Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

Visual serial dependence in an audiovisual stimulus.

Serial dependence is a phenomenon that biases the perception of features or objects systematically toward sensory input from the recent past (Fischer & Whitney, 2014). There is an active debate whether this effect is rooted directly in perception or reflects biases in decision making. We investigated serial dependence across three experiments by manipulating the decision made on each trial. A multimodal audiovisual stimulus comprising a Gabor and a vowel sound was presented repeatedly. On each trial, participants reported either the Gabor orientation or the vowel sound. Participants either ignored one modality (Experiment 1) or attended to both modalities (Experiments 2 and 3). In Experiments 2 and 3, the response task was randomized to prevent anticipating which modality to respond to until the response phase. In Experiment 3, no-response trials were additionally interleaved. Results across the three experiments demonstrated serial dependence only when participants reported the visual modality. Serial dependence was also present in visual reports when participants completed auditory reports or made no reports on previous trials. The previous stimulus alone was enough to elicit an effect. Serial dependence is unlikely to be an effect of the previous decision on the stimulus, but rather an effect of perceiving the previous stimulus.

Directional biases for blink adaptation in voluntary and reflexive eye blinks.

The oculomotor system is subject to noise, and adaptive processes compensate for consistent errors in gaze targeting. Recent evidence suggests that positional errors induced by eye blinks are also corrected by an adaptive process: When a fixation target is displaced during repeated blinks, subsequent blinks are accompanied by an automatic compensating eye movement anticipating the updated target location after the blink. Here, we further tested the extent of this "blink adaptation." Participants were tasked to look at a white target dot on a black screen and encouraged to blink voluntarily, or air puffs were used to elicit reflexive blinks. In separate runs, the target was displaced by 0.7° in either of the four cardinal directions during blinks. Participants adapted to positional changes during blinks, i.e., the postblink gaze position was biased in the direction of the dot displacement. Adaptation occurred for both voluntary and reflexive blinks. However, adaptation was unequal across different adaptation directions: Horizontally, temporal displacements experienced larger adaptation than nasal displacements; vertically, downward displacements led to larger adaptation than upward displacements. Results paralleled anisotropies commonly found for saccade amplitudes, and thus it is likely that gaze corrections across eye blinks share general constraints of the oculomotor system with saccades.

Synthesis of the Ca2+-mobilizing messengers NAADP and cADPR by intracellular CD38 enzyme in the mouse heart: Role in ß-adrenoceptor signaling.

Nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR) are Ca2+-mobilizing messengers important for modulating cardiac excitation-contraction coupling and pathophysiology. CD38, which belongs to the ADP-ribosyl cyclase family, catalyzes synthesis of both NAADP and cADPR in vitro However, it remains unclear whether this is the main enzyme for their production under physiological conditions. Here we show that membrane fractions from WT but not CD38-/- mouse hearts supported NAADP and cADPR synthesis. Membrane permeabilization of cardiac myocytes with saponin and/or Triton X-100 increased NAADP synthesis, indicating that intracellular CD38 contributes to NAADP production. The permeabilization also permitted immunostaining of CD38, with a striated pattern in WT myocytes, whereas CD38-/- myocytes and nonpermeabilized WT myocytes showed little or no staining, without striation. A component of ß-adrenoreceptor signaling in the heart involves NAADP and lysosomes. Accordingly, in the presence of isoproterenol, Ca2+ transients and contraction amplitudes were smaller in CD38-/- myocytes than in the WT. In addition, suppressing lysosomal function with bafilomycin A1 reduced the isoproterenol-induced increase in Ca2+ transients in cardiac myocytes from WT but not CD38-/- mice. Whole hearts isolated from CD38-/- mice and exposed to isoproterenol showed reduced arrhythmias. SAN4825, an ADP-ribosyl cyclase inhibitor that reduces cADPR and NAADP synthesis in mouse membrane fractions, was shown to bind to CD38 in docking simulations and reduced the isoproterenol-induced arrhythmias in WT hearts. These observations support generation of NAADP and cADPR by intracellular CD38, which contributes to effects of ß-adrenoreceptor stimulation to increase both Ca2+ transients and the tendency to disturb heart rhythm.

Two-pore Channels (TPC2s) and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) at Lysosomal-Sarcoplasmic Reticular Junctions Contribute to Acute and Chronic ß-Adrenoceptor Signaling in the Heart.

Ca(2+)-permeable type 2 two-pore channels (TPC2) are lysosomal proteins required for nicotinic acid adenine dinucleotide phosphate (NAADP)-evoked Ca(2+) release in many diverse cell types. Here, we investigate the importance of TPC2 proteins for the physiology and pathophysiology of the heart. NAADP-AM failed to enhance Ca(2+) responses in cardiac myocytes from Tpcn2(-/-) mice, unlike myocytes from wild-type (WT) mice. Ca(2+)/calmodulin-dependent protein kinase II inhibitors suppressed actions of NAADP in myocytes. Ca(2+) transients and contractions accompanying action potentials were increased by isoproterenol in myocytes from WT mice, but these effects of ß-adrenoreceptor stimulation were reduced in myocytes from Tpcn2(-/-) mice. Increases in amplitude of L-type Ca(2+) currents evoked by isoproterenol remained unchanged in myocytes from Tpcn2(-/-) mice showing no loss of ß-adrenoceptors or coupling mechanisms. Whole hearts from Tpcn2(-/-) mice also showed reduced inotropic effects of isoproterenol and a reduced tendency for arrhythmias following acute ß-adrenoreceptor stimulation. Hearts from Tpcn2(-/-) mice chronically exposed to isoproterenol showed less cardiac hypertrophy and increased threshold for arrhythmogenesis compared with WT controls. Electron microscopy showed that lysosomes form close contacts with the sarcoplasmic reticulum (separation ∼ 25 nm). We propose that Ca(2+)-signaling nanodomains between lysosomes and sarcoplasmic reticulum dependent on NAADP and TPC2 comprise an important element in ß-adrenoreceptor signal transduction in cardiac myocytes. In summary, our observations define a role for NAADP and TPC2 at lysosomal/sarcoplasmic reticulum junctions as unexpected but major contributors in the acute actions of ß-adrenergic signaling in the heart and also in stress pathways linking chronic stimulation of ß-adrenoceptors to hypertrophy and associated arrhythmias.

Small changes in thermal conditions hinder marathon running performance in the tropics.

We examined marathon performance of the same group of runners in relation to small changes in dry bulb temperature (Tdb) and wet bulb temperature (Twb) across 3 consecutive y, and investigated whether performance was poorer during an evening marathon compared with morning marathons. Marathon results were obtained from the 2017, 2018, and 2019 Standard Chartered Singapore Marathons. Tdb, Twb, Td, relative humidity, and absolute humidity were gathered for each marathon. K-means clustering and linear regressions were performed on 610 runners who participated in all three marathons. Analysis of the 610 runners' marathon performance was contrasted with Tdb and Twb. Linear regressions were also performed on 190 runners filtered by percentile, yielding similar results. For clusters with similar Tdb from all runners K-means clustering, an increase in mean Twb by 1.5°C coincided with an increase in finishing time by 559 s (9.3 min) (p < 0.033). Twb hinders marathon performance more than Tdb, with each percentage rise in Tdb and Twb resulting in an increase in net time by 7.6% and 39.1%, respectively (p < 0.025). Male and female runners' response to Tdb and Twb changes were similar (overlap in 95% confidence intervals for the respective regression coefficients). In conclusion, small variations in environmental parameters affected marathon performance, with Twb impairing marathon performance more than Tdb. Marathon performance was likely better in the morning than evening, possibly due to time of day differences, along with unfavorable Tdb that superseded training effects and the effects of lower Twb.

Significance of breast carcinoma-associated antigens as a monitor of tumor burden: characterization by monoclonal antibodies.

Use of monoclonal antibodies (Mc 3 and Mc 8) prepared against human mammary-epithelial antigens of human mild fat globule membranes has enabled characterization of breast carcinoma (BC) associated antigens (BCAA), antibodies, and circulating immune complexes (CIC). For this study, BC patients were grouped on the basis of measurable tumor burden: Group I patients with no evidence of disease at sampling time; Group II patients with tumor burden less than or equal to 5 g; and Group III patients with known regional or distal metastases. In an in vitro simulation of tumor burden change, selected BC patients' sera were admixed with Mc 3 and Mc 8 at optimal concentration. CIC reduction (dissociation) for Groups I and III and increment (formation) for Group II were noted. Unlike Group I sera, Groups II and III sera required 4- to 16-fold dilution of Mc 3 and 4-fold more concentrated Mc 8 to achieve maximal CIC changes. Serum BCAA isolated by use of both Mc 3 and Mc 8 immunobead procedures showed apparent Mr 33,000 monomer, 66,000 dimer, and 95,000 trimer. When BCAA were added to BC patients' sera, autologous combinations resulted in small (7.7S) CIC for Groups I and III, and medium (9 to 12S) CIC for Group II. Conversely, allogenic combinations resulted in mainly small CIC for Group I, and intermediate CIC for Group II and Group III. Evaluation of circulating BCAA concentration by use of a three-step radioligand technique demonstrated significant discrimination between BC patients' sera (mean = 105 ng/ml) and normal control sera (less than or equal to 20 ng/ml). BCAA were found to be elevated in 31 of 46 (67%) Group I (mean = 70 ng/ml), 41 of 43 (95%) Group II (mean = 197 ng/ml), and 30 of 46 (65%) Group III (mean = 50 ng/ml) patients' sera, as compared to "background" levels in malignant melanoma and normal controls. Benign breast disease sera showed moderate BCAA increases (mean = 48 ng/ml) in 20 of 35 (57%) patients. Furthermore, serial sample determination of BCAA in 36 selected BC patients confirmed the above pattern, indicating that this assay can be used with some restriction to monitor tumor burden. Whereas in early breast carcinoma increase in BCAA concentration was concurrent with or antedated clinical objective evidence of tumor burden increase, significant decreased BCAA concentration was observed with tumor burden reduction. Overall, increased BCAA levels were associated with limited tumor burden (Group II) while decreased BCAA levels were observed with no evidence of disease (Group I) and known regional or distal metastatic advanced disease (Group III) during patients' follow-up.

Trends in Patterns of Posterior Uveitis and Panuveitis in a Tertiary Institution in Singapore.

PURPOSE: The study aims to analyze the trends of posterior uveitis and panuveitis patients seen by a tertiary eye center in Singapore between 2004 and 2012. METHODS: We conducted a retrospective analysis of 363 consecutive new cases of posterior uveitis and panuveitis. The cases were segregated into idiopathic, infectious, or noninfectious. RESULTS: We found statistically significant differences between etiologies and ethnicity (p = 0.014). We noticed a statistically significant downward trend (Spearman's rho (ρ) = -0.812, p = 0.008) for dengue uveitis, and an upward trend for the idiopathic category (Spearman's rho (ρ) = 0.753, p = 0.019). CONCLUSIONS: We observed differences between etiologies and ethnicity, pointing toward potential susceptibility variations. There was an upward trend of idiopathic causes, possibly due to better control of systemic and infectious etiologies. The dengue uveitis incidence correlates well with our national statistics. The downward trend of dengue uveitis could be due to the introduction of Singapore's dengue surveillance in 2005, emphasizing the importance of controlling the disease.

Characteristics of Cytomegalovirus Uveitis in Immunocompetent Patients.

PURPOSE: To present the clinical characteristics of patients with anterior uveitis who had evidence of cytomegalovirus (CMV) infection on polymerase chain reaction PCR-based assays for viral DNA in aqueous samples. METHODS: This was a retrospective observational case series of 16 patients with CMV infection on qualitative polymerase chain reaction PCR-based assays for viral DNA in aqueous samples. Case records of 16 patients were reviewed and relevant clinical information was collected using a standardized data sheet. RESULTS: There were 10 male and 6 female patients, with 16 eyes included. The median age at the first attack was 52 years (range 27-77 years). Thirteen patients (81.3%) presented with an initial BCVA of 20/40 or better. Eleven eyes (68.8%) had anterior chamber inflammation of 1+ cells or less. Eight eyes (50.0%) had concomitant sectoral iris atrophy, while 2 eyes were noted to have heterochromic irides. Eleven patients (68.8%) presented with an elevated intraocular pressure. Seven patients (43.8%) had clinical features that led to a presumptive diagnosis of Posner-Schlossman syndrome, while 3 patients (18.8%) were initially diagnosed with Fuchs heterochromic iridocyclitis. Six patients were initially treated for uveitic glaucoma or anterior uveitis of unknown cause. CONCLUSIONS: There is a spectrum of clinical manifestations of CMV anterior uveitis. A high index of suspicion of a possible viral etiology, especially CMV, and subsequent accurate identification of the virus involved are fundamental to the overall therapeutic approach.

Immunomagnetic isolation and long-term culture of mouse type A spermatogonia.

In the mammalian testis, type A spermatogonia proliferate and differentiate into sperm under the tight control of both endocrine and paracrine factors. In order to study the complex process of spermatogenesis at the molecular level, an in vitro system must be devised in which type A spermatogonia can be cultured for a prolonged period of time. Therefore, cocultures including type A spermatogonia and Sertoli cells, which act as nurse cells to the developing germ cells, are desirable. We have developed a method for the specific isolation of type A spermatogonia using magnetic beads and antibodies that recognize the c-kit receptor or the homophilic adhesion molecule, Ep-CAM. Purified spermatogonia could survive for a period of 25 days when cocultivated on Sertoli cell monolayers. Moreover, we recently established Sertoli cell lines that produce growth factors that are essential for the maintenance of spermatogonia in a proliferative state. Some of these Sertoli cell lines are able to reorganize into tubular structures when cultivated on a layer of Matrigel as extracellular matrix. We show here that type A spermatogonia associate specifically with the Sertoli cell tubules, and are able to replicate their DNA in this environment. Thus, these in vitro culture systems could be used for the long-term culture of primary, nonimmortalized type A spermatogonia.

Synthesis and characterization of the 6 alpha- and 6 beta-hydroxylated derivatives of corticosterone, 11-dehydrocorticosterone, and 11-deoxycortisol.

This report describes the synthesis of 6 alpha, 17,21- and 6 beta, 17,21-trihydroxypregn-4-ene-3,20-dione, 6 alpha, 7,21- and 6 beta, 11 beta, 21-trihydroxypregn-4-ene-3,20-dione, and--for the first time--that of 6 alpha, 21- and 6 beta, 21-dihydroxypregn-4-ene-3,11,20-trione. The former four compounds were prepared by 6-hydroxylation of 17,21-trihydroxypregn-4-ene-3,20-dione and 11 beta, 21-dihydroxypregn-4-ene-3,20-dione, respectively. This was achieved by autoxidation or by oxidation with 3-chloroperbenzoic acid, of the 3-methoxy-pregna-3,5-dienes of the latter two steroids. The yield of the 6 beta-hydroxylated steroids, but not of their corresponding 6 alpha-epimers, was higher using autoxidation than the peracid. The two 6-hydroxylated pregnenetriones were prepared from 6 alpha, 21-diacetoxy-11 beta-hydroxypregn-4-ene-3,20-dione and 6 beta, 21-diacetoxy-11 beta-hydroxypregn-4-ene-3,20-dione, respectively, by oxidation with pyridinium chlorochromate. The above-mentioned six steroids were identified and characterized by nuclear magnetic resonance, infrared, ultraviolet, high performance liquid chromatography, gas chromatography, and mass spectrometry.

Immune complexes and human neoplasia. I.

Recent technical improvements in circulating immune complexes (CIC) detection have resulted in a proliferation of data reporting increased CIC levels in a variety of human diseases. The overall result being a better understanding of the inferred pathogenic role of IC in disease, and their possible clinical significance. We will pay particular attention to human neoplasia and those clinical conditions which may provide relevant pathophysiologic information. The immunobiology of cancer derangement involving CIC is dependent on a number of factors such as size, number, valence and composition. In addition, mechanisms involved in IC formation, removal, deposition, IC-induced inflammatory reaction, and the role of IC in regulation of humoral and cellular immune response are discussed. While CIC are frequently detected in cancer patients, a uniformly predictable pathologic role has not been fully identified nor is there always proven evidence that CIC are involved either in the pathogenesis or as products of the disease progression. In spite of several methods of CIC detection that have been reported, none of them has been entirely satisfactory for clinical use. Effective management of CIC positive cancer patients require knowledge of the number of IC and their molecular size composition, as well as a concomitant evaluation of antigen and antibody components interacting in the system. In view of the complexity in this extensive field, we present this review in two parts: Review I comprises biological and physicochemical mechanisms involved in IC formation, removal, deposition and its pathogenic significance, and Review II contains a concised nonexhaustive discussion of possible clinical significance of CIC in human neoplasia.

Immune complexes and human neoplasia.

The vast data pertaining to circulating immune complexes (CIC) detection and their possible clinical significance in human neoplasia have been reviewed. The clinical relevance of CIC occurrence in cancer patients' sera provide important non-diagnostic information on staging, evaluation of prognosis, detection of early recurrence, and quantitation of tumor response to treatment. A variable prevalence of CIC in cancer patients is now well established. The several reasons which made no available test entirely satisfactory for clinical use, have been discussed indicating the importance of molecular size and composition heterogeneity of CIC detected in cancer patients. Although the evaluation of CIC by current assays represents the antithesis of pre-diagnostic patients management, there are solid reports to suggest its possible clinical application. Those studies noting the relevance of CIC fluctuation to the evaluation of prognosis, monitoring of therapy and assessment of tumor burden were best attained when an effort to quantitate residual disease was undertaken. In addition, attempts to remove CIC from cancer patients circulation by plasma exchange alone or with extracorporeal immunoadsorption have resulted in a better understanding of a frequently observed immunomodulation. This modality provided a challenging and provocative new approach to cancer therapy which deserved prompt corroboration.

RH-3421 action and toxicokinetics in the trout: reduced brain involvement versus mammals.

The action and distribution of the insecticidal dihydropyrazole RH-3421 was examined in the trout and mouse. RH-3421 antagonized the depolarizing effect of the Na(+) channel activator veratridine and inhibited K(+)-stimulated uptake of (45)Ca(++) through voltage-sensitive calcium channels in trout brain synaptosomes. RH-3421 was a weaker inhibitor of these cellular targets in fish brain compared to mammalian brain. [(14)C]RH-3421 distributed rapidly following systemic administration to trout. Trunk kidney, muscle, liver and fat are important sites of accumulation, however, accumulation of [(14)C]RH-3421 in trout brain was low and polar metabolites were only found in bile. Mice administered an equivalent dose accumulated [(14)C]RH-3421 more efficiently into brain, and overall metabolism was more extensive. In trout, the brain is unlikely to be a major site of action of dihydropyrazoles. Our data indicate that perturbation of neuronal sites outside of brain cannot be excluded as contributing to the comparatively high acute toxicity of dihydropyrazoles in fish.

Effects of cyclic temperature changes on water sorption and solubility of composite restoratives.

This study investigated the effects of cyclic temperature changes on the water sorption and solubility of four commercial composite resins (Silux Plus, Z100, Ariston pHc and Surefil). The methodology was based upon ISO 4049 procedures with modifications for specimen dimension and thermal-cycling. Eighteen disc specimens (10 +/- 1 mm diameter and 1 +/- 0.1 mm thick) were made for each composite and randomly divided into three groups. The specimens were stored in a desiccator maintained at 35 +/- 1 degrees C until a constant mass was achieved and treated as follows: Group 1--stored in distilled water at 356 degrees C for 178 hrs; Group 2--stored in distilled water at 35 degrees C for 173 hours and subjected to five hours of thermal-cycling with an upper temperature of 45 degrees C; and Group 3--stored in distilled water at 35 degrees C for 173 hours and subjected to five hours of thermal-cycling with an upper temperature of 60 degrees C. Mass after treatment was measured and specimens were re-conditioned to constant mass. The volume of the specimens was obtained and water sorption/solubility calculated. Data was analyzed using factorial ANOVA/Scheffe's post-hoc test at significance level 0.05. The effects of thermal-cycling on water sorption was material dependent. Thermal-cycling at an upper temperature of 60 degrees C significantly increased water sorption of Silux Plus. A significant increase in water sorption was also observed when Z100 was thermal-cycled at an upper temperature of 45 degrees C. The water sorption of Ariston pHc and Surefil was not affected by thermal-cycling. Thermal-cycling did not affect the solubility of all composites. For all treatment groups, Surefil had significantly lower water sorption than the other composites evaluated. The water sorption of Z100 and Surefil was significantly lower than Silux Plus and Ariston pHc.

Effects of cyclic temperature changes on hardness of composite restoratives.

The clinical durability of some composite restorative materials may be significantly affected by cyclic temperature changes. This study investigated the effects of cyclic temperature changes on surface hardness of four commercial composite resins (Silux, Z100, Ariston and Surefil). Eighteen specimens of each material were divided into three treatment groups comprising a control and two different thermal cycling regimes. Control specimens were stored in distilled water at 35 degrees C for 178 hours. Thermal cycled specimens were stored in distilled water at 35 degrees C for 173 hours and subjected to five hours (300 cycles) of a thermal cycling regime consisting of the cycle ABAC, where A and B represent the fixed temperatures of 35 degrees C (28 seconds) and 15 degrees C (two seconds) and C, depending on the treatment group, either 45 degrees C or 60 degrees C (two seconds). All specimens were subsequently subjected to hardness testing (KHN) using a digital microhardness tester (load = 500 gf; dwell time = 15 seconds). Results were analyzed using ANOVA/Scheffe's test (p<0.05). The effect of thermal cycling on hardness was material-dependent. While thermal cycling significantly increased the surface hardness of Z100 and Surefil, it significantly decreased the hardness of Ariston. The hardness of Silux was not significantly affected by cyclic temperature changes. For all treatment groups, Z100 was significantly harder than the other composite resins evaluated and Surefil was significantly harder than Silux and Ariston. For both thermal cycled groups, Silux was significantly harder than Ariston.

Influence of thermal cycling on OCA wear of composite restoratives.

This study investigated the effects of thermal cycling on wear of four commercial composite resins (Silux, Z100, Ariston and Surefil). Specimens of each material were divided into three treatment groups comprising a control and two different thermal cycling regimes. Control specimens were stored in distilled water at 35 degrees C for 178 hours. Thermal cycled specimens were stored in distilled water at 35 degrees C for 173 hours and subjected to five hours (300 cycles) of a thermal cycling regime consisting of the cycle ABAC, where A and B represent the fixed temperatures of 35 degrees C (28 seconds) and 15 degrees C (two seconds) and C, depending on the treatment group, was either 45 degrees C or 60 degrees C (two seconds). All specimens were subsequently subjected to wear testing at 20 MPa contact stress against SS304 counterbodies with distilled water as the lubricant. Wear depth (microm; n=6) was measured using profilometry every 2,000 cycles up to 10,000 cycles. Results were analyzed using ANOVA/Scheffe's test (p<0.05). The effect of thermal cycling on wear was material-dependent. The wear of Silux and Z100 were not significantly affected by thermal cycling. Thermal cycling of Ariston at an upper temperature of 60 degrees C significantly decreased wear resistance. Thermal cycling affected only the early wear resistance of Surefil.

Disputed paternity: the historical perspectives.

Requests for blood tests to resolve issues of disputed paternity fall under three main categories: (1) Proof of adultery; (2) Proof of kinship (a) in claims for citizenship, (b) to make material changes to the Birth Certificate, (c) for settlement of family disputes usually in inheritance matters; and (3) Investigation of sex crimes like rape and incest where a child is the result of the union. A broad overview is given on the venous red cell and serum blood groups used for paternity investigations. The laws of inheritance as applied to blood group investigations for disputed paternity are discussed. A survey of cases investigated on red cell and serum genetic markers since 1978 till 1990 showed an average of 5.5 cases a year with exclusion of the putative father in 19% of cases.

Sudden death due to granulomatous myocarditis: a case of sarcoidosis?

INTRODUCTION: We report a case of sudden death due to granulomatous myocarditis and propose that cardiac sarcoid could have been the underlying aetiology. This is the first case reported in Singapore. The differential diagnoses for granulomatous myocarditis including sarcoidosis and its cardiac manifestations as well as idiopathic giant cell myocarditis are discussed. CLINICAL PICTURE: A 53-year-old Indian woman died suddenly and autopsy revealed bilateral hilar adenopathy and myocardial infiltrates which proved to be granulomatous in nature. CONCLUSION: Sarcoidosis may not be a rarity here and it is important to recognise the different clinical manifestations.

Trends in patterns of intermediate uveitis in a tertiary institution in Singapore.

PURPOSE: The study aims to describe the characteristics and etiologic causes of intermediate uveitis (IU) patients seen by a tertiary eye center in Singapore over 8 years. METHODS: This was a retrospective analysis of the clinical records of consecutive new cases of IU that presented to the uveitis subspecialty clinic from 2004-2011 at Tan Tock Seng Hospital. Data collected included demographics, clinical and laboratory findings. Diagnoses were based on standardized clinical history, ophthalmological examination and investigations. RESULTS: There were 66 new cases of IU, comprising 5.7% of 1168 new uveitis patients. The median age of diagnosis was 40 years (mean 39.4±15.9), with largest subgroup of the patients in the age group of 41-60 years (36.4%). The majority was Chinese (57.6%), followed by Asian Indians (18.2%) and Malays (16.7%). The ethnicity distribution was dissimilar to our ethnic distribution in Singapore (p<0.001) with an increased incidence of IU in the Asian Indian population. Most were idiopathic (59.1%) in etiology, followed by tuberculosis (TB) (15.2%). Ocular complications developed in 21 patients (31.8%), with cystoid macular edema (CME) being the commonest (28.8%). Severe vitritis occurred in 9.1% of patients, and was significantly associated with TB-associated IU (p<0.001). There was a downward trend for the incidence of the proportion of IU patients over the total uveitis patients (p = 0.021), with Spearman's rho of -0.786. CONCLUSIONS: Despite the downward trend, TB-associated IU was still of higher prevalence compared to less endemic areas, emphasizing the need for increased TB surveillance. A high index of suspicion for TB-associated IU is required in patients with severe vitritis. Comparisons with other countries revealed disparities in the IU etiologies, indicating possible geographical differences. Prevalence of known immune-mediated etiologies of IU is less compared to the western population. Our study also suggests a probable predisposition of the Singapore local Indian population for IU.