Molecular docking of competitive phosphodiesterase inhibitors.

Mammalian phosphodiesterases types 3 and 4 (PDE3 and PDE4) hydrolyze cAMP and are essential for the regulation of this intracellular second messenger. These enzymes share structural and biochemical similarities, but each can be distinguished by its sensitivity to isoenzyme-specific, substrate-competitive inhibitors. We present a model configuration for the PDE4 substrate (cAMP) and a PDE4-specific inhibitor (rolipram) within the active site of the enzyme. The docked models were also used to examine the structural consequences of mutations that confer resistance to rolipram and other PDE4-specific inhibitors. The proposed rolipram-binding configuration is consistent with the substrate-competitive nature of inhibition and also provides a structural basis for the observed specificity of binding to the R- versus S-enantiomer. For mutations that render the enzyme rolipram-insensitive, there was generally an inverse relationship between the magnitude of the drug resistance and the distance of the altered residue from the predicted binding site. We observed a direct correlation between the net loss of protein residue interactions (van der Waals contacts and hydrogen bond interactions) and the degree of rolipram resistance. The positions of several drug sensitivity-determinant residues define a surface leading to the substrate- and drug-binding sites, suggesting a possible approach channel leading to the enzyme active site. The binding of other PDE4 inhibitors (high- and low-affinity) was also modeled and used to predict the involvement of residues that were not previously implicated in pharmacological interactions.     

Characteristics of falls in hospitalized patients

BACKGROUND: The high incidence of patient falls in a hospital setting is a major concern in any health system. Research findings have reported the risk factors for these falls as age, gender, certain medications, mental status, chronic diseases and environmental factors. Falls may lead to fear, pain, slight or severe injuries, increase the duration of hospital stay, cause patient discomfort and affect quality of life. AIM: The aim of this paper is to report a study of the characteristics of patient falls during hospitalization in 1998 and compare them with those in the period 1978-1981. METHODS: A retrospective study was performed in a large, 2000-bed medical center in Israel. Reports of 711 fall incidents in 1998 were compared with 328 reports in 1978-1981. Information gathered included age, gender, department, shift, reasons, severity of injury, tests and treatment after injury. RESULTS: The rates of falls per 1000 admissions in psychiatric, elder care and rehabilitation departments in 1998 were statistically significantly higher than in the earlier period. Rates of 115, 91, 85, respectively, per 1000 admissions were reported in 1998 compared with 34, 9, 19, respectively, in the period 1978-1981. The percentage of reported falls in the younger age group (under 50) was higher in the later survey (1998), and a higher proportion occurred outside the patient's room. Most of the reported falls in 1998 occurred during the morning shift (P < 0.001). CONCLUSIONS: The increased number of falls could be an outcome of increased awareness. Nevertheless, the causes and place of falls differ for the two periods. Some of the reasons may be related to an intervention programme carried out after the first survey. The latest survey results will serve as an important basis for a further intervention programme in specific departments to ensure patient safety.     

Extended-spectrum beta-lactamases among Enterobacter isolates obtained in Tel Aviv, Israel

The extended-spectrum beta-lactamase (ESBL)-producing phenotype is frequent among Enterobacter isolates at the Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. We examined the clonal relatedness and characterized the ESBLs of a collection of these strains. Clonal relatedness was determined by pulsed-field gel electrophoresis. Isoelectric focusing (IEF) and transconjugation experiments were performed. ESBL gene families were screened by colony hybridization and PCR for bla(TEM), bla(SHV), bla(CTX-M), bla(IBC), bla(PER), bla(OXA), bla(VEB), and bla(SFO); and the PCR products were sequenced. The 17 Enterobacter isolates studied comprised 15 distinct genotypes. All isolates showed at least one IEF band (range, one to five bands) whose appearance was suppressed by addition of clavulanate; pIs ranged from 5.4 to > or = 8.2. Colony hybridization identified at least one family of beta-lactamase genes in 11 isolates: 10 harbored bla(TEM) and 9 harbored bla(SHV). PCR screening and sequence analysis of the PCR products for bla(TEM), bla(SHV), and bla(CTX-M) identified TEM-1 in 11 isolates, SHV-12 in 7 isolates, SHV-1 in 1 isolate, a CTX-M-2-like gene in 2 isolates, and CTX-M-26 in 1 isolate. In transconjugation experiments with four isolates harboring bla(TEM-1) and bla(SHV-12), both genes were simultaneously transferred to the recipient strain Escherichia coli HB101. Plasmid mapping, PCR, and Southern analysis with TEM- and SHV-specific probes demonstrated that a single transferred plasmid carried both the TEM-1 and the SHV-12 genes. The widespread presence of ESBLs among Enterobacter isolates in Tel Aviv is likely due not to clonal spread but, rather, to plasmid-mediated transfer, at times simultaneously, of genes encoding several types of enzymes. The dominant ESBL identified was SHV-12.     

Nemaline body myopathy caused by a novel mutation in troponin T1 (TNNT1)

Introduction: Nemaline myopathy is a rare disorder characterized by skeletal muscle weakness of varying severity and onset, with the presence of nemaline rods on muscle biopsy. Congenital nemaline body myopathy due to mutations in TNNT1 has hitherto only been described as a result of a single founder mutation in patients of Amish origin and in 2 other individuals with different recessive mutations. Methods: Autozygosity mapping and whole exome sequencing were applied after we identified 9 Palestinian patients from 7 unrelated families who have nemaline myopathy. Results: All patients were homozygous for a novel complex rearrangement of the TNNT1 gene (c.574_577delinsTAGTGCTGT | NM_003283) leading to C‐terminal truncation of the protein (p.L203* | NP_003274.3). Their clinical course was remarkable for early respiratory failure and striking stiffness of the cervical spine. Conclusions: This report exemplifies the utility of combining autozygosity mapping and whole exome sequencing and expands the phenotype associated with TNNT1 mutations. Muscle Nerve 53 : 564–569, 2016     

Cell-specific expression of immunoreactive cholesterol side-chain cleavage cytochrome P-450 during follicular development in the rat ovary

Using a specific antiserum against rat cholesterol side-chain cleavage cytochrome P-450 (P-450scc), we examined the expression of this key steroidogenic enzyme during follicular development in PMSG-treated immature rats. The accumulation of the enzyme was monitored in ovary homogenates by quantitative immunodot blot assay, while expression of P-450scc in various cell types was visualized concomitantly by immunofluorescent staining of ovarian cryosections. Before PMSG treatment, no labeling of P-450scc could be observed in follicular granulosa cells. In contrast, steroidogenic cytochrome was markedly expressed in interstitial cells, part of theca interna cells, and hypertrophied theca of atretic follicles. As a result of PMSG treatment, the interstitial thecal cells promptly enriched their P-450scc content within 24 h, whereas the granulosa cells acquired the enzyme at a later time, between 30 and 48 h after hormone administration. After ovulation, many corpora lutea filled most of the ovarian volume, and the ovarian content of P-450scc was 47 times higher than that in control ovaries of untreated rats. In granulosa cell population of a single preovulatory follicle, a downward gradient of P-450scc expression was observed, starting high in the cells abutting the basal lamina and decreasing toward the cells lining the antrum. Cumulus cells failed to express P-450scc. Referring to the basal lamina, theca interna cells exhibited a reverse gradient of P-450scc expression, starting high in peripheral cells close to the theca externa layer and decreasing in cells located near the follicular basement membrane. Immunofluorescent labeling revealed a major difference between P-450scc expression in thecal cells compared to that in granulosa cells. While expression of P-450scc in granulosa cells was restricted exclusively to cells within preovulatory follicles, P-450scc labeling was observed throughout the ovary in thecal and interstitial cells associated with follicles at any phase of follicular maturation. Therefore, it may be proposed that the thecal and interstitial cells represent an all ovarian network which expresses its steroidogenic capacity at early stages of follicular maturation and thereby is able to supply androgens necessary for the follicular development.     

Developmental Trajectories in Siblings of Children with Autism: Cognition and Language from 4 Months to 7 Years

We compared the cognitive and language development at 4, 14, 24, 36, 54 months, and 7 years of siblings of children with autism (SIBS-A) to that of siblings of children with typical development (SIBS-TD) using growth curve analyses. At 7 years, 40% of the SIBS-A, compared to 16% of SIBS-TD, were identified with cognitive, language and/or academic difficulties, identified using direct tests and/or parental reports. This sub-group was identified as SIBS-A-broad phenotype (BP). Results indicated that early language scores (14–54 months), but not cognitive scores of SIBS-A-BP and SIBS-A-nonBP were significantly lower compared to the language scores of SIBS-TD, and that the rate of development was also significantly different, thus pinpointing language as a major area of difficulty for SIBS-A during the preschool years.     

Incidence of schizophrenia among second-generation immigrants in the jerusalem perinatal cohort

Objective: Increased incidence of schizophrenia is observed among some immigrant groups in Europe, with the offspring of immigrants, ie “second-generation” immigrants particularly vulnerable. Few contemporary studies have evaluated the risk of schizophrenia among second-generation immigrants in other parts of the world. Methods: We studied the incidence of schizophrenia in relation to parental immigrant status in a population-based cohort of 88 829 offspring born in Jerusalem in 1964–1976. Parental countries of birth were obtained from birth certificates and grouped together as (1) Israel, (2) Other West Asia, (3) North Africa, and (4) Europe and industrialized countries. Cox proportional hazards methods were used in adjusting for sex, parents’ ages, maternal education, social class, and birth order. Results: Linkage with Israel''s Psychiatric Registry identified 637 people admitted to psychiatric care facilities with schizophrenia-related diagnoses, before 1998. Incidence of schizophrenia was not increased among second-generation immigrants in this birth cohort, neither overall nor by specific group. Conclusions: The difference in risk of schizophrenia among second-generation immigrants in Europe and in this Israeli birth cohort suggests that the nature of the immigration experience may be relevant to risk, including reasons for migration, the nature of entry, and subsequent position in the host country for immigrants and their offspring. Minority status may be of importance as, in later studies, immigrants to Israel from Ethiopia had increased risk of schizophrenia.