Racial differences in primary cytogenetic abnormalities in multiple myeloma: a multi-center study.

We examined four clinically assessed cytogenetic subtypes (t(11;14), t(4;14), monosomy 13/del13q and monosomy 17/del17p in 292 black patients with newly diagnosed multiple myeloma (MM) from four medical centers, who had fluorescent in situ hybridization testing results available in their medical records. We then compared the prevalence of these abnormalities with a previously characterized Mayo Clinic cohort of 471 patients with MM. We found a significant difference in the prevalence of the t(11;14) immunoglobulin heavy chain (IgH) translocation between blacks and whites, 6.5% versus 17.6%, respectively, P<0.0001. Blacks also had lower rates of the t(4;14) IgH translocation, (5.5% versus 10%); monosomy 13/del13q (29.1 versus 49.3%); and monosomy 17/del17p (7.9% versus 13%). Consequently, 63.4% of blacks versus 34.6% of whites did not have any of the four abnormalities that we studied, P<0.001. As almost all MM is associated with either an IgH translocation or trisomies, we hypothesize that MM in blacks is associated with either excess prevalence of either the trisomic (hyperdiploid) form of MM or an IgH translocation besides t(11;14) or t(4;14). We conclude that there are significant differences in the cytogenetic subtypes of MM that occur in blacks and whites.

Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12,482 persons from the National Health and Nutritional Examination Survey.

Multiple myeloma (MM) incidence is markedly higher in blacks compared with whites, which may be related to a higher prevalence of monoclonal gammopathy of undetermined significance (MGUS). Our objective was to define the prevalence and risk factors of MGUS in a large cohort representative of the US population. Stored serum samples from the National Health and Nutritional Examination Survey (NHANES) III or NHANES 1999-2004 were available for 12,482 individuals of age ⩾50 years (2331 'blacks', 2475 Hispanics, 7051 'whites' and 625 'others') on which agarose-gel electrophoresis, serum protein immunofixation, serum-free light-chain assay and M-protein typing were performed. MGUS was identified in 365 participants (2.4%). Adjusted prevalence of MGUS was significantly higher (P<0.001) in blacks (3.7%) compared with whites (2.3%) (P=0.001) or Hispanics (1.8%), as were characteristics that posed a greater risk of progression to MM. The adjusted prevalence of MGUS was 3.1% and 2.1% for the North/Midwest versus South/West regions of the United States, respectively (P=0.052). MGUS is significantly more common in blacks, and more often has features associated with higher risk of progression to MM. A strong geographic disparity in the prevalence of MGUS between the North/Midwest versus the South/West regions of the United States was found, which has etiologic implications.

Relationship between initial clinical presentation and the molecular cytogenetic classification of myeloma.

Multiple myeloma (MM) consists of several distinct cytogenetic subtypes, and we hypothesized that each subtype may have a unique mode of initial presentation and end-organ damage. We studied 484 patients with newly diagnosed MM to determine the relationship between specific myeloma-defining event (MDE) and the cytogenetic subtype. Patients were divided into four non-overlapping groups based on the MDE at diagnosis: isolated renal failure, isolated anemia, isolated lytic bone disease or a combination (mixed). MM with translocations without trisomies accounted for 30% of all patients, but accounted for 50% of patients with renal failure. Specifically, the t(14;16) translocation accounted for only 5% of all MM patients, but was present in 13.5% of patients with renal failure as MDE. Among patients with t(14;16), 25% presented with renal failure only as MDE. Patients with isolated renal failure as MDE had significantly poorer survival compared with all other groups, whereas patients with bone disease as MDE had the best outcome (P<0.001). Our findings support the hypothesis that in addition to prognostic differences, there is significant heterogeneity in clinical presentation associated with the cytogenetic subtype, suggesting that MM encompasses a group of cytogenetically and phenotypically distinct disorders rather than a single entity.

Disparities in the prevalence, pathogenesis and progression of monoclonal gammopathy of undetermined significance and multiple myeloma between blacks and whites.

There is marked racial disparity in the incidence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma, with a two to threefold increased risk in blacks compared with whites. The increased risk has been seen both in Africans and African Americans. Similarly, an increased risk of monoclonal gammopathies in blacks compared with whites has been noted after adjusting for socioeconomic and other risk factors, suggesting a genetic predisposition. The higher risk of multiple myeloma in blacks is likely a result of the higher prevalence of the premalignant MGUS stage; there are no data to suggest that blacks have a higher progression rate of MGUS to myeloma. Studies are emerging that suggest the baseline cytogenetic characteristics, and progression may differ by race. In contrast, to the increased risk noted in blacks, studies suggest that the risk may be lower in certain racial and ethnic groups, notably persons from Japan and Mexico. We review the literature on racial disparity in the prevalence, pathogenesis and progression of MGUS and multiple myeloma between blacks and whites. We also discuss future directions for research that could inform management of these conditions and positively influence patient outcomes.

GAGA factor isoforms have distinct but overlapping functions in vivo.

The Drosophila melanogaster GAGA factor (encoded by the Trithorax-like [Trl] gene) is required for correct chromatin architecture at diverse chromosomal sites. The Trl gene encodes two alternatively spliced isoforms of the GAGA factor (GAGA-519 and GAGA-581) that are identical except for the length and sequence of the C-terminal glutamine-rich (Q) domain. In vitro and tissue culture experiments failed to find any functional difference between the two isoforms. We made a set of transgenes that constitutively express cDNAs coding for either of the isoforms with the goal of elucidating their roles in vivo. Phenotypic analysis of the transgenes in Trl mutant background led us to the conclusion that GAGA-519 and GAGA-581 perform different, albeit largely overlapping, functions. We also expressed a fusion protein with LacZ disrupting the Q domain of GAGA-519. This LacZ fusion protein compensated for the loss of wild-type GAGA factor to a surprisingly large extent. This suggests that the Q domain either is not required for the essential functions performed by the GAGA protein or is exclusively used for tetramer formation. These results are inconsistent with a major role of the Q domain in chromatin remodeling or transcriptional activation. We also found that GAGA-LacZ was able to associate with sites not normally occupied by the GAGA factor, pointing to a role of the Q domain in binding site choice in vivo.

Tuberculosis transmission among five school bus drives and students in two New York countries

OBJECTIVE: Between November 1994 and April 1995, more than 3300 students in 49 schools in two countries in New York were potentially exposed to five school bus drivers with tuberculosis. This investigation was carried out to determine the extent of transmission of Mycobacterium tuberculosis among students. METHODS: Components of the epidemiologic investigation included tuberculin skin-test screening and collection of demographic information for students exposed to a driver with tuberculosis, chest radiography and medical evaluation of individuals with positive skin tests, and DNA fingerprinting of M tuberculosis isolates. A positive skin test was defined as >/=10 mm induration, and a converter was an individual with an increase in reaction size of >/=10 mm in the past 2 years. RESULTS: The rates of positive skin tests were 0.8 percent, 0.3 percent, 9.9 percent, 1.1 percent and 0.7 percent among US-born student exposed to drivers 1 through 5, respectively. The relative risk for a positive tuberculin skin test was significant only for student expose to driver 3 and the only secondary case identified among students was exposed to driver 3. The DNA fingerprinting patterns of isolates from drivers 3 and 4 matched. CONCLUSION: There was no clear evidence of transmission of M tuberculosis to students from driver 1, 2, 4, or 5. However, evidence suggests the driver 3 transmitted M tuberculosis to students and another driver. Routine annual tuberculin skin-test screening of drivers would not have prevented these tuberculosis exposures(AU)

Tuberculosis transmission among five school bus drivers and students in two New York counties.

OBJECTIVE: Between November 1994 and April 1995, more than 3300 students in 49 schools in two counties in New York were potentially exposed to five school bus drivers with tuberculosis. This investigation was carried out to determine the extent of transmission of Mycobacterium tuberculosis among students. METHODS: Components of the epidemiologic investigation included tuberculin skin-test screening and collection of demographic information for students exposed to a driver with tuberculosis, chest radiography and medical evaluation of individuals with positive skin tests, and DNA fingerprinting of M tuberculosis isolates. A positive skin test was defined as >/=10 mm induration, and a converter was an individual with an increase in reaction size of >/=10 mm in the past 2 years. RESULTS: The rates of positive skin tests were 0.8%, 0.3%, 9.9%, 1.1%, and 0.7% among US-born students exposed to drivers 1 through 5, respectively. The relative risk for a positive tuberculin skin test was significant only for students exposed to driver 3, and the only secondary case identified among students was exposed to driver 3. The DNA fingerprint patterns of isolates from drivers 3 and 4 matched. CONCLUSION: There was no clear evidence of transmission of M tuberculosis to students from drivers 1, 2, 4, or 5. However, evidence suggests that driver 3 transmitted M tuberculosis to students and another driver. Routine annual tuberculin skin-test screening of drivers would not have prevented these tuberculosis exposures.

Tuberculosis in a correctional facility.

BACKGROUND: After the identification of five suspected cases of tuberculosis (TB) in a Nassau County (New York) jail during a 3-week period, an epidemiologic investigation was begun to document the number of cases of TB infection and disease associated with the jail, the characteristics of current or former inmates with TB disease, and the factors contributing to TB transmission in the jail. METHODS: The county TB register was matched against the inmate files of the jail. Medical records from hospitals, the health department, and the jail were then reviewed. All inmates in the jail were skin tested during a mass screening. RESULTS: From January 1, 1988, through March 16, 1990, of 205 TB cases in the county, 49 (24%) were associated with the jail. Forty of the cases occurred among current or former inmates, one in a corrections officer, and eight among community contacts of inmates. The 40 inmates with TB were predominantly nonwhite (75%), unmarried (80%) men (90%), with a median age of 32 years. Twenty-three (58%) had a history of injecting drug use, and 14 (35%) were known to be seropositive for the human immunodeficiency virus. Thirty (75%) of the inmates had culture-confirmed pulmonary TB. Five (29%) of 17 Mycobacterium tuberculosis isolates had the same phage type and DNA fingerprint, which was consistent with transmission of infection within the jail. The mass screening revealed that 374 (20%) of 1855 inmates were tuberculin positive. CONCLUSIONS: Without an effective program of TB control, jails can act as reservoirs of disease for inmates and staff, and for the community into which the inmates are released.

High prevalence of syphilis detected through a jail screening program. A potential public health measure to address the syphilis epidemic.

BACKGROUND: In June 1990, a syphilis initiative was undertaken to help control New York's most extensive syphilis epidemic since the 1940s. METHODS: To evaluate the usefulness of syphilis screening in local jails, were reviewed demographic and syphilis screening data from a county jail in an area with a high prevalence of syphilis that has routinely tested incoming inmates. RESULTS: Of 12,685 inmates, 9797 (77%) were screened for syphilis, and 321 (3.3%) had a positive test result; 258 (80%) of the positive results were confirmed. Data were available for 244 of the inmates with a confirmed positive result: 162 (67%) had newly diagnosed syphilis (overall rate, 1.6%), 112 of whom had early syphilis; 50 (20%) had been previously treated for syphilis; and 32 (13%) were unavailable for follow-up. Of 162 inmates with newly diagnosed syphilis, 122 (75%) were treated in jail, and 40 were treated after their release from jail. The median time from screening to treatment was 17 days. The median jail stay was 45 days for inmates who were evaluated for treatment vs 5 days for those who were unavailable for follow-up. CONCLUSIONS: Screening inmates for syphilis was a productive public health measure, as inmates accounted for 20% of the county's syphilis morbidity. Given the high prevalence of syphilis among inmates and the inability to reach them for treatment after release, strategies are needed to rapidly screen and treat inmates before their release from jail.

Echovirus type 30 infection associated with aseptic meningitis in Nassau County, New York, USA.

An outbreak of echovirus type 30, primarily affecting infant under 1 year old, was documented in Nassau County, N.Y., USA. Twenty-four of the 40 infected patients were definitively diagnosed with aseptic meningitis. A positive correlation was found between the proportion of polymorphonuclear leukocytes and the overall cerebrospinal fluid white cell count.

An oligosaccharide biosynthetic defect in concanavalin A-resistant Chinese hamster ovary (CHO) cells that enhances NK reactivity in vitro and in vivo.

We have examined a concanavalin A-resistant (Con AR) Chinese hamster ovary cell (CR-7) that has a defect in the synthesis of asparagine-linked oligosaccharides and consequently an altered expression of membrane carbohydrate. The CR-7 mutant, which has a decreased ability to incorporate mannose into oligolipid and membrane glycoprotein and an increased membrane fucose, was more sensitive to natural killer (NK) cell lysis than the parental wild type (CHO-WT). Splenocytes mediating the lysis of the CR-7 line were asialo GM1+, nonadherent, IFN stimulatable, absent in the bg/bg mutant, and co-fractionated on Percoll density gradients with cells mediating lysis of the YAC-1 murine lymphoma. The increase in NK lysis correlated with enhanced binding of NK cells to the mutant determined by adsorption on tumor monolayers, cold target inhibition, and target binding analysis. A revertant of CR-7 (RCR-7), which showed wild-type levels of NK lysis, was intermediate in its ability to bind or cold target inhibit NK cells. The CR-7, CHO-WT, and RCR-7 lines were equally sensitive to hypotonic lysis and cytotoxicity by human lymphokine-activated killer (LAK) cells suggesting that the mutation did not nonspecifically alter membrane fragility. The NK-sensitive CR-7 line was less tumorigenic after subcutaneous injection in nude mice when compared with the parental CHO-WT or RCR-7 lines. This decreased tumorigenicity could be reversed by the i.v. injection of antiserum directed at the NK cell determinant asialo GM1. In conclusion, a ConAR tumor cell with a demonstrable oligosaccharide biosynthetic defect, exhibited enhanced NK lytic sensitivity and was poorly tumorigenic in vivo, a feature which may also be a consequence of its altered NK reactivity.

Total lymphatic irradiation and bone marrow in human heart transplantation.

Six patients, aged 36 to 59 years, had heart transplants for terminal myocardial disease using total lymphatic irradiation (TLI) and donor bone marrow in addition to conventional therapy. All patients were poor candidates for transplantation because of marked pulmonary hypertension, unacceptable tissue matching, or age. Two patients are living and well more than four years after the transplants. Two patients died of infection at six and seven weeks with normal hearts. One patient, whose preoperative pulmonary hypertension was too great for an orthotopic heart transplant, died at 10 days after such a procedure. The other patient died of chronic rejection seven months postoperatively. Donor-specific tolerance developed in 2 patients. TLI and donor bone marrow can produce specific tolerance to donor antigens and allow easy control of rejection, but infection is still a major problem. We describe a new technique of administering TLI with early reduction of prednisone that may help this problem.

Congenital vertical talus and congenital calcaneovalgus deformity: a comparison.

It is essential to distinguish congenital vertical talus from calcaneovalgus deformity in infants as the proper treatment must begin at an early age. The key clinical finding in the differential diagnosis of flexible and rigid flatfoot conditions is the range of motion at the subtalar joint. In rigid flatfoot conditions, subtalar joint motion is impossible because of the rigidity of the deformity. Also, in the rigid type of deformity, the calcaneus will be in an equinus position.

The effects of ketamine enantiomers on schedule-controlled behavior in the rat.

Male Sprague-Dawley rats were trained to barpress under a FL-300 sec schedule of food presentation until responding patterns were stable. The effects of the ketamine optical isomers (enantioners) on this schedule-controlled behavior were examined over a dose range of 3.75 to 60 mg/kg i.p. At doses of 15 mg/kg and above, (-)-ketamine increased rate of responding, with a maximum increase of about 3 times control rate. This effect was rate-dependent, being more marked at lower control rates. In contrast (+)-ketamine did not increase overall fixed-interval response rate at any dose, but decreased rate of responding in a rate-dependent fashion at doses of 30 mg/kg and above. Spontaneous locomotor activity was increased about equally by equimolar doses of both enantiomers.