Association of cigarette smoking with a past history and incidence of herpes zoster in the general Japanese population: the SHEZ Study.

Few studies have examined the impact of cigarette smoking on the risk for herpes zoster. The Shozu Herpes Zoster (SHEZ) Study is a community-based prospective cohort study over 3 years in Japan aiming to clarify the incidence and predictive and immunological factors for herpes zoster. We investigated the associations of smoking status with past history and incidence of herpes zoster. A total of 12 351 participants provided valid information on smoking status and past history of herpes zoster at baseline survey. Smoking status was classified into three categories (current, former, never smoker), and if currently smoking, the number of cigarettes consumed per day was recorded. The participants were under the active surveillance for first-ever incident herpes zoster for 3 years. We used a logistic regression model for the cross-sectional study on the association between smoking status and past history of herpes zoster, and a Cox proportional hazards regression model for the cohort study on the association with risk of incidence. The multivariable adjusted odd ratios (95% CI) of past history of herpes zoster for current vs. never smokers were 0·67 (0·54-0·80) for total subjects, 0·72 (0·56-0·93) for men and 0·65 (0·44-0·96) for women. The multivariable adjusted hazard ratios (95% CI) of incident herpes zoster for current vs. never smokers were 0·52 (0·33-0·81) for total subjects, 0·49 (0·29-0·83) for men and 0·52 (0·19-1·39) for women. Smoking status was inversely associated with the prevalence and incidence of herpes zoster in the general population of men and women aged ⩾50 years.

A new simple score (ABS) for assessing behavioral and psychological symptoms of dementia.

In addition to cognitive impairment, behavioral and psychological symptoms of dementia (BPSD) are another important aspect of most dementia patients. This study was designed for a new simple assessment of BPSD. We first employed a clinical survey for the local community with sending an inquiry letter to all members (n=129) of dementia caregiver society, and then attempted to create a new BPSD score for dementia with 10 BPSD items. This new simple BPSD score was compared to a standard-detailed BPSD score neuropsychiatric inventory (NPI) for a possible correlation (n=792) and a time to complete (n=136). Inter-rater reliability was examined comparing scores between main and second caregivers (n=70) for AD. Based on the clinical survey for local caregivers, a new BPSD score for dementia (ABS, Abe's BPSD score) was newly created, in which each BPSD item was allotted by an already-weighted score (maximum 1-9) based on the frequency and severity, and was finalized with taking temporal occurrences into account. ABS was filled by the main caregiver with a full score of 44, was well correlated with NPI (r=0.716, **p<0.01) in 792 AD patients (age 78.6 ± 7.0 years, MMSE 19.0 ± 5.9), and took a shorter time as only 56.8 ± 38.8s (**p<0.01) than NPI score (132.7 ± 94.0 s) with 136 AD patients. A high inter-rater reliability was obtained (r=0.964, **p<0.01) with a little smaller score (0.877 time) of ABS in secondary than the main caregivers. ABS provides a new simple and quick test for BPSD assessment, with a good correlation to NPI but a shorter time, and with a high inter-rater reliability. Thus ABS is useful for evaluating BPSD for mild to moderate dementia patients.

Switching dynamics and linear response spectra of a driven one-dimensional nonlinear lattice containing an intrinsic localized mode.

An intrinsic localized mode (ILM) represents a localized vibrational excitation in a nonlinear lattice. Such a mode will stay in resonance as the driver frequency is changed adiabatically until a bifurcation point is reached, at which point the ILM switches and disappears. The dynamics behind switching in such a many body system is examined here through experimental measurements and numerical simulations. Linear response spectra of a driven micromechanical array containing an ILM were measured in the frequency region between two fundamentally different kinds of bifurcation points that separate the large amplitude ILM state from the two low amplitude vibrational states. Just as a natural frequency can be associated with a driven harmonic oscillator, a similar natural frequency has been found for a driven ILM via the beat frequency between it and a weak, tunable probe. This finding has been confirmed using numerical simulations. The behavior of this nonlinear natural frequency plays important but different roles as the two bifurcation points are approached. At the upper transition its frequency coalesces with the driver and the resulting bifurcation is very similar to the saddle-node bifurcation of a single driven Duffing oscillator, which is treated in an Appendix. The lower transition occurs when the four-wave mixing partner of the natural frequency of the ILM intersects the topmost extended band mode of the same symmetry. The properties of linear local modes associated with the driven ILM are also identified experimentally for the first time and numerically but play no role in these transitions.

Assessment of skin test with varicella-zoster virus antigen for predicting the risk of herpes zoster.

The Shozu Herpes Zoster (SHEZ) Study was designed to clarify the incidence of and predictive and immunological factors for herpes zoster in a defined community-based Japanese population. As part of this series, a total of 5683 residents aged ≥50 years received a varicella-zoster virus (VZV) skin test with VZV antigen, and 48 h later, the erythema and oedema were assessed by measuring the longest diameter. The diameters of both the erythema and oedema decreased with the increasing age of the subject. Sixty-three subjects contracted herpes zoster within a year after receiving the VZV skin test. Analysis of the herpes zoster incidence rate vs. the skin test reaction revealed that the shorter the diameter of erythema or oedema, the greater the likelihood of herpes zoster. These results demonstrated that the VZV skin test is an excellent surrogate marker for predicting the risk of herpes zoster.

Cognitive and affective impairments of a novel SCA/MND crossroad mutation Asidan.

BACKGROUND: A variety of hereditary spinocerebellar ataxia (SCA) develops a broad spectrum of both ataxia and non-ataxia symptoms. Cognitive and affective changes are one such non-ataxia symptoms, but have been described only in hereditary SCAs with exonic CAG gene expansion. METHODS: We newly found intronic hexanucleotide GGCCTG gene expansion in NOP56 gene as the causative mutation (=SCA36) in nine unrelated Japanese familial SCA originating from Asida river area in the western part of Japan, thus nicknamed Asidan for this mutation. These patients show unique clinical balance of cerebellar ataxia and motor neuron disease (MND), locating on the crossroad of these two diseases. In the nine families, 14 patients were clinically examined and genetically confirmed to Asidan. In the present study, we examined cognitive and affective analyses on 12 patients (seven men and five women) who agreed to join the examination with average age at onset of 53.1 ± 3.2 years, average duration of 12.1 ± 5.2 years, and current average age at 65.1 ± 6.2 years. RESULTS: The 12 Asidan patients demonstrated a significant decrease in their frontal executive functions measured by frontal assessment battery (FAB) and Montreal cognitive assessment (MoCA) compared with age- and gender-matched controls, whilst mini-mental state examination (MMSE) and Hasegawa dementia score-revised (HDS-R) were within normal range. The decline of frontal executive function was related to their disease duration and scale for the assessment and rating of ataxias (SARA). They also demonstrated mild depression and apathy. Single-photon emission tomography (SPECT) analysis showed that these Asidan patients showed decline of regional cerebral blood flow (rCBF) in a particular areas of cerebral cortices such as Brodmann areas 24 and 44-46. CONCLUSION: These data suggest that the patients with Asidan mutation show unique cognitive and affective characteristics different from other hereditary SCAs with exonal CAG expansion or MND.

Experimental observation of the bifurcation dynamics of an intrinsic localized mode in a driven 1D nonlinear lattice.

Linear response spectra of a driven intrinsic localized mode in a micromechanical array are measured as it approaches two fundamentally different kinds of bifurcation points. A linear phase mode associated with this autoresonant state softens in frequency and its amplitude grows as the upper frequency bifurcation point is approached, similar to the soft-mode kinetic transition for a single driven Duffing resonator. A lower frequency bifurcation point occurs when the four-wave-mixing partner of this same phase mode intercepts the top of the extended wave branch, initiating a second kinetic transition process.

Effects of cementum-dentine junction and cementum on the mechanical response of tooth supporting structure.

OBJECTIVES: The aim of the present work is to investigate the effects of cementum-dentine junction (CDJ) and cementum on the stress distribution in the periodontal ligament (PDL) and alveolar bone. METHODS: Based on the anatomical profiles and the recently reported theories about the tooth attachment mechanism, the finite element (FE) model of a mandibular second premolar along with its detailed supporting structures was developed. The effect of CDJ and cementum was evaluated by comparing the resulting stresses of FE models of the second mandibular premolar with and without CDJ and cementum in tooth supporting structure. RESULTS: The stress levels are higher in the structure without CDJ and cementum than that with CDJ and cementum. The function of CDJ and cementum is as a cushion pad decreasing the stress in the PDL and alveolar bone under loading. CONCLUSIONS: As a major result of this study, it can be concluded that the CDJ and cementum significantly influence the stress distribution within the tooth supporting structure. However, most of the reported FE analysis did not take CDJ and cementum into account, which possibly resulted in overestimated stress values in the PDL and alveolar bone. From a bio-engineering perspective, the results of this study provide guidance for the design of dental implants and the application of orthodontic force system as well.

Surface characteristics and in vitro biocompatibility of titanium anodized in a phosphoric acid solution at different voltages.

The surface of commercially pure titanium was modified by anodization treatment in a phosphoric acid solution at different voltages: 100 V, 200 V and 300 V. The surface characteristics of anodic TiO2 layers and their influence on the cell response were investigated. Micrographs by scanning electron microscopy revealed that the dense and uniform oxide layer obtained at 100 V exhibits a nanostructured surface which is similar to the surface of natural tooth cementum. In contrast, porous oxide layers without nanometer features were produced at higher voltages. Thin film x-ray diffraction analysis confirmed the existence of anatase in the oxide layer obtained at 300 V, but not in oxide layers obtained at 100 V and 200 V. The in vitro biocompatibility study of oxide layers demonstrated greater cell adhesion and proliferation of the oxide layer obtained at 100 V compared to the other two kinds of oxide layers.

Elevation of neuron-specific enolase in serum and cerebrospinal fluid of early stage Creutzfeldt-Jakob disease.

OBJECTIVE: To investigate the levels of neuron-specific enolase (NSE) in serum and cerebrospinal fluid (CSF) of patients with early stage Creutzfeldt-Jakob disease (CJD). METHODS: The levels of NSE in serum and CSF were examined in 6 cases with CJD patients. The levels of NSE in CSF were measured in 8 age matched control patients with other neurological diseases and the levels of serum NSE were also measured in another 8 age matched control patients with other neurological diseases. The groups of 8 age matched control patients consisted of 1 same patient and 7 different patients in the 2 control groups both for serum and CSF. RESULTS: The level of serum NSE in CJD (17.3 +/- 7.0 ng/ml, mean +/- SD) was significantly higher than that of controls (6.5 +/- 1.6) (P < 0.02) as was the case in CSF (79.3 +/- 53.3 ng/ml) vs (9.6 +/- 2.9) (P < 0.03). CONCLUSION: Although mean NSE levels of CJD were higher in CSF than in the serum, there still is a case with higher serum NSE level than CSF. These results suggest that the mechanism of elevation of serum NSE may not be a simple leakage from CSF, and that the measurement of serum NSE level may be useful for diagnosis of early stage CJD.

Diclofenac and flurbiprofen with or without clonidine for postoperative analgesia in children undergoing elective ophthalmological surgery.

We conducted a prospective, randomized study to compare the efficacy of preoperative diclofenac, flurbiprofen, and clonidine, given alone, as well as the combination of diclofenac and clonidine, and flurbiprofen and clonidine in controlling postoperative pain in 125 children. The patients (ASA I, 2-12 years) undergoing elective ophthalmological surgery were allocated to one of five groups: rectal diclofenac 2 mg.kg(-1) following oral placebo premedication, i. v. flurbiprofen 1 mg.kg(-1) following placebo premedication, oral clonidine premedication, rectal diclofenac 2 mg.kg(-1) following clonidine, and i.v. flurbiprofen 1 mg.kg(-1) following clonidine. The children received clonidine (4 microg.kg(-1)) or placebo 105 min before anaesthesia. Diclofenac or flurbiprofen was given immediately after induction of anaesthesia. Anaesthesia was induced and maintained with sevoflurane and nitrous oxide in oxygen. Postoperative pain was assessed by a blinded observer using a modified objective pain scale (OPS). No opioids were administered throughout the study. Rectal diclofenac 2 mg.kg(-1) i.v. flurbiprofen 1 mg.kg(-1), oral clonidine 4 microg.kg(-1) provided similar OPS scores and requirement for supplementary analgesics during 12 h after surgery. Combination of oral clonidine and one of these nonsteroidal analgesics minimized postoperative pain. Our findings suggest that this combined regimen may be a promising prophylactic approach to postoperative pain control in children undergoing ophthalmological surgery.

Alteration of colonic mucin after ureterosigmoidostomy.

PURPOSE: Patients undergoing urinary diversion by ureterosigmoidostomy after complete cystectomy for malignant bladder tumors show a high incidence of neoplasia at and near the site of anastomosis. We examined a risk factor for tumor occurrence in the area of anastomosis, alterations of mucus glycoproteins in the surrounding colonic mucosa. METHODS: Colonoscopy was performed in 37 patients who had undergone ureterosigmoidostomy. Biopsy specimens were obtained near the ureteral anastomosis and were stained with hematoxylin and eosin, high iron-diamine alcian blue (pH 2.5), and a fluorescent lectin conjugate (peanut agglutinin). RESULTS: At the anastomotic site colonoscopy showed protruding lesions in 26 of 37 patients (71 percent), all histologically representing inflammatory granulomas. The mucosa around the anastomosis was normal in endoscopic appearance; however, histologically, slight inflammatory cell infiltration, edema, and increased numbers of Paneth cells were observed. Alcian blue staining revealed an increase in mucosal sialomucin postoperatively compared with preoperatively. The proportion of peanut agglutinin-binding mucin, not observed in normal mucosa but seen in malignant or premalignant tissue, was increased. CONCLUSION: As postoperative interval increases, changes in properties of the "background" mucosa become greater, which suggests an association with colonic carcinogenesis.

Ethanol patch test: a simple method for identifying the effectiveness of cyanamide in alcoholics.

BACKGROUND: To identify the pharmacological effectiveness of cyanamide, 144 alcoholics treated with cyanamide were subjected to a test that used an acetaldehyde dehydrogenase (ALDH) inhibitor, the ethanol patch test, which is considered to be a good indicator of ALDH2 phenotype. METHODS: We placed 100 microl of 70% ethanol on a lint pad and, as a control, placed the same volume of distilled water on a second pad. The ethanol patch test was performed on 144 alcoholics more than 2 weeks after abstinence from alcohol before and after treatment with cyanamide for 1 week. The dose of cyanamide was increased up to 150 mg until the patch test yielded a positive result. RESULTS: In the ethanol patch test, 36 alcoholics (25.0%) gave a positive result before treatment with cyanamide and might have been ALDH2(1)/2(2) heterozygotes. Among 108 alcoholics who were not positive, the distribution of the cyanamide dose that yielded a positive ethanol patch test result was 30 mg in 42 cases (38.9%), 50 mg in 33 cases (30.6%), 70 mg in 5 cases (4.6%), 100 mg in 6 cases (5.6%), and 150 mg in 2 cases (1.9%). Prevalence of liver cirrhosis was significantly higher in alcoholics who showed a positive ethanol patch test result at doses of less than 50 mg cyanamide than those at doses more than 70 mg (p = 0.029). The prevalence of adverse effects was significantly higher in alcoholics who showed a positive ethanol patch test result at doses of more than 70 mg than at doses of less than 50 mg cyanamide (p = 0.002). CONCLUSIONS: The ethanol patch test is a useful method for identifying pharmacological effectiveness of cyanamide and may reduce the prevalence of side effects in cyanamide-treated alcoholics.

A comparison of rabeprazole, lansoprazole, and ranitidine for improving preoperative gastric fluid property in adults undergoing elective surgery.

UNLABELLED: Acid aspiration syndrome at the induction of anesthesia is still a potentially life-threatening complication. Its severity is affected by both pH and volume of the gastric juice that is aspirated. We compared the effects of rabeprazole (a new proton pump inhibitor), lansoprazole, and ranitidine on gastric fluid properties in a prospective, randomized, double-blinded fashion in 180 adult patients undergoing elective surgery. Patients were divided into six groups (n = 30 in each) according to their premedication. Patients in each group received placebo-rabeprazole (PLA-RAB), rabeprazole-placebo (RAB-PLA), rabeprazole-rabeprazole (RAB-RAB), lansoprazole-lansoprazole (LAN-LAN), placebo-ranitidine (PLA-RAN), or placebo-placebo (PLA-PLA) for the first-second medication. Each dose of the study drug was 20 mg for rabeprazole, 30 mg for lansoprazole, and 150 mg for ranitidine. The first medication was given orally at 9:00 PM on the day before surgery and the second at 5:30 AM on the day of surgery. Each patient fasted overnight and took the drug with 20 mL of water. After tracheal intubation, gastric fluid was aspirated via an orogastric tube, and the volume and pH of the aspirate was measured. Preoperative gastric fluid acidity and volume were improved by the study drugs in the following order: PLA-RAN (pH 5.3, volume 0.10 mL/kg), RAB-RAB, LAN-LAN, PLA-RAB, and RAB-PLA (pH 3.8, volume 0.22 mL/kg). The proportion of patients at risk of acid aspiration syndrome according to the traditional criteria (pH < 2.5 and volume > 0.4 mL/kg) was minimized in Groups RAB-RAB and PLA-RAN (0%). We concluded that a single morning dose of ranitidine rather than two doses (bedtime and morning) of rabeprazole was the most effective premedicant to control gastric fluid properties and to minimize the risk of aspiration pneumonitis. IMPLICATIONS: Acid aspiration syndrome at the induction of anesthesia is rare but still a potentially life-threatening complication. We compared rabeprazole, lansoprazole, and ranitidine for reduction of preoperative gastric fluid acidity and volume in elective surgery and found that a combination of bedtime and morning doses of rabeprazole, or a morning dose of ranitidine, similarly minimized the variables. In adult patients who are at risk of aspirating gastric contents, improvement of gastric fluid environment by rabeprazole can reasonably be anticipated to provide protection against pneumonitis should regurgitation and aspiration of gastric contents occur.

[Reduction of the influence of the liver uptake to the myocardial uptake on technetium-99m myocardial SPECT; usefulness and problems of a mask processing method].

The aim of this study is to evaluate the usefulness of a mask processing method for obtaining the true myocardial tracer distribution by eliminating the influence of the liver uptake to the myocardial uptake on myocardial SPECT images by using technetium-99m (99mTc) blood flow agents. A SPECT imaging was performed with a two-head SPECT system (GCA-7200A/DI) in both phantom and clinical studies. The mask processing method was applied to the reconstructed and projection images. The phantom consisted of heart, lung, liver and spine. A defect was located in the inferior wall of the left ventricle and other parts of the heart and liver were filled with 99mTc solution. For clinical study 10 patients with difficulty in the interpretation of the inferior wall were selected for the evaluation of usefulness of the mask method. In the phantom study, the mask processing method applied to the reconstructed images was able to remove the overlapped liver from the heart, but was not able to remove the influence of the liver uptake to the myocardial uptake. Nevertheless, the mask processing method applied to the projection images successfully eliminated not only the overlapped liver but also the influence of the liver uptake to the myocardial uptake. In the clinical study, the liver uptake could be removed from the uptake in the inferior wall in 8 of 10 patients with the mask processing methods. In 2 patients, the overlapped liver uptake could not be eliminated from the uptake in the inferior wall because the distance between the liver and heart was too short. The mask processing method applied to the projection images was thought to be superior to that applied to the reconstruction images in both phantom and clinical studies. The mask processing method, especially applied to the projection images, seems to be useful for the elimination of the liver uptake from the inferior wall of the myocardium on myocardial SPECT images using 99mTc blood flow agents.

Effects of exogenous surfactant on acute lung injury induced by intratracheal instillation of infant formula or human breast milk in rabbits.

BACKGROUND: An animal experimental model of acute lung injury after intratracheal instillation of acidified milk products has been recently demonstrated. Exogenous administration of surfactant has proved to be successful treatment for acute lung injury induced by many causes including acid aspiration. The authors conducted this study to investigate whether exogenous surfactant can reduce the magnitude of lung damage induced in rabbits by acidified milk products. METHODS: The lung injury was induced by intratracheal instillation of acidified human breast milk or acidified infant formula (0.8 ml/kg, pH 1.8). Thirty minutes after the insult, some animals were treated with intratracheal surfactant 100 or 200 mg/kg. Lung compliance and alveolar-to-arterial oxygen gradient were recorded during ventilation. After 4 or 12 h, the lungs were excised to determine physiologic and histologic lung damage. Albumin, interleukin-8, and eicosanoids in bronchoalveolar lavage fluid and superoxide production by neutrophils were measured. RESULTS: The acidified milk products increased A-aD(O2)(550+/-52 and 156+/-28 mmHg; mean+/-SD at 4 h in saline solution and infant formula groups, respectively), lung wet-to-dry weight ratio (6.6+/-0.5 and 5.6 +/- 0.2), %neutrophils in bronchoalveolar lavage fluid (84+/-4% and 8+/-20%), and decreased compliance (0.76+/-0.09 and 1.90+/-0.11 ml/cm H2O). Surfactant improved these variables in a dose-dependent manner (A-aDO2 = 363+/-50 and 237+/-55 mmHg in 100-mg/kg and 200-mg/kg surfactant groups). Surfactant attenuated extensive histologic changes caused by the milk products. Superoxide production was less in rabbits receiving surfactant than in those not receiving it. CONCLUSION: Exogenous surfactant improved physiologic, histologic, and biochemical lung injury induced by acidified milk products in a dose-dependent manner. The effectiveness of surfactant may be caused, in part, by inhibition of neutrophils' sequestration and activation. These data indicate that intratracheal instillation of surfactant may be a promising therapeutic modality in acute lung injury resulting from aspiration of acidified milk products.

CD9 is expressed on the cell surface of human granulosa cells and associated with integrin alpha6beta1.

The CD9 molecule is a 24-27 kDa cell surface glycoprotein which is reported to be involved in cell adhesion and migration. Recently, CD9 was shown to be associated with beta1-related integrins. We have previously found that integrin alpha6beta1 is expressed on human granulosa cells (GC) and regulates luteinization of GC in concert with its ligand laminin. In this study, we examined the expression of CD9 in human ovary and the relationship between CD9 and integrin alpha6beta1 in GC. By immunohistochemistry, CD9 was detected on GC in a small antral follicle of <1 mm in diameter. In growing follicles, CD9 was moderately expressed on both GC and theca interna cells (TI). The expression intensity of CD9 on GC increased in preovulatory follicles. In the early luteal phase, CD9 was expressed in both luteinizing GC and TI. The expression intensity on large luteal cells decreased in the mid-luteal phase. In the corpus luteum (CL) of pregnancy, CD9 continued to be expressed on large luteal cells, but not on small luteal cells. By flow cytometry, CD9 was detected on the cell surface in approximately 90% of the isolated GC from patients undergoing in vitro fertilization. The molecular weight of CD9 in the isolated GC was shown to be 26.5 kDa by Western blotting. CD9 mRNA was also detected in the isolated GC and CL by reverse transcription-polymerase chain reaction (RT-PCR). The proteins purified from GC by immunoaffinity chromatography using anti-integrin alpha6 monoclonal antibodies were shown by Western blotting to include CD9 as well as integrin beta1. These findings suggest that CD9 is a differentiation-related molecule of GC and TI and that it is associated with integrin alpha6beta1 on the cell surface of GC, suggesting that CD9 is implicated in the function of human GC in cooperation with integrin alpha6beta1.

Cinedefecographic evidence of difficult evacuation in constipated patients with complex symptoms.

Patients with constipation may have various pelvic complaints of difficult evacuation coexisting with infrequent evacuation and other abdominal complaints, and the overlapping of symptoms makes it difficult to select appropriate therapy based on clinical history and routine office examination alone. Cinedefecography is an objective method for examining patients who have complex subjective symptoms. This study assessed the value of cinedefecography for evaluating patients with constipation with multiple complaints. We divided 185 patients with constipation into two those with (group 1) or without (group 2) cinedefecographic evidence of difficult evacuation. These groups were compared relative to complaints, manometric results, cinedefecography findings, and the success of biofeedback treatment. Group 1 patients were further evaluated according to the type of abnormal findings: sigmoidocele, rectocele, intussusception, and perineal descent. We found no significant differences in patient complaints between the groups. However, there were more patients in group 2 with intussusception than in group 1; there were also significant differences between the groups in mean resting pressure, maximum resting pressure, and maximum squeeze pressure. In group 1 patients with rectocele complained more frequently of excessive straining, and those with intussusception complained more frequently of incomplete evacuation. Sensory threshold and maximal tolerable capacity were significantly higher in patients with intussusception. Rectocele was predominant in women, and biofeedback treatment was extremely advantageous (86%) for patients in group 1 with a rectocele in association with other pathology. Whether the intussusception or the descent causes decreased mean resting and mean and maximum squeeze pressures is unknown but is an additional and potentially important finding which needs further elucidation for it to have therapeutic significance.