A multidisciplinary approach for prenatal diagnosis of FRASER SYNDROME-report of a novel variant in FRAS1.

OBJECTIVE: With this case report, we would like to highlight the importance of a multidisciplinary approach and atypical findings of congenital high airway obstruction sequence (CHAOS), anhydramnios, and renal dysgenesis in the prenatal diagnosis of Fraser syndrome (FS). CASE REPORT: A 25-year-old primigravida at 19 weeks of routine anomaly scan revealed abnormal sonographic findings such as fetal bilateral dysplastic small kidneys and gross oligohydramnios. The further detailed evaluation revealed that both fetal lungs were hyperechogenic with prominent (dilated) trachea and bronchi suggestive of CHAOS. Based on these findings, a diagnosis of FS was suspected. The couple was counseled and the pregnancy was terminated. The postmortem evaluation and novel homozygous variant in the FRAS1 gene confirmed the diagnosis of FS. CONCLUSION: The diagnosis and counseling of the patient were supported by a well-coordinated, multidisciplinary approach involving an obstetrician, a fetal medicine specialist, a medical geneticist, and a fetal pathologist.

Prenatal Ventriculomegaly - Diagnosis, Prognostication and Management.

Fetal ventriculomegaly (VM) refers to the abnormal enlargement of one or more ventricles of the brain in-utero. The enlargement may or may not be related to ventricular obstruction and increased intracranial pressure; therefore, the term "hydrocephalus" is not used. VM is diagnosed usually in the mid-trimester when the atrial diameter (AD) of the lateral ventricle is more than 10 mm on one or both sides. A thorough workup is then required to identify the cause as the etiology is diverse. Fetal magnetic resonance imaging (MRI) may yield additional information. Serial ultrasound follow-up would be required to assess its progression with advancing gestation. The prognosis and long-term outcomes greatly depend upon the etiology, the severity at diagnosis, progression, and associations. This article reviews the definitions, diagnosis, and workup of fetal VM, discusses follow-up protocols and prognosis, and examines the role of fetal therapy, including fetoscopic surgery in its prenatal management.

Detection of an aging-related increase in advanced glycation end products in fast- and slow-twitch skeletal muscles in the rat.

Glycation, a non-enzymatic addition of reducing sugars to ε-amino groups of proteins, is a post-translational modification that results in the formation of irreversible advanced glycation end products (AGEs). Ageing related decline in myofibrillar protein function is effected by a number of structural and functional modifications including glycation. Functional properties of skeletal muscles, such as maximum velocity of unloaded shortening, are known to be profoundly affected by ageing at the motor unit, cellular and tissue levels. However, the contribution of protein modifications to a decline in muscle function is not well understood. In this study we measured AGEs of intracellular and sarcolemmal proteins, using an anti-AGE antibody in soleus (SOL) and extensor digiotorum longus (EDL) muscles of male and female rats of five different age groups. Using a fluorescent secondary antibody to visualize AGEs in the confocal microscope, we found that myosin is glycated in both fiber types in all age groups; an ageing related increase in AGEs was observed in both intracellular and sarcolemmal regions in all age groups, with the exception of sarcolemma of SOL (unchanged) and EDL (reduced) in female rats; the greatest concentration of AGEs was found intracellularly in the SOL of the oldest age group (27-30) of females. While an ageing related decline in motor properties can be partially attributed to the observed increase in myofibrillar protein glycation, our results also indicate that intracellular and the less well studied sarcolemmal protein modification likely contribute to an aging-related decline in muscle function. Further studies are required to establish a link between the observed ageing related increase in glycation and muscle function at the motor unit, cellular and tissue levels.

Septo-optic dysplasia: an autopsy study of a 23-week fetus.

Septo-optic dysplasia is a rare congenital anomaly with an incidence of 1 in 10,000 live births. Recognizing this anomaly early can help parents take an informed decision. There are very few reports of pathological descriptions of this anomaly. We present neuropathological findings at autopsy following medical termination of pregnancy of a 23-week fetus with septo-optic dysplasia (SOD), optic nerve hypoplasia, absent septum pellucidum with aplastic posterior pituitary.

Assessment of diagnostic accuracy of high-resolution ultrasonography in determination of temporomandibular joint internal derangement.

AIM: The aim of this study was to determine the value of dynamic high-resolution ultrasonography (HR-US) in the evaluation of internal derangements of a temporomandibular joint (TMJ) in the open and closed mouth position. SETTINGS AND DESIGN: The study designed to collect the sample from the Outpatient Department of Oral Medicine and Radiology at GDC, Bangalore. Patients with pain, clicking, deviation, and tenderness were included in the study as a symptomatic group. The asymptomatic group was free of any symptoms. MATERIALS AND METHODS: Maximum mandibular range of motion (Open and Closed) was performed during HR-US of TMJ in 100 consecutive patients, (50 symptomatic and 50 asymptomatic cases, a total of 400 joints, with 200 joints in the right and left closed and open mouth position;36 males and 64 females; age range, 16-50 years; mean age 27.56 years). Subsequently, the entire group, after clinical diagnosis, went for HR-US. Sonography confirmed the diagnosis by showing internal derangement in 34 (68%) of the symptomatic group and the remaining 16 (32%) patients failed to show any derangement. In the asymptomatic group 40 patients did not show any pathology associated with TMJ, whereas, 10 patients showed internal derangement. The data obtained was analyzed statistically. RESULTS: HR-US performed during the maximal range of motion (Open and Closed) helped to detect 34 instances (68 joints) of internal derangement, which were true positive cases, whereas, 16 patients (32 joints) showed a false positive finding for internal derangement (ID). The results obtained showed a sensitivity of 64%, specificity of 88%, positive predictive value of 84%, and a negative predictive value of 71%, with an accuracy of 76%. CONCLUSIONS: Dynamic HR-US being non-invasive can provide valuable information about internal derangement of the TMJ in mandibular closed mouth than open mouth position.

Surgical and visual outcomes for posterior polar cataract.

AIMS: The aims of this study were to report the surgical and visual outcomes of posterior polar cataract and to assess the risk factors for posterior capsule rupture. METHOD: Medical records of 81 eyes of 59 patients were reviewed. The surgical procedure used, intraoperative complications and postoperative visual outcome were recorded. RESULTS: Of the 81 eyes, 61 eyes (75%) underwent phacoemulsification. Seventeen eyes had extra-capsular cataract extraction, and manual small incision cataract surgery was performed on three eyes. Posterior capsule rupture occurred in 25 (31%) eyes: it was more common in young patients (<40 years) and in the extra-capsular cataract extraction group. Two eyes had nucleus drop during phacoemulsification. The postoperative visual acuity was >or=20/30 in 76 eyes. CONCLUSION: Posterior capsule rupture occurred more frequently in extra-capsular cataract extraction compared with phacoemulsification and in patients below 40 years of age. Phacoemulsification, done carefully, leads to good visual outcome.

Analysis of nuclear fiber cell cytoplasmic texture in advanced cataractous lenses from Indian subjects using Debye-Bueche theory.

Alterations in ultrastructural features of the lens fiber cells lead to scattering and opacity typical of cataracts. The organelle-free cytoplasm of the lens nuclear fiber cell is one such component that contains vital information about the packing and organization of crystallins critical to lens transparency. The current work has extended analysis of the cytoplasmic texture to transparent and advanced cataractous lenses from India and related the extent of texturing to the nuclear scattering observed using the Debye-Bueche theory for inhomogeneous materials. Advanced age-related nuclear cataracts (age-range 38-75 years) and transparent lenses (age-range 48-78 years) were obtained following extracapsular cataract removal or from the eye bank, at the L.V. Prasad Eye Institute. Lens nuclei were Vibratome-sectioned, fixed and prepared for transmission electron microscopy using established techniques. Electron micrographs of the unstained thin sections of the cytoplasm were acquired at 6500x and percent scattering for wavelengths 400-700 nm was calculated using the Debye-Bueche theory. Electron micrographs from comparable areas in an oxidative-damage sensitive (OXYS) rat model and normal rat lenses preserved from an earlier study were used, as they have extremely textured and smooth cytoplasms, respectively. The Debye-Bueche theoretical approach produces plots that vary smoothly with wavelength and are sensitive to spatial fluctuations in density. The central lens fiber cells from advanced cataractous lenses from India and the OXYS rat, representing opaque lens nuclei, produced the greatest texture and scattering. The transparent human lenses from India had a smoother texture and less predicted scattering, similar to early cataracts from previous studies. The normal rat lens had a homogeneous cytoplasm and little scattering. The data indicate that this method allowed easy comparison of small variations in cytoplasmic texture and robustly detected differences between transparent and advanced cataractous human lenses. This may relate directly to the proportion of opacification contributed by the packing of crystallins. The percent scattering calculated using this method may thus be used to generate a range of curves with which to compare and quantify the relative contribution of the packing of crystallins to the loss of transparency and scattering observed.

Glutathione reverses early effects of glycation on myosin function.

Nonenzymatic glycosylation (glycation) has been recognized as an important posttranslational modification underlying alterations of structure and function of extracellular proteins during aging and diabetes. Intracellular proteins may also be affected by this modification, and glycation has been suggested to contribute to aging-related impairment in skeletal muscle function. Glycation is the chemical reaction of reducing sugars with primary amino groups resulting in the formation of irreversible advanced glycation end products. Glutathione is an abundant tripeptide in skeletal muscle. To understand the effect of glutathione on glycated myosin function, we used a single-fiber in vitro motility assay in which myosin is extracted from a single muscle fiber segment to propel fluorescent-labeled actin filaments. Myosin function responded to glucose exposure in a dose-dependent manner, i.e., motility speeds were reduced by 10, 34, and 90% of preincubation values after 30-min exposure to 1, 3, and 6 mM glucose, respectively. The 30-min 6 mM glucose incubation was followed by a 20-min 10 mM glutathione incubation. Glutathione treatment restored motility (0.98 +/- 0.06 microm/s, n = 3; P < 0.001) after glucose exposure (0.10 +/- 0.07 microm/s, n = 3), close to preincubation levels (1.12 +/- 0.06 microm/s, n = 3). It is concluded that glucose modifies myosin function in a dose-dependent manner and that glutathione reverses the effect of glucose on myosin function.

Changes in myosin structure and function in response to glycation.

Nonenzymatic glycosylation (glycation) is recognized as an important post-translational modification underlying alterations of structure and function of extracellular proteins. The effect of glycation on intracellular proteins is, on the other hand, less well known despite the vital importance of intracellular proteins for cell, tissue, and organ function. The aim of this study was to explore the effects of glycation on the structure and function of skeletal muscle myosin. Myosin was incubated for up to 30 min with glucose and subsequently tested for structural and functional modifications by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry and a single-fiber in vitro motility assay, respectively. MALDI spectra revealed glycation-related structural alterations as evidenced by the disappearance of specific Lys-C proteolysis products and the appearance of higher mass peaks that are attributed to cross-linking by glucose. This change was paralleled by a significant reduction in the in vitro motility speed, suggesting a structure-related decline in myosin mechanics in response to glucose exposure. Further evidence that early glycation products form in the regulatory regions of the myosin molecule is derived from the fact that there is complete reversal of motility speed after reaction with the Schiff base-cleaving agent hydroxylamine hydrochloride. Thus, glycation of skeletal muscle myosin has a significant effect on both the structural and functional properties of the protein, a finding that is important in understanding the mechanisms underlying the impairment in muscle function associated with aging and diabetes.

Effects of aging on regulation of muscle contraction at the motor unit, muscle cell, and molecular levels.

Rodent motor units, muscle fibers, and motor proteins undergo significant aging-related changes. Such changes include spatial organization and physiological properties of fast- and slow-twitch single motor units, regulation of contractile speed and force generation capacity at the muscle fiber level, and altered functional properties of the motor protein myosin. In addition to specific changes, there also appears to be a "disorganization" of the coordinated expression of contractile, sarcoplasmic reticular, and mitochondrial protein isoforms in aging skeletal muscle. This is suggested to have a strong impact on aging-related impairments in muscle function in addition to the changes in specific muscle proteins.

Aging-related changes in skeletal muscle. Mechanisms and interventions.

The aging-related motor handicap and the growing population of elderly citizens have enormous socioeconomic effects on the modern healthcare system. The mechanisms underlying impaired motor performance in old age are complex and involve the central and peripheral nervous systems and the muscle tissue itself. It is widely accepted that the aging-related loss of muscle mass, strength and quality has a significant detrimental impact on motor performance in old age and on the ability to recover from falls, resulting in an increased risk of fractures and dependency. Therefore, the prevention of falls and gait instability is a very important safety issue, and different intervention strategies have been used to improve motor performance among the aging population. There is general consensus that physical exercise is a powerful intervention to obtain long term benefits on muscle function, reduce the frequency of falls, and to maintain independence and a high quality of life in older persons. The results from studies using different types of hormone supplementation therapies have shown interesting and encouraging effects on skeletal muscle mass and function. However, the potential risks with both growth hormone and androgen treatment are not known and long term clinical trials are needed to address safety concerns and the effects on skeletal muscle. Recent advancements in cellular/molecular, physiological and molecular biological techniques will significantly facilitate our understanding of aging-related impairments of muscle function and contribute to the evaluation of different intervention strategies.

An overview of carbohydrate-protein interactions with specific reference to myosin and ageing.

Non-enzymatic glycosylation (glycation), a post-translational modification of proteins, results from the reaction of proteins with reducing sugars. Glycation is implicated in various pathologies like diabetes, Alzheimer's disease and it has been suggested to play an important role in the ageing process. Research on protein glycation has primarily studied extracellular proteins such as albumin, haemoglobin and collagen. However, there is increasing evidence that intracellular proteins may also be affected by glycation, and glycation of myosin is reported to decrease myosin ATPase activity. Glycated adducts are detected by various techniques such as chromatography, electrophoresis, fluorescence and immunochemistry. Inhibition or removal of these adducts has been achieved by chemical compounds such as aminoguanidine (amG), beta-mercaptoethanol (bME) and N-phenacylthiazolium bromide (PTB). In the present pilot study, using a novel in vitro motility assay, we have observed an attenuation in the motility speed of actin (approximately 13%) on myosin extracted from single muscle fibre segments after 15-min glucose incubation. Addition of bME to the incubation medium maintained actin motility speed.

Analogues of 10-deazaaminopterin and 5-alkyl-5,10-dideazaaminopterin with the 4-substituted 1-naphthoyl group in the place of 4-substituted benzoyl.

10-Deaza modifications of classical antifolate analogues bearing the 1,4-disubstituted naphthalene ring in place of the 1,4-disubstituted benzene ring were prepared and tested for antitumor activity. Naphthalene analogues (9a-c, respectively) of 10-deazaaminopterin, 5-methyl-5, 10-dideazaaminopterin, and 5-ethyl-5,10-dideazaaminopterin were prepared by a route consisting of C-alkylations of the anion derived from 4-carboxyl-1-naphthaleneacetic acid dimethyl ester (2) by 6-(bromomethyl)-2,4-diaminopteridine (1a) and 6-(bromomethyl)-2,4-diamino-5-methyl- and -5-deazapteridines (1b and 1c, respectively) followed by ester hydrolysis and subsequent decarboxylation to give naphthalene analogues (7a-c, respectively) of 4-amino-4-deoxy-10-deazapteroic acid and 4-amino-4-deoxy-5- methyl- and -5-ethyl-5,10-dideazapteroic acids. Peptide coupling of 7a-c with L-glutamic acid dialkyl ester followed by mild ester hydrolysis gave target compounds 9a-c. The key advantage of this route is circumvention of a hydrogenation step requiring selectivity as in earlier approaches involving 9,10-olefinic precursors. Steric limitations thwarted plans to prepare the naphthalene analogue of 10-ethyl-10-deazaaminopterin; attempted alkylations of 2-(4-carboxy-1-naphthyl)butyric acid dimethyl ester with 1a failed as did attempted further alkylation (by EtBr) of the product derived from 1a and 2. Growth inhibition tests against three tumor cell lines (L1210, S180, and HL60) showed 9a to be 4-6-fold more inhibitory than methotrexate but not as inhibitory as 10-ethyl-10-deazaaminopterin; 9b and 9c were no more inhibitory than MTX. In tests against the EO771 mammary adenocarcinoma in mice, 9a was less active than MTX.

Potential and limitations of angle-independent flow detection algorithms using radio-frequency and detected echo signals.

New techniques to estimate local blood and tissue velocities have been developed by several groups, including our own. The performance of these techniques is ultimately limited by the characteristics of ultrasonic imaging systems that determine the second-order statistics of speckle. These statistical parameters vary widely depending on the dimension of analysis in the image plane (lateral or axial) and on the echo input signal (radio-frequency or detected data). We use experiments and theory to examine these factors and describe their impact on the performance of our correlation-based technique for angle-independent tracking of blood or tissue motion. The results indicate that the second-order statistics determine the performance of our correlation-based algorithm and can be used to predict the performance of other angle-independent flow detection techniques.

Synthesis and antitubercular activity of N-(2-naphthyl)glycine hydrazide analogues.

N-(2-Naphthyl)glycine hydrazide analogues were synthesized and tested for possible in vitro antitubercular activity. N-(2-Naphthyl)alanine hydrazide (3), N-methyl-N-(2-naphthyl)glycine hydrazide (5), N-(6-methoxy-2-naphthyl)glycine hydrazide (7), and 3-(2-naphthylamino)butyric acid hydrazide (23) showed potent inhibitory action against Mycobacterium tuberculosis H37Rv in Youman's medium at concentrations ranging from 0.5 to 10.0 micrograms/mL. These compounds showed significant inhibitory action against isonicotinic acid hydrazide and streptomycin-resistant strains of M. tuberculosis. N-(6-Quinolyl)glycine hydrazide (18) and 3-(2-quinolylamino)butyric acid hydrazide (24), which are bioisosteres of compounds 1 and 23, showed loss of antitubercular activity at low concentrations.

Family structure and mental illness in old age.

A random sample of subjects aged over 60 in the community was studied. Out of 181 subjects studied 50 were found to suffer from functional disorders such as depression and anxiety, and 11 from organic brain syndrome. 120 are found psychiatrically normal. Over 50% of the elderly subjects studied were widowed and about 70% were unemployed and nearly 80% belonged to lower middle class and low socio-economic group.The families of the elderly subjects and their living condition were studied in detail. The family was divided into 'joint', 'nuclear' and loosely joint' on the basis of living arrangement financial support and other help they received. Functional disorder was found high in old age subjects living in nuclear family and living alone. 33 psychosocial variables affecting the health of the elderly subjects were studied and their correlation to psychiatric illness was determined, by computer. Further factorial analysis was carried out, and three factors were extracted. It was found that Factor II and Factor III were about family and living conditions. Hence it could be stated that the family and living conditions are significant factors affecting the mental health of the elderly subjects.