Cellular differentiation in the thymus. 3. Surface properties of rat thymus and lymph node cells separated on density gradients.

Young adult rat thymus and lymph node cell subpopulations were obtained by differential flotation on discontinuous BSA density gradients and assayed for properties characteristic of mature thymus-derived lymphocytes. One such subpopulation (C) of thymocytes was enriched in its ability to respond mitotically to a hemiallogeneic MLR stimulus, to localize in the parenchyma of lymph nodes and spleen, and to initiate a GVH reaction in a suitable host. These cells did not respond well to mitotic stimulation by PHA, they were lighter in density than the majority of mature lymph node thymus-derived lymphocytes, and they possessed a thymus-specific antigen (RTA) not present on peripheral lymphoid cells. We conclude that the acquisition of peripheral properties occurs sequentially, during an intrathymic differentiation cycle or shortly after the cells leave the thymus.

Gun trauma and ophthalmic outcomes.

PurposeThis retrospective cohort study assesses the visual outcomes of patients who survive gunshot wounds to the head.MethodsThe Elmhurst City Hospital Trauma Registry and Mount Sinai Data Warehouse were queried for gun trauma resulting in ocular injury over a 16-year period. Thirty-one patients over 16 years of age were found who suffered a gunshot wound to the head and resultant ocular trauma: orbital fracture, ruptured globe, foreign body, or optic nerve injury. Gun types included all firearms and air guns. Nine patients were excluded due to incorrect coding or unavailable charts. Statistical analysis was performed using a simple bivariate analysis (χ2).ResultsOf the 915 victims of gun trauma to the head, 27 (3.0%) sustained ocular injuries. Of the 22 patients whose records were accessible, 18 survived. Eight of the 18 surviving patients (44%) suffered long-term visual damage, defined as permanent loss of vision in at least one eye to the level of counting fingers or worse. Neither location of injury (P=0.243), nor type of gun used (P=0.296), nor cause of gun trauma (P=0.348) predicted visual loss outcome. The Glasgow Coma Scale eye response score on arrival to the hospital also did not predict visual loss outcome (P=0.793).ConclusionThere has been a dearth of research into gun trauma and even less research on the visual outcomes following gun trauma. Our study finds that survivors of gun trauma to the head suffer long-term visual damage 44% of the time after injury.

Microdomain elements of airway smooth muscle in calcium regulation and cell proliferation.

Airway remodeling manifested by hyperplasia of airway smooth muscle cells (ASMCs) and other structural and functional changes is a pathological condition in asthma not addressed by current treatment. Ca2+ signaling is crucial for ASMC proliferation. Inositol-1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) mediate Ca2+ release from endoplasmic reticulum/sarcoplasmic reticulum (ER/SR). Upon sensing the depletion of Ca2+ in ER/SR, stromal interaction molecule 1 (STIM1) aggregates and redistributes at the microdomain of ER/SR-plasma membrane (PM) and activates Orai1, a component of the store-operated Ca2+ (SOC) channels, to initiate Ca2+ influx. The STIM1/Orai1-mediated SOC entry is the main cause of a sustained intracellular calcium ([Ca2+]i) elevation, which is different from a transient rise of [Ca2+]i mediated by IP3R and RyR. Extended-synaptotagmin 1 (E-Syt1) is recruited to the ER/SR-PM junction and anchors to the PM lipid phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) in a SOC-dependent manner. The subsequent strengthening of the ER/SR-PM connection by E-Syt1 facilitates the phosphatidylinositol (PI) transfer protein, Nir2, to supplement PI, a PI(4,5)P2 substrate, for the generation of IP3 and the propagation of Ca2+ signaling. Calcineurin and nuclear factor of activated T cells are the downstream signaling factors of elevated [Ca2+]i contributing to ASMC proliferation. Mitochondrial Ca2+ uptake/efflux, mitochondrial fission/fusion and mitochondrial-ER/SR coupling also play important roles in modulating [Ca2+]i and ASMC proliferation. Together, these pathways and mechanisms represent new therapeutic targets for airway remodeling. The present review provides an overview of our current understanding of the mechanisms of ASMC proliferation involving Ca2+ and highlights potential directions to control airway remodeling in asthma.

Microalbuminuria prevalence study in hypertensive patients with type 2 diabetes mellitus in Singapore.

INTRODUCTION: Microalbuminuria is a marker of increased cardiovascular morbidity and mortality. It represents the earliest clinical evidence of diabetic nephropathy. Its early detection allows for implementation of individually-tailored cardiovascular risk reduction management programmes. Despite this, information on the prevalence of microalbuminuria in hypertensive patients with type 2 diabetes mellitus in Singapore is limited. METHODS: The Microalbuminuria Prevalence Study (MAPS) assessed the prevalence of macroalbuminuria and microalbuminuria in consecutively-screened hypertensive adult patients with type 2 diabetes mellitus in ten Asian countries. This paper presents the results of a sub-analysis of data from patients in Singapore. RESULTS: Singapore contributed seven percent of the overall enrolment into MAPS; a total of 499 patients were enrolled and 388 constituted the per-protocol population (patients with bacteriuria and haematuria were excluded). Overall, the prevalence of diabetic kidney disease was high. In our study population, 23.5 percent of patients had macroalbuminuria (95 percent confidence interval [CI] 21.3-25.6), and 48.5 percent of patients had microalbuminuria (95 percent CI 45.9-51.0). Only 28.1 percent (95 percent CI 25.8-30.4) of patients were normoalbuminuric. Associated factors were poor glycaemic control and poor blood pressure control. CONCLUSION: The high prevalence (72 percent) of microalbuminuria and macroalbuminuria found in hypertensive patients with type 2 diabetes mellitus in Singapore is a cause for concern. These findings highlight the need to screen for microalbuminuria and better manage hypertensive patients with type 2 diabetes mellitus, if we are to avoid a major increase in end-stage renal disease.

Inhibition of HT-29 human colon cancer growth under the renal capsule of severe combined immunodeficient mice by an analogue of 1,25-dihydroxyvitamin D3, DD-003.

An analogue of 1,25-dihydroxyvitamin D3, 22(S)-24-homo-26,26,26,27,27,27-hexafluoro-1 alpha,22,25-trihydroxyvitamin D3 (DD-003), showed 10-fold greater inhibiting effect than 1,25-dihydroxyvitamin D3 on the growth of HT-29 human colonic adenocarcinoma cells in culture. To examine the anticancer activity of DD-003 in vivo, a fibrin clot of HT-29 cells was prepared with fibrinogen and thrombin and implanted under the renal capsule of the severe combined immunodeficient mouse. Starting 7 days after implantation of HT-29 tumor, mice were given 3 micrograms/kg body weight of DD-003 or the vehicle i.p. every other day for 5 times. The HT-29 tumor grew rapidly in control mice; malignant growth was clearly observed with mitosis, massive tumor angiogenesis, and invasion into normal kidney tissue. Tumors in DD-003 treated mice were smaller with less invasion compared to the control. Administration of DD-003 inhibited growth of HT-29 tumor by 63%. Serum calcium concentrations and body weights of the treated mice were similar to those of the control. DD-003 inhibited growth of HT-29 tumor in a dose-dependent manner over the range of 0.1-10 micrograms/kg body weight, with no increase of serum calcium concentration observed at any dose level. When DD-003 was withdrawn after 2 weeks of treatment, tumor growth resumed. Since chemosensitivity tested by the subrenal capsule assay correlates well with clinical response, DD-003 may be clinically applicable in procedures such as postsurgical chemotherapy of colon cancer.

Mutation of the MENIN gene in sporadic pancreatic endocrine tumors.

Pancreatic endocrine tumors occur both sporadically and as part of the multiple endocrine neoplasia type 1 (MEN1) syndrome. MEN1 is an autosomal dominant disease characterized by parathyroid hyperplasia, pancreatic endocrine tumors, and pituitary adenomas. The MEN1 gene called MENIN maps to chromosome 11q13 and is thought to function as a tumor suppressor gene. We previously demonstrated loss of heterozygosity (LOH) at 11q13 in approximately 40% of sporadic pancreatic endocrine tumors and hypothesize that MENIN is involved in the development of these tumors. Thirty-one sporadic pancreatic endocrine tumors were analyzed for mutation of MENIN by nonradioactive single-stranded conformation polymorphism. Twelve mutations were detected in 31 sporadic pancreatic endocrine tumors (34%). Twelve of these 31 tumors previously demonstrated loss of heterozygosity at 11q13. Of the tumors with LOH, seven contained mutations of the MENIN gene (58%). The majority of the MENIN mutations occurred within exon 2. Two independent mutations in MENIN were detected in a gastrinoma that also revealed LOH, leading to the possibility of another tumor suppressor gene locus at 11q13. Mutations were present in both benign and malignant pancreatic endocrine tumors, suggesting that a MENIN gene mutation is a frequent and early event in the tumorigenesis. The high incidence of truncating mutations in tumors with LOH at 11q13 support the hypothesis that MENIN is a tumor suppressor gene.

Nasal glomus tumors: report of two cases with emphasis on immunohistochemical features and differential diagnosis.

We describe 2 cases of nasal glomus tumor that presented as nasal polyps. Grossly, each of the polypectomy specimens consisted of small fragments of polypoid soft tissue with glistening mucosa. Histopathological examination of each of the specimens showed sheets and nests of monomorphic round cells intimately associated with capillary-sized blood vessels. The tumor cells were strongly cytoplasmic positive for vimentin, smooth-muscle specific actin, muscle-specific actin, and CD34. Collagen IV showed pericellular positivity. Nasal glomus tumors are extremely rare and represent less than 0.5% of nasal nonepithelial tumors. Nasal polyps are common surgical pathological specimens, with the majority of nasal polyps being inflammatory polyps or a respiratory epithelial proliferation. Histologically, many nasal polyps show vascular proliferation with an inflammatory cell infiltrate, which may be confused with the rare glomus tumor. In addition, other nasal vascular tumors, in particular nasal hemangiopericytoma and neural tumors, may histologically mimic nasal glomus tumors.

Pentaglobin in steroid-resistant severe acute respiratory syndrome.

SETTING: The treatment of severe acute respiratory syndrome (SARS) is at best controversial, although there is considerable anecdotal experience to show the benefits of corticosteroid therapy for selected patients. Some patients deteriorate relentlessly despite treatment with antibiotic, corticosteroid and mechanical ventilation. OBJECTIVE: To attempt to determine the clinical efficacy of pentaglobin, an IgM-enriched immunoglobulin preparation, on 12 severe SARS patients who continued to deteriorate despite corticosteroid and ribavirin therapy. DESIGN: Retrospective analysis of daily quantitative and radiographic data on the cohort in a regional teaching hospital. RESULTS AND CONCLUSION: There was significant improvement in radiographic scores, when compared with day 1, on days 5, 6 and 7 (P < 0.05) after commencement of pentaglobin treatment. Similarly, there was significant improvement in oxygen requirement, when compared with day 1, on days 6 and 7 (P < 0.05) after commencement of pentaglobin treatment. There were no reported adverse events attributable to pentaglobin administration. Ten patients made an uneventful recovery after treatment. One elderly man died from cardiorespiratory arrest despite clinical and radiological improvement, and another patient is making good progress. Pentaglobin is safe and probably effective in the treatment of steroid-resistant SARS. A double-blind placebo-controlled study should therefore be considered.

Utility of immediate on-site cytopathological procurement and evaluation in fine needle aspiration biopsy of head and neck masses.

The utility of on-site microscopic evaluation of fine needle aspirates (FNAs) of the head and neck was assessed by comparing the diagnostic yield in 336 specimens obtained with immediate on-site cytopathological procurement and evaluation to that achieved in 548 cases performed without immediate on-site evaluation. Three hundred six (91%) of 336 immediate evaluation specimens were adequate for cytopathologic diagnosis, compared to 391 (71%) of 548 specimens not evaluated immediately (P < .001, chi-squared test). The higher satisfactory rate in immediate evaluation cases was related primarily to 1. immediate reaspiration of the masses until sufficient cytopathologic material was obtained for diagnosis; and 2. optimal specimen preparation. It is concluded that immediate on-site cytopathological procurement and evaluation of fine needle aspirates of head and neck masses is a valuable practice which assures a higher yield of adequate specimens compared to biopsies taken without immediate evaluation. The technique of immediate on-site evaluation of FNAs is discussed and a cost-benefit analysis of immediate on-site evaluation of FNAs is presented.

Effects of triple therapy on the progression of mesangial proliferative glomerulonephritis.

Fifty-two pairs of patients with idiopathic diffuse mesangial proliferative glomerulonephritis entered a controlled 3-year prospective trial of a combination regimen of cyclophosphamide, dipyridamole and warfarin. In the treatment group proteinuria decreased significantly (p less than 0.01) and renal function remained stable, but in the control group there was no change in proteinuria and creatinine clearance (Ccr) decreased significantly (p less than 0.01). The time patients with renal impairment in the control group and those in the treatment group took to reach end stage renal failure was significantly different (6.1 years versus 8.9 years, p less than 0.02). Among the patients with IgA nephritis, those in the treatment group (n = 27) had stable renal function and a significant decrease in proteinuria (p less than 0.01) but in the control group (n = 21) there was a significant fall in Ccr (p less than 0.01) and rise in serum creatinine (p less than 0.02) with no change in proteinuria. Among 23 pairs of patients in the study who were matched for renal function and degree of glomerulosclerosis, those in the treatment group had stable renal function and decrease in proteinuria (p less than 0.01) whereas those in the control group had decreased Ccr (p less than 0.01) but no change in proteinuria.

The natural history of IgA nephritis in Singapore.

The clinical and histological features of 151 patient with IgA nephritis were analyzed to determine the prognostic features of the disease. The mean duration of follow up examinations was 50 +/- 34 months (range 6 to 168 months). The majority of the patients were young males and showed no signs of IgA nephritis. The disease was detected by routine screening before induction into national service. The plot of the reciprocals of serum creatinine against time in the patients with progressive disease showed that the patients ran two different courses when they developed renal impairment; one was a slow progressive course over an average of 7.7 years before reaching end stage renal failure (ESRF), while the other was a more rapid decline to ESRF within an average of 3.3 years in which severe uncontrolled hypertension seemed to be the major adverse factor. Hypertension was present in 23% of patients. Nine percent had renal impairment at the end of the follow up period while 5% progressed to ESRF. The cumulative renal survival was 91% after 6 years with no further development of renal failure up to 14 years. Unfavorable long term prognostic indices were proteinuria of more than 2 gm, hypertension and presence of crescents on renal biopsy.

Threshold selection using quadtrees.

A simple class of piecewise constant approximations to an image is constructed as follows: start with the entire image, subdivide it into quadrants if its gray level standard deviation is high, and repeat the process for each quadrant. This yields a decomposition of the image into blocks, each having low standard deviation, so that each of them can be approximated by a constant value, namely, its mean. The histogram of this approximated image tends to have sharper peaks than that of the original image since the block averaging reduces the variability of the gray levels within homogeneous regions. A possible way of further improving the histogram is based on the fact that small blocks tend to occur near region borders; thus, suppressing these blocks should tend to deepen the valleys on the histogram, making threshold selection (to separate regions of different types) easier. Conversely, the histogram of the small blocks only represents a population of pixels near region borders, and if there are only two types of regions (e.g., objects and background), the mean of this histogram should be a useful threshold for separating them; but in practice, this method is not very reliable since background fluctuations also give rise to border pixels.

A medial axis transformation for grayscale pictures.

Blum's medial axis transformation (MAT) for binary pictures yields medial axis points that lie midway between opposite borders of a region or along angle bisectors. This note discusses a generalization of the MAT in which a score is computed for each point P of a grayscale picture based on the gradient magnitudes at pairs of points that have P as their midpoint. These scores are high at points that lie midway between pairs of antiparallel edges or along angle bisectors, so that they define a MAT-like ``skeleton,'' which we may call the GRADMAT. However, this skeleton is rather sensitive to the presence of noise edges or to irregularities in the region edges, and it also is subject to artifacts created by pairs of edges belonging to different objects.

Parallel computation of contour properties.

Some contour properties can be derived in parallel by a string or cycle of automata in linear time, faster than can be done with a single processor. In particular, the intersection points of two contours, the straightness of a line, the union or intersection of two contours, and polygonal approximations of a contour are computed in linear time.

Parallel region property computation by active quadtree networks.

Given a binary image stored in a cellular array, a local reconfiguration process can be used to reconnect some of the cells into a quadtree network representing the image. This quadtree can also be ``roped,'' i.e., nodes representing adjacent image blocks of the same size can be joined. Using the roped quadtree network as a parallel (cellular) computer, image properties such as perimeter and genus, as well as the quadtree distance transform, can be computed in O(tree height) = O(log image diameter) time. The area and centroid of the image can be computed in O(height) time without the need for roping.

Image approximation from gray scale ``medial axes''.

Several types of gray-weighted ``medial axes'' have been defined. This paper shows that one of them, the min-max medial axis, can be used to reconstruct good approximations to the original image based on a relatively small amount of information.

Approximating large convolutions in digital images.

Computing discrete two-dimensional (2-D) convolutions is an important problem in image processing. In mathematical morphology, an important variant is that of computing binary convolutions, where the kernel of the convolution is a 0-1 valued function. This operation can be quite costly, especially when large kernels are involved. We present an algorithm for computing convolutions of this form, where the kernel of the binary convolution is derived from a convex polygon. Because the kernel is a geometric object, we allow the algorithm some flexibility in how it elects to digitize the convex kernel at each placement, as long as the digitization satisfies certain reasonable requirements. We say that such a convolution is valid. Given this flexibility we show that it is possible to compute binary convolutions more efficiently than would normally be possible for large kernels. Our main result is an algorithm which, given an m x n image and a k-sided convex polygonal kernel K, computes a valid convolution in O(kmn) time. Unlike standard algorithms for computing correlations and convolutions, the running time is independent of the area or perimeter of K, and our techniques do not rely on computing fast Fourier transforms. Our algorithm is based on a novel use of Bresenham's (1965) line-drawing algorithm and prefix-sums to update the convolution incrementally as the kernel is moved from one position to another across the image.

Glomerulonephritis in Singapore: an overview.

The pattern of glomerulonephritis (GN) consisting of 1057 renal biopsies is presented. Primary GN accounted for 91% and secondary GN 9% of which the commonest is lupus nephritis. Asymptomatic haematuria and proteinuria was the commonest mode of presentation (41%), gross haematuria 9%, nephrotic syndrome 29% while 5.5% presented with renal impairment and 4.3% with hypertension. Mesangial proliferative GN is the commonest histopathological lesion forming 66% of all primary GN. Minimal Lesion, Focal Global Sclerosis and Focal Segmental Glomerulosclerosis accounted for 7% each. Membranous GN was uncommon (3%) while Mesangiocapillary GN, Diffuse Endocapillary GN and Crescentic GN were even rarer. If the presenting feature was asymptomatic haematuria and proteinuria the likely diagnosis was IgA nephritis, and, if nephrotic syndrome it was likely to be Idiopathic Mesangial Proliferative GN but with negative staining on immunofluorescence. The course and prognosis of the various forms of GN are next discussed. Nephrotic syndrome with Minimal Lesion has an excellent prognosis while Crescenteric GN usually carries a grim prognosis. Finally, factors affecting the progression of IgA nephritis, the commonest form of GN occurring in Singapore are examined. Patients who developed renal failure ran two different courses; one was a slowly progressive course over an average of 7.7 years before reaching end stage renal failure (ESRF), while the other was a more rapid decline to ESRF within an average of 3.3 years where severe uncontrolled hypertension seemed to be the major adverse factor. 9% had renal impairment at the end of a follow up of 50 + 1/2 - 34 months while 5% progressed to ESRF. The cumulative renal survival was 91% after 6 years with no further loss up to 14 years. Unfavourable long term prognostic indices were proteinuria of more than 2 gms, hypertension, crescents on renal biopsy, severe segmental sclerosis and medial hypertrophy of blood vessels.

[Treatment of male breast cancer].

From Mar. 1958 through 1985, 50 male patients with breast cancer were treated in our hospital. The ratio of male and female with primary breast cancer was 1:90 during the same period. All were proven by pathology except one case. Forty seven have been followed for more than 5 years. There were 12 stage I lesions, 19 stage II and 16 stage III. Radical mastectomy was performed in 22 patients, total mastectomy in 11 and lobectomy in 12, supplemented by radiotherapy, chemotherapy, hormonal therapy or their combination. Two were not indicated for surgery and were only given a combination combination therapy without operation. The irradiation after radical mastectomy was to deliver to the regional lymph nodes and for the rest, a dose of 5,000-6,000 cGy/5-6 weeks should be added to the chest wall. The chemotherapy, including Thio-TEPA, 5-fluorouracil, cyclophosphamide and methotrexate etc, in the form of single or multi-drug for 1-3 courses, was given. The overall 5 and 10 year survival rates were 51% and 22.5%. The 5 year survival rates of stage I, II and III patients were 83%, 53% and 25%. The 5 year survivals of radical mastectomy, total mastectomy and lobectomy combined with radiotherapy, chemotherapy and hormonal therapy were 59%, 27% and 67%. In those who failed, 50% developed local recurrence or regional metastasis or both and 60% had extensive dissemination. The results indicate that the combination therapy comprising radical mastectomy and lobectomy has a good prognosis. The authors believe that the male breast cancer is more hormone-dependent than the female breast cancer, orchiectomy plays an important role in the treatment of advanced lesions.