Dynamic thiol-disulphide homeostasis as a biomarker for predicting the development of contrast medium-associated acute kidney injury in the endovascular treatment of peripheral arterial disease: should intravenous N-acetylcysteine be given before the procedure?

AIM: To determine the predictive ability of serum thiol-disulphide levels for contrast medium-associated acute kidney injury (CA-AKI) after endovascular treatment (EVT) of peripheral arterial disease (PAD) and evaluate the efficacy of intravenous N-acetylcysteine (NAC) in preventing CA-AKI. MATERIAL AND METHODS: This double-blind, randomised controlled study included 85 consecutive adult patients who underwent EVT for PAD. Patients were divided into NAC negative (NAC-) and positive (NAC+) groups. While the NAC- group received only 500 ml saline, the NAC + group received 500 ml saline plus intravenous 600 mg NAC before the procedure. Intra- and intergroup patient characteristics, procedural details, preoperative thiol-disulphide levels, and ischaemia-modified albumin (IMA) levels were recorded. RESULTS: There was a significant difference between NAC- and NAC + groups regarding native thiol, total thiol, disulphide/native thiol ratio (D/NT), and disulphide/total thiol ratio (D/TT). There was also a significant difference between the NAC- (33.3%) and NAC+ (13%) groups in CA-AKI development. Logistic regression analysis showed that the D/TT (OR 2.463) and D/NT (OR 2.121) were the most influential parameters for CA-AKI development. In the receiver operating characteristic (ROC) curve analysis, the sensitivity of native thiol to detect the development of CA-AKI was 89.1%. The negative predictive values of native thiol and total thiol were 95.6% and 94.1%, respectively. CONCLUSION: The serum thiol-disulphide level can be used as a biomarker to detect CA-AKI development and reveal patients with a low risk for CA-AKI development before EVT of PAD. Furthermore, thiol-disulphide levels allow for the indirect quantitative monitoring of NAC. Preprocedural intravenous NAC administration significantly inhibits CA-AKI development.

Reliability of reporting the presence of transformation zone material in Papanicolaou smears using an automated screening system.

OBJECTIVE: This study was conducted to evaluate the reliability of using an interactive automated screening system (IAS) to determine the presence of endocervical and/or metaplastic cells (transformation zone material; TZM) in liquid-based cytology (LBC) Papanicolaou (Pap) smear slides. MATERIALS AND METHODS: A series of LBC Pap smears was manually screened to determine the presence or absence of TZM. The results were compared to those obtained through IAS. RESULTS: ThinPrep® Imaging System (Imager)-assisted screening indicated that 22.4% of the slides did not contain TZM in cases in which previous manual screening revealed that 100% of the slides did contain TZM. CONCLUSION: The reliability of determining TZM through IAS is limited. Manual screening of the slides appears to be necessary to report the presence of TZM accurately.

Familial Mediterranean fever gene (MEFV) mutations and disease severity in systemic lupus erythematosus (SLE): implications for the role of the E148Q MEFV allele in inflammation.

OBJECTIVE: Observed low prevalence of SLE among familial Mediterranean fever (FMF) patients in several large cohorts suggests a possible protective effect of the MEFV mutations from SLE. In contrast, SLE patient carriers for the common MEFV mutations had rather complex disease expression with an increased frequency of febrile episodes and pleurisy and a decreased renal complication rate. Our aim was to investigate the prevalence of MEFV gene mutations in patients with SLE and their effect on organ involvement in a well-defined group of biopsy-proven SLE nephritis patients. MATERIAL AND METHOD: The prevalence of four MEFV gene mutations (M694V, M680I, V726A and E148Q) was investigated in 114 SLE patients and effect on disease severity was analyzed in patients with biopsy-proven SLE nephritis. RESULTS: None of the SLE patients fulfilled the revised Tel-Hashomer criteria. Fourteen of 114 SLE patients (12.2%) were found to carry at least one MEFV mutation. A single patient in the SLE-Nephritis group was compound heterozygous for M694V/M680I mutations and only one patient in the SLE-Mild group was homozygous for E148Q mutation. Carrier frequency was similar to controls in SLE patients (12.2 vs 18.8%, p = 0.34). After the exclusion of the less penetrant E148Q mutation, re-analysis revealed an association between exon 10 mutations and SLE nephritis (p = 0.050, odds ratio (OR) = 4.16, 95% confidence interval (CI) = 1.04-16.6). Carrier rate for the E148Q mutation decreased in the SLE group (controls vs. SLE = 20/186 vs. 3/114, p = 0.08) and E148Q mutation was absent in SLE nephritis (controls vs. SLE nephritis = 20/186 vs. 0/47, p = 0.016, OR = 11.69, 95% CI = 0.69-197.13). CONCLUSIONS: Carrier rate for the studied MEFV mutations was slightly lower in the SLE group, which is in agreement with previous observations that FMF may confer some protection from SLE. Exon 10 mutations were associated with SLE nephritis after the exclusion of the E148Q mutation. The significance of the E148Q as a disease-causing mutation is controversial, and whether E148Q substitution is a polymorphism generally affecting inflammatory pathways is not addressed in the current literature. In this regard, absence of the E148Q mutation in SLE nephritis may serve as a clue for further investigation into its role as a general modulatory polymorphism for inflammation. This clarification is necessary to conclude whether other more penetrant MEFV gene mutations confer susceptibility to nephritis in SLE.

Frostbite injury of the breast: a case report.

This paper presents an unusual case of frostbite injury to the breast area caused by faulty cryotherapy application. Cryotherapy, commonly used by patients and health professionals, relieves pain and edema after trauma and sports injuries. However, applying cold therapy is not common for surgical procedures involving soft tissue. The frostbite injury to the breast presented here occurred due to persistent use of a self-prepared ice pack following a needle aspiration biopsy. Cold exposure to soft tissue may cause frostbite. It is crucial to inform patients about proper application of cryotherapy and possible complications, particularly for the procedures in which cold therapy is not widely used.

Cet article présente un cas inhabituel d'engelures à la zone de la poitrine provoqué par l'application inappropriée de la cryothérapie. La cryothérapie, couramment utilisée par les patients et les professionnels de la santé, soulage la douleur et l'oedème après un traumatisme et les blessures sportives. Toutefois, l'application de thérapie par le froid n'est pas commune pour les procédures chirurgicales impliquant les tissus mous. Les engelures au sein présentées ici ont eu lieu en raison de l'utilisation persistante d'un sac de glace auto-préparé à la suite d'une biopsie à l'aiguille. L'exposition au froid des tissus mous peut causer des gelures. Il est essentiel d'informer les patients sur la bonne application de la cryothérapie et les complications possibles, en particulier pour les procédures dans lesquelles la thérapie par le froid n'est pas largement utilisée.

Efficacy of intravenous paracetamol and dexketoprofen on postoperative pain and morphine consumption after a lumbar disk surgery.

BACKGROUND: We compared the analgesic effects of intravenous (IV) paracetamol with that of dexketoprofen on postoperative pain and morphine consumption during the first 24 hour after a lumbar disk surgery. METHODS: This prospective, placebo-controlled, double blind study investigated the analgesic effects of IV paracetamol and dexketoprofen on postoperative pain, morphine consumption, and morphine-related side effects after a lumbar disk surgery. Sixty American Society of Anesthesiologists 1 or 2 status patients scheduled for elective lumbar disk surgery under general anesthesia were included in the study. Patients were treated using patient-controlled analgesia with morphine for 24 hours after a lumbar disk surgery and randomized to receive IV paracetamol 1 g, dexketoprofen 50 mg, or isotonic saline (placebo). The primary endpoint was pain intensity measured by the visual analogue scale, and secondary endpoints were morphine consumption and related side effects. RESULTS: Pain intensity was lower in the dexketoprofen group (P=0.01) but not in the paracetamol group (P=0.21) when compared with the control group. Cumulative morphine consumption and morphine-related side effects did not reveal significant differences between the groups. CONCLUSIONS: The study showed that pain intensity during 24 hours after the lumbar disk surgery was significantly lowered by dexketoprofen, but not with paracetamol, as a supplemental analgesic to morphine patient-controlled analgesia when compared with controls.

Sudden death due to a rare brain tumor: an autopsy case.

UNLABELLED: Sudden death in persons with intracranial neoplasms is a rare mechanism of death detected in the forensic autopsies. 10 years-old girl was brought to a local clinic death shortly after analgesic therapy for headache. Autopsy findings showed a large, solid cerebellar mass. Histological diagnosis was pilomyxoid astrocytoma, low-grade tumor with features alike to pilocytic astrocytomas. In this case report we present and discuss rare autopsy case of pilomyxoid astrocytoma from medicolegal point of view. KEYWORDS: sudden death - brain - pilomyxoid astrocytoma - autopsy.

Age-related histopathological changes in the cardiac conducting system in the Turkish population: an evaluation of 202 autopsy cases.

BACKGROUND: Histopathological features of the cardiac conducting system (CCS) in the Turkish population have not been investigated previously. MATERIAL AND METHODS: We examined CCS of 202 autopsy heart specimens dissected between the years 2004 and 2005 in Bursa Forensic Medicine Institution. Of the 202 cases from all age groups, 154 were males and 48 were females. RESULTS: In our cases, an increase in fibrous and adipose tissue concordant with age, indicating an age-related nature, were detected. Fibrous and fatty tissue infiltration appeared at the age of 35. Fatty infiltration started between the ages 20 and 34 years at the sinoatrial node (SAN). There was no relationship between obesity and fatty tissue infiltration in SAN and atrioventricular node (AVN). In 4 cases calcification and in 19 cases inflammation was observed. Amyloid accumulation was not present. In 7 cases myocardial infarction not involving CCS was seen. In 1 case fibroelastoma was detected. CONCLUSIONS: In the Turkish population age-related fibrosis and fatty infiltration in CCS appeared at the age of 35 years and increased with age. Fatty infiltration in the SAN started at a younger age than that reported in the literature. In cases where the cause of death could not be determined, we could not detect lethal pathological features. However, we think that examination of the CCS will improve the quality of autopsy diagnosis.

Preliminary evidence of an association between the functional c-kit rs6554199 polymorphism and achalasia in a Turkish population.

BACKGROUND: C-kit-positive interstitial cells of Cajal (ICC) of the lower esophageal sphincter are reduced in achalasia. Two functional gene polymorphisms (rs2237025 and rs6554199) within the c-kit gene may affect its transcriptional activity. In this pilot study, we hypothesized that these polymorphisms would be associated with achalasia. METHODS: Genomic DNA was extracted and real-time PCR reactions were used to determine the rs2237025 and rs6554199 c-kit polymorphisms in 88 Turkish patients with achalasia and 101 healthy controls. KEY RESULTS: The frequency of the T allele of rs6554199 was significantly higher in patients with achalasia [odds ratio (OR): 1.55; 95% confidence interval (CI), 1.03-2.34; P = 0.038] compared with the G allele. Under a dominant model of inheritance, the carriage of at least one T allele was significantly more frequent in patients with achalasia (80.7%) than in controls (65.3%; OR: 2.21; 95% CI, 1.13-4.33; P = 0.022). No association of the c-kit rs2237025 polymorphism with achalasia was detected. CONCLUSIONS & INFERENCES: Despite the small sample size and the possibility of a false positive finding, our preliminary data support the hypothesis that the T allele of the c-kit rs6554199 polymorphism may be associated with achalasia in the Turkish population. These findings need to be replicated in other racial-ethnically diverse populations.

Adenoid cystic carcinoma of the Bartholin's gland: case report and systematic review of the literature.

Adenoid cystic carcinoma (ACC) of the Bartholin's gland is a rare malignancy of the female genital tract. Seventy-nine cases have been reported in the literature. A 40-year-old women presented to our clinic with twice locally recurrent ACC of Bartholin's gland of the left vulva despite hemivulvectomy. Adjuvant radiotherapy was delivered after the third resection. There was no local recurrence after three years follow-up, although she developed lung metastases that remain under control with oral cyclophosphamide. Our case confirms the literature review, which indicates a slow growing tumor with frequent local recurrences (30%) and distant metastases (31%). Adjuvant radiotherapy and/or chemotherapy should be considered in the management of ACC of Bartholin's gland.

Serum levels of soluble receptor for advanced glycation endproducts (sRAGE) are higher in ulcerative colitis and correlate with disease activity.

UNLABELLED: Interaction of the receptor for advanced glycation endproducts (RAGE) with its ligands results in expression of inflammatory mediators, activation of NF-κB, and induction of oxidative stress, all of which have been implicated in the pathogenesis of inflammatory bowel diseases (IBD). Soluble receptor for advanced glycation endproducts (sRAGE) has recently emerged as a reliable biomarker of inflammation in numerous RAGE-mediated disorders. OBJECTIVE: To assess sRAGE levels in adult patients with IBD. METHOD: Serum was collected from adult patients with Crohn's disease (CD, 56 patients), ulcerative colitis (UC, 60 patients), and healthy controls (HC, 113 subjects). Levels of sRAGE were determined by enzyme-linked immunosorbent assay. RESULTS: Serum sRAGE levels were elevated in IBD compared to HC and were higher in UC patients compared to CD and HC. Levels of sRAGE were significantly higher in the serum of UC patients with active disease compared to patients with inactive disease, but no association with the Montreal Classification was evident. Serum sRAGE was lower in CD patients with biological therapies. CONCLUSIONS: These findings suggest that serum levels of sRAGE are altered in patients with intestinal inflammation and may reflect distinct immunoinflammatory pathogenesis of UC and CD.

High prevalence of TSHR/Gsα mutation-negative clonal hot thyroid nodules (HNs) in a Turkish cohort.

Whereas the majority of hot thyroid nodules are caused by somatic TSH-receptor mutations, the percentage of TSH-receptor mutation negative clonal hot nodules (HN) and thus the percentage of hot nodules likely caused by other somatic mutations are still debated. This is especially the case for toxic multinodular goiter (TMNG). 35 HNs [12 solitary hot nodules (SHN), 23 TMNG] were screened for somatic TSHR mutations in the exons 9 and 10 and for Gsα mutations in the exons 7 and 8 using DGGE. Determination of X-chromosome inactivation was used for clonality analysis. Overall TSHR mutations were detected in 14 out of 35 (40%) HNs. A nonrandom X-chromosome inactivation pattern was detected in 18 out of 25 (72%) HNs suggesting a clonal origin. Of 15 TSHR or Gsα mutation negative cases 13 (86.6%) showed nonrandom X-chromosome inactivation, indicating clonal origin. The frequency of activating TSHR and/or Gsα mutations was higher in SHNs (9 of 12) than in TMNGs (6 of 23). There was no significant difference for the incidence of clonality for HNs between TMNGs or SHNs (p: 0.6396). Activating TSHR and/or Gsα mutations were more frequent in SHNs than in TMNG. However, the frequency of clonality is similar for SHN and TMNG and there is no significant difference for the presence or absence of TSHR and/or Gsα mutations of clonal or polyclonal HNs. The high percentage of clonal mutation-negative HNs in SHN and TMNG suggests alternative molecular aberrations leading to the development of TSHR mutation negative nodules.

The effect of low level laser therapy on pain during dental tooth-cavity preparation in children.

AIM: To evaluate the effect of low level laser therapy on pain during cavity preparation with laser in paediatric dental patients. STUDY DESIGN AND METHODS: The study was carried out on 10 children aged 6 to 9 years old for a total of 20 primary molar teeth. For laser preparation an Er: YAG laser was used. Half of the preparations were treated by low level laser therapy (LLLT) before laser preparation and the remaining half without LLLT (non-LLLT) before laser preparation. All cavities were prepared by ER:YAG laser, restored with light-cured composite resin following the application of acid etching and bonding agent. Children were instructed to rate their pain on the visual analogue scale (VAS) from 0 to 5 points. Statistical analyses were performed using Mann Whitney U test. RESULTS: VAS Median (min-max) scores were 1(0-2) for LLLT and 3(1-4) for the non-LLT treated children. Between LLLT and non- LLLT groups results were statistically significant (p<0.01). CONCLUSIONS: The use of LLLT before cavity preparation with laser decreased pain in paediatric dental patients.

The effect of laser-activated Acidulated Phosphate Fluoride on enamel submitted to erosive solution only: an in vitro preliminary evaluation.

AIM: The purpose of this in vitro study was to evaluate the potential effect of laser therapy on the prevention of erosive demineralisation either alone or combined with acidulated phosphate fluoride gel on human enamel. It was hypothesized that such a treatment would decrease enamel solubility. STUDY DESIGN: Efficacy of 2940 nm Er:YAG laser with preset parameters--alone or combined with APF (Acidulated Phosphate Fluoride) gel--was tested on freshly extracted human permanent molars. MATERIALS AND METHODS: Ten sound human third molars were sectioned into 5 surfaces (2 x 3 mm) with hard tissue microtome and were randomly allocated into different treatment groups as follows. The Vicker's hardness of each surface was obtained at the baseline. Group 1, negative control group: no treatment. Group 2, positive control group: only 1.23% APF gel (Denti-Care gel, Medicom) 1 minute application. Group 3: irradiated with surface modification mode (2940 nm, 1.2j/cm², 10 Hz, 300 µm) Er:YAG laser. Group 4: Er:YAG laser application following 1.23% APF gel. Group 5: 1.23% APF gel following Er:YAG laser application. The demineralisation process was obtained by immersion of specimens in a soft drink for 10 minutes and then the Vickers hardness was reevaluated. STATISTICS: For statistical analyses within groups the Kruskal Wallis test was used, while for comparing groups the paired sample t test (significance p<0.05) was used. RESULTS: The difference in microhardness values of each group obtained following the treatments was not statistically significant (p>0.05). Beside, no statistical difference was found in Vickers value related to the application of fluoride prior or after laser therapy. Conclusion Er:YAG laser irradiation alone or combined with APF decreased the enamel solubility but combined treatment did not show any significant additional effect.

Comparison of Color Flow Doppler Sonography (CFDS) and immunohistologic detection of microvessels for the assessment of the malignancy of thyroid nodules.

The assessment of tumor vascularization by color flow Doppler sonography (CFDS) has been suggested for the distinction between benign and malignant thyroid nodules. Our objective was to investigate if the CFDS results reflect the percentage of histologically determined microvessels in adenomas (As), adenomatous nodules (ANs), and papillary carcinomas (PCs). Tissue sections from 10 adenomas, 8 ANs and 13 PC and surrounding tissue of 10 PCs and 2 benign nodules were immunostained for CD34. A computerized image analysis was used to determine the microvessel density in four hot spots and ten systematically selected fields. Preoperatively CFDS was performed and classified according to Frates et al. We found a consistent percentage increase of CD34 stained microvessels in PCs (83 and 96%) as compared to adenomas and ANs (38 and 49%) determined by the hot spot analysis and systematic field analysis. A ROC analysis on the basis of the histologically determined number of microvessels demonstrated 70% microvessels as an optimal cut point for the diagnosis of PC with the highest sensitivity of 92% and highest specificity of 89%. The analysis of the CFDS-classification IV for the distinction between PCs and adenomas and ANs showed a sensitivity of 62% with a specificity of 100%. The lower sensitivity of the CFDS classification as compared with the immunohistologic determination of the microvessel density indicates that the CFDS classification detects the pathognomonic intranodular microvessels only incompletely. The higher CFDS specificity is most likely due to the detection of other vascular aspects of malignancy in addition to intranodular microvessels.

Increased percentage of microvessels but decreased density of large vessels in papillary carcinomas as compared to hot and cold thyroid nodules.

OBJECTIVE: For thyroid tumors increased as well as decreased vessel densities have been reported. Because of different morphometric methods and specificities of previously used antibodies for small and large vessels our objective was to investigate and compare the density of large vessels and microvessels by different morphometric methods and antibodies in hot nodules(HN), cold nodules (CN), papillary carcinoma (PC) and Graves' disease (GD) to try to clarify some of these discrepancies. DESIGN: Tissue sections from 29 HN, 22 CN, 19 PC and 8 GD thyroids were stained with the antibodies for CD34 and alpha-SMA. A computerized image analysis was used to calculate the mean area of endothelium (mEA) and the mean endothelium to tumor epithelial nucleus area ratio (mE/N) in four hot spots and ten systematically selected fields. MAIN OUTCOME: We found a consistent increase of the CD34 stained percentage of microvessels in PC as compared to HN and CN determined by the hot spot analysis and systematic field analysis. This increased microvessel density in PC is of a similar magnitude as in GD, which is characterised by a prominent increase of vascularisation during its active disease stage. Our SMA staining results reveal a kind of mirror image of the CD34 staining results with higher vessel counts in the normal surrounding tissues as compared to HN, CN and PC. CONCLUSIONS: The specific immunohistologic detection of microvessels with the CD34 antibody combined with their specific evaluation is able to clearly differentiate PCs from normal tissue, HN and CN.

Ovarian enlargement associated with massive oedema.

Massive ovarian oedema is a rare entity described as accumulation of oedema fluid within the ovarian stroma, separating normal follicular structures. Our case was a 27-year-old woman who presented with a large solid pelvic mass after recurrent episodes of self-limited abdominal pain. On physical examination, she had left abdominal tenderness with minimal rebound and guarding. With a diagnosis of malignant ovarian tumor, an exploratory laparotomy was done and a twisted ovarian mass was found which was excised completely. Histopathological evaluation of the mass revealed massive oedema of the ovary. Massive ovarian oedema should be suspected in women at the fertile age range with solid enlargement of the ovary.

Squamous cell carcinoma developing in a huge dermoid cyst of the ovary in an 80-year-old woman--case report.

A case of an 80-year-old patient with squamous cell carcinoma originating from a huge septated dermoid cyst of the right ovary is reported. There were bilateral dermoids in the patient. The tumor sizes were 30 x 40 x 20 cm and 4 x 3 x 5 cm in the right and left ovary, respectively, confirmed by ultrasound and computed tomography. Squamous cell carcinoma arose in the solid part of a huge dermoid cyst of the left ovary. Total abdominal hysterectomy and bilateral salpingo-oophorectomy, omentectomy and appendectomy were performed. The tumor was confined to the right ovary. The patient was categorized as FIGO Stage IA. She recovered uneventfully and there was no evidence of recurrence in the early-stage case during one year of follow-up. The clinical and pathological features, treatment modalities and prognosis of squamous cell carcinoma are described.

Primary yolk sac tumor (endodermal sinus tumor) of the vulva: case report and review of the literature.

INTRODUCTION: Endodermal sinus tumor (EST) or primary yolk sac tumor (YST) of the vulva is extremely rare and a highly malignant germ cell tumor. Only nine cases of vulvar YST have been reported to the world literature to date. We present the tenth case of endodermal sinus tumor of the vulva. CASE: A 32-year-old white virgin presented with a 3.5 cm right labial mass without any other signs or symptoms. Excisional biopsy showed YST with a predominantly solid pattern. Unilateral hemivulvectomy with bilateral inguinal lymphadenectomy was performed. Six months after surgery there was a recurrence. She was treated with three courses of the BEP regimen (bleomycin, etoposide, cisplatin). The patient refused to take any further treatment including radiotherapy. The serum alpha-fetoprotein (AFP) was not elevated at the initial diagnosis however it was elevated during recurrence. The patient is alive with the disease 42 months after the first appearance of the vulvar mass.

Bilateral metastatic breast cancer as the first manifestation of ovarian cancer: case report.

BACKGROUND: Breast metastasis from primary ovarian cancer is extremely rare. The rarity of this finding may be the reason for its common misinterpretation as primary breast carcinoma. DESIGN: Case report. SETTING: A university hospital. RESULTS: A case of a patient with primary ovarian papillary serous cystadenocarcinoma who initially presented with a solitary bilateral breast mass and abdominal distention is reported. CONCLUSIONS: Blood-borne metastasis from the ovary to the breast can show a varied clinical picture that should be differentiated from that of primary breast carcinoma.

Benign glandular cells in posthysterectomy vaginal smears: the incidence is higher than expected.

In this study, we have investigated the frequency and clinical significance of glandular cells in posthysterectomy vaginal smears. The slides of vaginal cuff smears of 290 patients were reviewed. The glandular cells were categorized into three groups: (1) squamous metaplastic-like cells; (2) columnar endocervical-like cells; and (3) small round cuboidal cells. Glandular cells were found in 39 (13%) of the 290 vaginal smears. Group 1 type cells were seen in 76% (n = 30), group 2 type cells in 38% (n = 15) and group 3 type cells in 47% (n = 19) of the smears. In 19 (48%) of the smears combination of two or three groups were seen. The presence of glandular cells showed a strong association with inflammation/repair as a background finding in the smears. No correlation could be found between the presence of atrophy and history of chemotherapy or radiotherapy. Apart from these there was a prominent increase in reporting benign glandular cells after the application of the current Bethesda 2001 reporting criteria in our laboratory. As a result our study showed that the finding of glandular cells in posthysterectomy vaginal smears is more frequent than expected and most of them could be related to inflammatory and regenerative processes in the absence of a clearly identified underlying cause.