Steroid-resistant nephrotic syndrome (SRNS) represents the second most frequent cause of chronic kidney disease in the first three decades of life. It manifests histologically as focal segmental ...glomerulosclerosis (FSGS) and carries a 33% risk of relapse in a renal transplant. No efficient treatment exists. Identification of single-gene (monogenic) causes of SRNS has moved the glomerular epithelial cell (podocyte) to the center of its pathogenesis. Recently, mutations in >30 recessive or dominant genes were identified as causing monogenic forms of SRNS, thereby revealing the encoded proteins as essential for glomerular function. These findings helped define protein interaction complexes and functional pathways that could be targeted for treatment of SRNS. Very recently, it was discovered that in the surprisingly high fraction of ∼30% of all individuals who manifest with SRNS before 25 years of age, a causative mutation can be detected in one of the ∼30 different SRNS-causing genes. These findings revealed that SRNS and FSGS are not single disease entities but rather are part of a spectrum of distinct diseases with an identifiable genetic etiology. Mutation analysis should be offered to all individuals who manifest with SRNS before the age of 25 years, because (i) it will provide the patient and families with an unequivocal cause-based diagnosis, (ii) it may uncover a form of SRNS that is amenable to treatment (e.g. coenzyme Q
), (iii) it may allow avoidance of a renal biopsy procedure, (iv) it will further unravel the puzzle of pathogenic pathways of SRNS and (v) it will permit personalized treatment options for SRNS, based on genetic causation in way of 'precision medicine'.
Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came ...from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.
A new species, Collybiopsis pakistanica, from Margalla Hills National Park, Pakistan, is described based on micro‐morphological and molecular phylogenetic analyses. This species is characterized by ...its milky white pileus, yellowish orange or light yellow to orange at central disc and margins, lacrymoid basidiospores, cheilocystidia with median construction, and broadly utriform and clavate to narrowly utriform pleurocystidia and epithelioid hymeniderm pileipellis. Its placement as a new taxon of Collybiopsis is confirmed by phylogenetic analyses of ITS and nrLSU sequences. Two new combinations, Collybiopsis ugandensis and Collybiopsis pleurocystidiata are also proposed as these species are transferred from Gymnopus.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important ...implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients.
To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children's Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD.
By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients.
Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.
During an assessment of exploration of Macrofungi from Margalla Hills National Park, Islamabad, Pakistan,
Collybiopsis contraria
comb. nov.,
Favolus grammocephalus, Hexagonia glabra, Hypoxylon ...crocopeplum
and
Panus conchatus
were recorded as new records for Pakistan. The identity of all the newly reported taxa was confirmed through morpho-anatomical observations coupled with molecular data using nrITS region.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A novel mushroom species occurring on soil was collected from Margalla Hills National Park, Pakistan, during July and August 2018 and 2019. Phylogenetic analyses of the nrDNA ITS and nuLSU regions ...revealed that this species clustered within the genus
Termitomyces
. Further morpho-anatomical analyses confirmed its uniqueness, and it is here referred to as a new species under the name
Termitomyces islamabadensis
. It differs from
T. heimii,
which is a species it closely resembles, by having a fusiform stipe, large obovoid to lacrymoid basidiospores 8.4–11.5 × 5–7.3 μm, narrowly pyriform to broadly pyriform cheilocystidia 24.3–40.3 × 8.5–22.5 μm, and narrowly utriform to oblong pleurocystidia 12.5–23.4 × 4.5–7.3 μm. A key to all existing species of the genus
Termitomcyes
in Pakistan is also given.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In this paper, we offer a numerical study on heated non-Newtonian fluid with a Newtonian heating effect towards thermally stable stretching surfaces. A comparative analysis for two stretched ...surfaces, namely, plate and cylinder, is offered. The Casson fluid model is considered to be a non-Newtonian fluid model. By applying the suitable set of transformations, the non-linear coupled PDEs are transformed into non-linear ODEs. It is difficult to obtain the exact solution of such non-linear differential equations; therefore, we used the shooting method along with Runge–Kutta scheme. The influence of pertinent flow variables on velocity and temperature is presented through graphs. Notably from the results, heat generation parameters, Newtonian heating, and magnetic parameters enhanced the temperature profile, whereas Casson fluid and magnetic field parameters reduced the fluid velocity. It is also observed that increases in fluid temperature were more influenced at the cylindrical surface as compared with the flat plate. Moreover, we obtained remarkable results for the heat transfer rate by imposing Newtonian heating conditions at the surface; tables are used to present variations in the skin friction coefficient and Nusselt number at the thermally stable surfaces.
Objectives: To find out occurrence of ovarian hyperstimulation in patients who were hyper responders in in vitro fertilization cycles. Secondary outcome was to assess number of metaphase II oocyte ...and fertilization rate, cleavage rate and pregnancy outcome when GnRHa is used for final maturation and triggering ovulation.
STUDY DESIGN, SIZE, and DURATION: This is retrospective descriptive analysis of cases managed at single center from June 2017 till May 2018.
PATIENTS & METHODS: Twenty patients were identified as hyper responders based on baseline, ovarian reserve characteristics, that is antral follicle count, (AFC) > 25, AMH > 4ng/ml and on day of trigger, follicles >-25 in number of ≥ 11mm were administered GnRHa trigger and 1500IU hCG on oocyte retrieval day while luteal phase was supported with daily vaginal progesterone and twice daily estradiol valerate. Sixteen patients underwent fresh transfer while four patients had their embryos frozen.
MAIN RESULTS: Twenty patients were identified as high risk and their baseline characteristics were, mean age 31.7 ± 4.50, mean antral follicle count 25.7 ± 5.01, Anti Mullerian hormone level mean 4.64 ± 2.52 and PCOS was present in 35% cases. Peak estradiol level mean 13455-± 6632pmol/l and mean follicles count of 25.45 ± 8.78 confirmed a high response. Oocyte yield was 11.45+ Metaphase oocyte retrieved were 85.5% and cleavage rate of 93%. No case of early onset OHSS was identified. Only one patient developed moderate OHSS. Pregnancy rate was 31.25%. Miscarriage rate was 6.3% and ongoing pregnancy was 25%.
CONCLUSION: This small retrospective descriptive analysis supports the view of current literature that GnRH trigger not only prevents early onset OHSS also achieves increase of M11 oocytes. In addition, pregnancy outcome is not statistically different to those cycles where hCG is used as trigger.
Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. ...SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The genus of basidiomycetous fungi,
, occurs worldwide, from subtropical to boreal latitudes. Several collections of
were made during mycological field trips conducted in different forests of ...Margalla, Pakistan. An integrative framework combining morphological and phylogenetic data was employed for their study. As a result, the two species
and
are here described as new to science. Detailed macro- and micro-morphological descriptions, and a molecular phylogenetic reconstruction based on nrITS and LSU sequence data are provided and used to discriminate the new species from morphologically and phylogenetically close taxa. Whereas, our phylogenetic tree inference gave unequivocal support for the inclusion of these two species within the section Leucoagaricus.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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