Joint replacement risk is markedly increased in alkaptonuria (AKU) in those with prior arthroplasty.

Background: Increased homogentisic acid (HGA) in alkaptonuria (AKU) causes severe arthritis. Nitisinone reduces the production of HGA, but whether it also decreases arthroplasty was examined in 237 AKU patients. Patients and methods: Patients attending the United Kingdom National Alkaptonuria Centre (NAC) and the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) study were studied. Assessments included questionnaires eliciting details of arthroplasty. Nitisinone was administered from baseline, 2 mg in the NAC and 10 mg in SONIA 2. In SONIA 2, subgroups consisted of those with baseline arthroplasty on and not on nitisinone (BR + N+, BR + N-), as well as those without baseline arthroplasty on and not on nitisinone (BR-N+, BR-N-). Results: In the SONIA2 subgroups, new joint replacement (JR) probabilities after baseline were significantly different (BR + N+, BR + N-, BR-N+, BR-N-) (χ2 = 23.3, p < 0.001); mean (SD) was 3.8 (0.1) years in BR-N-, 3.7 (0.1) years in BR-N+, 3.4 (0.3) years in BR + N-, and 3.0 (0.3) years in BR + N+. Further, the BR + N- showed more JR than the BR-N- subgroup (p < 0.01), while BR + N+ similarly showed more JR than the BR-N+ subgroup (p < 0.001).In the NAC, the BR- group had a mean age of 51.6 (7.0) years at baseline but 57.7 (8.7) years at final follow up during nitisinone therapy and showed only 7 incident JR. The BR+ group had an age at baseline of 57.4 (8.5) years and had undergone 94 JRs at baseline. Conclusion: The incidence of arthroplasty was earlier and more frequent after the first JR and was not affected by nitisinone.

White matter lesions in euthymic patients with bipolar disorder.

OBJECTIVE: We aimed to quantify both load and regional distributions of hyperintensities on magnetic resonance imaging (MRI) in prospectively verified euthymic bipolar patients and matched controls. METHOD: Cerebral hyperintensities on T2, proton density and fluid-attenuated inversion recovery (FLAIR) MRI were compared between 48 bipolar and 47 control subjects using semi-quantitative rating scales. RESULTS: Bipolar subjects had more severe frontal deep white matter lesions (DWML). Hyperintensity load was independent of age in bipolar patients but increased with age in controls. Global prevalence and severity of hyperintensities did not differ between groups. Exploratory analysis showed DWML in excess in the left hemisphere in bipolar subjects but not in controls. CONCLUSION: Findings are consistent with clinical, particularly some neurocognitive, features of bipolar disorder and implicate fronto-subcortical circuits in its neurobiology. They more probably reflect a trait abnormality or illness scar rather than a mood state-dependent finding. Processes other than ageing and vascular factors may underlie their development.

The symptoms and recognition of post-traumatic stress reactions.

The three most common clinical sequelae of trauma have been outlined above. However, the vast majority of cases will produce a normal reaction, which would not fulfil any of the diagnostic criteria. Overall, therefore, clinically significant traumatic responses are rare in the military environment, and for the most part short lived. For the conditions that are not self-limited, there are effective treatment options available which will be outlined later in this series.

Computed tomography features of recurrent ovarian carcinoma according to time to relapse.

BACKGROUND: Although the sites of recurrent ovarian cancer are individually described in the literature, patterns of recurrent disease are poorly understood. PURPOSE: To describe CT patterns of disease in recurrent ovarian cancer. To emphasize common patterns, recognise subtle and unusual sites of recurrent disease. MATERIALS AND METHODS: We identified patients between 1981-2004 presenting with clinical recurrence or elevated CA 125 after complete primary clinical and radiological response. CT imaging at primary diagnosis, during and after treatment and at recurrence was retrospectively reviewed. Site, distribution, stage of disease and time to relapse was recorded. RESULTS: 400 patients were treated for ovarian cancer. 214(54%) achieved complete primary response. 161(75%) relapsed with complete imaging available in 67 patients. Of the 67 patients, 14 (21%) recurred within 1 year, 44 (66%) relapsed between 1-5 years. Therefore 87% of relapses occurred within 5 years following primary treatment. Five (8%) relapsed between 5-10 years and 4 (6%) relapsed after 10 years. Commonest pattern of relapse was pelvic mass in 35 (48%) patients, solitary in 15 (22%). 27 (45%) relapsed with peritoneal thickening, 27 (45%) had small or large bowel serosal disease, 22 (33%) had enlarged lymphadenopathy, 6 as sole manifestation of recurrence, 20 (30%) presented with unusual sites of recurrence: 6 splenic, 10 hepatic, 2 biliary, 3 brain and 2 muscle. CONCLUSION: Our study is the first to describe common patterns of recurrence in ovarian cancer. Most frequent site is pelvis, followed by peritoneum, serosal surfaces and nodal disease. 30% presented with disease at 'unusual' sites.

Fine-needle aspiration cytology of small-cell carcinoma of the parotid.

Small-cell carcinomas arise uncommonly in extrapulmonary sites and are rare primary neoplasms in the salivary glands. We report on the aspiration cytology and immunohistochemical findings of a small-cell carcinoma of the parotid gland in an 81-yr-old man.

Simulated microgravity impairs respiratory burst activity in human promyelocytic cells.

The concept of microgravity (free-fall) influencing cellular functions in nonadherent cells has not been a part of mainstream scientific thought. Utilizing rotating wall vessels (RWVs) to generate simulated microgravity conditions, we found that respiratory burst activity was significantly altered in nonadherent promyelocytic (HL-60) cells. Specifically, HL-60 cells in simulated microgravity for 6, 19, 42, 47, and 49 d had 3.8-fold fewer cells that were able to participate in respiratory burst activity than cells from 1 x g cultures (P = 0.0011, N = 5). The quantity of respiratory burst products from the cells in simulated microgravity was also significantly reduced. The fold increase over controls in mean fluorescence intensities for oxidative products from cells in microgravity was 1.1+/-0.1 versus 1.8+/-0.3 for cells at 1 x g (P = 0.013, N = 4). Furthermore, the kinetic response for phorbol ester-stimulated burst activity was affected by simulated microgravity. These results demonstrate that simulated microgravity alters an innate cellular function (burst activity). If respiratory burst activity is impaired by true microgravity, then recovery from infections during spaceflight could be delayed. Finally, RWVs provide an excellent model for investigating the mechanisms associated with microgravity-induced changes in nonadherent cells.

Epstein-Barr virus latently infected cells are selectively deleted in simulated-microgravity cultures.

Rotating-wall vessels (RWVs) allow for the cultivation of cells in simulated microgravity. Previously, we showed that the cultivation of lymphoblastoid cells in simulated microgravity results in the suppression of Epstein-Barr virus (EBV) reactivation. To determine if the suppression generated by simulated microgravity could be reversed by changing to static culture conditions, cells were cultured in an RRWV for 5 d, and then switched to static conditions. Following the switch to static conditions, viral reactivation remained suppressed (significantly lower) relative to static control cultures over a 4-d period. Additionally, experiments were conducted to determine if chemical treatment could induce viral reactivation in cells from simulated-microgravity cultures. Cells were cultured in static flask cultures and in simulated microgravity in RWVs for 4-7 d. The cells were then transferred to 50-cm3 tubes, and treated with 3 mM n-butyrate for 48 h, or 18 ng/ml of phorbol ester, viz., 12-0-tetradecanoylphorbol-13 acetate (TPA) for either 2 or 48 h, under static conditions. Although EBV was inducible, the cells from simulated-microgravity cultures treated with n-butyrate displayed significantly lower levels of viral-antigen expression compared with the treated cells from static cultures. Also, incubation with TPA for 2-3 h, but not for 48 h, reactivated EBV in cells from RWV cultures. In contrast, EBV was inducible in cells from static cultures treated for either 2-3 or 48 h with TPA. TPA reactivation of EBV following a 2-3-h period of treatment indicates that the protein kinase C signal-transduction pathway is not impaired in lymphoblastoid cells cultured in simulated microgravity. However, the exposure of B-lymphoblastoid cells from simulated-microgravity cultures to TPA for more than 3-4 h triggered a lytic event (apoptosis or necrosis), which prevented replication of the virus. Thus, EBV-infected cells in simulated microgravity were negatively selected in the absence of any cytotoxic cells.

Fine-needle aspiration cytology of lymphangioma of the parotid gland in an adult.

Lymphangioma or cystic hygroma is an uncommon benign congenital tumor of lymphatics that is seen in children and, rarely, adults. Lymphangioma primarily involving the parotid gland is an extremely uncommon occurrence in adults. We report on the cytologic findings of a parotid lymphangioma in a 34-yr-old man which showed 13 cc of yellow fluid with red blood cells, lymphocytes, and rare fragments of benign-appearing salivary gland epithelium. The differential diagnosis of cystic parotid gland lesions in adults may include Warthin's tumor, lymphoma, benign lymphoepithelial lesions, branchial cleft cysts, chronic sialadenitis, cystic low-grade mucoepidermoid carcinoma, and cystic pleomorphic adenoma. In this case, the fine-needle aspiration findings along with the magnetic resonance imaging (MRI) findings of a multiloculated cystic mass in the parotid gland allowed the diagnosis of lymphangioma.

Effects of acute tryptophan depletion on mood and suicidal ideation in bipolar patients symptomatically stable on lithium.

BACKGROUND: Previous studies suggest that brain serotonin neurotransmission may mediate the actions of lithium carbonate. Acute tryptophan depletion reduces brain serotonin and allows the study of this neurotransmitter in patient groups. AIMS: To examine the effects of acute tryptophan depletion on mood and suicidal ideation in bipolar patients who were symptomatically stable on lithium. METHOD: Nineteen subjects satisfying DSM-IV criteria for bipolar I disorder participated in a within-subject, double-blind, placebo-controlled random-order crossover study. Symptoms were evaluated following acute tryptophan depletion, which was induced by a 100 g amino acid drink following an overnight fast. RESULTS: Plasma tryptophan fell significantly after the depleting drink, but not after the control drink (P < 0.05, paired t-test, mean reduction 83%). No significant changes in mood or suicidality scores were recorded after acute tryptophan depletion. CONCLUSIONS: Acute tryptophan depletion does not reverse lithium's effects on mood and suicidality in bipolar disorder.

The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma.

BACKGROUND: The prognostic significance and nature of p53 dysfunction in ovarian carcinoma is unclear. The relation between p53 overexpression, p53 mutations, and their effects on overall survival in primary ovarian carcinoma is explored. METHODS: Tumor specimens from 171 consecutive epithelial ovarian carcinomas were examined for overexpression of p53 protein with DO7 antibody. P53 mutations were determined by direct sequencing. The influences of conventional histopathologic prognostic factors and various p53 molecular alterations on overall survival were assessed. RESULTS: Overall, 48.5% and 57.3% of the samples showed p53 overexpression and p53 mutation, respectively. Although neither p53 overexpression nor the mere presence of a p53 mutation impacted overall survival, the combination did prognosticate survival both in univariate and multivariate models. The authors' results suggest 4 mechanisms that may affect p53 dysfunction in nearly 100% of advanced stage ovarian carcinomas. These include null mutation, nonresponsive p53 (wild-type [wt] p53 sequence, DO7 negative), sequestration (wt p53 sequence, DO7 positive), and missense mutation. Median survival for these groups that constitute sequentially 21.3%, 20.5%, 12.3%, and 45.9% of the 122 Stage III or IV (International Federation of Gynecology and Obstetrics) cancers was 1.49, 1.31, 3.09, and 3.6 years, respectively. The nonresponsive p53 and null sequence tumors grouped together as functionally null convey the worst prognosis relative to missense mutations in a univariate model (P = 0.006). Functionally null p53 (P = 0.002), stage (P = 0.008), and optimal cytoreduction (P = 0.008) were independent prognostic factors by multivariate analysis. CONCLUSIONS: Sequestration of wt p53 is unique to advanced stage ovarian carcinoma. Functionally null p53 represents an independent molecular predictor of compromised survival.

Effect of clinical history on diagnostic accuracy in the cytologic interpretation of bronchial brush specimens.

There has been little study of the effect of clinical history on pathologic diagnostic accuracy. Five pathologists retrospectively examined 97 bronchial brush specimens with and without clinical historic information. Forty-nine patients had a biopsy-proven malignant lesion, and 48 had a benign lesion. Diagnostic accuracy with and without history for each pathologist was determined with likelihood ratios and receiver operating characteristic curves. The overall diagnostic accuracy with and without history was 0.84 and 0.76, respectively. The average negative predictive value of a benign diagnosis decreased from 89.2% (with history) to 74.0% (without history). Overall, the cytopathologists were more reluctant to make a definitive malignant diagnosis without history compared with history. The average positive predictive value of a malignant diagnosis with and without history was almost identical. The absence of history leads to lower diagnostic accuracy in the cytologic interpretation of bronchial brush specimens partly because pathologists underdiagnose malignant lesions.

Brain 5-HT function in bipolar affective disorder.

BACKGROUND: Previous studies suggest that brain serotonin neurotransmission may mediate the actions of lithium carbonate. Acute tryptophan depletion (ATD) reduces brain serotonin and allows the study of this neurotransmitter in patient groups. Serotonin modulates electroencephalographic (EEG) activity, which is abnormal in bipolar disorder, and EEG abnormalities persist in euthymic bipolar patients. The EEG may therefore be a sensitive marker of 5-HT function in bipolar disorder. AIMS: This study examined the effects of ATD on mood, suicidal ideation and EEG activity in bipolar patients who were symptomatically stable on lithium. METHODS: 19 subjects satisfying DSM-IV criteria for bipolar I disorder participated in a within-subject, double-blind, placebo-controlled random-order crossover study. Following acute tryptophan depletion (induced by a 100g amino acid drink following an overnight fast) symptoms were evaluated, quantitative power spectrum brain mapping and measurement of auditory evoked potentials were carried out. RESULTS: ATD produced a significant fall in the amplitude of N1P2 and P300 components of the auditory evoked potential, but no significant changes in the power spectrum. There was an 83% reduction in plasma tryptophan (p<0.05, paired t-test) after the depleting but not the control drink. No significant changes in mood or suicidally scores were recorded after ATD. CONCLUSIONS: ATD attenuates auditory evoked potentials in bipolar disorder but does not reverse lithium's effects on mood and suicidally in bipolar disorder.

The cytologic diagnosis of low-grade transitional cell carcinoma.

Current theory suggests that transitional cell carcinoma (TCC) occurs as either of 2 disease processes, each of which has a distinct cytologic appearance and clinical course: low-grade and high-grade TCC. Urinary cytology has become a mainstay technique for monitoring disease recurrence in patients with TCC. Most cases of high-grade TCC can be diagnosed accurately in urinary cytology specimens. However, the cytologic diagnosis of low-grade TCC is difficult; these tumors exhibit subtle cytomorphologic alterations that are difficult to distinguish from benign or reactive processes. The cytologic criteria most useful for diagnosing low-grade TCC in urinary cytology specimens are reviewed. Additionally, the discussion includes some of the new ancillary tests that are emerging as possible diagnostic aids for the detection of low-grade urothelial neoplasms.

Nephrogenic adenoma mimicking carcinoma: a potential pitfall in cytodiagnosis.

Nephrogenic adenoma of the urinary bladder and urethra is an uncommon benign lesion of the urinary epithelium that can cytologically and histologically mimic malignancy. We report on the cytologic findings of a case of nephrogenic adenoma of the urethra that mimicked malignancy in an 84-yr-old woman. The differential diagnosis of this problematic lesion is discussed, and the literature describing the cytologic features is reviewed.

The role of fine-needle aspiration cytology in the evaluation of metastatic clear cell tumors.

BACKGROUND: Clear cell tumors (CCTs) occur as primary neoplasms in a number of anatomic sites. Due to their overlapping morphologic features, these tumors can be challenging for the cytologist, particularly when they present as metastatic lesions. METHODS: Forty-nine fine-needle aspirations (FNA) of metastatic CCTs from 46 patients (age range, 29-87 years; mean, 64 years) were reviewed retrospectively. In addition to the routine smears and cell block preparations, ancillary studies were performed in selected cases. Clinical and/or histologic follow-up was obtained for all patients. RESULTS: The sites of the 49 FNAs were the lung (12 cases), lymph nodes (9 cases), liver (7 cases), bone (7 cases), soft tissue (4 cases), pelvis (2 cases), adrenal gland (2 cases), pancreas (1 case), thyroid (2 cases), peritoneum (2 cases), and vagina (1 case). Twenty-seven patients had a previous history of a CCT and the FNA material in these cases was consistent with a metastasis. The primary anatomic sites in these cases were the kidney (20 cases), ovary (2 cases), salivary gland (1 case), and cervix (1 case). On light microscopy, these tumors had a similar appearance and often were indistinguishable. Nineteen patients did not have a prior history of malignancy; 12 of these patients had a concurrent renal mass and the diagnosis of metastatic renal cell carcinoma was made. The anatomic site of origin of seven of the ten remaining tumors (kidney [2 cases], lung [2 cases], ovary [1 case], germ cell [1 case], and endometrium [1 case]) was established through immunocytochemical studies of cytologic material and clinical follow-up. CONCLUSIONS: FNA plays an important role in the diagnosis of metastatic CCT. Cytologic examination, ancillary studies, and clinical information can establish the anatomic site of origin in the majority (95%) of cases, precluding the necessity of obtaining additional tissue. Cancer (Cancer Cytopathol)

MOC-31 aids in the differentiation of metastatic adenocarcinoma from hepatocellular carcinoma.

BACKGROUND: Fine-needle aspiration biopsy (FNAB) is frequently used to diagnose mass lesions in the liver. Differentiating metastatic adenocarcinoma from primary hepatocellular carcinoma can be difficult. Despite a number of morphologic criteria, there remain occasional cases in which the cytologic features fail to resolve this differential reliably; in these cases ancillary studies may be useful. Recently, it has been reported that the antibody MOC-31 reliably separates metastatic adenocarcinoma from hepatocellular carcinoma. In this study we examine the utility of MOC-31 in liver FNAB material. METHODS: Thirty-three archival, alcohol-fixed, paraffin-embedded cell blocks representing 17 cases of hepatocellular carcinomas and 16 cases of metastatic adenocarcinoma were retreived. After protease digestion, the sections were immunostained with the antibody MOC-31 (Dako, Carpinteria, CA) utilizing a modified avidin-biotin complex technique. Only membrane-based reactivity was considered positive. RESULTS: In five cases there was insufficient diagnostic material remaining in the cell block for immunohistochemical staining. Among the remaining cases, MOC-31 reactivity was observed in 10 of 12 metastatic adenocarcinomas and 2 of 16 hepatocellular carcinomas. For metastatic adenocarcinoma the presence of MOC-31 reactivity yields a sensitivity of 83%, a specificity of 87%, a positive predictive value of 83%, and a negative predicitive value of 87%. CONCLUSIONS: MOC-31 is useful in separating metastatic adenocarcinoma from hepatocellular carcinoma in FNAB cell block material. Cancer (Cancer Cytopathol)

Suppression of Epstein-Barr virus reactivation in lymphoblastoid cells cultured in simulated microgravity.

Rotating-wall vessels allow for the growth of cells in simulated microgravity. Lymphoblastoid cells cultured in rotating-wall vessels exhibited significant differences in the expression of both early and late Epstein-Barr Virus (EBV) antigens. Viral protein expression (as measured by indirect immunofluorescence) was significantly suppressed in cells cultured in simulated microgravity. A significantly greater percentage of P3HR-1 cells and Daudi cells were positive for the expression of BamH1-Z-DNA fragment of Epstein-Barr replication activator (ZEBRA), early antigen restricted (EA-R), and viral capsid antigen (VCA) in cells cultured in static tissue culture flasks as compared to cells cultured in rotating-wall vessels. We observed a 7, 11, and 25-fold reduction, respectively, for EA-R, VCA, and ZEBRA protein in P3HR-1 cells cultured in simulated microgravity. Additionally, suspension cultures of P3HR-1 cells exhibited significantly greater ZEBRA antigen expression than cells cultured in rotating-wall vessels. As an independent confirmation of the reduction in ZEBRA-protein production in simulated microgravity in P3HR-1 cells, ZEBRA-mRNA was quantitated by reverse transcription polymerase chain reaction. We observed between a 4 to 10-fold reduction in ZEBRA-mRNA in cells cultured in simulated microgravity as compared to cells cultured at 1 x g in tissue culture flasks. Rotating-wall vessels, by virtue of providing a simple culture environment triggering marked differences in viral activation, provide a model whereby both host and viral factors involved in regulating the maintenance of EBV latency can be examined.

Fine-needle aspiration cytology of esophageal leiomyomatosis.

Leiomyomata are the most common benign neoplasms of the esophagus, but they are still very rare in comparison to malignant tumors of this organ. We report on the aspiration cytology findings of a case of esophageal leiomyomatosis in a 19-yr-old man. Diagn. Cytopathol. 1999;21:197-199.