[Chronic renal insufficiency with hypercalcemia in a 60-year-old patient]. / Chronische Niereninsuffizienz mit Hyperkalzämie bei einem 60-jährigen Patienten.

A 60-year-old man developed stomach pains and early morning vomiting as well as fatigue over the last few months. Severe hypercalcemia was found in combination with a significantly reduced renal function. Laboratory tests as well as histological findings from the kidneys led to the working diagnosis of sarcoidosis with renal and possible osseous manifestations. After 14 days of oral medication with steroids the symptoms were significantly improved and renal parameters normalized.

Analysis of microbial diversity on deli slicers using polymerase chain reaction and denaturing gradient gel electrophoresis technologies.

Cross-contamination of pathogenic and spoilage bacteria from food-contact surfaces to food products is a serious public health issue. Bacteria may survive and attach to food-contact surfaces by residual food components and/or background bacteria which may subsequently transfer to other food products. Deli slicers, generally used for slicing ready-to-eat products, can serve as potential sources for considerable bacterial transfer. The objective of this study was to assess the extent and distribution of microbial diversity of deli slicers by identification of pathogenic and background bacteria. Slicer-swab samples were collected from restaurants in Arkansas and Texas in the United States. Ten surface areas for each slicer were swabbed using sterile sponges. Denaturing gradient gel electrophoresis (DGGE) was applied to investigate the fingerprint of samples, and each band was further identified by sequence analysis. Pseudomonads were identified as the dominant bacteria followed by Enterobacteriaceae family, and lactic acid bacteria such as Lactococcus lactis and Streptococcus thermophilus were also found. Bacterial distribution was similar for all surface areas, while the blade guard exhibited the greatest diversity. This study provides a profile of the microbial ecology of slicers using DGGE to develop more specific sanitation practices and to reduce cross-contamination during slicing.

Heterogeneous drying stresses in stratum corneum.

We study the drying of stratum corneum, the skin's outermost layer and an essential barrier to mechanical and chemical stresses from the environment. Even though stratum corneum exhibits structural features across multiple length-scales, contemporary understanding of the mechanical properties of stratum corneum is based on the assumption that its thickness and composition are homogeneous. We quantify spatially resolved in-plane traction stress and deformation at the interface between a macroscopic sample of porcine stratum corneum and an adherent deformable elastomer substrate. At length-scales greater than a millimeter, the skin behaves as a homogeneous elastic material. At this scale, a linear elastic model captures the spatial distribution of traction stresses and the dependence of drying behavior on the elastic modulus of the substrate. At smaller scales, the traction stresses are strikingly heterogeneous and dominated by the heterogeneous structure of the stratum corneum.

(E,Z)-3-(3',5'-Dimethoxy-4'-hydroxy-benzylidene)-2-indolinone blocks mast cell degranulation.

(E,Z)-3-(3',5'-Dimethoxy-4'-hydroxy-benzylidene)-2-indolinone (indolinone) is an alkaloid that has been identified as a pharmacologically active compound in extracts of the traditional anti-inflammatory herb Isatis tinctoria. Indolinone has been shown to inhibit compound 48/80-induced mast cell degranulation in vitro. Application of indolinone to bone marrow derived mast cells showed that it was uniformly distributed in the cytoplasm and that cellular uptake was terminated within minutes. Pre-treatment of IgE-sensitized mast cells with 100nM indolinone rendered them insensitive against FcvarepsilonRI-receptor dependent degranulation. However, upstream signalling induced by antigen such as activation of PI3-K and MAPK remained unaffected. We conclude that indolinone blocks mast cell degranulation at the level of granule exocitosis with an IC(50) of 54nm.

Apoptosis and differentiation commitment: novel insights revealed by gene profiling studies in mouse embryonic stem cells.

Mouse embryonic stem (ES) cells remain pluripotent in vitro when grown in the presence of leukemia inhibitory factor (LIF). LIF starvation leads to apoptosis of some of the ES-derived differentiated cells, together with p38alpha mitogen-activated protein kinase (MAPK) activation. Apoptosis, but not morphological cell differentiation, is blocked by a p38 inhibitor, PD169316. To further understand the mechanism of action of this compound, we have identified its specific targets by microarray studies. We report on the global expression profiles of genes expressed at 3 days upon LIF withdrawal (d3) compared to pluripotent cells and of genes whose expression is modulated at d3 under anti-apoptotic conditions. We showed that at d3 without LIF cells express, earlier than anticipated, specialized cell markers and that when the apoptotic process was impaired, expression of differentiation markers was altered. In addition, functional tests revealed properties of anti-apoptotic proteins not to alter cell pluripotency and a novel role for metallothionein 1 gene, which prevents apoptosis of early differentiated cells.

Pharmacokinetics and pharmacodynamics of methylprednisolone after one bolus dose compared with two dose fractions.

OBJECTIVE: Although the elimination half-life of most glucocorticoids is short, they are usually administered once daily, or even on alternate days. Our hypothesis was that this practice might compromise the immunosuppressive effect of those drugs during the second part of the administration interval. METHODS: Eight healthy male volunteers were randomly assigned to receive intravenous methylprednisolone either 32 mg in the morning, or 16 mg in the morning and 16 mg in the evening in a cross-over design. Methylprednisolone concentrations were determined in plasma by high-pressure liquid chromatography. The total number of CD3+ lymphocytes, and CD4+ and CD8+ T-cell subpopulations was measured in blood. The suppression of these cells was used as a surrogate parameter for the immunosuppressive response, and expressed as reduction of the area under the effect time curve (AUETC). Possible adverse effects on blood pressure, glucose, insulin, and endogenous cortisol levels were monitored. RESULTS: There were no significant differences in methylprednisolone half-life (2.2 +/- 0.4 h), clearance (575 +/- 113 mL/min), volume of distribution (106 +/- 22 l), concentration producing the half-maximum effect on CD4+ T-cells (1.5 +/- 0.7 ng/mL), and Hill-coefficient (1.2 +/- 0.1), after single or divided dose. However, the total 24 h effect area (AUETC) of lymphocytes, and mainly CD4+ T-cells was significantly more suppressed (P = 0.008) with the divided dosage regimen than after the single dose (8422 +/- 2163 vs. 11,545 +/- 3020 h cells/microL). The surrogate markers for adverse events were not different, except for cortisol. CONCLUSION: Within a 24-h interval, two dose fractions of methylprednisolone produce a stronger and more sustained immunosuppressive response than one single bolus dose.

Fatal cytomegalovirus pneumonia after preemptive antiviral therapy in a renal transplant recipient.

Cytomegalovirus (CMV) infections occur with an incidence of up to 70% in renal transplant patients and mortality is low due to effective antiviral drugs. We report here the case of a patient who suffered from an uncommonly severe and therapy-resistant pulmonary CMV infection. During the disease course, CMV-PCR from alveolar cells and lung biopsy material was repeatedly negative despite high CMV pp65 antigenemia. CMV pneumonia was finally diagnosed from a biopsy obtained by open thoracotomy revealing positive CMV immunostaining of lung tissue. The patient died of respiratory failure though double-treatment using both ganciclovir and foscavir was administered. Post mortem, the clinically suspected resistance to both antiviral drugs, but not to cidofovir, could be proven by bioassay testing of in vitro growth responses using viral cultures. CMV pneumonia may thus not be diagnosed by standard PCR techniques in rare cases and may be resistant to the available antiviral therapy. Severe CMV pneumonia may benefit from novel antiviral drugs such as cidofovir, which is currently used in the treatment of CMV retinitis in HIV patients.

Multispecific CD4+ T cell response to a single 12-mer epitope of the immunodominant heat-shock protein 60 of Yersinia enterocolitica in Yersinia-triggered reactive arthritis: overlap with the B27-restricted CD8 epitope, functional properties, and epitope presentation by multiple DR alleles.

Yersinia heat-shock protein 60 (Ye-hsp60) has recently been found to be a dominant CD4 and CD8 T cell Ag in Yersinia-triggered reactive arthritis. The nature of this response with respect to the epitopes recognized and functional characteristics of the T cells is largely unknown. CD4+ T cell clones specific for Ye-hsp60 were raised from synovial fluid mononuclear cells from a patient with Yersinia-triggered reactive arthritis. and their specificity was determined using three recombinant Ye-hsp60 fragments, overlapping 18-mer synthetic peptides as well as truncated peptides. Functional characteristics were assessed by cytokine secretion analysis in culture supernatants after specific antigenic stimulation. Amino acid positions relevant for T cell activation were detected by single alanine substitutions within the epitopes. Fragment II comprising amino acid sequence 182-371 was recognized by the majority of clones. All these clones were specific for peptide 319-342. Th1 clones and IL-10-secreting clones occurred in parallel, sometimes with the same fine specificity. The 12-mer core epitope 322-333 is a degenerate MHC binder and is presented to some T cell clones in a "promiscuous" manner. This epitope is almost identical with a B27-restricted CTL epitope of Ye-hsp60. Cross-reactivity of Ye-hsp60-specific T cell clones with self-hsp60 was not observed. In conclusion, an interesting Ye-hsp60 T cell epitope has been identified and characterized. It remains to be determined whether this epitope is also relevant in other reactive arthritis patients.

Individualized drug dosage in patients treated with continuous hemofiltration.

BACKGROUND: Subtherapeutic drug dosing may be even more dangerous than overdosage, especially for intensive care patients requiring hemofiltration. PROPOSAL: According to Dettli's fundamental equation, body clearance of any drug (Cl) is a linear function of creatinine clearance (Cl = Cl anur + a x C(Cr)), with [a = (Cl norm - Cl anur)/C(Cr), norm]. We propose to individualize drug dosage during high-flux hemofiltration by basing it on Dettli's equation and on total C(Cr) (C(Cr) tot = C(Cr) ren + C(Cr) filt). Using this approach, drug clearance will eventually be overestimated for drugs with substantial tubular secretion and for high-efficiency hemofiltration (C(Cr) tot > 30 ml/min). CONCLUSION: In patients undergoing hemofiltration, the total C(Cr) approach might be a practical alternative to standardized dosing schemes for deriving an individualized dosage from published pharmacokinetic data and functions.

The 19 kDa protein of Yersinia enterocolitica O:3 is recognized on the cellular and humoral level by patients with Yersinia induced reactive arthritis.

OBJECTIVE: Gastrointestinal infections with Yersinia enterocolitica O:3 (YE O:3) can trigger reactive arthritis (ReA). The cellular immune response seems to be of pathogenic importance in ReA, since synovial fluid mononuclear cells (SFMC) of patients with ReA have been shown to recognize YE O:3 antigens. One of these, a 19 kDa protein identified as the beta-urease subunit of YE, has been identified as a target of SFMC. We investigated the humoral immune response to this antigen. METHODS: Sera of 32 patients with SFMC proliferation to YE O:3 diagnosed as having ReA (n = 16) and undifferentiated oligoarthritis (UOA, n = 16), and of patients with other rheumatic diseases (n = 32) and healthy persons (n = 12) were investigated for the humoral response to the biochemically purified 19 kDa protein of YE. Anti-19 kDa antibodies (ab) were identified by immunoblotting; ab to the Yersinia outer membrane protein (YOP) antigen were detected by ELISA. Proliferation of SFMC to 19 kDa and other YE O:3 antigens was tested in 12 patients in parallel. RESULTS: SFMC of all 32 patients with ReA and UOA showed the highest proliferation to YE O:3 (13.7+/-7.5), and 10/12 of these patients had the highest stimulation index to the 19 kDa (14.9+/-6.4). Anti-19 kDa IgG ab were detected in 93% and 55% and anti-19 kDa IgA ab in 56% and 36% of the ReA and UOA patients, respectively, compared to 26% (p = 0.002) and 8% (p = 0.001) in controls. IgG ab to the 19 kDa were sensitive (93%) and IgA ab specific (92%) to detect patients with a synovial cellular response to YE. IgG ab to YOP were found in 62% and IgA ab in 46% of the ReA patients and in 32% (p = 0.002) and 13% (p = 0.004) of the controls. CONCLUSION: This study provides evidence of a cellular and a significant humoral immune response to the 19 kDa protein in Yersinia triggered arthritis. Detection of IgG antibodies to the 19 kDa correlates with a synovial cellular immune response in YE induced arthritis. These antibodies can be used as a screening system for research and possibly also for clinical purposes, since absence of such antibodies seems to negatively predict YE O:3 directed immune reactivity.

Substance dependence and externalizing psychopathology in adolescent boys with small, average, or large P300 event-related potential amplitude.

To determine if the P300 component of the event-related potential indexes risk for substance use and related disorders, we presented a community sample of 377 16-18-year-old males a visual oddball task and selected 31 subjects with the smallest and 31 subjects with the largest P300 amplitudes. An additional 31 subjects whose amplitudes fell in the middle of the amplitude distribution were assigned to the average group. The small and average amplitude groups were more likely to have alcohol dependence and more symptoms of alcohol dependence than the large amplitude subjects. The small amplitude group had more symptoms of illicit drug dependence than the other groups. There was also a significantly larger proportion of subjects with externalizing disorders in the small amplitude group than in the large P300 group. These findings suggest that P300 amplitude may index a spectrum of risk for disinhibited psychopathology.

Increased frequency of Sjögren's syndrome in patients with spondyloarthropathy.

OBJECTIVE: To determine the prevalence of sicca symptoms and Sjögren's syndrome (SS) in spondyloarthropathy (SpA) patients with ankylosing spondylitis (AS) and undifferentiated SpA (uSpA). METHODS: Patients with SpA with inflammatory back pain and/or peripheral arthritis presenting to the university outpatient clinic were diagnosed as AS (n = 40) and uSpA (n = 65) according to established criteria. Patients with SpA with sicca symptoms and/or positive antinuclear antibody (ANA) were investigated for SS by minor salivary gland biopsy and/or sialography. To assess sicca symptoms in this cohort systematically we mailed a validated questionnaire with 6 questions on dryness of eyes and mouth to all 105 SpA patients and 150 healthy controls, a positive answer to > or = 3 questions was taken as suggestive of SS. There was no significant difference in baseline characteristics between patients and controls. RESULTS: In 8/105 SpA patients (5 uSpA, 3 AS; 6 female, 2 male) SS diagnosis by the European criteria indicated a frequency of 7.6%. Of 105 SpA patients, 12 were ANA+ (11.4%), of whom 7 had SS; thus, ANA were detected in 7/8 SpA patients with SS (88%). Of the 84 SpA patients responding to the questionnaire (80%), 10 gave a positive answer to > or = 3 questions (11.9%) compared to 2 of 131 (1.5%) controls (87.3%) (odds ratio = 8.7, 95% CI 2.3-32.5, p < 0.01). CONCLUSION: The data suggest increased prevalence of sicca symptoms and SS in SpA patients with AS and uSpA. The occurrence of a secondary SS in a variety of inflammatory diseases suggests that salivary gland involvement in these conditions results from as yet unidentified shared pathogenic mechanisms resulting in nonspecific inflammation in this location.

Characterization of the synovial T cell response to various recombinant Yersinia antigens in Yersinia enterocolitica-triggered reactive arthritis. Heat-shock protein 60 drives a major immune response.

OBJECTIVE: In Yersinia enterocolitica-triggered reactive arthritis (Yersinia ReA), the synovial T cell response is primarily directed against bacterial components, which are mostly unknown. This study was performed to investigate the synovial proliferative T cell response to a panel of recombinant Yersinia antigens in patients with Yersinia ReA and in controls. METHODS: Synovial fluid mononuclear cells (SFMC) were obtained from 4 patients with Yersinia ReA and from 14 patients with arthritides of different etiology. SFMC were stimulated with 5 recombinant Yersinia antigens (the 19-kd urease beta subunit, 13-kd ribosomal L23 protein, 32-kd ribosomal L2 protein, 18-kd outer membrane protein H, and Y. enterocolitica heat-shock protein 60 [hsp60]), and with human, Chlamydia trachomatis, and Borrelia burgdorferi hsp60. Three T cell clones specific for Y. enterocolitica hsp60 were generated from 1 patient with Yersinia ReA. Antigen-induced cytokine release was measured by enzyme-linked immunosorbent assay. RESULTS: SFMC from all 4 patients with Yersinia ReA responded to each of the Yersinia antigens except the 13-kd protein. These antigens were also recognized by SFMC from a subgroup of patients with undifferentiated arthritis (n = 4), but not by SFMC from other patients with arthritis of different etiology (n = 10). Y. enterocolitica hsp60 induced the strongest proliferative response in all cases. Two types of hsp60-reactive T cell clones could be obtained. One clone responded to all hsp60 variants, including the human variant, and showed a type 2 T helper (Th2)-like cytokine-secretion pattern. In contrast, another clone with specificity for the bacterial hsp60 proteins, but not the human equivalent, reacted with a more Th1-like pattern. CONCLUSION: In Y. enterocolitica-triggered ReA, at least 4 immunodominant T cell antigens exist, which might be used in lymphocyte proliferation assays to identify patients with Yersinia ReA. The hsp60 is a strong antigen, inducing both bacteria-specific and potentially autoreactive CD4+ T cells of both the Th1 and Th2 type.

A specific immunoassay for the determination of morphine and its glucuronides in human blood.

The development of specific antisera for immunochemical determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide is described. Morphine was N-demethylated to normorphine and N-alkylated to give N-aminopropyl-normorphine as hapten for antisera against morphine. As haptens for antisera against morphine-3-glucuronide and morphine-6-glucuronide, N-aminopropyl-nor-morphine was glucuronidated in position 3 or 6 respectively. Each of these three haptens were coupled to BSA employing the glutaraldehyde method to obtain three different immunogens. Immunisation of rabbits with these conjugates gave anti-morphine, anti-morphine-3-glucuronide and anti-morphine-6-glucuronide antisera, which were tested in a competitive, heterogeneous radioimmunoassay. Tracers for this radioimmunoassay procedure were synthesised by substitution of morphine and morphine-6-glucuronide in position 2 with 125I and indirect iodination of the morphine-3-glucuronide hapten according to the method of Bolton and Hunter. The resulting antisera show very specific reactions with morphine, morphine-3-glucuronide and morphine-6-glucuronide. Cross reactivities of each antiserum with structurally related opiates and opioides are very low. The cross reactivities of the anti-morphine antiserum against morphine-3-glucuronide, morphine-6-glucuronide, codeine, codeine-6-glucuronide or dihydrocodeine were less than 0.3%, the anti-morphine-3-glucuronide antiserum against morphine, morphine-6-glucuronide, codeine, codeine-6-glucuronide or dihydrocodeine less than 0.1% and the anti-morphine-6-glucuronide antiserum against morphine, morphine-3-glucuronide, codeine or dihydrocodeine less than 0.1%, against codeine-6-glucuronide less than 2.3%. The determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide in blood samples (limit of detection= 3, 1, 0.5 ng/g) of nine cases of fatal heroin overdose with this radioimmunoassay method and the comparison with a GC/MS method is described.

Abnormal XY interchange between a novel isolated protein kinase gene, PRKY, and its homologue, PRKX, accounts for one third of all (Y+)XX males and (Y-)XY females.

XX males and XY females have a sex reversal disorder which can be caused by an abnormal interchange between the X and the Y chromosomes. We have isolated and characterized a novel gene on the Y chromosome, PRKY. This gene is highly homologous to a previously isolated gene from Xp22.3, PRKX, and represents a member of the cAMP-dependent serine threonine protein kinase gene family. Abnormal interchange can occur anywhere on Xp/Yp proximal to SRY. We can show that abnormal interchange happens particularly frequently between PRKX and PRKY. In a collection of 26 XX males and four XY females, between 27 and 35% of the interchanges take place between PRK homologues but at different sites within the gene. PRKY and PRKX are located far from the pseudoautosomal region where XY exchange normally takes place. The unprecedented high sequence identity and identical orientation of PRKY to its homologous partner on the X chromosome, PRKX, explains the high frequency of abnormal pairing and subsequent ectopic recombination, leading to XX males and XY females and to the highest rate of recombination outside the pseudoautosomal region.

FISH-deletion mapping defines a 270-kb short stature critical interval in the pseudoautosomal region PAR1 on human sex chromosomes.

Deletions of the pseudoautosomal region (PAR1) of the sex chromosomes have recently been discovered in individuals with short stature, and a minimal common deletion region of 700 kb within PAR1 has subsequently been defined. We have cloned this entire region, which is bounded by the Xp/Yp telomere, as an overlapping cosmid contig. In the present study, we have used fluorescence in situ hybridization (FISH) to study four patients with X-chromosomal rearrangements, two with normal height and two with short stature. Genotype-phenotype correlations have narrowed down the the critical "short stature interval" to a 270-kb region containing the gene with an important role in growth. A minimal tiling path of 6-8 cosmids bridging this interval is now available for interphase and metaphase FISH and provides a valuable tool for diagnostic investigations of patients with idiopathic short stature.

Nested polymerase chain reaction strategy simultaneously targeting DNA sequences of multiple bacterial species in inflammatory joint diseases. I. Screening of synovial fluid samples of patients with spondyloarthropathies and other arthritides.

OBJECTIVE: Bacteria play a crucial pathogenetic role in Lyme arthritis (LA), reactive arthritis (ReA), other forms of spondyloarthropathy (SpA), and possibly in undifferentiated oligoarthritis (uOligo). Polymerase chain reaction (PCR) technology has been applied to detect bacterial DNA of individual microbes in synovial fluid (SF) of patients with arthritides. We screened for DNA sequences of 8 bacterial species simultaneously in SF of patients with inflammatory joint disease. METHODS: We examined 104 SF samples of 96 patients with ReA (n = 13), undifferentiated SpA (uSpA, n = 10), uOligo (n = 50), juvenile chronic arthritis (JCA, n = 13), and rheumatoid arthritis (RA, n = 10). A nested PCR approach was developed to detect DNA sequences of 8 bacteria: Chlamydia trachomatis, C. pneumoniae, Yersinia enterocolitica, Salmonella enteritidis, Campylobacter jejuni, Shigella flexneri, Klebsiella pneumoniae, and Borrelia burgdorferi. The detection limit was determined at 10 bacterial/sample. Serology and lymphocyte proliferation assay were done in parallel in most patients. RESULTS: In 12 cases bacterial DNA of B. burgdorferi (n = 7), C. trachomatis (n = 2), C. jejuni (n = 2), and C. pneumoniae (n = 1) was detected in patients with uOligo (n = 9) and JCA (n = 3), while no evidence of bacterial DNA was found in patients with ReA, uSpA, and RA. Shigella flexneri DNA was detected in 4 cases, but the significance of this finding remains uncertain due to the high sequence homology of this species with Escherichia coli. DNA of Y. enterocolitica, S. enteritidis, or K. pneumoniae was not found. A positive serologic response was found in 7/9 PCR positive patients. In 11/96 cases antibodies to 2 or more bacteria were found in parallel (11.5%). Antigen specific lymphocyte proliferation was observed in 5/9 PCR positive patients. CONCLUSION: Bacterial DNA was detected in peripheral joint of patients with uOligo and JCA, but not in ReA, uSpA, or RA in this study. The detection of bacterial DNA in synovial material by PCR technology gives useful diagnostic information, especially when antibodies against several microbes are present or antibodies are not detectable. Failure to detect bacterial DNA in patients with ReA and uSpA with longstanding disease suggests that in later stages autoimmune mechanisms may operate.

Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome.

Growth retardation resulting in short stature is a major concern for parents and due to its great variety of causes, a complex diagnostic challenge for clinicians. A major locus involved in linear growth has been implicated within the pseudoautosomal region (PAR1) of the human sex chromosomes. We have determined an interval of 170 kb of DNA within PAR1 which was deleted in 36 individuals with short stature and different rearrangements on Xp22 or Yp11.3. This deletion was not detected in any of the relatives with normal stature or in a further 30 individuals with rearrangements on Xp22 or Yp11.3 with normal height. We have isolated a homeobox-containing gene (SHOX) from this region, which has at least two alternatively spliced forms, encoding proteins with different patterns of expression. We also identified one functionally significant SHOX mutation by screening 91 individuals with idiopathic short stature. Our data suggest an involvement of SHOX in idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients.

Molecular studies of an X;Y translocation chromosome in a woman with deletion of the pseudoautosomal region but normal height.

A translocation chromosome in a woman with the karyotype 46,X,der(X)t(X;Y)(p22.3; q11.2) was investigated by FISH and STS analysis with molecular probes derived from the sex chromosomes. Due to the partial deletion of the short arm pseudoautosomal region (PAR1) from DXYS14 to DXYS147 in the translocation chromosome, the proband is hemizygous for the gene responsible for growth control (SS) located in this region, yet does not show growth retardation. Molecular analysis of the Yq arm of the translocation chromosome revealed the presence of markers DYS273 to DYS246 harboring the hypothesized growth control gene critical region (GCY) on Yq, thereby placing the deletion breakpoint between markers DYS11 and DYS273. These results suggest that the Y-specific growth gene GCY on Yq compensates for the missing growth gene SS on Xp22.3.