Homozygous nonsense mutation in SCHIP1/IQCJ-SCHIP1 causes a neurodevelopmental brain malformation syndrome.

We report a consanguineous Arab family with 3 affected siblings who display a disorder of global developmental delay, learning difficulties, facial dysmorphism, hearing impairments, and cataract. The clinical phenotype was associated with characteristic brain magnetic resonance imaging (MRI) features of axonal guidance defects involving anterior commissure agenesis as well as scattered areas of polymicrogyria-cobblestone complex. Whole genome sequencing revealed a novel nonsense mutation (159609921C>T) that segregated in the family consistent in an autosomal recessive pattern. This mutation located in the C-terminal region shared by the Schwanomin-Interacting Protein1 (SCHIP1) isoforms including the IQCJ-SCHIP1. The in vitro expression of SCHIP1 and IQCJ-SCHIP1 truncated mutant isoforms (NM_001197109.1; p.R209* and NM_001197114.1; p.R501*, respectively) were markedly reduced as compared to their full-length versions suggesting protein stability/folding impairment. The pathogenic nature of this mutation is supported by a previously reported mouse knockout of Schip1 isoforms, which phenocopied the human axon guidance abnormality. This is the first report of a SCHIP1/IQCJ-SCHIP1 point mutation in humans associated with a neurological-developmental phenotype.

Non-truncating LIFR mutation: causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction?

We present a Qatari family with two children who displayed a characteristic phenotype of congenital marked pain insensitivity with hypohidrosis and progressive aseptic destruction of joints and vertebrae resembling that of hereditary sensory and autonomic neuropathies (HSANs). The patients, aged 10 and 14, remained of uncertain genetic diagnosis until whole genome sequencing was pursued. Genome sequencing identified a novel homozygous C65S mutation in the LIFR gene that is predicted to markedly destabilize and alter the structure of a particular domain and consequently to affect the functionality of the whole multi-domain LIFR protein. The C65S mutant LIFR showed altered glycosylation and an elevated expression level that might be attributed to a slow turnover of the mutant form. LIFR mutations have been reported in Stüve-Wiedemann syndrome (SWS), a severe autosomal recessive skeletal dysplasia often resulting in early death. Our patients share some clinical features of rare cases of SWS long-term survivors; however, they also phenocopy HSAN due to the marked pain insensitivity phenotype and progressive bone destruction. Screening for LIFR mutations might be warranted in genetically unresolved HSAN phenotypes.

Histochemical structure and immunolocalisation of the hyaluronan system in the dromedary oviduct.

We investigated the local modulation of some histochemical properties of oviducts of the dromedary (Camelus dromedarius), focusing on the immnolocalisation of hyaluronic acid (HA) synthases (HAS2 and HAS3), hyaluronidases (HYAL2 and HYAL1) and the HA receptor CD44 in the ampulla and isthmus. Abundant acidic mucopolysaccharides (glycosaminoglycans) were detected by Alcian blue staining along the luminal surface of both ciliated and non-ciliated epithelial cells (LE). Staining for HAS2 was higher in the primary epithelial folds of the ampulla compared with the isthmus, especially in secretory cells, adluminal epithelial surface and supranuclear cell domain. HAS3 staining was stronger in the LE of the isthmus than ampulla. HYAL2 was detected in the LE in the ampulla and isthmus and was more intense in the adluminal projections of secretory cells. HYAL1 was weakly detected in the LE with no difference between the ampulla and isthmus. Strong CD44 immunostaining was present in the LE of the ampulla and isthmus. CD44 staining was higher in secretory cells than in ciliated epithelial cells and was higher in the supranuclear region than the basal region of the cytoplasm. In conclusion, we provide evidence that HA synthesis and turnover occur in the camel oviduct. Differences in HAS2 and HAS3 expression suggest regional differences in the molecular size of HA secreted in oviductal fluid that may influence oviduct-gamete interaction in the camel.

Therapeutic potential of myrrh and ivermectin against experimental Trichinella spiralis infection in mice.

Trichinosis is a parasitic zoonosis caused by the nematode Trichinella spiralis. Anthelmintics are used to eliminate intestinal adults as well as tissue-migrating and encysted larvae. This study aimed to investigate the effects of ivermectin and myrrh obtained from the aloe-gum resin of Commiphora molmol on experimental trichinosis. Ninety albino mice were orally infected with 300 T. spiralis larvae. Drugs were tested against adult worms at day 0 and day 5 and against encysted larvae on day 15 and day 35 post-infection (PI). Mature worms and encysted larvae were counted in addition to histopathological examination of muscle specimens. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, albumin, globulin, urea, and creatinine values were estimated. Significant reductions in mean worm numbers were detected in ivermectin treated mice at day 0 and day 5 PI achieving efficacies of 98.5% and 80.0%, while efficacies of myrrh in treated mice were 80.7% and 51.5%, respectively. At days 15 and 35 post-infection, ivermectin induced significant reduction in encysted larval counts achieving efficacies of 76.5% and 54.0%, respectively, while myrrh efficacies were 76.6% and 35.0%, respectively. AST, ALT, urea, and creatinine levels were reduced, while total proteins were increased in response to both treatments compared to their values in the infected non-treated mice. Ivermectin use for controlling T. spiralis could be continued. Myrrh was effective and could be a promising drug against the Egyptian strains of T. spiralis with results nearly comparable to ivermectin.

Chilblains as a diagnostic sign of aicardi-goutières syndrome.

Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous disorder showing variability in age of onset and clinical features. Chilblain lesions have been described in AGS patients and recent papers have discussed the clinical, molecular and cutaneous histopathological overlap with chilblain lupus. Here we report on 2 unrelated children with AGS and chilblain lesions, whose clinical histories and examination findings well illustrate the wide phenotypic variability that can be seen in this pleiotropic disorder. Although both patients show remarkable similarity in the histopathology of their associated skin lesions, with thrombi formation, fat necrosis and hyalinization of the subcutaneous tissue, we note that the histopathology reported in other AGS cases with chilblains does not necessarily demonstrate this same uniformity. Our findings highlight the significant role of the characteristic chilblain skin lesions in the diagnosis of AGS, and variability in the associated histopathology which may relate to the stage and severity of the disease.

Expanding CEP290 mutational spectrum in ciliopathies.

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

Hormonal changes during the first year of use of subdermal levonoregestrel implants, Norplant.

Sixty-three women had NORPLANT implants inserted during the first eight days of the menstrual cycle. Blood specimens were withdrawn at the time of insertion and every three days during one of the following months of observation; the first, third, sixth, ninth and twelfth month after insertion. Ten subjects were sampled at multiple times during implant use. A total of 83 months of observation was available. The serum concentrations of levonorgestrel (LNG), FSH, LH, prolactin (PRL), estradiol (E2) and progesterone (prog) were measured in each specimen. LNG concentration rapidly declined during the first 15 days of use, the decline became more gradual during the subsequent two weeks, and an almost steady level was reached during the remainder of the year. There were no significant trends of change in the levels of FSH, LH, E2 and prog during the year. Frequent peaks in E2 concentration were observed and were generally associated with or followed by LH surges. PRL concentration showed a slight but significant rise during the second half of the year. Rises in prog concentration suggestive of ovulation occurred in 36 percent of the months of observation. However, in all these instances, there were evidences suggestive of deficient luteal phase. The bleeding episodes were usually, but not always, related to decline in E2 and prog concentrations.

Synthesis and anti-inflammatory activity of certain new N,N'-oxamides.

Some new amides of substituted oxamic acid which embody different moieties of the anti-inflammatory drugs were prepared through two routes of synthesis. The physico-chemical properties as well as the anti-inflammatory activity of these compounds were determined. Preliminary pharmacological testing revealed the superiority of most of the screened compounds as anti-inflammatory agents with relatively low toxicity as compared with acetylsalicylic acid. Correlation between structure and biological activity was suggested.

Synthesis of some functionalized arylaminomethyl-1 ,2,4-triazoles, 1,3,4-oxa- and thiadiazoles.

Thiosemicarbazides undergo different cyclization reactions to give five membered heterocycles. The product of cyclization depends on the reagent used. This cyclization leads to the formation of 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole derivatives. The reaction of thioglycolyl hydrazide derivatives of the 1,2,4-triazole compounds was discussed. The activity against hepatitis B virus (HBV) has been tested.

The molar tooth sign: a new Joubert syndrome and related cerebellar disorders classification system tested in Egyptian families.

Joubert syndrome and related cerebellar disorders (JSRD) are a group of recessive congenital ataxia conditions usually showing neonatal hypotonia, dysregulated breathing rhythms, oculomotor apraxia, and mental retardation. The pathognomonic finding in JSRD is the unique molar tooth sign (MTS) on brain imaging. There is a tremendously broad spectrum of signs and symptoms mainly including kidney, retina, and liver disease, along with polydactyly and facial dysmorphisms. Here we propose a new diagnostic classification within JSRD that includes four major subtypes. To test this classification, we performed a systematic recruitment and genetic evaluation from a single referral center in Egypt. Thirteen families were identified, four showed evidence of linkage to one of the four known genetic loci, three showed novel AHI1 mutations, and nine were excluded from known loci. Each family could be classified into one of the four subtypes. This classification may thus be useful in the evaluation of patients with JSRD.

The recovery of fertility during breast-feeding in Assiut, Egypt.

A longitudinal study of twenty-six breast-feeding and twelve non-breast-feeding postpartum women was conducted in Assiut, Egypt in order to determine the time that ovulation resumed after childbirth, and the effect of breast-feeding frequency on the period of lactational anovulation. Breast-feeding women experienced the onset of follicular development, vaginal bleeding, ovulation and pregnancy significantly later than women who did not breast-feed. Ovulatory and non-ovulatory breast-feeders reported similar frequencies of breast-feeding episodes. The introduction of dietary supplements commonly preceded ovulation. An algorithm using three simple variables observable to the breast-feeding mother was found to predict up to 100% of the first ovulations. All breast-feeding women who did not give supplements and did not have a vaginal bleeding episode by 6 months postpartum were anovular by strict criteria for ovulation. Ovulation did not precede bleeding or supplementation in the women who experienced these events before 6 months, yielding a highly effective formula for preventing unplanned pregnancy by the informed use of breast-feeding.

PIP: A longitudinal study of 26 breastfeeding and 12 non-breastfeeding postpartum women was conducted in Assiut, Egypt in order to determine the time that ovulation resumed after childbirth, and the effect of breastfeeding frequency on the period of lactational anovulation. The breastfeeding group consisted of women ages 18-40 who had successfully breastfed at least 1 child. Breastfeeding women experienced the onset of follicular development, vaginal bleeding, ovulation and pregnancy significantly later than women who did not breastfeed. Ovulatory and non-ovulatory breastfeeders report similar frequencies of breastfeeding episodes (9-10 times in 24 hours). The introduction of dietary supplements commonly preceded ovulation. An algorithm using 3 simple variables observable to the breastfeeding mother was found to predict up to 100% of the 1st ovulations. All breastfeeding women who did not give supplements and did not have a vaginal bleeding episode by 6 months postpartum were anovular by strict criteria for ovulation. Ovulation did not precede bleeding or supplementation in the women who experienced these events before 6 months, yielding a highly effective formula for preventing unplanned pregnancy by the informed use of breastfeeding.

The perineal groove and canal in males and females--a third look.

We present 5 uncommon cases: One case of perineal canal in a female; two cases of perineal groove in females, one with normal anus and another with ectopic perineal anus. Two cases of perineal canal in males. The canal is deep in the perineum, runs forward above the root of scrotum, close to the floor of the urethra (which is normal), and opens on the undersurface of the penis. One of them is associated with covered anus incomplete with anocutaneous fistula as well opening on the scrotal raphe. In all 5 cases the perineal canal or gutter opens posteriorly in the ectodermal anal canal, immediately below the line of anal valves. A third look to the origin of these conditions will be discussed versus the 1st and 2nd looks of Stephens and Chatterjee. Embryological and histopathological studies will support our point of view.

Synthesis of 3'-O-(2-aminoethyl)-2'-deoxyuridines.

Methyl 2-deoxy-3-O-[2-(formylamino)ethyl]-5-O-trityl-D-erythro- pentofuranoside (4) was obtained in a 3-O alkylation reaction by treatment with 2-chloroethylamine in DMF. Compound 4 afforded alpha nucleosides as the main products when condensed with uracils under the Vorbrüggen conditions. The nucleosides were deblocked by treatment with 80% acetic acid and subsequently with sodium methoxide in methanol.