Citation classics in pediatric orthopaedics.

BACKGROUND: The purpose of this study was to identify the clinical pediatric orthopaedic articles with at least 100 citations published in all orthopaedic journals and to examine their characteristics. METHODS: All journals dedicated to orthopaedics and its subspecialties were selected from the Journal Citation Report 2001 under the subject category "orthopedics." Articles cited 100 times or more were identified using the database of the Science Citation Index Expanded (SCI-EXPANDED, 1900 to present). The articles were ranked in a comprehensive list. Two authors independently reviewed the full text of each article and applied the inclusion and exclusion criteria to the list of articles. The 2 lists were then compared. All disagreements were resolved by consensus with input from the senior author. The final list of pediatric orthopaedic articles was then compiled. RESULTS: There were a total of 49 journals under the search category "orthopedics." Five journals were excluded as they were non-English journals. The remaining 44 journals were screened for articles with at least 100 citations. A total of 135 clinical pediatric orthopaedic articles cited at least 100 times were included. The most cited article was cited 692 times. The mean number of citations per article was 159 (95% confidence interval, 145-173). All the articles were published between 1949 and 2001, with 1980 and 1989 producing the most citation classics (34). The majority (90) originated from the United States, followed by the United Kingdom (12) and Canada (11). Scoliosis/kyphosis was the most common topic with 26 papers. The second most common subject was hip disorders (24). Therapeutic studies were the most common study type (71). Ninety-seven papers were assigned a 4 for level of evidence. CONCLUSIONS: The list of citation classics in pediatric orthopaedic articles is useful for several reasons. It identifies important contributions to the field of pediatric orthopaedics and their originators; it facilitates the understanding and discourse of modern pediatric orthopaedic history and reveals trends in pediatric orthopaedics.

Future employment among homeless single mothers: the effects of full-time work experience and depressive symptomatology.

This study examines the relationship between work and depressive symptomatology for extremely destitute single mothers-mothers who have experienced an episode of homelessness. Using longitudinal data collected from 294 respondents who became homeless in 1992 and were followed for approximately two years, we find that a history of full-time work is the best predictor of whether a woman will find full-time employment in the aftermath of an episode of homelessness. Even an extensive history of part-time or informal work was not predictive of finding employment after leaving a homeless shelter. A woman's level of depressive symptomatology at the onset of homelessness predicted her strategy in dealing with the shelter bureaucracy. Women with full-time work histories who experienced high levels of depressive moods at the onset of a shelter episode were likely to leave the shelter quickly. Those with lower levels of depressive symptomatology stayed and were more likely than others to complete an education or job training program. Both types of women with full-time work histories were more likely than others to find full-time employment after a homeless episode. These findings suggest that policy makers must focus on providing full-time, and not part-time, work for impoverished mothers and take depressive symptomatology into account when offering assistance to homeless mothers.

Porphobilinogen deaminase gene in African and Afro-Caribbean ethnic groups: mutations causing acute intermittent porphyria and specific intragenic polymorphisms.

Acute intermittent porphyria (AIP), the most common acute hepatic porphyria, is a low-penetrant autosomal dominant disorder caused by mutations in the porphobilinogen deaminase (PBGD) or hydroxymethylbilane synthase (HMBS) gene. Although AIP has been identified in all the main ethnic groups, little is known about PBGD gene defects in Africans, Afro-Caribbean and Afro-Americans. We have carried out PBGD gene screening among seven unrelated AIP families and 98 controls belonging to the Afro-Caribbean (French West Indies) and the sub-Saharan African (Morocco, Algeria, Cameroon, Mali, and Burkina Faso) populations. Using denaturing-gradient gel electrophoresis (DGGE) and direct sequencing we characterized six different mutations, including four novel, from the seven AIP families: three splicing defects (IVS 5+2 Ins G; IVS 7+1 G to A in two families; IVS 10-1 G to T); a small deletion (1004 Del G); and two missense mutations (R116 W; A270G). The allele frequencies of the 14 polymorphic sites, previously known in the normal Caucasian population, were similar in Africans and Afro-Caribbean control populations. Interestingly, two common new intragenic polymorphic sites, close to intron/junction boundaries, were identified only in blacks: 1) in intron 2, a single base-pair G deletion at position 3167 (G:0.88; delG:0.12); 2) in intron 10, a A/G dimorphism at position 7052 (A:0.56; G:0.44). These two single nucleotide polymorphisms (SNPs) were never encountered in 750 unrelated Caucasian subjects. The allele frequency distributions of populations within black ethnic groups (Africans and Afro-Caribbean) are similar. This study highlights differences both in PBGD gene mutations causing AIP and in SNPs between white and black peoples; the allele frequencies provided contribute to a better knowledge of the variability of these markers among the major population groups, especially in sub-Saharan West African and Afro-Caribbean populations.

Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors.

BACKGROUND/AIMS: Previous retrospective studies have suggested an association between hepatocellular carcinoma and acute hepatic porphyrias. The incidence, the relative risk, the characteristics and the outcome of primary liver cancer were prospectively evaluated in patients with acute hepatic porphyrias; the molecular mechanism of carcinogenesis in these patients was also pointed out. METHODS: A cohort of 650 patients with acute hepatic porphyria was followed over 7 years. Standardized rate ratio was used to measure the relative risk of primary liver cancer after indirect standardization. Morphological and clinical aspects of primary liver cancer were investigated, and survival rates were calculated using the Kaplan-Meier method. Common etiological factors involved in liver carcinogenesis were screened. Excretion rates of porphyrin precursors, serum melatonin levels and mutations in the genes encoding for heme biosynthetic enzymes were studied. RESULTS: Hepatocellular carcinoma was found in four symptomatic and three asymptomatic patients (four female, three male). The overall standardized rate ratio was 36 (95% CI: 14-74). The 5-year disease-free survival was 43% in patients with hepatocellular carcinoma. Usual risk factors for primary liver cancer were not confounding factors. Hepatocellular carcinoma was not related to specific heme biosynthesis gene mutations. Heme precursors were significantly increased in porphyric patients with hepatocellular carcinoma, and serum melatonin levels were low. CONCLUSIONS: Acute hepatic porphyrias are risk factors for hepatocellular carcinoma. Hepatic porphyrias should be sought in patients with hepatocellular cancer without obvious etiology, and a periodic screening for hepatocellular carcinoma should be evaluated in these patients. Genes encoding for heme biosynthetic pathway may not act as tumor suppressor genes. Chronic increased levels of delta aminolevulinic acid could lead to the generation of free radicals and subsequently to hepatic carcinogenesis.

Identification of a prevalent nonsense mutation (W283X) and two novel mutations in the porphobilinogen deaminase gene of Swiss patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by decreased activity of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthetic pathway. We report the first molecular analysis of PBGD gene mutations in AIP patients of Swiss origin. The PBGD gene of 18 Swiss AIP patients was analyzed by denaturing gradient gel electrophoresis screening of the genomic DNA and direct sequencing. Thirteen of the 18 patients (72%) carried a nonsense mutation G(849)-->A, W283X. In addition, 4 different mutations including 2 novel mutations (Q217L and Q292X), were identified in the 5 remaining AIP patients originating from both German- and Italian-speaking regions of Switzerland.

Cloning and characterization of AOEB166, a novel mammalian antioxidant enzyme of the peroxiredoxin family.

Using two-dimensional electrophoresis, we have recently identified in human bronchoalveolar lavage fluid a novel protein, termed B166, with a molecular mass of 17 kDa. Here, we report the cloning of human and rat cDNAs encoding B166, which has been renamed AOEB166 for antioxidant enzyme B166. Indeed, the deduced amino acid sequence reveals that AOEB166 represents a new mammalian subfamily of AhpC/TSA peroxiredoxin antioxidant enzymes. Human AOEB166 shares 63% similarity with Escherichia coli AhpC22 alkyl hydroperoxide reductase and 66% similarity with a recently identified Saccharomyces cerevisiae alkyl hydroperoxide reductase/thioredoxin peroxidase. Moreover, recombinant AOEB166 expressed in E. coli exhibits a peroxidase activity, and an antioxidant activity comparable with that of catalase was demonstrated with the glutamine synthetase protection assay against dithiothreitol/Fe3+/O(2) oxidation. The analysis of AOEB166 mRNA distribution in 30 different human tissues and in 10 cell lines shows that the gene is widely expressed in the body. Of interest, the analysis of N- and C-terminal domains of both human and rat AOEB166 reveals amino acid sequences presenting features of mitochondrial and peroxisomal targeting sequences. Furthermore, human AOEB166 expressed as a fusion protein with GFP in HepG2 cell line is sorted to these organelles. Finally, acute inflammation induced in rat lung by lipopolysaccharide is associated with an increase of AOEB166 mRNA levels in lung, suggesting a protective role for AOEB166 in oxidative and inflammatory processes.

Homeless mothers and depression: misdirected policy.

This paper is a critique of recent service-intensive shelter programs for homeless mothers and the policies that underlie these shelters. We first document the process by which mental health problems and family homelessness became so closely but mistakenly linked. We then demonstrate empirically that shelter programs for homeless families nonetheless presume that mental health problems are part of the causal nexus of family homelessness and indiscriminately deliver mental health services to homeless mothers. Simultaneously, shelter programs encourage the isolation of their residents from what they presume to be their "problematic" social networks. We show that, while mental health services had little impact on depression levels among homeless mothers, isolation from social networks did increase depression among homeless mothers. Our findings suggest that policy should put more emphasis on rapid reintegration into the community through providing housing, and it should put less emphasis on providing services.

Heme and acute inflammation role in vivo of heme in the hepatic expression of positive acute-phase reactants in rats.

Acute-phase protein synthesis in the liver during inflammation is regulated via cytokines and glucocorticoids. Using quantitative reverse transcription (RT)-PCR analysis and immunoassay, we explored, in the rat, the response of the acute-phase protein, alpha-2 macroglobulin (A2M), after systemic inflammation induced by lipopolysaccharide (LPS) or localized inflammation induced by turpentine oil (TO). The results indicate that synthesis of A2M is higher following TO-induced inflammation than LPS-induced inflammation and is not correlated with interleukin (IL)-6 or glucocorticoid levels. We studied the putative role of heme in this differential A2M expression following localized vs. systemic inflammation; addition of heme during LPS-induced inflammation can boost the expression of A2M, whereas blocking heme synthesis (by succinyl acetone) or enhancing its consumption in parallel biosynthetic pathways (cytochrome P450 induction by phenobarbital) decreases A2M expression. This decrease was abolished by exogenous heme supplementation. Finally, we demonstrate that heme supplementation is also able to increase the A2M response in female rats to a level similar to that in male rats providing a new insight into the puzzling sexual dimorphism observed previously during localized inflammation. We propose that heme should be considered a new regulatory element in controlling liver A2M expression during inflammation.

Evaluation of mutation screening by heteroduplex analysis in acute intermittent porphyria: comparison with denaturing gradient gel electrophoresis.

Acute intermittent porphyria is the major autosomal dominant form of acute hepatic porphyrias. The disease is due to mutations in the gene encoding for porphobilinogen deaminase (PBGD). Many different strategies have been developed to screen for mutations. However the high prevalence (0.6 per thousand) of PBGD gene defect, the large allelic heterogeneity of mutations (n = 130), and the limitations of the PBGD enzymatic assay for asymptomatic patients' detection, require for diagnosis an efficient and easy to handle strategy for locating mutations within the PBGD gene. In a recent study the sensitivity of the denaturing gradient gel electrophoresis (DGGE) technique was 100%. However DGGE requires the preparation of gradient gels and the use of primers with long GC-clamps; thus alternative methods should be preferable in the clinical laboratory. We have compared the detection rate of DGGE with heteroduplex analysis (HA) using 16 characterized PBGD gene mutations. Six different HA conditions were used to determine the efficiency of the method, including: (1) MDE (mutation detection enhancement) gel concentration; (2) addition of urea and sodium dodecyl sulfate (SDS); (3) radioactive labelling. The sensitivity of each HA condition varied from 31 to 81% vs. 100% in DGGE analysis. HA using 1 x MDE with 15% urea with or without 0.55% SDS was the most sensitive condition. This first comparative study of DGGE and HA mutation screening methods suggests that DGGE is a more sensitive screening assay than optimized HA. However, because of its simplicity HA should be considered as an efficient alternative mutation screening method.

Epidemiology of hepatitis C and G in sporadic and familial porphyria cutanea tarda.

From 1995 to 1997, we prospectively evaluated the prevalence of hepatitis C virus (HCV) RNA in 124 patients with porphyria cutanea tarda (PCT) from Northern France (83 sporadic and 41 familial PCT). Serum samples were analyzed for ferritin, transaminases, HCV antibodies, and HCV RNA. In addition, genotyping of HCV and searches for HCV infection risk factors (blood transfusion, iv drug abuse, and surgical intervention) were performed. Twenty-six of 124 patients (21%; 95% CI: 13.9-28) were positive for serum HCV antibodies. All of them were also positive for HCV RNA. The prevalence of HCV infection was higher in the sporadic PCT group (26.5%, 22 out of 83) than in the familial PCT group (9.7%, 4 out of 41). Risk factors for hepatitis C infection were found to be significantly increased in the HCV-positive group when compared with the HCV-negative PCT group. In all HCV-positive patients with a risk factor, the suspected date of exposure to the virus always preceded the clinical onset of PCT. The HCV genotype pattern in PCT patients was similar to that observed in nonporphyric HCV patients in western European countries. Serum ferritin level was increased in both HCV-positive and HCV-negative porphyric patients. Transaminase levels were significantly higher in HCV-infected PCT patients. Sixty-seven out of 124 patients were retrospectively studied for hepatitis G virus (HGV) infection. Six of these 67 patients (8.9%; 95% CI: 2.1-15.8) were positive for HGV RNA. None of the six HGV-infected patients were positive for HCV RNA. The HGV-infected patients did not differ statistically from those without HGV infection with regard to age, ferritin, transaminase levels, and PCT treatment. These results support the view that sporadic cases of HGV infection may occur frequently. This study of a large cohort of HCV and PCT patients further documents an increasing gradient in HCV prevalence from northern to southern Europe, and shows that HCV infection acts as a triggering factor of PCT. Finally, the HGV prevalence found in the PCT patients was comparable with that found in French blood donors, suggesting that HGV is not a PCT triggering factor.

Level of intrateam agreement on candidate scores in a structured interview process.

This study examined the intrateam reliability of a structured interview process used to help select students to a professional education program in physical therapy. Two hundred and twenty academically qualified applicants were interviewed by one of six two-member teams using a standardized format. Each member of a team independently rated the applicant on each of four performance skills using a 5-point ordinal scale; the maximal total score possible was 16 points. A weighted kappa (Kw) statistic was used to estimate intrateam agreement for both 1993 and 1994 on each performance skill and overall interview score. We observed wide variation in intrateam Kw scores for each of the four performance skills between the 1993 and 1994 admission cycles. According to Kw values for overall score agreement, five of the six interview teams either remained the same or increased at least one level between 1993 and 1994. Intrateam variability may be reduced by having team members review specific criteria used to rate a skill before the interview process commences each year.

Stimulus-response compatibility effects in a manual tracking task.

The purpose of this study was to determine whether there are stimulus-response (S-R) compatibility effects in a manual tracking task for male and female subjects of different ages. 20 healthy men and 20 healthy women in each of three different age groups (20 to 39, 40 to 59, and 60 to 79 years) participated (total N = 120). Subjects performed extension and flexion movements of the index finger metacarpophalangeal joint to track a computer-screen cursor along a target sine wave. The hand and forearm were positioned so that the finger movement was either vertical or horizontal, and the computer monitor was positioned so that the voluntary cursor movement was either vertical or horizontal. Each subject performed four different tracking tests corresponding to the four different ensembles of hand-forearm position and monitor position. There were significant differences in tracking performance between test ensembles in both women and men aged 60 to 79 years, and the compatible ensembles showed the superior performance. The results suggest that S-R compatibility effects exist in elderly women and elderly men performing a finger-movement tracking task, and these effects are consistent with impaired information processing in elderly persons. More research is needed on how S-R compatibility affects performance in persons with cerebral lesions.

Finger-movement tracking scores in healthy subjects.

The purpose of this study was to examine the effects of age, sex, and hand preference on precise control of voluntary movement at the index finger metacarpophalangeal joint in able-bodied volunteers. An electrogoniometer was attached to this joint and connected to a computer. The computer screen displayed a sine wave target that each subject attempted to track with careful extension and flexion finger movements. Accuracy index scores were calculated for the extension phases, flexion phases, and the total sine wave. Each subject performed three tracking trials and the average for each of the above scores was computed. The results showed that younger subjects tracked significantly more accurately than older subjects and men tracked significantly more accurately than women. Also, the subjects tracking with the nonpreferred hand (15 right, 105 left) tracked significantly more accurately than those subjects tracking with the preferred hand (112 right, 8 left) in the flexion phases of the test. The data from these able-bodied subjects provide a base for comparison of patients' data, which may be helpful in the early recognition and monitoring of problems with precision in movement control.

Reliability of goniometric measurements and visual estimates of ankle joint active range of motion obtained in a clinical setting.

We examined intratester and intertester reliability for goniometric measurements of ankle dorsiflexion (ADF) and ankle plantar flexion (APF) active range of motion (AROM). Parallel-forms intratester reliability for ankle AROM measurements obtained by the universal goniometer (UG) and by visual estimation (VE) and intertester reliability for VE of ADF and APF were examined. Repeated measurements were obtained on 38 patients with orthopedic problems by 10 physical therapists in a clinical setting. For intratester reliability of measurements obtained with UG, intraclass correlation coefficients (ICC) for all physical therapists were 0.64 to 0.92 (median, 0.825) for ADF and 0.47 to 0.96 (median, 0.865) for APF. Intertester reliability was quantified with use of ICC. ICCs for measurements obtained by UG were 0.28 for ADF and 0.25 for APF; ICC of VE for ADF was 0.34 and was 0.48 for APF. ICC for parallel-forms intratester reliability obtained with UG and VE ranged from 0 to 0.94 (median, 0.58) for ADF and 0 to 0.86 (median, 0.625) for APF. Thus, a physical therapist should use a goniometer when making repeated measurements of ankle joint AROM. Considerable inconsistency exists when two or more physical therapists make repeated goniometric and visual measurements of ankle motion on the same subject. Physical therapists may erroneously conclude that a patient's AROM has changed because of treatment when the change could be attributed to a lack of intertester reliability.

Normal range of motion of the cervical spine: an initial goniometric study.

The purposes of this study were (1) to determine normal values for cervical active range of motion (AROM) obtained with a "cervical-range-of-motion" (CROM) instrument on healthy subjects whose ages spanned 9 decades, (2) to determine whether age and gender affect six cervical AROMs, and (3) to examine the intratester and intertester reliability of measurements obtained. Measurements were made on 337 subjects (171 females and 166 males) whose ages ranged from 11 to 97 years. Measurements were taken by five physical therapists with 7 to 30 years of clinical and teaching experience. Among male and female subjects of the same age, females had a greater AROM than did males for all AROMs except neck flexion. Among both males and females, each of the six cervical AROMs decreased significantly with age. From two pilot studies separate from the acquisition of the normal database, we determined our intratester and intertester reliabilities for making neck AROM measurements with the CROM instrument. We concluded that AROM measurements on the cervical spine with the CROM instrument demonstrated good intratester and intertester reliability, because the intraclass correlation coefficients were generally greater than .80.

A herpes simplex virus ribonucleotide reductase deletion mutant is defective for productive acute and reactivatable latent infections of mice and for replication in mouse cells.

Herpes simplex virus encodes a ribonucleotide reductase that is not essential for virus growth in dividing cells at 37 degrees. This enzyme has been proposed as a target for antiviral drugs; its utility in this regard could depend upon its importance in vivo. To test the requirement of viral ribonucleotide reductase in a mammalian host, we tested a mutant virus, lacking most of the gene encoding the ribonucleotide reductase large subunit, in a mouse eye model of pathogenesis and latency where the wild-type virus establishes reactivatable latent infections in trigeminal ganglia following corneal inoculation. The deletion mutant was severely impaired in its ability to replicate acutely in the eye and in the trigeminal ganglion and failed to establish reactivatable latent infections. In contrast, a recombinant virus in which the deleted sequences were restored was competent for both acute and latent infections. The defects of the deletion mutant in the mouse may be related to its severely impaired growth at 38 degrees in mouse cells relative to its growth in Vero cells. These results indicate that ribonucleotide reductase is critical for productive acute and reactivatable latent infections in mice and replication in mouse cells at 38 degrees and suggest that caution be exercised in extrapolating from studies conducted in mice to human infections when judging the utility of this enzyme as a target for antiviral chemotherapy.

A deletion mutant of the latency-associated transcript of herpes simplex virus type 1 reactivates from the latent state with reduced frequency.

We have generated and characterized a deletion mutant of herpes simplex virus type-1, dlLAT1.8, which lacks the putative promoter region, transcriptional start site, and 1,015 base pairs of the DNA sequences specifying the latency-associated transcripts (LATs). When tested in a CD-1 mouse ocular model, dlLAT1.8 was replication competent in the eye and in ganglia during acute infection but reactivated from explant cultures of ganglia with reduced efficiency (49%) relative to those of wild-type and marker-rescued viruses (94 and 85%, respectively) despite the fact that levels of mutant viral DNA in ganglia during latent infection were comparable to wild-type levels. The neurovirulence of KOS was not significantly altered by the removal of sequences specifying the LATs, as judged by numbers of animals dying on or before 30 days postinfection. Examination of ganglia latently infected with dlLAT1.8 by in situ hybridization revealed no LAT expression. The genotype of reactivated virus was identical to that of input dlLAT1.8 virus as judged by Southern blot analysis. These studies suggest that although the LATs are not essential for the establishment and reactivation of latency in our model, they may play a role in determining the frequency of reactivation of virus from the latent state.

Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate.

Herpes simplex virus infection of mammalian hosts involves lytic replication at a primary site, such as the cornea, translocation by axonal transport to sensory ganglia and replication, and latent infection at a secondary site, ganglionic neurons. The virus-encoded thymidine kinase, which is a target for antiviral drugs such as acyclovir, is not essential for lytic replication yet evidently is required at the secondary site for replication and some phase of latent infection. To determine the specific stage in viral pathogenesis at which this enzyme is required, we constructed virus deletion mutants that were acyclovir resistant and exhibited no detectable thymidine kinase activity. After corneal inoculation of mice, the mutants replicated to high titers in the eye but were severely impaired for acute replication in trigeminal ganglia and failed to reactivate from ganglia upon cocultivation with permissive cells. Nevertheless, latency-associated transcripts were expressed in neuronal nuclei of ganglia from mutant-infected mice and superinfection of the ganglia with a second virus rescued the latent mutant virus. Thus, contrary to a widely accepted hypothesis, the thymidine kinase-negative mutants established latent infections, implying that neither thymidine kinase activity nor ganglionic replication is necessary for establishment of latency. Rather, thymidine kinase appears to be necessary for reactivation from latency. These results suggest that acyclovir-resistant viruses could establish latent infections in clinical settings and have implications for the use of genetically engineered herpesviruses to deliver foreign genes to neurons.