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Objective: The purpose of this study was to determine whether maternal methadone dosage correlates with neonatal withdrawal in a large heroin-addicted pregnant population.Study Design: A retrospective review of all maternal/neonatal records of pregnancies that were maintained on methadone therapy in our institution was conducted. After in-hospital stabilization, women were given daily methadone therapy under direct surveillance, with liberal dosage increases according to maternal withdrawal symptoms. Neonatal withdrawal was assessed objectively by the neonatal abstinence score. The average methadone dose in the last 12 weeks of pregnancy and the last methadone dose before delivery (cutoffs of 40, 60, or 80 mg) were correlated to various objective measures of neonatal withdrawal.Results: One hundred mother/neonate pairs on methadone therapy were identified. Women who received an average methadone dose of <80 mg (n=50 women) had a trend toward a higher incidence of illicit drug abuse before delivery than women who received doses of >/=80 mg (n=50 women; 48% vs 32%; P=.1). Women who received an average methadone dose of <80 mg had similar highest neonatal abstinence score, need for neonatal treatment for withdrawal, and duration of withdrawal compared with women whose condition was maintained with dosages of >/=80 mg (score, 11.1 vs 11.5; 68% vs 66%; and 13.3 vs 13.6 days, respectively; all P>.5). For all cutoffs that were used for high versus low dose and for both the average and last methadone dosage analyses, neonatal withdrawal was similar.Conclusion: The maternal methadone dosage does not correlate with neonatal withdrawal; therefore, maternal benefits of effective methadone dosing are not offset by neonatal harm. [ABSTRACT FROM AUTHOR]

Background: There is limited measurement and reporting of quality of life (QoL) outcomes for patients with contact dermatitis (CD)., Objective: The purpose of this study is to develop a standardized Contact Dermatitis Quality of Life index (CDQL) for adult patients., Methods: A list of 81 topics was compiled from a review of QoL measures used previously in CD research. A total of 2 rounds of web-based Delphi surveys were sent to physicians who registered to attend the 2018 American Contact Dermatitis Society meeting, asking that they rank the relevance of topics for measuring QoL in CD using a 4-point scale. Items met consensus for inclusion if at least 78% of respondents ranked them as relevant or very relevant, and their median score was ≥3.25., Results: Of the 210 physicians contacted, 34 physicians completed the initial survey and 17 completed the follow-up survey. A total of 22 topics met consensus for inclusion in the CDQL, addressing symptoms, emotions, functions of daily living, social and physical functions, work/school functions, and treatment., Conclusions: This study was limited by the following factors: few open-ended questions in the initial survey, a lack of direct patient feedback, and long survey length, which likely contributed to lower survey participation. The CDQL is a comprehensive, CD-specific QoL measure developed on the basis of expert consensus via a modified Delphi process to be used by physicians and other health care professionals who care for adult patients with contact dermatitis., (©Mary K Hill, Melissa R Laughter, Cecile I Harmange, Robert P Dellavalle, Chandler W Rundle, Cory A Dunnick. Originally published in JMIR Dermatology (http://derma.jmir.org), 16.12.2021.)

Background: The lateral hypothalamic orexin (hypocretin) system has a well-established role in the motivation for reward. This has particular relevance to substance use disorders since orexin-1 receptors play a critical role in alcohol-seeking behavior, acting at multiple nodes in relapse-associated networks., Aims: This study aimed to further our understanding of the role of orexin-1 receptor signaling within the lateral hypothalamus and bed nucleus of the stria terminalis, specifically in context-induced relapse to alcohol-seeking following punishment-imposed abstinence., Methods: We trained inbred male alcohol-preferring rats to self-administer alcohol in one environment or context (Context A) and subsequently punished their alcohol-reinforced lever presses in a different environment (Context B) using contingent foot shock punishment. Finally, we tested rats for relapse-like behavior in either context following systemic, intra-lateral hypothalamus or intra-bed nucleus of the stria terminalis orexin-1 receptor antagonism with SB-334867., Results/outcomes: We found that systemic orexin-1 receptor antagonism significantly reduced alcohol-seeking in both contexts. Intra-lateral hypothalamus orexin-1 receptor antagonism significantly reduced alcohol-seeking in Context A whereas intra-bed nucleus of the stria terminalis orexin-1 receptor antagonism had no effect on alcohol-seeking behavior., Conclusions/interpretation: Our results suggest a role for the orexin-1 receptor system in context-induced relapse to alcohol-seeking. Specifically, intra-lateral hypothalamus orexin microcircuits contribute to alcohol-seeking.

Google+ sets itself apart from other social media platforms through a number of unique features, including search engine optimization services and high user satisfaction. The purpose of this study was to evaluate the presence of dermatological entities on Google+. Searches were conducted to locate any Google+ accounts associated with the most popular dermatology journals, dermatological patient-centered organizations, and professional dermatology-related organizations on social media. Additionally, "dermatology Google+" was searched via Google, and Google+ profiles retrieved in the first page of results were assessed. Four of the five active Google+ profiles identified in the first page of Google search results were run by private dermatology practices. Only one of the 13 searched journals was active on Google+. Twenty-six of the 34 patient-centered and professional organizations had Google+ accounts, but only seven of these accounts were active in the last year. Therefore, unlike some private practices, the majority of dermatology journals and organizations have yet to take advantage of the exclusive opportunities offered by Google+ to expand their audiences and bolster their overall online presence.

Despite the increasing prevalence of social media usage, the activity of dermatology journals and professional and patient-centered organizations on top social media platforms has not been investigated since 2012. We investigated a total of 124 dermatology journals, 242 professional organizations, and 78 patient-centered organizations to assess their presence and popularity on social media. Searches were conducted to identify journals and organizations on Facebook and Twitter. Similar searches were done for organizations on LinkedIn. The number of Facebook likes, Twitter followers, and LinkedIn followers of the dermatological entities were quantified. There were 22 (17.7%) dermatology journals active on Facebook and 21 (16.9%) on Twitter. Amongst the professional organizations, 114 (47.1%) were on Facebook, 69 (28.5%) on Twitter, and 50 (20.7%) on LinkedIn. In comparison, 68 (87.2%) patient-centered organizations were on Facebook, 56 (71.8%) on Twitter, and 56 (71.8%) on LinkedIn. Our results demonstrate that the popularity of dermatology journals and professional and patient-centered organizations on top social networking sites has grown markedly since 2012. Although the number of dermatology journals on social media has increased since 2012, their presence continues to trail behind professional and patient-centered dermatological organizations, suggesting underutilization of a valuable resource.

Cutaneous tuberculosis (TB) may present in various clinical manifestations. Skin involvement may occur as a result of exogenous inoculation, contiguous spread from a nearby focus of infection, or by hematogenous spread from a distant focus. Because the clinical presentation of cutaneous TB can vary widely, it is important to have a high index of suspicion in appropriate clinical settings. In this chapter, the various clinical manifestations of clinical TB are classified by source of infection (exogenous, endogenous, and hematogenous spread). These are linked to the clinical appearance and histology of the skin lesions. Hopefully, this will resolve the confusion created by the myriad of terms previously used in the medical literature. Once a diagnosis of cutaneous TB is entertained, a biopsy for both culture and histopathology should be submitted. In some cases histopathology may show nonspecific inflammation without classic granuloma formation. In these cases, monoclonal antibodies and polymerase chain reaction (PCR) testing may be useful. In fact, in recent years, PCR amplification has proven to be invaluable in assisting identification of M. tuberculosis from skin biopsies in patients with negative TB cultures. In most instances, treatment of cutaneous TB requires combination chemotherapy. This is especially important in patients with extra cutaneous disease, multiple skin lesions, and those with profound immunosuppression. Surgery also may play both a diagnostic and therapeutic role.

Background: A significant number of instruments exist that are aimed at quantifying atopic dermatitis (AD) outcomes., Objective: We sought to assess recent trends in the use of disease severity and quality of life (QOL) outcome instruments in randomized controlled trials (RCTs) conducted on patients with AD between July 2010 and July 2015., Methods: A total of 540 nonduplicate records were identified through searches of Scopus and Ovid MEDLINE. Included studies were RCTs conducted on humans with AD that were published in English between July 2010 and July 2015 and that reported the results of disease severity or QOL outcome measures., Results: All of the 135 included studies assessed disease severity. Only 45 studies assessed QOL. Sixty-two disease severity measures and 28 QOL scales were identified., Limitations: This study was limited by its timeframe of 5 years and by the exclusion of non-RCTs and gray literature., Conclusion: Disease severity and QOL outcome measures are instrumental in evaluating AD treatment efficacy. The number of such tools used in RCTs on patients with AD continues to rise. Standardization of outcomes instruments is essential for comparability among studies and improved quality of evidence., (Published by Elsevier Inc.)

Background: Contact dermatitis (CD) has been assessed by numerous disease severity indices resulting in heterogeneity across published research., Objective: This study aims to evaluate published CD severity scales and identify a criterion standard for assessment., Methods: Scopus and Ovid MEDLINE were searched for human randomized controlled trials (RCTs) on CD severity measures published during a 10-year period. Eligible studies were English-language RCTs reporting disease severity outcome measures for CD in humans. Studies were excluded if they were duplicates, not available in English, not related to CD, not RCTs, not conducted on human subjects, or did not report relevant outcome measures., Results: A total of 22 disease outcome measures were used in 81 included RCTs. Instrument-based measures were used in 40 (49.4%) studies, and visual assessments were used in 66 (81.5%) RCTs. Only 5 (6.2%) studies reported quality of life (QoL) outcomes. Two (2.5%) studies used a clinical severity scale, which combined both QoL and visual assessments., Limitations: This study was limited by the exclusion of non-RCTs and gray literature., Conclusions: Wide variation in CD outcome measures exists including instrument-based measures, visual assessments, and QoL outcomes. A standardized outcome measure must be generated to reduce heterogeneity.

Background: Traumatic posterior hip dislocation in children is a rare injury that typically is treated with closed reduction. Surgical treatment is typically recommended for nonconcentric reduction with joint space asymmetry with entrapped labrum or an osteochondral fragment. The surgical hip dislocation (SHD) approach allows for full assessment of the acetabulum and femoral head and has been our preferred surgical strategy. The purpose of this study was to (1) describe the intra-articular pathologic findings seen at the time of SHD; and (2) to investigate hip pain, function, and activity level of a cohort of children and adolescents after open treatment of a posterior hip dislocation using the SHD approach., Methods: Following IRB approval, 23 patients who sustained a traumatic posterior hip dislocation between January 2009 and December 2013 were identified. In 8/23 (34.8%) patients there was evidence of nonconcentric reduction after closed treatment and surgical treatment was performed using the SHD approach. Seven male and 1 female (mean age, 11.2 y; range, 6 to 14.6 y) were followed for an average of 28 months (range, 13 to 67 mo). The modified Harris Hip Score (mHHS) and the University of California Los Angeles activity score assessed clinical hip outcome and activity level at minimum of 1 year after surgery., Results: Six patients were treated after an acute trauma, whereas 2 were treated after recurrent dislocations. Five patients were involved in motor vehicle accidents and 3 in sports-related injuries. Intraoperative findings include posterior labral avulsion in all patients, fracture of the cartilaginous posterior wall (n=3), and femoral head chondral injuries (n=5) and fracture (n=1). The labral root was repaired using suture anchor technique in 7/8 patients and resected in 1. In 2 patients, labral repair was complemented by screw fixation of the posterior wall. All but one patient (mHHS=94) reported maximum mHHS. The University of California Los Angeles activity score was 10 for 5/8 patients and 7 in 3 patients. No case of femoral head osteonecrosis was noted. One patient developed an asymptomatic heterotopic ossification., Conclusions: When open reduction is recommended for the treatment of intra-articular pathologies and hip instability following traumatic dislocation of the hip in children and adolescents, the SHD is an excellent approach that allows surgical correction of the damaged bony and soft-tissue structures including repair of the capsule-labral complex, and reduction and internal fixation of the cartilaginous posterior wall and femoral head fractures., Level of Evidence: Level IV.

Background: Femoroacetabular impingement (FAI) deformity has been associated with posterior hip instability in adult athletes., Purpose: To determine if FAI deformity is associated with posterior hip instability in adolescents, the femoral head-neck junction or acetabular structure in a cohort of adolescent patients who sustained a low-energy, sports-related posterior hip dislocation was compared with that in a group of healthy age- and sex-matched controls with no history of hip injury or pain., Study Design: Cross-sectional study; Level of evidence, 3., Methods: We identified 12 male patients (mean age, 13.9 years; range, 12-16 years) who sustained a sports-related posterior hip dislocation and underwent a computed tomography (CT) scan after closed reduction. For each patient, 3 age- and sex-matched healthy controls were identified. Femoral head-neck type was assessed by measurement of the alpha angle on the radially oriented CT images at the 12-, 1-, 2-, and 3-o'clock positions. Age, body mass index (BMI), alpha angle at each position, acetabular version, Tönnis angle, and lateral center-edge angle (LCEA) on the involved hip in the dislocation group were compared with those of the matched controls using a mixed-effects model. A logistic regression analysis using a generalized estimating equation was used to compare the percentage of subjects with cam-type FAI deformity (alpha angle >55°) in each group., Results: The dislocation and control groups were similar in age distribution and BMI (P > .05). The mean alpha angles were statistically significantly higher in the dislocation group compared with the control group at the superior (46.3° ± 1.1° vs 42.7° ± 0.6°; P = .0213), superior-anterior (55.5° ± 1.9° vs 46.0° ± 1.3°; P = .0005), and anterior-superior (54.9° ± 1.5° vs 48.9° ± 1.0°; P = .0045) regions. Cam deformity was present in a larger proportion of patients in the dislocation group than in the control group (P < .0035). An alpha angle greater than 55° was present in 16.7% of the dislocation group and 0% of the control group at the 12-o'clock position (P = .1213), 41.7% versus 0% at the 1-o'clock position (P = .0034), 58% versus 6% at the 2-o'clock position (P = .0004), and 25% versus 2.8% at the 3-o'clock position (P = .0929). Acetabular anteversion was lower in the dislocation group (9.6° ± 1.4°) compared with the control group (15.1° ± 0.8°) (P = .0068). Mean acetabular LCEA was within a normal range in both groups., Conclusion: A significantly higher mean alpha angle from the superior to the anterior-superior regions of the femoral head-neck junction and lower acetabular version were found in adolescents who sustained low-energy, sports-related posterior hip dislocations., (© 2016 The Author(s).)

Background: Osteonecrosis of the femoral head is a major complication that negatively impacts the clinical and radiographic long-term outcome after treatment of developmental hip dysplasia (DDH). There are conflicting results in the literature whether age at the time of closed or open reduction and a specific surgical approach are associated with osteonecrosis. Better understanding of the impact of age at reduction and surgical approach is important to reduce the risk of osteonecrosis in patients with DDH., Questions/purposes: We aimed to evaluate the association between occurrence of osteonecrosis and (1) age at closed reduction; (2) age at open reduction; and (3) medial versus anterior operative approaches., Methods: A systematic review identified studies reporting osteonecrosis occurrence after treatment of DDH and at least 2 years of followup. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Methodologic quality was assessed using the methodologic index for nonrandomized studies. Generalized logistic models were used to estimate pooled odds ratios (ORs) in the meta-analysis. Sixty-six studies were included in the systematic review and 24 in the meta-analysis. Data on 481 hips treated by closed reduction and 584 hips treated by open reduction were available to evaluate the association between osteonecrosis and age. The association between osteonecrosis and operative approach was assessed using data on 364 hips treated by medial open reduction and 220 hips treated by anterior open reduction., Results: Age at reduction (> 12 months versus ≤ 12 months) was not associated with osteonecrosis after closed reduction (OR, 1.1; 95% confidence interval [CI], 0.4-3.2; p = 0.9) or open reduction (OR, 1.1; 95% CI, 0.7-1.9; p = 0.66). The overall, adjusted incidence of osteonecrosis (≥ Grade II) was 8.0% (95% CI, 2.8%-20.6%) among patients treated with closed reduction at or before 12 months of age and 8.4% (95% CI, 3.0%-21.5%) among those treated after 12 months. Similarly, the odds of osteonecrosis after open reduction did not differ between patients treated after the age of 12 months compared with those treated at or before 12 months (OR, 1.1; 95% CI, 0.7-1.9; p = 0.7). The incidence of osteonecrosis (≥ Grade II) was 18.3% (95% CI, 11.7%-27.4%) among patients who had index open reduction at or before 12 months of age and 20.0% (95% CI, 13.1%-29.4%) among those who had index open reduction after 12 months of age. Among hips treated with open reductions, there was no difference in osteonecrosis after medial versus anterior approaches (18.7% medial versus 19.6% anterior; OR, 1.1; 95% CI, 0.5-2.2; p = 0.9). Conclusions We did not find an association between closed or open reduction performed at or before 12 months of age and an increased risk of osteonecrosis of the femoral head. Delayed treatment past 1 year of age as a strategy to reduce the development of osteonecrosis was not supported by this meta-analysis. Open reduction through a medial or anterior approach may be recommended based on surgeon's preference, because we found no association between development of osteonecrosis and the type of surgical approach. However, many of the studies in the current literature are nonrandomized Level III or IV observational studies of inconsistent quality. Higher quality evidence is needed to better understand the effects of age at reduction and operative approach on the development of osteonecrosis after DDH treatment., Level of Evidence: Level III, therapeutic study.

Pediatric femoral neck fractures are rare injuries that are associated with a high risk of osteonecrosis of the femoral head. This study compared pediatric patients with fully displaced femoral neck fractures treated with either open reduction and internal fixation (ORIF) or closed reduction and internal fixation (CRIF). After institutional review board approval was obtained, the authors identified 53 patients who were treated for femoral neck fracture between 2003 and 2012. Inclusion criteria were as follows: (1) diagnosis of a fully displaced femoral neck fracture with no anatomic cortical contact; (2) age of at least 4 years; and (3) clinical/radiographic follow-up of at least 1 year. Medical records and radiographs were retrospectively reviewed. Excluded from the study were 16 patients who had fractures that were not fully displaced, 4 who were outside of the eligible age range, 1 who had insufficient radiographs, and 10 who had insufficient follow-up. Of the 22 patients included, 6 were treated with ORIF and 16 were treated with CRIF. Treatment groups were compared with Fisher's exact test for categorical outcome data and the Wilcoxon rank-sum test for continuous variables. There was a significantly (P=.051) greater occurrence of osteonecrosis after CRIF (50%) than after ORIF (0%). Further, patients who underwent ORIF had a higher (P=.009) quality of reduction, a higher (P=.046) rate of anatomic union, and fewer (P=.009) complications than those who underwent CRIF. Major complications occurred in significantly fewer (P=.015) hips after ORIF than after CRIF. No significant difference (P=.477) was seen between groups, according to the Ratliff assessment of final results. Fully displaced pediatric femoral neck fractures treated with ORIF had a significantly higher quality of reduction, with fewer complications, including osteonecrosis, than those treated with CRIF., (Copyright 2015, SLACK Incorporated.)

Background: In situ pinning is the conventional treatment for a stable slipped capital femoral epiphysis (SCFE). However, with a severe stable SCFE the residual deformity may lead to femoroacetabular impingement and articular cartilage damage. A modified Dunn subcapital realignment procedure has been developed to allow for correction at the level of the deformity while preserving the blood supply to the femoral head., Questions/purposes: We compared children with severe stable SCFE treated with the modified Dunn procedure or in situ pinning in terms of (1) proximal femoral radiographic deformity; (2) Heyman and Herndon clinical outcome; (3) complication rate; and (4) number of reoperations performed after the initial procedure., Methods: In this nonmatched retrospective study, 15 patients treated with the modified Dunn procedure (between 2007 and 2012) and 15 treated with in situ pinning (between 2001 and 2009) for severe but stable SCFE were followed for a mean of 2.5 years (range, 1-6 years). During the period in question, the decision regarding which procedure to use was based on the on-call surgeon's discretion; six surgeons performed in situ pinning and three surgeons performed the modified Dunn procedure. A total of 15 other patients were treated for the same diagnosis during the study period but were lost to followup before 1 year; of those, 12 were in the in situ pinning group. Radiographs were reviewed to measure the AP and lateral alpha angles, femoral head-neck offset, and Southwick angle preoperatively and at the latest clinical visit. The Heyman and Herndon clinical outcome, complications, and subsequent hip surgeries were recorded., Results: At latest followup, the median AP alpha angle (52°, range 41°-59° versus 76°, interquartile range [IQR]: 68°-88°; p = 0.0017), median lateral alpha angle (44°, IQR: 40°-51° versus 87°, IQR: 74°-96°; p < 0.001), median head-neck offset (7 mm, IQR: 5-9 mm versus -5, IQR: -11 to -4 mm; p < 0.001), and median Southwick angle (16°, IQR: 6°-23° versus 58°, IQR: 47°-66°; p < 0.001) revealed better deformity correction with the modified Dunn procedure compared with in situ pinning. Nine patients had good or excellent results in the modified Dunn group compared with four of 15 in the in situ pinning group (p = 0.0343; odds ratio, 5.86; 95% CI, 1.13-40.43). With the numbers available, there were no differences in the numbers of complications in each group (five versus three complications in the in situ and modified Dunn groups, respectively; p = 0.66), but there were more reoperations in the in situ pinning group (three versus seven; p = 0.0230)., Conclusions: The modified Dunn procedure results in better morphologic features of the femur, a higher rate of good and excellent Heyman and Herndon clinical outcome, a lower reoperation rate, and a similar occurrence of complications when compared with in situ pinning for treatment of severe stable SCFE., Level of Evidence: Level III, therapeutic study.

The HIV-1 gp120-gp41 complex, which mediates viral fusion and cellular entry, undergoes rapid evolution within its external glycan shield to enable escape from neutralizing antibody (NAb). Understanding how conserved protein determinants retain functionality in the context of such evolution is important for their evaluation and exploitation as potential drug and/or vaccine targets. In this study, we examined how the conserved gp120-gp41 association site, formed by the N- and C-terminal segments of gp120 and the disulfide-bonded region (DSR) of gp41, adapts to glycan changes that are linked to neutralization sensitivity. To this end, a DSR mutant virus (K601D) with defective gp120-association was sequentially passaged in peripheral blood mononuclear cells to select suppressor mutations. We reasoned that the locations of suppressors point to structural elements that are functionally linked to the gp120-gp41 association site. In culture 1, gp120 association and viral replication was restored by loss of the conserved glycan at Asn¹³⁶ in V1 (T138N mutation) in conjunction with the L494I substitution in C5 within the association site. In culture 2, replication was restored with deletion of the N¹³⁹INN sequence, which ablates the overlapping Asn¹⁴¹-Asn¹⁴²-Ser-Ser potential N-linked glycosylation sequons in V1, in conjunction with D601N in the DSR. The 136 and 142 glycan mutations appeared to exert their suppressive effects by altering the dependence of gp120-gp41 interactions on the DSR residues, Leu⁵⁹³, Trp⁵⁹⁶ and Lys⁶⁰¹. The 136 and/or 142 glycan mutations increased the sensitivity of HIV-1 pseudovirions to the glycan-dependent NAbs 2G12 and PG16, and also pooled IgG obtained from HIV-1-infected individuals. Thus adjacent V1 glycans allosterically modulate the distal gp120-gp41 association site. We propose that this represents a mechanism for functional adaptation of the gp120-gp41 association site to an evolving glycan shield in a setting of NAb selection.

The medical and psychosocial needs of children and adolescents differ from those of adults, and this should be reflected in the care they receive in all areas of a health service. Children and adolescents must be accommodated separately to adults to ensure that their unique needs are met and risks of harm are minimised. The Standards for the care of children and adolescents in health services have been developed by a working group of clinicians, health service providers and consumer advocates based on a combination of available research evidence, published best practice guidelines and multidisciplinary expert consensus. Stakeholder input was obtained through invitations to comment, and pilot testing of the Standards was conducted in six metropolitan, regional and rural hospitals. The Standards provide detailed recommendations in the areas of recognising rights; the provision of child-, adolescent- and family-friendly health service facilities; the availability of child- and adolescent-specific equipment; and the importance of appropriately trained staff. To facilitate implementation and allow ongoing performance monitoring, the Standards have been developed for use alongside the Australian Council on Healthcare Standards Evaluation and Quality Improvement Program. The Standards provide a vehicle to ensure patient safety and to facilitate the provision of high-quality care for children and adolescents in Australian health services.

Purpose: To conduct a systematic review of literature regarding population-based screening for fragile X syndrome in newborns and women of reproductive age, either before or during pregnancy., Methods: Seven electronic databases were searched for English language studies published between January 1991 and November 2009. Data extraction was performed for all included studies. Results were synthesized using a narrative approach., Results: One article that examined offering newborn screening for fragile X syndrome and 10 that examined the offer of fragile X syndrome screening to women of reproductive age were identified. Two of these articles also addressed psychosocial aspects of population screening for fragile X syndrome such as attitudes to screening and experiences of screening, and a further nine addressed these issues alone. Studies exploring psychosocial issues demonstrated challenges for counseling arising from a lack of awareness or personal experience with fragile X syndrome in the general population., Conclusions: Targeted counseling and educational strategies will be essential to support women from the general population. It is crucial that future studies offering screening for fragile X syndrome explore a range of psychosocial aspects in addition to looking at uptake of testing and mutation frequency.

The bias of A-rich codons in HIV-1 pol is thought to be a record of hypermutations in viral genomes that lack biological functions. Bioinformatic analysis predicted that A-rich sequences are generally associated with minimal local RNA structures. Using codon modifications to reduce the amount of A-rich sequences within HIV-1 genomes, we have reduced the flexibility of RNA sequences in pol to analyze the functional significance of these A-rich 'structurally poor' RNA elements in HIV-1 pol. Our data showed that codon modification of HIV-1 sequences led to a suppression of virus infectivity by 5-100-fold, and this defect does not correlate with, viral entry, viral protein expression levels, viral protein profiles or virion packaging of genomic RNA. Codon modification of HIV-1 pol correlated with an enhanced dimer stability of the viral RNA genome, which was associated with a reduction of viral cDNA synthesis both during HIV-1 infection and in a cell free reverse transcription assay. Our data provided direct evidence that the HIV-1 A-rich pol sequence is not merely an evolutionary artifact of enzyme-induced hypermutations, and that HIV-1 has adapted to rely on A-rich RNA sequences to support the synthesis of viral cDNA during reverse transcription, highlighting the utility of using 'structurally poor' RNA domains in regulating biological process.

The HIV-1 spacer peptide p1 is located in the C-terminus of the Gag polyprotein and separates the nucleocapsid (NC) and p6(Gag). Research centered on p1 has been limited and as yet no function has been ascribed to this spacer peptide. We have previously found that the conserved p1 proline residues (position 7 and 13) are critical for replication in the HIV-1 strain HXB2-BH10. In this study we have focused on the proline rich p1-p6(Gag) C-terminus of HIV-1. We individually examined the role of p1 proline's in multiple strains of HIV-1 and investigated the role of three proline residues in p6(Gag) (P24, P25 and P30). Assessment of the HXB2-BH10 based mutants revealed that Gag-Pol incorporation relative to Gag decreased in the p1 mutant virions, with the double proline mutant the most impaired. Mutating both p1 proline residues was found to abolish infectivity in multiple strains of HIV-1. Independent mutation of the p1 proline at position 7 resulted in a strain-dependent suppression of viral infectivity. This defect correlates with the presence of a tyrosine residue at position 9 of p1 and occurs in the early phase of the HIV-1 replication cycle. The p1 proline residues were found to be functionally distinct from P24, P25 and P30 in p6(Gag). This work affords novel insights into our understanding of the role of p1 in HIV-1 replication.

Family, adoption and twin studies demonstrate that many adult psychiatric disorders, including schizophrenia, major depression and bipolar disorder, have a clear genetic component. The aetiology of psychiatric disorders is a complex combination of both genetic and environmental components. While potential susceptibility genes for psychiatric disorders have been identified, interaction with the environment is a crucial component in disease development. Pharmacogenetics and genetic testing have the potential to play key roles in the future of clinical psychiatry. At present, an increased risk of psychiatric disorders can be identified through a detailed family history. The empirical risk of developing a disorder has been determined for many psychiatric disorders and can be used as a general guide. Genetic counselling can extend and enhance patient care by providing information to patients about the complexities of inheriting psychiatric disorders and the associated risks of recurrence. The genetic counselling process can facilitate informed decision making, alleviate misconceptions and reduce stigma through an improved understanding of the genetic cause of psychiatric disorders, and offer support to patients and their families.

Human immunodeficiency virus type 1 (HIV-1) contains two copies of genomic RNA that are noncovalently linked via a palindrome sequence within the dimer initiation site (DIS) stem-loop. In contrast to the current paradigm that the DIS stem or stem-loop is critical for HIV-1 infectivity, which arose from studies using T-cell lines, we demonstrate here that HIV-1 mutants with deletions in the DIS stem-loop are replication competent in peripheral blood mononuclear cells (PBMCs). The DIS mutants contained either the wild-type (5'GCGCGC3') or an arbitrary (5'ACGCGT3') palindrome sequence in place of the 39-nucleotide DIS stem-loop (NL(CGCGCG) and NL(ACGCGT)). These DIS mutants were replication defective in SupT1 cells, concurring with the current model in which DIS mutants are replication defective in T-cell lines. All of the HIV-1 DIS mutants were replication competent in PBMCs over a 40-day infection period and had retained their respective DIS mutations at 40 days postinfection. Although the stability of the virion RNA dimer was not affected by our DIS mutations, the RNA dimers exhibited a diffuse migration profile when compared to the wild type. No defect in protein processing of the Gag and GagProPol precursor proteins was found in the DIS mutants. Our data provide direct evidence that the DIS stem-loop is dispensable for viral replication in PBMCs and that the requirement of the DIS stem-loop in HIV-1 replication is cell type dependent.

The full-length human immunodeficiency virus type 1 (HIV-1) mRNA encodes two precursor polyproteins, Gag and GagProPol. An infrequent ribosomal frameshifting event allows these proteins to be synthesized from the same mRNA in a predetermined ratio of 20 Gag proteins for each GagProPol. The RNA frameshift signal consists of a slippery sequence and a hairpin stem-loop whose thermodynamic stability has been shown in in vitro translation systems to be critical to frameshifting efficiency. In this study we examined the frameshift region of HIV-1, investigating the effects of altering stem-loop stability in the context of the complete viral genome and assessing the role of the Gag spacer peptide p1 and the GagProPol transframe (TF) protein that are encoded in this region. By creating a series of frameshift region mutants that systematically altered the stability of the frameshift stem-loop and the protein sequences of the p1 spacer peptide and TF protein, we have demonstrated the importance of stem-loop thermodynamic stability in frameshifting efficiency and viral infectivity. Multiple changes to the amino acid sequence of p1 resulted in altered protein processing, reduced genomic RNA dimer stability, and abolished viral infectivity. The role of the two highly conserved proline residues in p1 (position 7 and 13) was also investigated. Replacement of the two proline residues by leucines resulted in mutants with altered protein processing and reduced genomic RNA dimer stability that were also noninfectious. The unique ability of proline to confer conformational constraints on a peptide suggests that the correct folding of p1 may be important for viral function.

The intracellular trafficking and subsequent incorporation of Gag-Pol into human immunodeficiency virus type 1 (HIV-1) remains poorly defined. Gag-Pol is encoded by the same mRNA as Gag and is generated by ribosomal frameshifting. The multimerization of Gag and Gag-Pol is an essential step in the formation of infectious viral particles. In this study, we examined whether the interaction between Gag and Gag-Pol is initiated during protein translation in order to facilitate the trafficking and subsequent packaging of Gag-Pol into the virion. A conditional cotransfection system was developed in which virion formation required the coexpression of two HIV-1-based plasmids, one that produces both Gag and Gag-Pol and one that only produces Gag-Pol. The Gag-Pol proteins were either immunotagged with a His epitope or functionally tagged with a mutation (K65R) in reverse transcriptase that is associated with drug resistance. Gag-Pol packaging was assessed to determine whether the Gag-Pol incorporated into the virion was preferentially packaged from the plasmid that expressed both Gag and Gag-Pol or whether it could be packaged from either plasmid. Our data show that translation of Gag and Gag-Pol from the same mRNA is not critical for virion packaging of the Gag-Pol polyprotein or for viral function.

Background: Breast reconstruction is currently offered on a more routine basis to patients after mastectomy for breast cancer. This paper analyzes the outcomes of breast cancer surgery, and the results and effects of breast reconstruction using free TRAM flaps., Methods: A retrospective review of 75 consecutive patients who had free transverse rectus abdominis myocutaneous (TRAM) flap breast reconstruction after breast cancer surgery was performed. A total of 92 free TRAM flaps were performed on 75 patients in Victoria, British Columbia, from January 1992 to May 1999. Thirty-three patients (44%) underwent primary breast cancer surgery and an immediate reconstruction (7 bilateral and 27 unilateral) and 42 patients (56%) had delayed reconstruction (10 bilateral and 32 unilateral)., Results: Twenty- one patients (28%) had stage 0 disease, 20 (26.7%) had stage I disease, 17 (22.7%) had stage IIA disease, 12 (15%) had stage IIB disease, and 4 (5.3%) had stage IIIA disease. In 1 patient the stage of disease was unknown. The mean patient age was 49.4 years (range 33 to 73). Of the patients undergoing immediate reconstruction 3 had postoperative chemotherapy and 1 had postoperative radiotherapy. Three patients had combined chemoradiotherapy. In none of these cases was the adjuvant therapy delayed by the reconstructive surgery. Overall mean follow-up time from cancer diagnosis was 56.8 months and from the time of TRAM flap reconstruction, 36.7 months. To date, 5 recurrences have been detected (6.6%). Mean time between reconstruction and detection of recurrence was 22.8 months. Detection of recurrence was achieved clinically and was not impaired in any of the cases by the presence of the free flap. Patient satisfaction was assessed via a telephone survey, with 93% of patients pleased with the cosmetic results of their surgery., Conclusions: For those patients with breast cancer requiring mastectomy, free TRAM flap reconstruction is a safe, cosmetically acceptable surgical alternative that impairs neither effective breast cancer surgery nor detection of recurrent disease.

Verticillium wilt is a vascular disease of cotton (Gossypium spp.) caused by the fungal pathogen Verticillium dahliae. To begin to understand the molecular mechanisms of the disease response in cotton cultivars that display superior wilt tolerance, such as Gossypium hirsutum cv. Sicala V-1, a cDNA library was constructed with mRNA isolated from root tissue of Sicala V-1, 24 h after inoculation with V. dahliae. The library was screened by a differential screening technique which was successful in identifying differences in gene expression between uninfected and V. dahliae-infected G. hirsutum root tissue. Among the differentially expressed clones, 51% represented up-regulated genes which had the potential to be involved in the defence response of G. hirsutum. The temporal expression patterns of nine suspected defence response genes were examined by northern blot analysis at several time intervals after inoculation with V. dahliae. The rapid increase in mRNA transcripts corresponding to each of these clones upon infection suggests a role for these genes in the defence response of G. hirsutum. Genes not previously associated with the defence response of the cotton plant, such as those for a 14-3-3-like protein and pathogenesis-related (PR) proteins, have been identified together with presumably novel genes, for which a definite function could not be ascribed.

Clinicians in the critical care setting see extensive, severe, and often necrotizing infection, as well as atypical or unusual infection that can be misdiagnosed, resulting in delays in treatment. Greater numbers of immunocompromised patients are at risk for both types of infection. A thorough understanding of various etiologies and presentations of these infections is essential, as is the ability to discriminate between infectious and noninfectious etiologies.

Leptospirosis, a spirochetal infection, causes a wide spectrum of disease ranging from asymptomatic infection, or influenza-like symptoms, to severe jaundice and renal failure. Humans become infected through skin or mucous membrane contact with infected animal urine or urine-contaminated water or soil. The most common source of human infection worldwide is rats. However, in the United States, dogs, livestock, wild mammals, and cats are also sources. Once leptospires penetrate mucous membranes or breaks in the skin, they disseminate to all parts of the body. Five to ten percent of those infected will have severe leptospirosis with jaundice, known as Weil's disease. The classical presentation of leptospirosis is that of a biphasic illness. The initial septicemic phase lasts 4 to 7 days and is characterized most commonly as a mild influenza-like illness. During the secondary immune phase, leptospires disappear from the blood and cerebrospinal fluid. However, circulating antibodies cause immune-mediated meningitis, uveitis, rash, and, very rarely, circulatory collapse associated with Weil's disease. Pulmonary involvement occurs in 20% to 70% of patients. The more severe pulmonary manifestations are rare. Although attempts should be made to isolate leptospires from the blood or cerebrospinal fluid, the diagnosis is usually established by serologic tests. The effectiveness of antimicrobial therapy in treating leptospirosis has been difficult to assess because of the high variability of the disease's clinical course, although in severe cases, antibiotic therapy is effective even when treatment is delayed. Prevention is difficult because it is almost impossible to eliminate the large animal reservoir of infection.

Mycobacterium avium is a causative agent of mycobacterioses in systemically immunocompromised individuals, whereas Mycobacterium intracellulare is responsible for causing infections in relatively immunocompetent hosts. In an attempt to identify components that could be involved in virulence, we characterised the 38 kDa-encoding gene of M intracellulare that is absent in M. avium. This antigen cross reacts immunologically with a major 38 kDa antigen of M. tuberculosis, and both antigens are homologues of the phosphate transport subunit S (PstS) of the pst complex of Escherichia coli. Unlike the M. tuberculosis complex the M. intracellulare coding gene was found to be duplicated. We also identified and characterised other pst genes that may constitute an operon. Considering that multiple isoforms of PstS are present in mycobacteria the possible role of pstS1 genes for pathogenesis is discussed.

Aeromonas hydrophila infections are a recognized complication of postoperative leech application, and can occur with measurable frequency in populations of patients treated with leeches. We review 11 previously reported leech-related Aeromonas infections and analyze seven unreported cases. These infections range from minor wound complications to extensive tissue loss and sepsis. Often, these infections followed leech application to tissue with questionable arterial perfusion. Onset of clinical infection in these patients ranged from within 24 hours of leech application to 10 days or more after leech application. Late infections may represent bacterial invasion from colonized necrotic tissue. Based on these observations, we recommend that leech applications be restricted to tissue with arterial perfusion to minimize contamination of necrotic tissue. We also recommend that patients treated with leeches receive antibiotics effective against Aeromonas hydrophila before leech application. Patients treated with leeches and discharged with eschars or open wounds might benefit from oral antibiotic therapy until wound closure. These precautions may minimize or eliminate this complication of leech use.

Anaerobic pleuropulmonary infections present in various ways. Aspiration pneumonitis occurs first and may be quite difficult to distinguish from the acute bacterial pneumonia caused by Streptococcus pneumoniae and other organisms. Although aspiration pneumonitis may be self-limiting, sequelae such as lung abscess, necrotizing pneumonia, and empyema can develop. Empiric antimicrobial therapy is now acceptable. The initial choice of antimicrobial agents is based on which pathogens are likely to be involved.

The yeast Pityrosporum orbiculare is thought to cause the folliculitis associated with seborrheic eczema. However, a combination of mechanical and microbiological factors may be involved, with follicular occlusion leading to yeast overgrowth and folliculitis. Scanning electron microscopy was used to investigate this hypothesis. Skin biopsy specimens obtained from patients with Pityrosporum folliculitis were examined by scanning electron microscopy before and after oral ketoconazole therapy. Patients with active disease showed occlusion of noninflamed follicles, which resolved after ketoconazole treatment. Follicular occlusion was not present in biopsy specimens obtained from unaffected controls nor was it related to the presence of P orbiculare. These findings suggest that follicular occlusion may be a primary event in the development of this folliculitis, with yeast overgrowth a secondary occurrence. The beneficial effect of ketoconazole in this disease may be due to direct effects on the follicle.

Many important species have been added to the genus Vibrio in the past several years. Vibrios have been associated with a wide variety of clinical syndromes ranging from mild gastroenteritis to life-threatening cellulitis. Most Vibrio infections follow consumption of raw shellfish or exposure to sea water. Although much has been learned about these organisms in the past several years, additional information is needed concerning pathogenesis, diagnosis, treatment, and prevention of Vibrio infections.

A case of a chronic odontogenic abscess that probably precipitated a frontopatrietal brain abscess by hematogenous spread has been presented. A thorough examination of the patient showed no other source of infection. Peptostreptococcus sp was found as the common pathogen despite 6 days of broad-spectrum antibiotic therapy. This case emphasizes the important role of dentistry in medical diagnosis and treatment implemented in the hospital setting.

Rat anterior hemipituitaries were incubated in Krebs-Ringer bicarbonate containing [3H]leucine. Newly synthesized [3H]prolactin and [3H]GH in the pituitary and incubation medium were assayed, as was the radioimmunoassayable prolactin released into the medium during a 5-h incubation. Dopamine (7.5 X 10(-8)M), ergocryptine (4 X 10(-10) M) and apomorphine (6 X 10(-8)M) all significantly inhibited both radioimmunoassayable prolactin release and newly-labeled [3H]prolactin release without affecting [3H]GH release. Conversely, dibutyryl cyclic AMP (2.5 mM) stimulated radioimmunoassayable prolactin release as well as [3H]prolactin and [3H]GH release. The addition of 2.5 mM dibutyryl cyclic AMP to media containing dopamine, ergocryptine or apomorphine completely restored both radioimmunoassayable prolactin release and [3H]prolactin release to at least control levels. Dopamine, ergocryptine and apomorphine all inhibited incorporation of [3H]leucine into prolactin but not into GH, whereas 2.5 mM dibltyryl cyclic AMP with any one of the inhibitors restored total incorporation into [3H]prolactin to levels insignificantly lower than the nucleotide-stimulated incorporation. Adenosine and guanosine at 2.5 mM also stimulated incorporation into [3H]prolactin and blocked the inhibitory effects of apomorphine upon [3H]prolactin synthesis and release. These nucleosides also stimulated [3H]GH release; and guanosine, but not adenosine, stimulated incorporation into [3H]GH. The ability of dibutryl cyclic AMP to block the effects of dopamine, ergocryptine and apomorphine upon prolactin release is consistent with these three inhibitors acting by a common mechanism. Cyclic AMP could be hypothesized as a second messenger for prolactin release, but the ability of adenosine and guanosine to mimic almost perfectly the effects of this cyclic nucleotide does not allow any conclusive interpretation.

Reports of electrocardiographic abnormalities in association with myoglobinuria have been sparse and have included conduction disturbances, ST segment shifts, and T-wave changes. In many instances, these changes were noted in patients with underlying heart disease. We report a case of a 34-year-old woman with ST segment depression and T-wave inversion in the inferolateral leads during the acute episode of myoglobinuria. There was no demonstrable underlying heart disease, and there was parallel resolution of these ECG changes with myoglobinuria. We conclude that these ECG changes were produced by cardiac muscle involvement in a manner similar to that observed in skeletal muscle in myoglobinuria.

1. The effects of defaunation of the rumen of lambs given low-protein-high-energy diets were studied using animals fed ad lib. a basal diet of sugar and oaten chaff which was supplemented with fish meal at various levels. These diets supported relatively large populations of protozoa in the rumen. 2. A nonyl phenol ethoxylate (15 g. Teric GN9:ICI Australian Ltd) given intraruminally, was shown to be an effective means of defaunating the rumen and the lambs were maintained protozoa-free by isolation. 3. In lambs given low levels of fish meal in the diet, the absence of rumen protozoa increased growth rate and improved the food conversion efficiency (g dry matter intake/g growth). These effects were not apparent at high levels of protein supplementation. 4. These results suggested that the absence of rumen protozoa resulted in an increased availability of nutrients supplying both energy and amino acids since the efficiency of food utilization and the rate of wool growth (which is sensitive to amino acid supply) were increased in lambs on the low level of protein supplementation without apparently increasing food intake.

Pulmonary sporotrichosis is an uncommon condition that may mimic tuberculosis. We present a patient who, years after antifungal therapy, presented with massive pulmonary hemorrhage. Although such life-threatening hemoptysis caused by sporotrichosis is rare, the possibility of this complication of progressive disease should influence decisions regarding medical and surgical treatment of patients with extensive cavitary involvement.

The physician should take a logical, systematic approach when choosing antimicrobial therapy. The recent proliferation of antimicrobial agents and changing susceptibility patterns amongst bacterial pathogens have made this a more arduous task. Classifying antibiotics according to their spectrum of activity, tissue penetration and potential side effects will aid in choosing empiric therapy for serious head and neck infections.