Influence of recent altitude exposure on sea level sympathetic neural & hemodynamic responses to orthostasis.

Although it has been shown that muscle sympathetic nerve activity increases during high altitude exposure, mechanisms of sympathoexcitation and blood pressure control after return from altitude are not well described. We hypothesized that: (1) living for 12days at 4300m (Pikes Peak, Colorado) would result in increased muscle sympathetic nerve activity 24h after return to sea level; (2) post-Pikes Peak sympathetic neural and hemodynamic responses to orthostasis would be decreased due to a potential 'ceiling effect' on sympathetic activity; and (3) the magnitude of individual increases in sympathetic nerve activity post-Pikes Peak would be inversely related to baseline sympathetic nerve activity before traveling to altitude. Muscle sympathetic nerve activity, heart rate and blood pressure were measured in 9 healthy individuals (24±8years) in supine, 30° and 45° head-up tilt positions. Measurements were conducted twice at sea level, once before (pre-Pikes Peak) a 12day residence at 4300m, and once within 24h of return (post-Pikes Peak). Supine muscle sympathetic nerve activity was higher (post: 27±5 vs pre: 17±6bursts/min) upon return from altitude (p<0.05). Individual values for pre-Pikes Peak sympathetic activity were inversely related to post-altitude sympathoexcitation (r=-0.69, p<0.05). There were no differences in neural or cardiovascular responses to tilt between pre and post- Pikes Peak (p>0.05). We conclude that 12days' residence at 4300m causes a sustained sympathoexcitation which does not impair the ability of muscle sympathetic nerves to respond appropriately to orthostasis.

Who mixes with whom among men who have sex with men? Implications for modelling the HIV epidemic in southern India.

In India, the identity of men who have sex with men (MSM) is closely related to the role taken in anal sex (insertive, receptive or both), but little is known about sexual mixing between identity groups. Both role segregation (taking only the insertive or receptive role) and the extent of assortative (within-group) mixing are known to affect HIV epidemic size in other settings and populations. This study explores how different possible mixing scenarios, consistent with behavioural data collected in Bangalore, south India, affect both the HIV epidemic, and the impact of a targeted intervention. Deterministic models describing HIV transmission between three MSM identity groups (mostly insertive Panthis/Bisexuals, mostly receptive Kothis/Hijras and versatile Double Deckers), were parameterised with behavioural data from Bangalore. We extended previous models of MSM role segregation to allow each of the identity groups to have both insertive and receptive acts, in differing ratios, in line with field data. The models were used to explore four different mixing scenarios ranging from assortative (maximising within-group mixing) to disassortative (minimising within-group mixing). A simple model was used to obtain insights into the relationship between the degree of within-group mixing, R0 and equilibrium HIV prevalence under different mixing scenarios. A more complex, extended version of the model was used to compare the predicted HIV prevalence trends and impact of an HIV intervention when fitted to data from Bangalore. With the simple model, mixing scenarios with increased amounts of assortative (within-group) mixing tended to give rise to a higher R0 and increased the likelihood that an epidemic would occur. When the complex model was fit to HIV prevalence data, large differences in the level of assortative mixing were seen between the fits identified using different mixing scenarios, but little difference was projected in future HIV prevalence trends. An oral pre-exposure prophylaxis (PrEP) intervention was modelled, targeted at the different identity groups. For intervention strategies targeting the receptive or receptive and versatile MSM together, the overall impact was very similar for different mixing patterns. However, for PrEP scenarios targeting insertive or versatile MSM alone, the overall impact varied considerably for different mixing scenarios; more impact was achieved with greater levels of disassortative mixing.

The predicted impact of immunosuppression upon population age-intensity profiles for schistosomiasis.

The slow development of acquired immunity is thought to be responsible for the characteristic convex age-intensity curve seen in human schistosome infection, which peaks earlier in more heavily infected populations (this is described as a peak shift). Schistosomes are able to suppress protective host responses, and it is hypothesized that this suppression is responsible for the delayed development of protective responses. A deterministic mathematical model is used to describe levels of infection and immunity in an endemic population, incorporating protective immune responses which either reduce adult worm burden or reduce superinfection. Suppression, related to current worm burden, is also included and acts against one or both protective responses. If suppression acts against the entire protective response, it is able to delay the development of protective immunity, and the peak shift is predicted to be reversed at higher infection intensities, with removal of the peaks altogether at the highest levels of infection and/or suppression. If only the anti-adult worm protective immune response is vulnerable to suppression, while the anti-reinfection response remains intact, then suppression does not remove the peak in the age-intensity curve. These findings are discussed in the light of existing field and experimental data.

Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis.

The iron chelator, Desferal, suppressed disease activity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), and it has been tested in pilot trials for MS. The administration regimen of Desferal is cumbersome and prone to complications. Orally-deliverable, iron chelators have been developed that circumvent these difficulties, and the objective of this study was to test an oral chelator in EAE. SJL mice with active EAE were randomly assigned to receive deferiprone (150 mg/kg) or vehicle (water) 2x/day via gavage. EAE mice given deferiprone had significantly less disease activity and lower levels of inflammatory cell infiltrates (revealed by H&E staining) than EAE mice administered vehicle. T-cell infiltration, assessed by anti-CD3 immunohistochemical staining, also was reduced, although not significantly. Splenocytes cultured from naïve SJL mice were stimulated with anti-CD3 and anti-CD28 with or without 250 microM deferiprone. While approximately 39% of costimulated splenocytes without deferiprone underwent division, only approximately 2.8% of costimulated splenocytes with deferiprone divided and the latter cells were only 53% as viable as the former. Deferiprone had no effect on proliferation or viability of cells that were not costimulated. In summary, deferiprone effectively suppressed active EAE disease and it inhibited T-cell function.

An aid to the early detection and management of diabetic nephropathy: assessment of a new point of care microalbuminuria system in the diabetic clinic.

AIMS: To compare the performance of the DCA2000 microalbuminuria system for albumin and creatinine concentrations and the albumin:creatinine ratio (ACR) with laboratory measurements in the hospital diabetes clinic and to assess the ease of use and applicability by standard clinic personnel. METHODS: Urine albumin and creatinine concentration and ACR were measured in 154 diabetic patient samples and in 77 normal subjects. Both albumin assays are based on immunoturbidimetry. The DCA2000 system utilizes reagent cartridges processed automatically. RESULTS: Control material within-run precision (coefficient of variation (CV)) for albumin and creatinine ranged up to 7.1% and 3.3% respectively. Between-run CVs ranged from 2.1% to 4.3%. Method comparisons yielded correlation coefficients > 0.99 for albumin, creatinine and ACR, only a small negative bias of 3.2 mg/l for albumin and 0.10 mg/mmol for ACR, no concentration-related bias for ACR and no between-method difference for either albumin (P = 0.195) or ACR (P = 0.341). At a laboratory albumin concentration cut-off of 20 mg/l the sensitivity, specificity, negative and positive predictive values were 92.4% 100% 92.7% and 100%. Normal reference range mean albumin, creatinine and ACR values for the DCA2000 and the laboratory were 7.7 mg/l vs. 9.0 mg/l 13.0 mmol/l vs. 12.6 mmol/l and 0.66 mg/mmol vs. 0.81 mg/mmol respectively. Clinic personnel found that the DCA2000 system was easy to use suited the clinic environment and generated confidence in the results. CONCLUSIONS: This point of care system safely substitutes laboratory-based measurements. Ease of use and low cost make it suitable for screening and monitoring diabetes treatment. It facilitates the use of random urines, and may obviate the need for timed samples. This approach has a clear place in the battle to reduce the diabetic vascular disease burden.

Activity-dependent nitric oxide concentration dynamics in the laterodorsal tegmental nucleus in vitro.

The behavioral-state related firing of mesopontine cholinergic neurons of the laterodorsal tegmental nucleus appears pivotal for generating both arousal and rapid-eye-movement sleep. Since these neurons express high levels of nitric oxide synthase, we investigated whether their firing increases local extracellular nitric oxide levels. We measured nitric oxide in the laterodorsal tegmental nucleus with a selective electrochemical microprobe (35 microm diam) in brain slices. Local electrical stimulation at 10 or 100 Hz produced electrochemical responses that were attributable to nitric oxide. Stimulus trains (100 Hz; 1 s) produced biphasic increases in nitric oxide that reached a mean peak concentration of 33 +/- 2 (SE) nM at 4.8 +/- 0.4 s after train onset and decayed to a plateau concentration of 8 +/- 1 nM that lasted an average of 157 +/- 23.4 s (n = 14). These responses were inhibited by N(G)-nitro-L-arginine-methyl-ester (1 mM; 92% reduction of peak; n = 3) and depended on extracellular Ca(2+). Chemically reduced hemoglobin attenuated both the electrically evoked responses and those produced by authentic nitric oxide. Application of the precursor, L-arginine (5 mM) augmented the duration of the electrically evoked response, while tetrodotoxin (1 microM) abolished it. Analysis of the stimulus-evoked field potentials indicated that electrically evoked nitric oxide production resulted from a direct, rather than synaptic, activation of laterodorsal tegmental neurons because neither nitric oxide production nor the field potentials were blocked by ionotropic glutamate receptor inhibitors. Nevertheless, application of N-methyl-D-aspartate also increased local nitric oxide concentration by 39 +/- 14 nM (n = 8). Collectively, these data demonstrate that laterodorsal tegmental neuron activity elevates extracellular nitric oxide concentration probably via somatodendritic nitric oxide production. These data support the hypothesis that nitric oxide can function as a local paracrine signal during the states of arousal and rapid-eye-movement sleep when the firing of mesopontine cholinergic neurons are highest.

Trends in the frequency and predictive value of reporting high grade abnormalities in cervical smears.

BACKGROUND: The "organized approach" to cervical screening in Australia includes standardized quality assurance measures for laboratories. This study examines changes in the frequency and the positive predictive value of reporting severe abnormalities in cervical smears over a 3-year period as a guide to the effects of implementing these measures. METHODS: The results of screening in 6-month periods from January 1995 to December 1997 were determined. Biopsy follow-up for results in the high grade epithelial abnormality ("HGEA") and "inconclusive: possible HGEA" categories was obtained from the Western Australian Cervical Cytology Registry (CCR). RESULTS: Approximately 40,000 smears were examined in each 6-month period. The frequencies of reporting HGEA were 0.47%, 0.59%, 0.79%, 0.85%, and 0.84%, and 0.91% for the study periods (P < 0.001). For the inconclusive category, they were 0.24%, 0.18%, 0.24%, 0.31%, 0.38%, and 0.35% (P < 0.001). Biopsy follow-up was available for 83. 9%, 80.5%, 89.9%, 92.4%, 93.1%, and 90.3% of the HGEA results and for 78.6%, 71.7%, 80.5%, 75.0%, 87.1%, and 85.9% of the inconclusive results over the study periods. The yield of high grade lesions for the biopsied cases was 82.6%, 82.3%, 83.1%, 79.5%, 80.9%, and 79% for HGEA cases and 58.2%, 41.9%, 60.6%, 52.8%, 47.5%, and 54.1% for inconclusive cases. CONCLUSIONS: There was a doubling in the reporting of HGEA results, whereas the positive predictive value for biopsied cases remained at about 80%. Reporting rates for inconclusive: possible HGEA cases also doubled, but the yield of biopsy-proven, high grade lesions remained at about 50%. These changes occurred in the absence of ancillary testing and with targeted rescreening methods. A high rate of reporting HGEA, in combination with a high positive predictive value, is among the most important indicators of cervical cytology laboratory performance. Large improvements in results may occur using conventional methods of quality assurance. Cancer (Cancer Cytopathol)

Diffuse leptomeningeal oligodendrogliomatosis: radiologic/pathologic correlation.

We present the radiologic and pathologic findings in a boy who presented with diffuse leptomeningeal enhancement and whose clinical status deteriorated over the course of 5 years. During this period, MR images showed progression of the enhancement in the subarachnoid spaces, formation of intraaxial cysts, and hydrocephalus. Autopsy findings revealed diffuse oligodendroglioma throughout the leptomeninges of the brain and spine, with no definite intraaxial focus. The radiologic and pathologic features of diffuse leptomeningeal oligodendrogliomatosis are reviewed.

Adrenal neuroblastoma in an adult with tumor thrombus in the inferior vena cava.

We describe the appearance of an adrenal neuroblastoma associated with tumor thrombus occurring in an adult patient. The tumor measured 14 x 12 x 12 cm, showed heterogeneous signal intensity on both T1-weighted and T2-weighted images, and displayed peripheral nodular enhancement on early post-gadolinium images. Tumor thrombus was identified within the inferior vena cava, which extended into the right atrium.

The "Inconclusive--possible high grade epithelial abnormality" category in Papanicolaou smear reporting.

BACKGROUND: The Australian Terminology for Cervical Cytology Reporting includes the category "Inconclusive-Possible high grade epithelial abnormality." METHODS: The frequency of use of this category, the types of associated cell patterns, and the yield of high grade lesions at biopsy were studied. RESULTS: One hundred and two cases categorized as "Inconclusive" were reported between January and June 1995, representing 0.24% of 41,712 Papanicolaou (Pap) smears screened. The abnormal cells were reported as squamous in 74.5% of cases, endocervical in 4.9% of cases, endometrial in 3.9% of cases, and indeterminate in 16.7% of cases. The main cellular patterns included disorganized groups of hyperchromatic squamous, glandular, or indeterminate cells (64.2% of cases) and atypical metaplastic squamous cells (28.4% of cases). Cell preservation was suboptimal. In 25.3% of cases the cells were highly degenerate or air-dried. Follow-up included biopsy (84.3% of cases), colposcopy alone (7.8% of cases), and repeat Pap smears without any detected abnormality (3.9% of cases). No follow-up was available in 3.9% of cases. High grade abnormalities were found in 66.3% of the biopsied cases and 55.9% of the total cases (48 cervical intraepithelial neoplasia [CIN] of Grade 2 or 3; 2 squamous cell carcinomas; 3 endocervical adenocarcinoma in situ [ACIS]; 3 adenocarcinomas of endocervical, ovarian, and endometrial origin; and 1 endometrial stromal sarcoma). In 16.2% of cases a low grade squamous lesion was present on biopsy (CIN, Grade 1 or human papillomavirus effect); and no lesion was found in 17.4% of cases. CONCLUSIONS: The "Inconclusive" category was not overused, and gave a high yield of biopsy abnormalities. Accepting uncertainty in the diagnosis of some high grade lesions reduces their likelihood of being classified incorrectly as reactive changes, ignored because of poor cell preservation, or lost in the larger group of classifications such as atypical cells of undetermined significance, borderline nuclear abnormality, or non-specific minor changes.

Direct measurement of glutamate release in the brain using a dual enzyme-based electrochemical sensor.

The in vivo measurement of the rapid changes in the extracellular concentrations of L-glutamic acid in the mammalian brain during normal neuronal activity or following excessive release due to episodes of anoxia or ischemia has not been possible to this date. Current techniques for the measurement of the release of endogenous glutamate into the extracellular space of the central nervous system are relatively slow and do not measure the actual concentration of free glutamate in the extracellular space. An enzyme-based electrode with rapid response times (about 1 s) and high degree of sensitivity (less than 2 microM) and selectivity for L-glutamic acid is described in this paper. This electrode has both L-glutamate and ascorbate oxidase immobilized on its surface. The latter enzyme removes almost completely any interferences produced by the high levels of extracellular ascorbate present in brain tissue. The response of the electrode to glutamate and other potentially interfering substances was fully characterized in vitro and its selectivity, sensitivity and rapidity in responding to a rise in extracellular glutamate concentrations was also demonstrated in vivo. Placement of the electrode in the dentate gyrus of the hippocampus led to the detection of both KCl-induced release of L-glutamic acid and the release induced by stimulation of the axons in the perforant pathway. The development of this selective, sensitive and rapidly responding glutamate sensor should make it now possible to measure the dynamic events associated with glutamate neurotransmission in the central nervous system.

Cathepsin-D expression in cervical carcinoma and its prognostic significance.

An immunohistochemical study was made of cathepsin-D protein expression in each of the three main types of uterine cervical carcinoma (squamous carcinoma, adenosquamous carcinoma and adenocarcinoma) with particular reference to lymph node status and prognosis. Of the 61 cases, 54.1% showed cytoplasmic staining in more than 2.5% of tumour cells counted. Cathepsin-D expression was significantly higher in adenocarcinoma (mean -3.128) than in squamous carcinoma and adenosquamous carcinoma (mean -3.709, p = 0.047 using logit transformation). Cathepsin-D had no prognostic value in any of the three tumour types. No relationship was found between cathepsin-D staining and lymph node status and there was no advantage in adding cathepsin-D values to lymph node status. These results suggest that immunostaining for cathepsin-D protein expression is unlikely to be of use as a prognostic marker.

Survey of histologic specimens of human cancer for human papillomavirus types 6/11/16/18 by filter in situ hybridization.

Histologic specimens (317) of genital and nongenital cancers and normal tissue were analyzed for the presence of the DNA of human papillomavirus (HPV) 6, 11, 16, and 18 by filter in situ hybridization performed on paraffin-embedded, formalin-fixed tissue (HISTOFISH). HPV DNA was found in 73 of 172 (42%) anogenital lesions and 17 of 116 (15%) nonanogenital carcinomas. No HPV DNA was found in normal mouse skin (five samples), human autopsy liver (two samples), or kidney (eight samples), or in carcinomas of the breast (three samples), bladder (five samples), or colon (nine samples). Of the nongenital tumors, HPV DNA was found in the carcinomas of the lung (2 of 5), anus (7 of 18), esophagus (9 of 39), buccal cavity (1 of 5), and larynx (5 of 50). HPV DNA was also detected in 2 of 11 histologically normal specimens of the cervix and 1 of 3 human skin lesions. The detection of HPV DNA in carcinomas of the lung, larynx, and esophagus as well as in the anogenital region confirms recent suggestions that HPV types 6, 11, 16, and 18 have a wider association with different types of cancer than previously believed. The study also shows that HISTOFISH is a useful method for detecting HPV-DNA in histologic specimens.

Coexisting bacterial pyelonephritis and bilateral ureteral fungus balls in a diabetic patient. Case report.

Bacterial pyelonephritis is a common precipitating factor in the development of diabetic ketoacidosis. Prompt diagnosis and appropriate antimicrobial therapy usually result in resolution of constitutional symptoms and adequate control of serum glucose. However, occasional cases of presumed bacterial pyelonephritis may not respond to appropriate empiric antibiotic therapy, then causes should be sought such as obstruction or untreated fungal infections of the urinary tract. In this case a diabetic patient with classical pyelonephritis was found to have bilateral ureteral fungus balls as the underlying cause of refractory infection.

Extragenital donovanosis: three cases from Western Australia.

Three unusual cases of extragenital donovanosis are described. The presenting features were ulceration of the anterior abdominal wall, discharging sinuses of the neck, and an abscess of bone, respectively. Two cases were diagnosed recently and were the only instances of extragenital infection in a series of 47 patients with confirmed donovanosis diagnosed at a public health laboratory in Perth, Western Australia, between 1979 and the beginning of 1985. The third case, which occurred in 1977, was found in the records of a major teaching hospital.

Donovanosis in Western Australia.

We report and discuss a series of 47 consecutive patients with donovanosis that were diagnosed in a public health laboratory in Western Australia during slightly more than six years. Most came from the tropical northern parts of Western Australia, there was a preponderance of women in the series, and vulval lesions were the most common manifestation of the disease. Two men had extragenital lesions, though each was eventually found to have concomitant genital lesions.

Primary colo-rectal linitis plastica type of carcinoma: report of two cases and review of the literature.

Linitis Plastica type of carcinoma can arise primarily in the colon or rectum. Fifty-two cases have been reported in the English medical literature over a 50-yr period. Two new cases are described. One patient had primary linitis plastica of the ascending colon, the other being in the rectum. Both patients died of widespread malignancy within 10 mth of diagnosis, the fate of most of the reported cases. This rare manifestation of colo-rectal carcinoma carries an ominous prognosis.

Renal oncocytoma.

Several authors have recently drawn attention to renal oncocytoma, a neoplasm hitherto rarely recognized. Their reports suggest that renal oncocytomas are not uncommon and that they are benign and possess distinctive gross, microscopical, ultrastructural, and behavioral features. Most examples were discovered on re-examination of neoplasms previously classified as renal adenocarcinoma or adenoma. In a survey of renal neoplasms filed in our Department, we identified 8 cases; these are reported and the literature is reviewed.