Search

Hypohidrotic ectodermal dysplasia (HED) is a rare genetic disorder caused by mutational inactivation of a developmental pathway responsible for generation of tissues of ectodermal origin. The X-linked form accounts for the majority of HED cases and is caused by Ectodysplasin (EDA) pathogenic variants. We performed a combined analysis of 29 X-linked hypohidrotic ectodermal dysplasia (XLHED) families (including 12 from our previous studies). In addition to the classical triad of symptoms including loss (or reduction) of ectodermal structures, such as hair, teeth, and sweat glands, we detected additional HED-related clinical features including facial dysmorphism and hyperpigmentation in several patients. Interestingly, global developmental delay was identified as an unusual clinical symptom in many patients. More importantly, we identified 22 causal pathogenic variants that included 15 missense, four small in-dels, and one nonsense, splice site, and large deletion each. Interestingly, we detected 12 unique (India-specific) pathogenic variants. Of the 29 XLHED families analyzed, 11 (38%) harbored pathogenic variant localized to the furin cleavage site. A comparison with HGMD revealed significant differences in the frequency of missense pathogenic variants; involvement of specific exons and/or protein domains and transition/transversion ratios. A significantly higher proportion of missense pathogenic variants (33%) localized to the EDA furin cleavage when compared to HGMD (7%), of which p.R155C, p.R156C, and p.R156H were detected in three families each. Therefore, the first comprehensive analysis of XLHED from India has revealed several unique features including unusual clinical symptoms and high frequency of furin cleavage site pathogenic variants.

Pyoderma gangrenosum is a rare neutrophilic dermatosis that is commonly treated with systemic corticosteroids; however, their potent side effects may warrant tapering, and non-steroidal systemic immunosuppressants may help maintain or bolster disease clearance during weaning. Although cyclosporine is regarded as a favorable corticosteroid-sparing agent, it is associated with several side effects, such as renal toxicity and hypertension, that may limit its feasibility. Mycophenolate mofetil is a well-tolerated alternative with limited data. Institutional review board approval was obtained to review patients from a single institution who received mycophenolate mofetil for pyoderma gangrenosum between January 1, 2010, and December 31, 2019. A systematic MEDLINE (PubMed) review was performed of articles containing linked keywords: “mycophenolate mofetil” and “pyoderma gangrenosum”. Patient demographics, presentation details, and treatment regimen characteristics were recorded. Fourteen of our pyoderma gangrenosum patients were treated with mycophenolate mofetil concomitantly with prednisone. Ninety-three percent of our patients achieved improvement within 12 months (mean 4.5 months), including five patients who experienced complete healing. Outcomes in literature patients were comparable; 77% either improved or maintained clearance with mycophenolate mofetil. Greater than 80% of total patients experienced healing or adequate disease control at a median dose of 2000 mg daily. The most common side effects of mycophenolate mofetil were myelosuppression and gastrointestinal upset, which were both seen in 18% of patients. Although this study is subject to publication bias, mycophenolate mofetil appears to be an efficacious and well-tolerated adjunctive therapy option for pyoderma gangrenosum.

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutational inactivation of the phenylalanine hydroxylase (PAH) gene. Missense mutations are the most common PAH mutation type detected in PKU patients worldwide. We performed PAH mutation analysis in 27 suspected Indian PKU families (including 7 from our previous study) followed by structure and function analysis of specific missense and splice/insertion–deletion/nonsense mutations, respectively. Of the 27 families, disease-causing mutations were detected in 25. A total of 20 different mutations were identified of which 7 “unique” mutations accounted for 13 of 25 mutation positive families. The unique mutations detected exclusively in Indian PKU patients included three recurrent mutations detected in three families each. The 20 mutations included only 5 missense mutations in addition to 5 splice, 4 each nonsense and insertion–deletion mutations, a silent variant in coding region and a 3′UTR mutation. One deletion and two nonsense mutations were characterized to confirm significant reduction in mutant transcript levels possibly through activation of nonsense mediated decay. All missense mutations affected conserved amino acid residues and sequence and structure analysis suggested significant perturbations in the enzyme activity of respective mutant proteins. This is probably the first report of identification of a significantly low proportion of missense PAH mutations from PKU families and together with the presence of a high proportion of splice, insertion–deletion, and nonsense mutations, points to a unique PAH mutation profile in Indian PKU patients. J. Cell. Biochem. 115: 566–574, 2014. © 2013 Wiley Periodicals, Inc.

Farber lipogranulomatosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the ASAH1 gene. In the largest ever study, we identified and characterized ASAH1 mutations from 11 independent Farber disease (FD) families. A total of 13 different mutations were identified including 1 splice, 1 polypyrimidine tract (PPT) deletion and 11 missense mutations. Eleven mutations were exclusive to the Indian population. The IVS6+4A>G splice and IVS5-16delTTTTC PPT deletion mutations resulted in skipping of exon 6 precluding thereby the region responsible for cleavage of enzyme precursor. A missense mutation (p.V198A) resulted in skipping of exon 8 due to inactivation of an exonic splicing enhancer (ESE) element. This is the first report of mutations affecting PPT and ESE in the ASAH1 gene resulting in FD.

Lynch syndrome (LS), the most common form of familial CRC predisposition that causes tumor onset at a young age, is characterized by the presence of microsatellite instability (MSI) in tumors due to germline inactivation of mismatch repair (MMR) system. Two MMR genes namely MLH1 and MSH2 account for majority of LS cases while MSH6 and PMS2 may account for a minor proportion. In order to identify MMR genes causing LS in India, we analyzed MSI and determined expression status of the four MMR genes in forty eight suspected LS patient colorectal tumor samples. Though a majority exhibited MSI, only 58% exhibited loss of MMR expression, a significantly low proportion compared to reports from other populations. PCR-DNA sequencing and MLPA-based mutation and exonic deletion/duplication screening respectively, revealed genetic lesions in samples with and without MMR gene expression. Interestingly, tumor samples with and without MMR expression exhibited significant differences with respect to histological (mucin content) and molecular (instability exhibited by mononucleotide microsatellites) features. The study has revealed for the first time a significant proportion of LS tumors not exhibiting loss of MMR expression.

Spiro phosphorus compounds play a vital role, in recent years, in imparting flame retardancy and intumescence to the polymers. To ascertain the mechanism of the intumescency, model spiro phosphorus compounds, i.e., 3,9-disubstituted-2,4,8,10-tetraoxa-3,9-diphosphaspiro-[5,5]-undecan- 3,9-dioxide, were chosen (compound 1: substitution is chloro group and compound II: substitution is hydroxo group). The model compounds were investigated using Differential Thermal Analysis (DTA) and Thermal Volatilization Analysis (TVA), Vacuum Pyrolysis-MS and Off-line Pyrolysis followed by degradation product analysis by GC-MS. Dichlorospiro compound (I) showed an eruptive release of gases at 320 °C and dihydroxo spiro compound (II) at about 350 °C. The major components of the gas released were found to be HCl and H 2 O in the case of compound I and H 2 O in the case of compound II. The degradation product analysis showed the formation of wide varieties of substituted and condensed aromatic compounds in measurable quantities. From the acquired data, it is confirmed that the intumescence takes place within a narrow range of temperature (10°) and in this temperature limit extensive dehydrohalogenation and dehydration are taking place. Highly thermally reactive unsaturated hydrocarbons are produced which mainly undergo polymerization to aromatic compounds and finally to char.

Three intense sweeteners, aspartame, acesulfame-K and sucralose, were incorporated singly in lime-lemon flavored carbonated beverage in optimized concentrations on a sucrose equivalence basis at controlled pH conditions. The beverages were stored for 60 days at 4, 27 and 37C and the sweetener concentration determined by HPLC. The loss of aspartame was maximum (29.5%) while that of sucralose was minimum (1.9%) at the end of 60 days' storage at 37C. In the case of acesulfame-K, the loss was 6.1%. Sucralose was more stable than the other sweeteners. Cette etude evalue la stabilite de 3 edulcorants intenses, l'aspartam, l'acesulfame-K et le sucralose. Ceux-ci sont incorpores separement dans une boisson gazeuse aromatisee au citron-citron vert selon des concentrations optimisees sur une base d'equivalent saccharose dans des conditions de pH controlees. Les boissons sont entreposees pendant 60 jours a 4, 27 et 37°C et la concentration en edulcorant est determinee par HPLC. La perte en aspartam est maximum (29,5%), tandis que celle du sucralose est minimum (1,9%) et celle de l'acesulfame-K de 6,1% a la fin des 60 jours a 37°C. Le sucralose est l'edulcorant le plus stable des 3.

A variety of metal complexes of 5,10,15-triphenyl-21-monooxa-corrole 4 have been investigated. This monooxa corrole, where one of the pyrrole ring is replaced by a furan moiety, is synthesized by the alpha-alpha coupling reaction of 16-oxa tripyrrane and dipyrromethane. The single crystal X-ray structure of 4 indicates only small deviation of the inner-core heteroatoms from planarity and this macrocycle arrange themselves into a columnar structure. Insertion of metals further flattens the corrole framework. Specifically, oxacorrole 4 binds to Nil(II), Cu(II), and Co(II) with the participation of all heteroatoms in the coordination. However, Rh(I) ion binds to only one imino and one amino nitrogen of the macrocycle. The bond angles at the metal center in the Ni(II) and Rh(I) complexes reveal square planar geometry completed by two CO molecules for Rh(I). The EPR spectra of the paramagnetic that Cu(II) and Col(II) complexes display significant decreases in the metal hyperfine couplings compared with the corresponding porphyrin complexes. The presence of superhyperfine coupling in the Cu(II) complex suggests delocalization of unpaired electron density into the ligand orbitals. Electrochemical studies reveal easier oxidations and harder reductions relative to the corresponding porphyrin derivatives while, the metallated derivatives did not show their characteristic metal reductions due to the high energy of their LUMO.

Meso aryl rubyrins exhibit three different structures. A planar (7) and two unusual inverted structures (8 and 9) have been characterised by X-ray and NMR spectroscopy.

An unprecedented coupling reaction of heteroatom-containing tripyrranes leads to the formation of core-modified sapphyrins 1 and 2, which self-assemble in the solid state to form supramolecular ladders. Weak C-H⋅⋅⋅S and C-H⋅⋅⋅Se hydrogen-bonding interactions in addition to C-H⋅⋅⋅N hydrogen bonds are responsible for the observed structures.

Eine unerwartete Kupplungsreaktion heterosubstituierter Tripyrrane lieferte die Sapphyrin-Analoga 1 und 2, die im Kristall supramolekulare Leitern bilden. Schwache C−H⋅⋅⋅S- bzw. C−H⋅⋅⋅Se-Brucken sind neben den ublicheren C−H⋅⋅⋅N-Brucken entscheidend fur das Auftreten dieser Strukturen.

The remarkably simple synthesis of tetrathia- and tetraoxarubyrins 1 and 2 is achieved by the routes presented here. Spectroscopic, 1 H NMR, and electrochemical data suggest that 1, 2, and their protonated derivatives are aromatic 26 π electron systems, and the protonated derivatives form stable complexes in solution with anions such as F - , N 3 - , and adenosine 5'-monophosphate.

In this article we apply perturbation analysis (PA), combined with conditional Monte Carlo, to obtain derivative estimators of the expected cost per period with respect to s and S, for a class of periodic review (s, S) inventory systems with full backlogging, linear holding and shortage costs, and where the arrivals of demands follow a renewal process. We first develop the general form of four different estimators of the gradient for the finite-horizon case, and prove that they are unbiased. We next consider the problem of implementing our estimators, and develop efficient methodologies for the infinite-horizon case. For the case of exponentially distributed demand interarrival times, we implement our estimators using a single sample path. Generally distributed interarrival times are modeled as phase-type distributions, and the implementation of this more general case requires a number of additional off-line simulations. The resulting estimators are still efficient and practical, provided that the number of phases is not too large. We conclude by reporting the results of simulation experiments. The results provide further validity of our methodology and also indicate that our estimators have very low variance. © 1994 John Wiley & Sons, Inc.

A synthetic access to the first members of expanded corroles 1 and 2 is achieved through formation of two direct pyrrole−pyrrole links by an oxidative coupling reaction. Spectroscopic and structural analysis reveal that 1 and 2 are 22Π aromatic macrocycles despite the nonplanar structure and properties resemble that of isocorroles rather than 22Π sapphyrins.