HDAC1,2 inhibition and doxorubicin impair Mre11-dependent DNA repair and DISC to override BCR-ABL1-driven DSB repair in Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia.

Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) expressing BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis. BCR-ABL1-expressing leukemic cells are highly dependent on double-strand break (DSB) repair signals for their survival. Here we report that a first-in-class HDAC1,2 selective inhibitor and doxorubicin (a hyper-CVAD chemotherapy regimen component) impair DSB repair networks in Ph+ B-cell precursor ALL cells using common as well as distinct mechanisms. The HDAC1,2 inhibitor but not doxorubicin alters nucleosomal occupancy to impact chromatin structure, as revealed by MNase-Seq. Quantitative mass spectrometry of the chromatin proteome along with functional assays showed that the HDAC1,2 inhibitor and doxorubicin either alone or in combination impair the central hub of DNA repair, the Mre11-Rad51-DNA ligase 1 axis, involved in BCR-ABL1-specific DSB repair signaling in Ph+ B-cell precursor ALL cells. HDAC1,2 inhibitor and doxorubicin interfere with DISC (DNA damage-induced transcriptional silencing in cis)) or transcriptional silencing program in cis around DSB sites via chromatin remodeler-dependent and -independent mechanisms, respectively, to further impair DSB repair. HDAC1,2 inhibitor either alone or when combined with doxorubicin decreases leukemia burden in vivo in refractory Ph+ B-cell precursor ALL patient-derived xenograft mouse models. Overall, our novel mechanistic and preclinical studies together demonstrate that HDAC1,2 selective inhibition can overcome DSB repair 'addiction' and provide an effective therapeutic option for Ph+ B-cell precursor ALL.

Voxel-based analysis of T2 hyperintensities in white matter during treatment of childhood leukemia.

BACKGROUND AND PURPOSE: White matter (WM) hyperintensities on T2-weighted MR imaging are the most common imaging manifestation of neurotoxic effects of therapy for central nervous system (CNS) prophylaxis in childhood acute lymphoblastic leukemia (ALL). This study uses voxel-based analyses (VBA) of T2-weighted imaging of patients during treatment to identify which WM regions are preferentially damaged. MATERIALS AND METHODS: Two sets of conventional T2-weighted axial images were acquired on a 1.5T MR imaging scanner from 197 consecutive patients (85 female, 112 male; aged 1.0-18.9 years) enrolled on an institutional ALL treatment protocol. Images were acquired after completion of induction therapy and after the final of the 4 courses of intravenous high-dose methotrexate in consolidation therapy (3.9 +/- 0.8 months apart). Voxel-wise statistical testing of the incremental change between normalized longitudinal T2 images was performed with radiologist reading (normal or abnormal) and treatment risk-group as covariates. RESULTS: Two highly significant bilateral clusters of T2 signal intensity change were identified in both 1-group and 2-group analyses. The regions were symmetric in size, shape, and average signal intensity. Increased T2-weighted signal intensity from these regions both within and between examinations were nonlinear functions of age at examination, and the difference between the examinations was greater for older subjects who received more intense therapy. CONCLUSIONS: These analyses identified specific WM tracts involving predominantly the anterior, superior, and posterior corona radiata and superior longitudinal fasciculus, which were at increased risk for the development of T2-weighted hyperintensities during therapy for childhood ALL. These vulnerable regions may be the cause of subsequent cognitive difficulties consistently observed in survivors.

Ultrasonic characterization of human cancellous bone in vitro using three different apparent backscatter parameters in the frequency range 0.6-15.0 mhz.

Ultrasonic techniques based on measurements of apparent backscatter may provide a useful means for diagnosing bone diseases such as osteoporosis. The term "apparent" means that the backscattered signals are not compensated for the frequency-dependent effects of attenuation and diffraction. We performed in vitro apparent backscatter measurements on 23 specimens of human cancellous bone prepared from the left and right femoral heads of seven donors. A mechanical scanning system was used to obtain backscattered signals from each specimen at several sites. Scans were performed using five different ultrasonic transducers with center frequencies of 1, 2.25, 5, 7.5, and 10 MHz. The -6 dB bandwidths of these transducers covered a frequency range of 0.6-15.0 MHz. The backscattered signals were analyzed to determine three ultrasonic parameters: apparent integrated backscatter (AIB), frequency slope of apparent backscatter (FSAB), and time slope of apparent backscatter (TSAB). Linear regression analysis was used to examine the correlation of these ultrasonic parameters with five measured physical characteristics of the specimens: mass density, X-ray bone mineral density, Young's modulus, yield strength, and ultimate strength. A total of 75 such correlations were examined (3 ultrasonic parameters x 5 specimen characteristics x 5 transducers). Good correlations were observed for AIB using the 5 MHz (r = 0.70 - 0.89) and 7.5 MHz (r = 0.75-0.93) transducers; for FSAB using the 2.25 MHz (r = 0.70 - 0.88), 5 MHz (r = 0.79 - 0.94), and 7.5 MHz (r = 0.80 - 0.92) transducers; and for TSAB using the 5 MHz (r = 0.68 - 0.89), 7.5 MHz (r = 0.75 - 0.89), and 10 MHz (r = 0.75 - 0.92) transducers.

Black patients with chronic hepatitis C have a lower sustained viral response rate than non-Blacks with genotype 1, but the same with genotypes 2/3, and this is not explained by more frequent dose reductions of interferon and ribavirin*.

In previous hepatitis C virus (HCV) treatment studies, Black patients not only had a lower sustained viral response (SVR) rate to interferon and ribavirin (RBV) than non-Black patients but also a higher frequency of HCV genotype 1 (GT-1) infection. The aim of this community-based study was to determine whether Black patients have a lower SVR rate independent of genotype. We prospectively enrolled 785 patients (24.8% Black, 71.5% White, 3.7% others) who received interferon alpha-2b 3 MU three times weekly + RBV 1000-1200 mg/day for 24 weeks (GT-2/3) or 48 weeks (GT-1). Black patients were more commonly infected with GT-1 (86.8%vs 64.8%, P < 0.001) and less frequently had an SVR compared with non-Black patients (8.4%vs 21.6%, P < 0.001). Within GT-1, Black patients had a lower SVR rate than non-Black patients (6.1%vs 14.1%, P = 0.004) but not within GT-2/3 (50.0%vs 36.5%, P = 0.47). Black patients had lower baseline haemoglobin levels (14.8 vs 15.3 g/dL, P < 0.001) and neutrophil counts (2900 vs 4100/mm(3), P < 0.001) and required more frequent dose reductions of RBV (29.8%vs 18.5%, P < 0.001) and interferon (4.7%vs 1.6%, P = 0.012). However, dose reductions were not associated with lower SVR rates while early treatment discontinuations were (2.9%vs 25.7%, P < 0.001). Independent predictors of SVR were GT-1 [odds ratio (OR) 0.33; 95% confidence interval (CI) 0.20-0.55; P < 0.001], Black race (OR 0.45; 95% CI 0.22-0.93; P = 0.030), and advanced fibrosis, stages 3 + 4 (OR 0.53; 95% CI 0.31-0.92; P = 0.023). In conclusion, Black patients infected with HCV GT-1 (but not GT-2/3) have a lower SVR rate than non-Black patients. This is not explained by their lower baseline haemoglobin levels and neutrophil counts that lead to higher rates of ribavirin and interferon dose reductions.

Reconstruction of the lateral patellar retinaculum following lateral release: a case report.

The recognition and treatment of iatrogenic medial subluxation of the patella following lateral retinacular release may be difficult. The diagnosis even by magnetic resonance imaging may be difficult. The use of a medial patellar stabilising brace may be helpful in the diagnosis, alleviating symptoms in the short term and to gain the confidence of the patient. A technique of direct repair that was used successfully is described in a case report.

The outcome of intra-articular debris, following anterior cruciate ligament reconstruction.

Following arthroscopic anterior cruciate ligament reconstruction, radio-opacities were noted on the post-operative radiographs in 40 of 50 consecutive cases. There was no correlation between the presence of these opacities and post-operative knee pain, joint effusion, arthrofibrosis or knee recovery. In 12 cases undergoing a subsequent radiograph between 3 and 18 months post-operatively, opacities were noted in only one case.

The anatomy of the patellar tendon.

The morphology of the attachment of the patellar tendon, its bundle orientation, the differential fascicles length and the position of the apex of the patella were assessed in 22 cadaveric human knees. The patellar apex was 39+/-6% of the width of the tendon from its medial edge. The bulk of tendon was attached to the distal two-thirds of the anterior aspect of the patella. In six cases tendon fibres originated from the posterior surface of the apex of the patella, forming a ridge on the back of tendon. This may represent an anatomical variant accounting for the increased tendon thickness noted on MRI, both incidentally and during assessment for patellar tendonitis. Fascicles were parallel in the sagittal plane but converged in the frontal plane toward their tibial attachment. When bone-patellar tendon-bone (B-PT-B) grafts were harvested, as for anterior cruciate ligament reconstruction, the grafts narrowed distally. When harvesting B-PT-B, the oblique orientation of the fibres in the coronal plane must be borne in mind.

Conservation of the 17-kilodalton antigen gene within the genus Bartonella.

The 17-kDa antigen of Bartonella henselae has previously been shown to elicit a strong humoral immune response in patients with cat scratch disease (CSD) and to be useful in screening human serum samples for CSD. In this study, PCR amplification of genes homologous to the 17-kDa antigen gene of B. henselae was performed using genomic DNAs from several species of Bartonella, including the currently recognized human pathogens. Amplicons of similar size were demonstrated using the following chromosomal DNA templates: B. henselae (two strains), B. quintana (two strains), B. elizabethae, B. clarridgeiae, B. vinsonii subsp. vinsonii, and B. vinsonii subsp. berkhoffii. No evidence of a B. bacilliformis homolog of the 17-kDa antigen gene was obtained using multiple primer pairs. DNA sequencing revealed open reading frames capable of coding for proteins with sizes similar to that of the 17-kDa antigen of B. henselae in all of the amplicons; however, extensive sequence divergence across the genus was noted. Cloning of the amplified products into pUC19 resulted in recombinants that directed synthesis of homologs of the 17-kDa protein. Immunoblot analysis using human sera from CSD cases demonstrated very little cross-reactivity among different species for this protein. In contrast, immunoblots using rabbit serum raised to the recombinant B. henselae antigen showed extensive cross-reactivity with the proteins of other Bartonella species. The data suggest that the use of the 17-kDa antigen as a serologic reagent may allow the development of more specific diagnostic assays. Furthermore, the nucleotide sequences from the various versions of the 17-kDa antigen gene should be useful for rapid identification of Bartonella at the species level.

Dermatologic complications in HIV.

The skin is unique in its accessibility for the diagnosis of diseases acquired because of decreased immunity in human immunodeficiency virus (HIV) infection. A majority of HIV-infected patients will have dermatologic problems at some time during their illness. Many of the cutaneous conditions identified will provide the means by which systemic opportunistic infections, neoplasms, and complications of therapy can be identified. The skin provides an opportunity for the recognition of new or foreign conditions as well as exotic manifestations of diseases that complicate HIV infection. A high degree of suspicion and a willingness to examine the entire skin thoroughly and frequently can enable practitioners to reduce the morbidity and mortality associated with HIV infection.

Magnetic resonance imaging of patellar tendonitis.

The radiological and MRI appearances of 24 knees with patellar tendonitis resistant to conservative therapy were analysed to identify the characteristic MRI appearance and to determine if the patellar morphology was abnormal. A significant thickening of the tendon was found in all cases; this was a more reliable diagnostic feature than a high signal within the superior posterior and central aspect of the tendon at its proximal attachment. The site of the lesion shown by MRI is more compatible with impingement of the inferior pole of the patella against the patellar tendon than a stress overload of the tendon. There were no significant differences in the length of the patella, inferior pole or length of the articular surface when the patellar morphology was compared with that of a matched control group.

The value of MR imaging in the diagnosis of the os trigonum syndrome.

OBJECTIVE: The objective of this study was to evaluate the value of magnetic resonance (MR) imaging in the diagnosis of the os trigonum syndrome. DESIGN: Sagittal and coronal spin echo MR sequences of the ankle were acquired along with sagittal images in both dorsiflexion and plantar flexion. PATIENTS: Three consecutive patients presenting with posterior triangle pain were assessed. RESULTS AND CONCLUSIONS: MR imaging delineated the anatomical site of the abnormality and demonstrated coexisting pathology in all patients. Flexion/extension MR images yielded additional information regarding the mobility of the os trigonum in one patient. MR imaging is the technique of choice for investigating the os trigonum syndrome.

Symptomatic synovial plicae of the knee.

Forty-five knees (thirty patients) with a specific diagnosis of synovial plica syndrome, and without any other known lesion, were randomized to be treated with either diagnostic arthroscopy alone or arthroscopy and division of all plicae. The diagnosis of synovial plica syndrome had been made on the basis of intermittent pain in the anterior aspect of the knee, painful clicking with activity, giving-way, and a palpable, tender plica. The patients were selected for arthroscopy only if the symptoms had continued unabated after a course of physical therapy. At the time of follow-up, improvement had occurred in only six (29 per cent) of the twenty-one knees in which the plicae had not been divided, in contrast with twenty (83 per cent) of the twenty-four knees in which they had been divided (p < 0.001). Ten (48 per cent) of the knees in which arthroscopic division had not been done were treated with another arthroscopic operation. Seven of these ten knees improved after the subsequent division of the plicae (p < 0.01). We concluded that synovial plicae of the knee may be a definite cause of anterior pain in children and adolescents.

Beneficial effects of continuous passive motion after total condylar knee arthroplasty.

A randomised, controlled study of the use of postoperative continuous passive motion (CPM) and immobilisation regimen after total condylar knee arthroplasty was performed. CPM resulted in a significant increase in both the early and late range of knee flexion. This increase occurred in both rheumatoid and osteoarthritic patients. The improvement of 10 degrees at 12 months allowed additional important function to be attained. CPM resulted in significantly earlier discharge from hospital. It did not increase the clinical incidence of wound healing problems, nor did it significantly increase the postoperative fixed flexion deformity or the extension lag. CPM can be recommended as a safe and effective modality to achieve more rapid and more successful postoperative rehabilitation after knee arthroplasty.

Religion and fertility in the United States: new patterns.

In the United States, the baby boom-era pattern of high Catholic and low Protestant fertility has ended. Among non-Hispanic whites in the 1980s, Catholic total fertility rates (TFRs) were about one-quarter of a child lower than Protestant rates (1.64 vs. 1.91). Most of the Protestant-Catholic difference is related to later and less frequent marriage among Catholics. Future research on the demography of religious groups should focus on explaining the delayed marriage pattern of Catholics, the high fertility of Mormons and frequently attending Protestants, and the very low fertility of those with no religious affiliation.