Recent studies on the reproductive biology of the schistosomes and their relevance to speciation in the Digenea

The members of the family Schistosomatidae, dioecious Digenea, are discussed with regard to their distribution, intermediate and definitive host-parasite relationships. The biological species concept is considered together with the difficulties of its application to Schistosoma spp. and the Digenea. The correlation between pairing of adult schistosomes, physical and sexual development and the maintenance of reproductive potential is emphasised. Development of the female reproductive system does not depend upon species-specific pairing. In some combinations, e.g., Schistosoma haematobium/Schistosoma intercalatum and Schistosoma bovis/Schistosoma curassoni, a specific mate choice system apparently does not exist, whereas it does in other combinations, e.g., Schistosoma mansoni/Schistosoma intercalatum. In mixed infections change of mate may occur and when the opportunity arises heterospecific pairs of worms will change partners to conspecific pairs. Interspecific pairing in adult schistosomes will lead to either hybridisation or parthenogenesis. Yet the majority of schistosomes that inhabit the same definitive host maintain their genetic identity: specific mate recognition, site selection within the host and heterologous immunity have been suggested as isolating mechanisms. Experimental intraspecific crosses have enabled evaluation of the degree to which some populations separated and became reproductively isolated through pre-mating isolating mechanisms, indicative of incipient speciation, e.g., the Lower Guinea and Zaire strains of S. intercalatum. The occurrence and significance of parthenogenesis in schistosomes and other species of Digenea are discussed. The consequences of interspecific mating interactions in schistosomes with regard to parasite epidemiology, interspecific competition and genetic heterogeneity are debated. Geographical isolation and host specificity represent important pre-zygotic isolating mechanisms. It is suggested that site selection within the host and heterologous immunity may both reduce interspecific genetic interchange when digenean parasites utilise the same definitive host.     

Anaesthesia for aortoesophageal fistula

Prolonged or recurrent typhoid fever and mainly salmonella septicaemia usually regarded as minor, or even episodes of salmonelluria are not uncommon in patients infested with Schistosoma spp. In such cases the salmonella infection is often apparently resistant to antibiotic therapy. Schistosoma-salmonella interactions have been described with all species of schistosoma, notably S. haematobium, S. mansoni, S. intercalatum and S. japonicum. The adult worms of schistosoma live in the mesenteric venous plexuses and, in some particular sites, salmonellas are electively stuck onto the outer wall of adult schistosomas. As a result of this, salmonella septicaemia is facilitated and sustained by the schistosomal infestation, and several varieties of salmonella may be involved. These salmonella infections cannot be cured without treatment of the associated schistosomiasis.     

Health-care technology transfer: expert and information systems for developing countries

The alkaline phosphatase immunoassay (APIA) is an antibody detection technique which permits the diagnosis of schistosomiasis using a butanolic extract preparation from adult worms. APIA has demonstrated high sensitivity and specificity in previous reports with well characterized human sera. Its potential as a diagnostic tool for epidemiological surveillance was assessed in comparison with three other diagnostic tests: stool examination, ELISA with soluble egg antigen (SEA) and the circumoval precipitin test (COPT). APIA was 100% specific in an area without Schistosoma mansoni transmission and had 89% sensitivity in an endemic area where 69% of the infected subjects excreted less than 100 eggs g of faeces. It was found to be less sensitive in children under 5 years of age who were positive by the COPT test. APIA can be applied as an initial screening test, based on its high sensitivity, specificity, absence of cross-reactivity with intestinal parasites and the fact that it is a technique suitable for use in epidemiological surveillance.     

Hematospermia: a new etiology of clinical interest

Ten Spanish male tourists developed hematospermia and ultrasonographic evidence of involvement of the prostate and/or seminal vesicles after recreational exposure in bodies of fresh water in the Dogon country of Mali. Schistosoma eggs were detected in the ejaculate of five men, in the others, eggs were observed in the urine or feces. Three different species were observed: S. intercalatum, S. haematobium, and S. mansoni. Hemospermia and clinical prostatitis may be frequently unrecognized clinical manifestations of the early stages of infection in previously nonexposed persons. Travelers to endemic areas should be advised on the potential dangers of swimming and other exposure in bodies of freshwater.     

Open versus stereotactic breast biopsy

BACKGROUND: Stereotactic breast biopsy has been developed as a less invasive means of performing biopsy for mammographic abnormalities. METHODS: From July 1994 through June 1995, 103 women with mammographic abnormalities requiring biopsy were prospectively evaluated. RESULTS: Fifty-one women had open biopsy, and 52 women had stereotactic biopsy. The average age in both groups was 60 years. Pathology revealed malignancy in 12% of stereotactic biopsies and 13% of open biopsies. Complications occurred in 6% of the open biopsies and 4% of the stereotactic biopsies and were limited to hematomas or seromas. The average cost was $2400 for open biopsy and $650 for stereotactic biopsy (P < 0.01). One hundred and one patients returned for a follow-up mammogram within 6 months, and 1 patient in each group required a second biopsy, which revealed benign pathology. A Patient Satisfaction Survey revealed no significant differences in patient satisfaction between the two types of procedures. CONCLUSION: There were no differences between open and stereotactic biopsies in regards to diagnostic accuracy, complications, or patient satisfaction. A significant difference was noted in charges during the time frame of our study.     

Predictive value of specimen radiography for core needle biopsy of noncalcified breast masses

OBJECTIVE: Our objective was to determine the predictive value of specimen radiography for large core (14-gauge) needle biopsy of noncalcified breast masses. SUBJECTS AND METHODS: Eighty-four biopsies of 83 breast masses yielded 403 specimens. Specimens showing dense material on specimen radiography were predicted to be diagnostic; specimens showing intermediate- or low-density material were predicted to be nondiagnostic. Specimen radiographic and histopathologic findings were correlated for each specimen using vital dyes to mark individual specimens. RESULTS: Of the 403 specimens, 307 (76%) contained diagnostic material representative of the lesion, with a specific diagnosis achieved for 82 (99%) of 83 lesions (62 benign, 20 malignant). Of the 293 passes containing dense material, 268 (91%) proved to be diagnostic; 11 (18%) of 62 specimens containing only low-density material proved to be diagnostic. Of the 25 (9%) of 293 specimens containing radiographically dense but nondiagnostic material, 18 (72%) showed focal fibrosis and had missed the lesion; 15 (83%) of 18 such specimens were obtained in dense parenchyma. The positive predictive value of specimen radiography was 13 (100%) of 13 in fatty breasts; 77 (96%) of 80 in breasts with minimal scattered fibroglandular elements; 91 (94%) of 97 in heterogeneously dense breasts; and 35 (70%) of 50 in breasts with extremely dense parenchyma. Of the 16 lesions sampled stereotactically, specimen radiography helped assess the inadequacy of initial sampling in three (19%). In six (9%) of 68 sonographically guided biopsies, only one or two specimens could be obtained; specimen radiography helped us predict whether material was adequate for diagnosis. CONCLUSION: Radiography of core specimens obtained from noncalcified breast masses accurately reveals the adequacy of sampling unless the breast parenchyma is extremely dense. Such immediate assessment can help ensure adequate material from lesions that are difficult to biopsy and can thereby improve the diagnostic yield of large core needle breast biopsy.     

Prognostic factors and scoring systems in myelodysplastic syndromes

The treatment of peptic ulcers has been revolutionized by the discovery that Helicobacter pylori (H. pylori) bacteria is a causative agent for ulcer formation. However, when patients present with dyspepsia or epigastric discomfort, more than 80% of patients will not have ulcer disease and empiric treatment of H. pylori is not recommended for these patients. Eradication of H. pylori has not been demonstrated to improve the symptoms of non-ulcer dyspepsia compared with non-ulcer dyspepsia patients treated with placebo. Therefore, we recommend that patients should first be evaluated for peptic ulcers with endoscopy or upper gastrointestinal series before the diagnosis and treatment of H. pylori. Generally, the treatment of H. pylori should be limited to patients with peptic ulcers, mucosal-associated lymphoid tissue lymphomas, and gastric cancers. Most diagnostic tests for H. pylori, including quantitative IgG antibody, urea breath tests, rapid urease tests (CLO), tests of gastric mucosal biopsies, and staining of gastric mucosal biopsies, have equivalent diagnostic characteristics. Therefore, the choice of diagnostic test for H. pylori should be based on cost, ease of use, and lack of complications. Multiple antibiotic regimens are available for the treatment of H. pylori. Triple antibiotic therapy is the least expensive but has the highest rate of side effects and the least compliance. Combining a proton pump inhibitor with clarithromycin and another antibiotic will eradicate H. pylori with fewer side effects and better compliance but this is the most expensive antibiotic regimen.     

Current methods in the diagnosis of deep venous thrombosis of the lower limbs

The diagnosis of lower limb deep vein thrombosis requires to use of complementary diagnostic tests. For a long time phlebography has been the only reliable examination and is always regarded as the gold standard by many people. In recent years, non invasive diagnostic modalities have been developed. Most significantly scintigraphy, plethysmography, color Doppler ultrasound and MR imaging. MRI is as reliable as venography but, at the present time, it is time-consuming and far less available than the other modalities. Scintigraphy and plethysmography may be useful but are less accurate and yield a somewhat higher rate of false positive and negative examinations. Color Doppler ultrasound has proved its effectiveness and is currently recommended as the diagnostic modality of choice. Venography is still a significant diagnostic tool for questionable cases or for technically inadequate Doppler ultrasound examinations.     

Transthoracic needle biopsy of mediastinal lymph nodes for staging lung and other cancers

PURPOSE: To determine the usefulness of transthoracic needle biopsy of mediastinal lymphadenopathy for staging suspected lung and other cancers. MATERIALS AND METHODS: Transthoracic needle biopsy of the hilum or mediastinum was performed in 111 patients with suspected neoplasms. Most biopsy procedures were performed with computed tomographic guidance on an outpatient basis. Forty-eight adult patients had enlarged lymph nodes (defined as < or = 30 mm in the long axis and > or = 10 mm in the short axis). Sixty-three lesions larger than 30 mm were arbitrarily considered to be masses and were excluded. RESULTS: Carcinoma was diagnosed in 40 patients. Four patients had true-negative and one patient had false-negative results. Sensitivity for carcinoma was therefore 98% (40 of 41). One patient with a negative biopsy result did not have surgical confirmation and was excluded from analysis. Lymphoma was excluded from analysis. Lymphoma was diagnosed in two patients (positive in one and suspicious in one). Pneumothorax occurred in 19 (34%) of 56 biopsy procedures. Chest tube treatment was required in eight (14%). CONCLUSION: Transthoracic needle biopsy of mediastinal lymphadenopathy is a safe, accurate diagnostic staging procedure. It can frequently be used as an alternative to mediastinoscopy in patients with lymphadenopathy.     

Complications of CT-guided biopsy of the spine and sacrum

This study reviews the results of 94 computed tomography (CT)-guided Craig needle biopsies of the spine and sacrum performed at one center. An indication for biopsy in this study was prompted by abnormal findings identified by one or more of the following diagnostic modalities: radiography, CT, magnetic resonance imaging (MRI), or bone scanning. These patients then underwent CT-guided Craig needle biopsy of the spine and sacrum for further evaluation. There were 1 biopsy of the cervical spine, 19 of the thoracic spine, 66 of the lumbar spine, and 8 of the sacrum. Biopsy sensitivity was 94.5% and specificity was 96.8%. This accuracy compared with other diagnostic modalities showed biopsy to be the gold standard for diagnosis of spine or sacral lesions. Of the 94 cases reviewed, 6 complications were noted. All complications were acute in nature and included 1 aortic puncture, 2 psoas punctures with associated psoas hematomas, 1 biopsy of an incorrect level, and 2 aborted procedures secondary to patient discomfort. No infections or neurological sequelae were seen. Although the benefits of CT-guided biopsy over open biopsy have been shown previously, this review demonstrates it is not without significant risk.     

Intraepidermal bile pigment in skin biopsy specimens for graft-versus-host disease versus erythema multiforme

The differentiation of graft-verus-host disease (GVHD) from erythema multiforme (EM) presents a common diagnostic challenge in skin biopsy specimens from patients who have received patients allogeneic bone marrow transplants. The presence of gastrointestinal involvement might be the only way to make a diagnosis of GVHD in these cases. In the absence of liver function tests, gastrointestinal biopsy, or molecular techniques such as microsatellite DNA analysis, the presence of intraepidermal bile pigment might prove helpful in elucidating hyperbilirubinemia and allowing a pathologist to favor a diagnosis of GVHD over EM. Routinely processed archival tissue from 50 cases of GVHD (42 Caucasian and 8 of unknown race) and 50 cases of EM (31 Caucasian and 19 of unknown race) was examined for pigmentation. Intraepidermal pigmentation was stained for bile pigment and melanin. Among the intraepidermal EM lesions, 4 (8%) stained for intracorneal melanin, but none stained for bile pigment. Among the intraepidermal GVHD lesions, 8 (16%) stained for intracorneal melanin, but 3 (6%) stained for intracorneal bile pigment. In addition, 13 (26%) GVHD lesions and 9 (18%) EM lesions showed melanosis with melanin in all layers of the epidermis as well as within papillary dermal melanophages. Thus, when presented with a differential diagnosis of GVHD versus EM, the presence of intraepidermal bile pigment might suggest liver involvement and a diagnosis of GVHD.     

Comparative profitability of hepatic biopsy and microbiological tests in patients with HIV infection

OBJECTIVES: Diagnostic liver biopsy is proposed in HIV-positive patients who present unexplained fever. This invasive procedure is truly useful if it allows establishing a difficult diagnosis or improves survival rate. We conducted a retrospective study to determine the diagnostic and prognostic power of liver biopsy in HIV-positive patients with fever. METHODS: One hundred thirty-eight liver biopsies were performed in 129 patients. Utility was defined as demonstration of the pathogen or identification of a tumoral process. RESULTS: The liver biopsy met the utility criteria in 27 cases showing mycobacterial infections (n = 22) and herpes hepatitis, type 1 herpes simplex virus, cytomegalovirus and cryptococcosis infections (n = 1 each). These last 4 diagnoses were also possible with other tests. Comparing non-contributive liver biopsies (n = 111) with those demonstrating hepatic mycobacterial infection (n = 22) showed that the two groups were not different in terms of demographic data. Splenomegalia was more frequent in the non-contributive group (68% vs 37%, p = 0.007) as was superficial lymph node enlargement (45% vs 12%, p < 10(-3)). Laboratory tests were not discriminating. Mycobacterial infection was diagnosed in 22 patients in the non-contributive group. Bacteriological samples were positive for mycobacterium in 20 of the 22 patients in the contributive group. The mean delay to the first positive test for mycobacterium was 15 +/- 8 days compared with 30 +/- 10 days for liver tissue cultures. Mean survival after liver biopsy was 10 months: patients with a positive Ziehl-Neelson stain on the liver biopsy did not have a longer survival (9.7 +/- 7.6 vs 10.2 +/- 10.4 months). CONCLUSION: In most cases, liver biopsy in HIV-positive patients with fever provides a diagnosis which can be obtained with non-invasive techniques without improving prognosis.     

Clinical diagnosis with the stable isotope 13C in CO2 breath tests: methodology and fundamental considerations

The methodology for measuring in vivo oxidation of substrates labeled with the nonradioactive carbon isotope 13C has been developed with isotope ratio mass spectrometry. The use of 13C offers the possibility of utilizing CO2 breath tests in infants, children, pregnant women, and all subjects in whom 14CO2 breath tests cannot be used. The excretion of 140 nmol/kg-hr of 13CO2 produced from the oxidation of the labeled substrate could be detected with 95% confidence during a total CO2 excretion of 9 mM/kg-hr. The precision of CO2 breath tests using 13C is limited by the natural fluctuations of the ratio of 13C/12C in expired CO2, which occur with a standard deviation of 0.72%, or approximately 7 parts 13CO2 per 10(6) parts expired CO2. Larger excursions in the ratio were observed if the subjects ate shortly before or during the breath test. Clinically significant diagnostic tests can reasonably be expected to require the excretion of 2 to 20 times as much labeled CO2, or 0.28 to 1.4 micronM/kg-hr.     

Efficacy of sonographically guided biopsy of thyroid masses and cervical lymph nodes

OBJECTIVE: We performed a prospective study in 96 patients to determine accuracy of sonographically guided fine-needle aspiration biopsy of thyroid masses and cervical lymph nodes. MATERIALS AND METHODS: Real-time sonography was used to guide biopsy of 112 cervical masses in 96 patients (71 patients with impalpable masses, 16 with failed unguided attempts, patient's or physician's preference in nine). The diameters of all masses were less than 3 cm, with a mean of 1.5 cm and a median of 1.5 cm. Twenty-nine masses measured 1 cm or less in diameter, 60 masses between 1.1 and 2.0 cm, and 23 masses between 2.1 and 3.0 cm. Cervical masses that were sampled by biopsy included 75 thyroid masses and 37 lymph nodes. RESULTS: Diagnostic specimens were obtained in 102 (91%) of 112 masses sampled. Sixty-eight (91%) of 75 biopsies of thyroid tissue and 34 (92%) of 37 biopsies of lymph nodes were diagnostic. Nondiagnostic thyroid biopsies included four of complex cysts and three of solid nodules. Sonographic follow-up (1 year) revealed no change or decrease in size of those seven lesions. Sixty of 68 diagnostic thyroid biopsies showed benign processes: 42 macrofollicular adenomas, six colloid adenomas, five microfollicular adenomas, four probable cases of thyroiditis, and three hemorrhagic cysts. The remaining eight diagnostic thyroid biopsies showed malignant processes: seven papillary carcinomas and one metastatic small-cell carcinoma. Of 34 diagnostic biopsies of lymph nodes, 26 showed malignant processes and eight showed benign processes. Surgery in the three patients with nondiagnostic biopsies of lymph nodes revealed two recurrent medullary cancers and one benign node. CONCLUSION: Sonographically guided fine-needle aspiration biopsy of neck masses has a high sensitivity (91%) and should be routinely used to evaluate indeterminate masses in the neck.     

Mutations of ret-proto-oncogene in thyroid medullary carcinoma

OBJECTIVE: To determine the importance of the molecular-genetic demonstration of germ-line mutation in the ret protooncogene for therapeutic measures in sporadic and hereditary medullary thyroid carcinoma (MTC). PATIENTS AND METHODS: Several molecular-genetic tests were performed on DNA of 35 families with hereditary and 81 patients with the sporadic form of MTC (isolation of genomic DNA; PCR amplification; DNA sequencing: demonstration of mutation in codon 918 with restriction enzyme FOK 1). RESULTS: A disease risk was demonstrated in 178 individuals among the 35 families, 159 of whom were investigated by molecular-genetic tests: 84 family members were found to be gene carriers. Germ-line mutation had already been suspected on clinical grounds in 76% of the carriers, 24% being discovered in a presymptomatic stage. Six children among the latter were treated prophylactically by thyroidectomy, histological evidence of C-cell hyperplasia being found in all of them, microcarcinomas in three of the older children. There were four patients among the non-carriers on whom thyroidectomy had been performed previously because of a false-positive pentagastrin-test; but germ-line mutation was now excluded. In one family, with familial MTC in two brothers, no mutation in ret-proto-oncogene has been demonstrated. The members of this family must now, as used to be routine, undergo a pentagastrin-test. Three of the 81 patients with "sporadic" MTC had a germ-line mutation, presumably a new one. CONCLUSION: Molecular-genetic tests have further improved the management of families with hereditary MTC and they thus take first place among essential diagnostic procedures. The diagnosis of sporadic MTC can be confirmed by excluding germ-line mutation in the ret-proto-oncogene.     

Colposcopy and selective biopsy in patients with abnormal cervical cytology

Patients with atypical or positive findings on cervical cytology should be referred to a special colposcopy clinic as the next step in investigation. Colposcopy complements cytology, and when combined with selective biopsy of the worst-affected area allows a high level of diagnostic accuracy (90,7%). The necessity for diagnostic conization with its risks is markedly reduced. When all three modalities were used in combination, only 0,7% of invasive cancers were missed.     

Diagnosis of canine hyperadrenocorticism

Diagnosis of canine hyperadrenocorticism can only be made when a suspicion of the disorder persists after completion of a thorough history and physical examination. The first diagnostic testing steps include a complete blood count, serum biochemical tests, and urinalysis with urine culture. Radiography or ultrasonography may also be necessary, depending on physical findings. Screening tests are next applied to support or exclude the clinical diagnosis of hyperadrenocorticism. After the diagnosis has been made, discrimination tests are applied to determine whether the cause is pituitary or adrenal. The limitations of screening tests, particularly in the presence of nonadrenal diseases, cannot be overemphasized. We recommend that neither screening tests nor discrimination tests for hyperadrenocorticism be used in dogs with concurrent nonadrenal disease.     

Liver biopsy in ambulatory patients. Diagnostic value in comparison to conventional and quantitative liver function tests

In this retrospective analysis we investigated the diagnostic yield of 148 consecutive liver biopsies performed as an outpatient procedure. In 144 patients, adequate specimens for histologic analysis were obtained. In these patients, 226 diagnoses were entertained. Clinical diagnosis was confirmed in 49.3%, modified in 43.8% and altered in 6.9%. Liver biopsy was particularly helpful in patients where an alcoholic etiology was suspected, since this could be confirmed in only 59.4% while in the others different, often treatable, causes of chronic liver disease were found. Neither conventional nor quantitative liver tests (galactose elimination capacity, aminopyrine breath test) served to differentiate reliably between severe and mild lesions. We conclude that liver biopsy remains an important diagnostic tool in patients with chronic liver disease, and that it can be safely performed on an outpatient basis in appropriately selected patients.     

Cytology of bronchial biopsy rinse fluid to improve the diagnostic yield for lung cancer

Sampling techniques are combined during bronchoscopy to increase the diagnostic yield for endobronchial malignant tumours. Bronchial biopsy provides the definitive histological diagnosis in most cases, but accompanying cytological procedures such as washing, brushing, needle aspiration or imprint cytology can increase diagnostic yield. In this prospective study, a different cytological technique, that could enhance the diagnostic yield of bronchoscopy without increasing its time or cost, was tested. Flexible bronchoscopy was performed in 93 patients suspected of having pulmonary neoplasms. Bronchial biopsies were initially placed in a balanced salt solution. When bronchoscopy was finished, all visible tissue fragments were removed and placed in formalin to undergo histopathological examination and the rinse fluid was sent for cytological examination. Washing was performed routinely but no cytological brushing was employed. Eighty-two patients had final diagnoses of malignant neoplasm. In four (4.8%) of these patients, the only positive result came from the cytological examination of the bronchial biopsy rinse fluid. No false-positive results were found. The agreement with the histological results was 81.8%. The addition of bronchial biopsy rinse-fluid examination increased the sensitivity of bronchoscopy from 65.8% to 70.7% (McNemar's p=0.009). The cytological study of bronchial biopsy rinse fluid offers reliable positive results in an additional 4.8% of cases, thus enhancing bronchoscopic diagnostic yield for malignant endobronchial tumours while neither prolonging the procedure nor increasing costs.     

Transbronchial lung biopsy: an analysis of 530 cases with reference to the number of samples

To evaluate the diagnostic yield (DY) of transbronchial lung biopsies (TBBs), as the relationship between the DY and the number of tissue specimens taken per TBB, we reviewed the histological and clinical data of 530 consecutive TBBs performed in 516 immunocompetent patients, having either a chronic diffuse lung infiltrate, a localized peripheral lung lesion or hilar adenopathies. The DY (positive TBBs/performed TBBs) varied significantly according to the radiographic pattern and the underlying disease. For chronic diffuse pulmonary infiltrates (n = 244), the overall DY was 50%, but higher figures were obtained for hypersensitivity pneumonitis (92%), sarcoidosis stage II-III (75%), lymphangitic carcinomatosis (68%) and pneumoconiosis (54%). The DY was lower in diffuse tuberculosis (38%) and interstitial pulmonary fibrosis (27%). For localized peripheral lung lesions (n = 205), the overall DY was only 29%, while for sarcoidosis stage I it was 56% (n = 63). Data analysis shows that there is a direct correlation between the number of samples obtained per TBB and the overall DY (i.e. 38% with one to three tissue fragments versus 69% with six to 10, p < 0.01). The increment itself depends on the radiographic pattern and/or the underlying disease which indicates that the probability of diagnostic confirmation per individual tissue sample is not always the same. The clinical implication of these findings is that whereas for some pulmonary diseases the DY is already good with few samples, more samples are to be taken to warrant a satisfactory overall DY. Accordingly, we recommend that at least five to six specimens per TBB should be taken. This number should allow a quite good overall DY in patients with diffuse lung infiltrate. On theoretical grounds, more specimens (seven to 10) should be taken for an optimal DY of localized peripheral lung lesions and of sarcoidosis at stage I. In these indications the clinician should therefore compare the risk-benefit of TBB with a high number of biopsies to the results of other diagnostic procedures.