in the pharmacological effects of mosapride to treat GI disorders.

Tricyclic antidepressant amitriptyline inhibits 5-hydroxytryptamine 3 receptor currents in NCB-20 cells

Amitriptyline, a tricyclic antidepressant, is commonly used to treat depression and neuropathic pain, but its mechanism is still unclear. We tested the effect of amitriptyline on 5-hydroxytryptamine 3 (5-HT₃) receptor currents and studied its blocking mechanism because the clinical applications of amitriptyline overlapped with 5-HT₃ receptor therapeutic potentials. Using a whole-cell voltage clamp method, we recorded the currents of the 5-HT₃ receptor when 5-HT was applied alone or co-applied with amitriptyline in cultured NCB-20 neuroblastoma cells known to express 5-HT₃ receptors. To elucidate the mechanism of amitriptyline, we simulated the 5-HT₃ receptor currents using Berkeley Madonna® software and calculated the rate constants of the agonist binding and receptor transition steps. The 5-HT₃ receptor currents were inhibited by amitriptyline in a concentration-dependent, voltage-independent manner, and a competitive mode. Amitriptyline accelerated the desensitization of the 5-HT₃ receptor. When amitriptyline was applied before 5-HT treatment, the currents rose slowly until the end of 5-HT treatment. When amitriptyline was co-applied with 5-HT, currents rose and decayed rapidly. Peak current amplitudes were decreased in both applications. All macroscopic currents recorded in whole cell voltage clamping experiments were reproduced by simulation and the changes of rate constants by amitriptyline were correlated with macroscopic current recording data. These results suggest that amitriptyline blocks the 5-HT₃ receptor by close and open state blocking mechanisms, in a competitive manner. We could expand an understanding of pharmacological mechanisms of amitriptyline related to the modulation of a 5-HT₃ receptor, a potential target of neurologic and psychiatric diseases through this study.

The Transient Intermediate Plexiform Layer, a Plexiform Layer-like Structure Temporarily Existing in the Inner Nuclear Layer in Developing Rat Retina

The retina is a highly specialised part of the brain responsible for visual processing. It is well-laminated; three layers containing five different types of neurons are compartmentalised by two synaptic layers. Among the retinal layers, the inner nuclear layer (INL) is composed of horizontal, bipolar, and amacrine cell types. Bipolar cells form one sublayer in the distal half of the IPL, while amacrine cells form another sublayer in the proximal half, without any border-like structure. Here, we report that a plexiform layer-like structure exists temporarily in the border between the bipolar and amacrine sublayers in the INL in the rat retina during retinal development. This transient intermediate plexiform layer (TIPL) appeared at postnatal day (PD) 7 and then disappeared around PD 12. Most apoptotic cells in the INL were found near the TIPL. These results suggest that the TIPL may contribute to the formation of sublayers and the cell number limit in the INL.

Reexamination of Dopaminergic Amacrine Cells in the Rabbit Retina: Confocal Analysis with Double- and Triple-labeling Immunohistochemistry

Dopaminergic amacrine cells (DACs) are among the most well-characterized neurons in the mammalian retina, and their connections to AII amacrine cells have been described in detail. However, the stratification of DAC dendrites differs based on their location in the inner plexiform layer (IPL), raising the question of whether all AII lobules are modulated by dopamine release from DACs. The present study aimed to clarify the relationship between DACs and AII amacrine cells, and to further elucidate the role of dopamine at synapses with AII amacrine cell. In the rabbit retina, DAC dendrites were observed in strata 1, 3, and 5 of the IPL. In stratum 1, most DAC dendritic varicosities—the presumed sites of neurotransmitter release—made contact with the somata and lobular appendages of AII amacrine cells. However, most lobular appendages of AII amacrine cells localized within stratum 2 of the IPL exhibited little contact with DAC varicosities. In addition, double- or triple-labeling experiments revealed that DACs did not express the GABAergic neuronal markers anti-GABA, vesicular GABA transporter, or glutamic acid decarboxylase. These findings suggest that the lobular appendages of AII amacrine cells are involved in at least two different circuits. We speculate that the circuit associated with stratum 1 of the IPL is modulated by DACs, while that associated with stratum 2 is modulated by unknown amacrine cells expressing a different neuroactive substance. Our findings further indicate that DACs in the rabbit retina do not use GABA as a neurotransmitter, in contrast to those in other mammals.

Serological Detection of Borrelia burgdorferi among Horses in Korea

Lyme disease is a tick-borne zoonotic infectious disease caused by Borrelia burgdorferi. The present study assessed the infection status of B. burgdorferi among horses reared in Korea using ELISA and PCR. Between 2009 and 2013, blood samples were collected from 727 horses throughout Korea. Data for each animal including age, gender, breed, and region of sample collection were used for epidemiological analysis. Overall, 38 (5.2%; true prevalence: 5.5%) of 727 horses were seropositive by ELISA. There were statistically significant differences according to breed and region (P<0.001) whose differences might be attributed to the ecology of vector ticks and climate conditions. Using 2 nested PCR, none of the samples tested positive for B. burgdorferi. Thus, a positive ELISA result can indicate only that the tested horse was previously exposed to B. burgdorferi, with no certainty over the time of exposure. Since global warming is likely to increase the abundance of ticks in Korea, continuous monitoring of tick-borne diseases in Korean horses is needed.

Otolith Function Tests in Patients with Orthostatic Dizziness / 대한평형의학회지

BACKGROUND AND OBJECTIVES: Orthostatic dizziness (OD) is defined as when dizziness is provoked by standing up from a supine or sitting position. It is usually considered as being associated with orthostatic hypotension (OH). On the other hand, it is recently suggested that otolith organ dysfunction and impaired vestibulosympathetic reflex may account for development of OH and OD. Vestibular evoked myogenic potential (VEMP) and subjective visual vertical and horizontal tests (SVV/SVH) are tools for detecting otolith organ dysfunction. We assessed cervical VEMP (cVEMP) and SVV/SVH test results in the patients with OD to evaluate the relationship between OD and otolith organ function. MATERIALS AND METHODS: Three hundred-eighty-seven patients who visited dizziness clinic were enrolled in this study. Seventy-three patients presented with OD (i.e., group O), while 314 patients did not present OD (i.e., group N). Vestibular function tests including cVEMP and SVV/SVH were performed. RESULTS: cVEMP showed abnormal response in 47.9% of group O and 60.2% of group N. Abnormal SVV was found in 35.6% of group O and 31.5% of group N. Abnormal SVH was highly found in both group O and group N (30.1%, 27.1%). CONCLUSION: The values of SVV/SVH and cVEMP abnormality from both groups were not significantly different between the groups O and N. This finding suggests that otolithic function may not be related with OD.

Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia

Gynecomastia is a benign enlargement of the male breast caused by the proliferation of glandular breast tissue. Determining the various causes of gynecomastia such as physiological causes, drugs, systemic diseases, and endocrine disorders is important. Androgen insensitivity syndrome (AIS) is a rare endocrine disorder presenting with gynecomastia and is a disorder of male sexual differentiation caused by mutations within the androgen receptor gene. All individuals with AIS have the 46 XY karyotype, although AIS phenotypes can be classified as mild, partial or complete and can differ among both males and females including ambiguous genitalia or infertility in males. We experienced a case of partial AIS presenting with gynecomastia and identified the androgen receptor gene mutation.

Serum Magnesium Level Is Associated with Type 2 Diabetes in Women with a History of Gestational Diabetes Mellitus: The Korea National Diabetes Program Study

Gestational diabetes mellitus (GDM) is a strong predictor of postpartum prediabetes and transition to overt type 2 diabetes (T2DM). Although many reports indicate that low magnesium is correlated with deteriorated glucose tolerance, the association between postpartum serum magnesium level and the risk for T2DM in women with a history of GDM has not been evaluated. We analyzed postpartum serum magnesium levels and development of prediabetes and T2DM in women with prior GDM according to American Diabetes Association (ADA) criteria using the Korean National Diabetes Program (KNDP) GDM cohort. During a mean follow-up of 15.6+/-2.0 months after screening, 116 women were divided into three groups according to glucose tolerance status. Ultimately, eight patients (6.9%) were diagnosed with T2DM, 59 patients (50.9%) with prediabetes, and 49 patients (42.2%) with normal glucose tolerance (NGT) after follow-up. The T2DM group had the lowest serum magnesium level (0.65 [0.63-0.68] mM/L) in the postpartum period, but there was no significant difference between the prediabetes group (0.70 [0.65-0.70] mM/L) and the NGT group (0.70 [0.65-0.70] mM/L) (P=0.073) Multiple logistic regression analysis showed that postpartum HOMA-IR was a significant predictor of both prediabetes and T2DM. Moreover, we found that postpartum serum magnesium level was also a possible predictor for T2DM development. Serum magnesium level in the postpartum period may be a possible predictor for T2DM development in women with a history of GDM.

Comparison of Acarbose and Voglibose in Diabetes Patients Who Are Inadequately Controlled with Basal Insulin Treatment: Randomized, Parallel, Open-Label, Active-Controlled Study

We studied the efficacy and safety of acarbose in comparison with voglibose in type 2 diabetes patients whose blood glucose levels were inadequately controlled with basal insulin alone or in combination with metformin (or a sulfonylurea). This study was a 24-week prospective, open-label, randomized, active-controlled multi-center study. Participants were randomized to receive either acarbose (n=59, 300 mg/day) or voglibose (n=62, 0.9 mg/day). The mean HbA1c at week 24 was significantly decreased approximately 0.7% from baseline in both acarbose (from 8.43% +/- 0.71% to 7.71% +/- 0.93%) and voglibose groups (from 8.38% +/- 0.73% to 7.68% +/- 0.94%). The mean fasting plasma glucose level and self-monitoring of blood glucose data from 1 hr before and after each meal were significantly decreased at week 24 in comparison to baseline in both groups. The levels 1 hr after dinner at week 24 were significantly decreased in the acarbose group (from 233.54 +/- 69.38 to 176.80 +/- 46.63 mg/dL) compared with the voglibose group (from 224.18 +/- 70.07 to 193.01 +/- 55.39 mg/dL). In conclusion, both acarbose and voglibose are efficacious and safe in patients with type 2 diabetes who are inadequately controlled with basal insulin. (ClinicalTrials.gov number, NCT00970528)

Meteorological Conditions Related to the Onset of Idiopathic Sudden Sensorineural Hearing Loss

PURPOSE: The objective of this study was to evaluate the effect of meteorological factors on the onset of idiopathic sudden sensorineural hearing loss (ISSHL). MATERIALS AND METHODS: Meteorological data from 2005 to 2011 were obtained from the web-based "Monthly Weather Reports of the Meteorological Administration" database. Patients with ISSHL who visited our hospital during this same period and presented the precise day on which hearing loss developed were included in this retrospective study. Twelve meteorological factors were analyzed between the days when ISSHL onset was observed as well as the days when ISSHL did not occur. The weather conditions occurring 1-7 days before ISSHL onset were also analyzed to assess any possible delayed effects of meteorological factors on the onset of ISSHL. RESULTS: During the study period, 607 patients were included for the study. Although mean and maximal wind velocities were higher for the days when ISSHL occurred than the days without ISSHL onset, after adjusting the value for multiple comparisons, we cannot find any significant relationship between any of meteorological factors and the onset of ISSHL. However, in analysis of time lag effect of the weather conditions, we found that there was still a significant difference in maximum wind speed on 5 days before ISSHL onset even after applying Bonferroni correction. CONCLUSION: The result of this study suggests that stronger wind speed may be related to the occurrence of ISSHL.

Hypothyroidism With Acute Renal Failure and Heart Failure

Here we report a 65-year-old male patient initially presented with dyspnea and chest discomfort. This patient was finally diagnosed with severe hypothyroidism accompanied by heart failure, pericardial effusion and acute renal failure. We suspected that heart failure, pericardial effusion and acute kidney injury were induced by severe hypothyroidism. Thus, we began thyroid hormone replacement therapy. After the therapy, the patient's dyspnea and chest discomfort were improved. Hypothyroidism has many complications, such as myxedema, dyslipidemia, and depression. In contrast, heart failure, pericardial effusion, and acute kidney injury are very rare complications of hypothyroidism. Only a few cases of heart failure or renal failure combined with hypothyroidism have been reported. Our case suggests that severe hypothyroidism can lead to multiorgan failure, such as heart failure as well as renal failure. Moreover, congestive heart failure induced by severe hypothyroidism can be reversed by thyroid hormone replacement therapy.

A Case of Acute Suppurative Thyroiditis with Thyrotoxicosis in an Elderly Patient

Acute suppurative thyroiditis (AST) is a rare condition, as the thyroid gland is relatively resistant to infection. Thyroid function tests are usually normal in AST. A few cases of AST associated with thyrotoxicosis have been reported in adults. We report a case of AST that was associated with thyrotoxicosis in a 70-year-old woman. We diagnosed AST with thyroid ultrasonography and fine needle aspiration of pus. The patient improved after surgical intervention and had no anatomical abnormality. Fine needle aspiration is the best method for the difficult task of differentiating malignancy and subacute thyroiditis from AST with thyrotoxicosis. Earlier diagnosis and proper treatment for AST might improve the outcome.

Small-Group Counseling in a Modified Tinnitus Retraining Therapy for Chronic Tinnitus

OBJECTIVES: The authors have treated chronic tinnitus patients using a combination of a simplified tinnitus retraining therapy (TRT) and medications, which we called modified TRT. In this clinical setting, we have attempted small-group counseling to find a time-effective equivalent of individual counseling. The aim of the present study was to evaluate the effectiveness of small-group counseling by comparing the treatment outcomes between individual and small-group counseling. METHODS: The patients who had distressing chronic tinnitus with normal hearing or mild hearing loss were included. The subjects were placed into the small-group (group 1:4) or the individual (group 1:1) counseling group, and underwent a modified TRT composed of a single session of directive counseling and ambient sound stimulation. In addition, alprazolam (0.25 mg) and ginkgo biloba extract (80 mg) were administered orally to the subjects for 3 months. The 3- and 6- month outcomes were assessed using the follow-up rates and tinnitus severity scores: awareness, tinnitus handicap inventory (THI), loudness, annoyance, and effect on life. The treatment responses were classified as improvement, no changes, and worsening. RESULTS: Of the total 149 patients (77 in group 1:1; 72 in group 1:4), 104 patients completed the protocol at 3 months, and 55 patients at 6 months. The follow-up rates were similar in both groups. Over the period of 6 months, all scores declined significantly except the loudness score at 3 months in both groups. Treatment responses showed no between-group differences. The success rate based on THI was 70% in group 1:1, and 64% in group 1:4 at 6 months. CONCLUSION: The small-group counseling of our modified TRT was comparable to the individual counseling for tinnitus relief. We suggest that this protocol can be implemented effectively in any crowded otolaryngology clinics.

Insulin secretion and insulin resistance in Korean women with gestational diabetes mellitus and impaired glucose tolerance

BACKGROUND/AIMS: The aim was to compare the insulin sensitivity and secretion index of pregnant Korean women with normal glucose tolerance (NGT), gestational impaired glucose tolerance (GIGT; only one abnormal value according to the Carpenter and Coustan criteria), and gestational diabetes mellitus (GDM). METHODS: A cross-sectional study was performed with 1,163 pregnant women with positive (1-hour plasma glucose > or = 7.2 mmol/L) in a 50-g oral glucose challenge test (OGCT). The 100-g oral glucose tolerance test (OGTT) was used to stratify the participants into three groups: NGT (n = 588), GIGT (n = 294), and GDM (n = 281). RESULTS: The GDM group had higher homeostasis model assessment of insulin resistance and lower insulin sensitivity index (ISOGTT), quantitative insulin sensitivity check index, homeostasis model assessment for estimation of index beta-cell secretion (HOMA-B), first and second phase insulin secretion, and insulin secretion-sensitivity index (ISSI) than the NGT group (p < or = 0.001 for all). Moreover, the GIGT group had lower ISOGTT, HOMA-B, first and second phase insulin secretion, and ISSI than the NGT group (p < 0.001 for all). Among the GIGT subjects, the 1-hour plasma glucose abnormal levels group showed significantly greater weight gain during pregnancy and higher values in the 50-g OGCT than the other two groups. Moreover, the 1-hour and 2-hour abnormal levels groups had poorer insulin secretion status than the 3-hour abnormal levels group. CONCLUSIONS: Korean women with GDM show impairments of both insulin secretion and insulin sensitivity. In addition, GIGT is associated with both beta-cell dysfunction and insulin resistance.

A Case of Metformin-Induced Acute Kidney Injury without Lactic Acidosis: A Case Report / 대한구급학회지

Metformin is an oral antidiabetic drug in the biguanide class, which is used for type 2 diabetes. The side effects of metformin are mostly limited to digestive tract symptoms, such as diarrhea, flatulence and abdominal discomfort. The most serious potential adverse effect of metformin is lactic acidosis. A 51-year-old man was admitted due to hypoglycemia as a result of an overdose of antidiabetic drugs. He took massive dose of metformin. Conservative treatment failed for metabolic acidosis without lactic acidosis accompanied by acute kidney injury. Hemodialysis was executed to correct the high anion gap metabolic acidosis and acute kidney injury, and the patient recovered fully from metabolic acidosis. This case illustrates that the presence of clinical conditions, such as metformin-induced acute kidney injury and metabolic acidosis, can be developed without lactic acidosis. Prompt recognition of metabolic acidosis and early intervention with hemodialysis can result in a successful clinical outcome.

Correlation of Threshold of Click-Evoked Auditory Brainstem Response with Pure-Tone Threshold Average in Various Formulas / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: The aim of this study is to assess the correlation between the threshold of click-evoked auditory brainstem response (ABR) and the pure-tone averages in various formulas. SUBJECTS AND METHOD: Data were obtained from 207 patients (326 ears) with sudden sensorineural hearing loss. All subjects underwent hearing threshold evaluation using pure tone audiogram (PTA), speech audiogram and click-evoked ABR. Linear regression analyses were applied to assess the relation between threshold of click-evoked ABR and threshold of separate frequencies of the PTA and to analyze the correlation between threshold for click-evoked ABR and various pure-tone averages. RESULTS: Results revealed a significant relation between the threshold of click-evoked ABR and PTA thresholds at 0.5 kHz, 1 kHz, 2 kHz, 3 kHz, and 4 kHz. The highest coefficients of regression and determination were 1.026 for 4 kHz and R2=0.663 for 3 kHz, respectively. The coefficient of regression was highest (=0.995) for the mean of PTA thresholds for 3 kHz and 4 kHz. The coefficient of determination was highest for the mean of PTA thresholds for 1, 2, 3 and 4 kHz (R2=0.732). Multiple regression analysis showed a significant relation between the ABR threshold and PTA thresholds for 1, 3, and 4 kHz (R2=0.732), with highest correlation coefficient at 3 kHz [ABR=11.79+(0.17x1 kHz)+(0.26x3 kHz)+(0.23x4 kHz), (p<0.05)]. CONCLUSION: The threshold of click-evoked ABR correlates best with the mean of PTA thresholds for 1, 2, 3 and 4 kHz. The PTA threshold for 3 kHz has highest correlation with the ABR threshold.

Role of Interleukin-10 on Mouse Otitis Media Model Using Lipopolysaccharide / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Interleukin (IL)-10 is a major regulator of innate immunity. It interferes with the production of inflammatory mediators by reacting with polymorphonuclear neutrophils, monocytes and macrophages. In addition, it also up-regulates the ex-pression of molecules that amplify the anti-inflammatory effect of IL-10. This study tested the hypothesis that injection of various concentrations of exogenous IL-10 in the middle ear cleft can inhibit the acute stage of otitis media induced by lipopolysaccharide (LPS). And if so, the level of concentration for inhibition can be determined. MATERIALS AND METHOD: IL-10 and/or LPS were injected transtympanically into the middle ear cavity of normal mice. Histopathological measurement of submucosal thickness and num-ber of inflammatory cell infiltration was performed at 24 hours after inoculation of IL-10 and/or LPS. RESULTS: At 24 hours after inoculation, every group of IL-10 inoculation reduced both thickening of the mucous and submucosal infiltration of inflammatory cells in a dose-dependent manner. As the concentrations of IL-10 inoculated increased, mucosal thickness and submucosal infiltration of inflammatory cells were more reduced. CONCLUSION: This study demonstrated that exogenous IL-10 injection into the middle ear can directly reduce LPS-induced otitis media in acute stage in a dose-dependent manner. These findings also indicate that IL-10 may be a candidate for local modulator of acute otitis media.

Erratum: ACKNOWLEDGMENTS

No abstract available.