White matter, cognition and psychotic-like experiences in UK Biobank.

BACKGROUND: Psychotic-like experiences (PLEs) are risk factors for the development of psychiatric conditions like schizophrenia, particularly if associated with distress. As PLEs have been related to alterations in both white matter and cognition, we investigated whether cognition (g-factor and processing speed) mediates the relationship between white matter and PLEs. METHODS: We investigated two independent samples (6170 and 19 891) from the UK Biobank, through path analysis. For both samples, measures of whole-brain fractional anisotropy (gFA) and mean diffusivity (gMD), as indications of white matter microstructure, were derived from probabilistic tractography. For the smaller sample, variables whole-brain white matter network efficiency and microstructure were also derived from structural connectome data. RESULTS: The mediation of cognition on the relationships between white matter properties and PLEs was non-significant. However, lower gFA was associated with having PLEs in combination with distress in the full available sample (standardized ß = -0.053, p = 0.011). Additionally, lower gFA/higher gMD was associated with lower g-factor (standardized ß = 0.049, p < 0.001; standardized ß = -0.027, p = 0.003), and partially mediated by processing speed with a proportion mediated of 7% (p = < 0.001) for gFA and 11% (p < 0.001) for gMD. CONCLUSIONS: We show that lower global white matter microstructure is associated with having PLEs in combination with distress, which suggests a direction of future research that could help clarify how and why individuals progress from subclinical to clinical psychotic symptoms. Furthermore, we replicated that processing speed mediates the relationship between white matter microstructure and g-factor.

[Mental health in Bonaire - an inspiration for the Dutch New Mental Health Movement]. / De ggz in Bonaire - een inspiratie voor de beweging 'de nieuwe ggz'.

BACKGROUND: In 2010 the bes-islands in the Caribbean became a special municipality of the Netherlands. Healthcare was upgraded to match Dutch standards over a short period of time. With a population of 15,518 inhabitants in 2010 (19,408 in 2016), Bonaire received its own fact-team (flexible assertive community treatment). It subsequently became a unique experiment for the Dutch New Mental Health Movement.
AIM: To describe the development of a modern mental health care system in a limited geographic area.
METHOD: Site visitation, interviews and analysis of historical data sources.
RESULTS: The local mental health team takes integral responsibility for all the mh care needs in Bonaire. There is no intricate diagnostic referral system. Consultation access lines are short. The team was able to dramatically reduce the need for hospitalization. Collaboration with the somatic hospital and general practitioners runs smoothly and the facilities offer complementary care. Societal integration is insured due to mental health professionals living interspersed in the neighborhood, the low threshold allowing them to respond to signals efficiently. There is a natural development of the following three domains of care: reduction of symptoms, societal participation and personal remission.
CONCLUSION: Integrated mental health services in a geographically small area, as presented by the Dutch New Mental Health Movement, enables the possibility of recovery oriented care.

A randomized controlled trial evaluating the efficacy of a 67% sodium bicarbonate toothpaste on gingivitis.

INTRODUCTION: In previous studies, toothpastes with high levels of sodium bicarbonate (>50%) have reduced gingival inflammation and oral malodour. This study compared the effects of brushing for 6 weeks with 67% (test group) or 0% (control group) sodium bicarbonate toothpaste on gingival health. METHODS: This was a single-centre, single examiner-blind, randomized, controlled, two-treatment, parallel-group study. Eligible subjects (≥18 years) had ≥20 gradable teeth, mild-to-moderate gingivitis, a positive response to bleeding on brushing and ≥20 bleeding sites. The primary objective was to compare the number of bleeding sites following twice-daily use of 67% sodium bicarbonate toothpaste or 0% sodium bicarbonate toothpaste after 6 weeks. Secondary endpoints included Modified Gingival Index (MGI), Bleeding Index (BI) and volatile sulphur compounds (VSC), assessed after 6 weeks. Safety was assessed by treatment-emergent oral soft tissue abnormalities and adverse events. RESULTS: Of 148 patients randomized (74 to each treatment), 66 (89.2%) completed the study in the test group, compared with 69 (93.2%) in the control group. Compared with the control group, the test group had a significant reduction in the number of bleeding sites at Week 6 (absolute difference - 11.0 [-14.0, -8.0], P < 0.0001; relative difference - 25.4%), together with significant reductions in MGI and BI (both P < 0.0001). Although the median reductions from baseline for VSC were numerically greater in the test group, the difference did not reach statistical significance (P = 0.9701). CONCLUSIONS: This 67% sodium bicarbonate toothpaste provided statistically significant improvements in gingival health and bleeding after 6 weeks of use.

Overexpression of PLIN5 in skeletal muscle promotes oxidative gene expression and intramyocellular lipid content without compromising insulin sensitivity.

AIMS/HYPOTHESIS: While lipid deposition in the skeletal muscle is considered to be involved in obesity-associated insulin resistance, neutral intramyocellular lipid (IMCL) accumulation per se does not necessarily induce insulin resistance. We previously demonstrated that overexpression of the lipid droplet coat protein perilipin 2 augments intramyocellular lipid content while improving insulin sensitivity. Another member of the perilipin family, perilipin 5 (PLIN5), is predominantly expressed in oxidative tissues like the skeletal muscle. Here we investigated the effects of PLIN5 overexpression - in comparison with the effects of PLIN2 - on skeletal muscle lipid levels, gene expression profiles and insulin sensitivity. METHODS: Gene electroporation was used to overexpress PLIN5 in tibialis anterior muscle of rats fed a high fat diet. Eight days after electroporation, insulin-mediated glucose uptake in the skeletal muscle was measured by means of a hyperinsulinemic euglycemic clamp. Electron microscopy, fluorescence microscopy and lipid extractions were performed to investigate IMCL accumulation. Gene expression profiles were obtained using microarrays. RESULTS: TAG storage and lipid droplet size increased upon PLIN5 overexpression. Despite the higher IMCL content, insulin sensitivity was not impaired and DAG and acylcarnitine levels were unaffected. In contrast to the effects of PLIN2 overexpression, microarray data analysis revealed a gene expression profile favoring FA oxidation and improved mitochondrial function. CONCLUSIONS/INTERPRETATION: Both PLIN2 and PLIN5 increase neutral IMCL content without impeding insulin-mediated glucose uptake. As opposed to the effects of PLIN2 overexpression, overexpression of PLIN5 in the skeletal muscle promoted expression of a cluster of genes under control of PPARα and PGC1α involved in FA catabolism and mitochondrial oxidation.

A severe case of disseminated cryptococcosis in a young French bulldog living in South-East Queensland caused by Cryptococcus gattii VGII.

BACKGROUND: Cryptococcus is one of the most common systemic mycosis worldwide, infecting young adults of the large to giant breed dogs. Infection is commonly acquired from the environment via the sinonasal cavity as the main portal of entry. It either remains there, or spreads to the central nervous system (CNS) and the eye (optic nerve and retina) by penetration of the cribriform plate, or haematogenously to other viscera. Lung involvement is uncommon in cats and dogs in contrast to human and equine patients. Whilst there is a wide genetic diversity amongst Cryptococcus neoformans and Cryptococcus gattii isolates along the West Coast and Northern parts of Australia, the molecular diversity of C. gatti is considered very low on the East Coast of Australia, with a huge preponderance of VGI cases. We report on a young small breed brachycephalic dog that presented with extreme gastrointestinal and respiratory signs, but no CNS involvement. It is the first reported case of C. gattii VGII genotype in a companion animal from Queensland. CASE REPORT: A 9-month old female entire French Bulldog presented initially for diarrhoea. Clinical progression was accompanied by the development of respiratory signs, so the patient was referred to a 24 h care facility. Following hospitalisation, the patient became hypoxemic requiring mechanical ventilation. A bronchoalveolar lavage performed antemortem confirmed abundant Cryptococcal spp. Further culturing and genotyping identified the species as Cryptococcus gattii VGII. Post-mortem findings indicated gross gastrointestinal and mesenteric involvement, with possible dissemination to the local mesenteric lymph node and lungs. CONCLUSION: This case describes a rare example of a Cryptococcus spp suspected of disseminating from the gastrointestinal tract to the lungs, without involvement of the CNS. The observation of this finding in a small brachycephalic breed is unusual, and the finding of genotype VGII on the East Coast of Queensland is extremely unusual as there is no prior travel history of the dog or owners. The presence of a miliary lung pattern with primary gastrointestinal disease in a small breed dog warrants adding cryptococcosis to the differential diagnosis.

Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice.

AIMS/HYPOTHESIS: High-fat, high-sucrose diet (HF)-induced reactive oxygen species (ROS) levels are implicated in skeletal muscle insulin resistance and mitochondrial dysfunction. Here we investigated whether mitochondrial ROS sequestering can circumvent HF-induced oxidative stress; we also determined the impact of any reduced oxidative stress on muscle insulin sensitivity and mitochondrial function. METHODS: The Skulachev ion (plastoquinonyl decyltriphenylphosphonium) (SkQ), a mitochondria-specific antioxidant, was used to target ROS production in C2C12 muscle cells as well as in HF-fed (16 weeks old) male C57Bl/6 mice, compared with mice on low-fat chow diet (LF) or HF alone. Oxidative stress was measured as protein carbonylation levels. Glucose tolerance tests, glucose uptake assays and insulin-stimulated signalling were determined to assess muscle insulin sensitivity. Mitochondrial function was determined by high-resolution respirometry. RESULTS: SkQ treatment reduced oxidative stress in muscle cells (-23% p < 0.05), but did not improve insulin sensitivity and glucose uptake under insulin-resistant conditions. In HF mice, oxidative stress was elevated (56% vs LF p < 0.05), an effect completely blunted by SkQ. However, HF and HF+SkQ mice displayed impaired glucose tolerance (AUC HF up 33%, p < 0.001; HF+SkQ up 22%; p < 0.01 vs LF) and disrupted skeletal muscle insulin signalling. ROS sequestering did not improve mitochondrial function. CONCLUSIONS/INTERPRETATION: SkQ treatment reduced muscle mitochondrial ROS production and prevented HF-induced oxidative stress. Nonetheless, whole-body glucose tolerance, insulin-stimulated glucose uptake, muscle insulin signalling and mitochondrial function were not improved. These results suggest that HF-induced oxidative stress is not a prerequisite for the development of muscle insulin resistance.

The effect of remote ischaemic preconditioning on postoperative cardiac and inflammatory biomarkers in pancreatic surgery: a randomized controlled trial.

BACKGROUND: Cardiac and inflammatory biomarkers have been associated with adverse outcome after major abdominal surgery. This study investigated the effect of remote ischaemic preconditioning (RIPC) on perioperative concentrations of high-sensitive cardiac troponin (hs-cTn) T and interleukin (IL) 6. METHODS: Adult patients scheduled for elective pancreatic surgery between March 2017 and February 2019 were randomized to either three cycles of upper-limb ischaemia and reperfusion (each 5 min) or a sham procedure before surgery. The primary endpoint was the maximum postoperative hs-cTnT concentration within 48 h after surgery. Secondary endpoints were postoperative myocardial injury (PMI), defined as an absolute increase of hs-cTnT of at least 14 ng/l above baseline concentration, maximum concentration of IL-6 within 48 h after surgery and postoperative complications within 30 days of surgery. RESULTS: Of 99 eligible patients, 46 underwent RIPC and 46 a sham procedure. RIPC did not reduce the maximum hs-cTnT concentration after surgery (12.6 ng/l RIPC, 16.6 ng/l controls, P = 0.225), nor did it lessen the incidence of PMI (15/45 RIPC, 18/45 controls, P = 0.375). The maximum postoperative IL-6 concentration was 265 pg/ml after RIPC versus 385 pg/ml in controls (P = 0.108). Postoperative complications occurred in 23 RIPC and 24 control patients respectively. CONCLUSIONS: Remote ischaemic preconditioning did not reduce the maximum postoperative hs-cTnT concentration. Postoperative myocardial injury, IL-6 concentrations and postoperative complications were similar between RIPC patients and controls. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT03460938.

Truncated mu (mu') chains in murine IgM. Evidence that mu' chains lack variable regions.

Secreted IgM was shown to contain truncated mu (mu') chains with an apparent molecular mass of approximately 55 kD. The estimated percentage of IgM heavy (H) chains in the mu' form ranged from less than or equal to 1% in the case of one tumor IgM protein (104E) to greater than or equal to 30% in normal serum IgM. Serum mu' chains lacked antigenic determinants characteristic of immunoglobulin variable regions and showed a restricted isoelectric focusing pattern compared with that of conventional mu chains. Intracellular mu' chains were readily detected in bone marrow cells but not in spleen or lymph node cells; mu' chains were also detected in IgM-producing tumor cells and in a hybridoma cell line that deleted its productive mu allele. These results predict irregularities in IgM structure and recall an old controversy concerning the valence of IgM molecules.

Radioimmune analysis of an unexpected mouse allotype.

We have used a radioimmune assay to confirm our earlier findings of an unexpected immunoglobulin allotype in Igb-congenic BALB/c mice. Although these mice were bred to exclude the IgG2a allotype of BALB/c (Ig-la), an Ig-la-like antigen was detected in the 7S Ig fraction of two (of five) pooled serum samples, it represented 0.1--0.3% of the total 7S protein and was indistinguishable from a reference Ig-la. The detection of putative Ig-la in Igb-congenic mice is inconsistent with the notion that allotypes are products of allelic structural genes. It appears rather that expression of Ig-la is controlled by allelic regulator genes and that its low and transient production in Igb-congenic mice results from incomplete negative regulation.

Prevention of IgG2a production as a result of allotype-specific interaction between T and B cells.

BALB/c T cells, which can prevent normal C57BL IgG2a allotype (G2) production of Ig-congenic partner mice (C.B mice), are shown capable of preventing the growth and G2 production of a C.B plasmacytoma (CBPC 101). Such cytotoxic or suppressor T cells are clearly allotype-specific (G2 Tcs cells). And since CBPC 101 B cells do not require specific helper T cells in order to grow, we infer that G2-bearing B cells (normal or neoplastic) must be the direct target of G2 Tcs cells. This mode of T cell prevention of allotype production contrasts that reported for suppressor T cells in (BALB/c x SJL)F1 mice.

Congenic mouse strains: the expression of a hidden immunoglobulin allotype in a congenic partner strain of BALB-c mice.

This paper derives from the unexpected observations of the "wrong immunoglobulin allotype" in a congenic partner strain of BALB/c mice from the Institute of Cancer Research (ICR CB-17). These mice were specially bred so as not to differ from BALB/c mice in any known way except to carry immunoglobulin structural genes of the C57BL/Ka allotype. In this respect, ICR CB-17 mice were defined as allotypically homozygous according to the Mendelian inheritance of mouse allotype markers. The homozygosity of these mice was challenged, however, when in certain instances immunoglobulins of the BALB/c allotype appeared in the serum of some ICR CB-17 mice. The appearance of this hidden allotype was usually transient and only associated with immunoglobulins of the IgG (IgG2a) class. The implications of these findings for the inheritance and expression of immunoglobulin structural genes are discussed.

Alteration of immunoglobulin phenotype in cell culture-adapted lines of two mouse plasmacytomas.

Murine plasmacytomas can be adapted to continuous in vitro culture by alternate passage between culture and animal. We have found that the kinetics of adaptation reflect a selection for the growth of variant plasmacytoma cells. The inclusion of an altered immunoglobulin phenotype in such variant cells could explain the Ig-producing variants that we observed in two of six transplantable lines of plasmacytomas that were adapted to culture. The first variant, an IgM-producing cell line (104-76), was adapted from a transplanted line of MOPC 104E that had stopped producing IgM with binding specificity for alpha1-3 Dextran. Unlike MOPC 104E, the IgM of 104-76 contains kappa- instead of lambda-light chains and probably contains an altered or different mu-heavy chain. A second variant (352-57) was found in an IgG2b-producing tumor (MOPC 352) which was induced in a BALB/c mouse strain (CB-6) that carried Ig genes of the C57BL/Ka allotype. This cell line apparently switched from producing IgG2b molecules of the C57BL allotype (H9) and of a known idiotype to IgG1 molecules of the BALB/c allotype (F19) without the idiotype marker. The propagation of a biclonal plasmacytoma from the time of original tumor induction does not appear as a likely explanation for these results. Rather, we seem to be dealing with plasmacytoma variants or with the possible induction of secondary tumors of host origin.

Extended duration of DH-JH rearrangement in immunoglobulin heavy chain transgenic mice: implications for regulation of allelic exclusion.

Here we show that suppression of VH-DJH rearrangement in mice bearing a mu heavy (H) chain transgene (mu-tg mice) is associated with an extended period of DH-JH rearrangement, the first step of Immunoglobulin H chain gene rearrangement. Whereas DH-JH rearrangement is normally initiated and completed at the pro-B cell stage, in mu-tg mice it continues beyond this stage and occurs most frequently at the small (late) pre-B stage. Despite ongoing DH-JH rearrangement in late pre-B cells of mu-tg mice, VH-DJH rearrangement is not detectable in these cells. We infer that the lack of VH-DJH rearrangement primarily reflects tg-induced acceleration of B cell differentiation past the stage at which rearrangement of VH elements is permissible. In support of this inference, we find that the normal representation of early B lineage subsets is markedly altered in mu-tg mice. We suggest that the effect of a productive VH-DJH rearrangement at an endogenous H chain allele may be similar to that of a mu-tg; i.e., cells that make a productive VH-DJH rearrangement on the first attempt rapidly progress to a developmental stage that precludes VH-DJH rearrangement at the other allele (allelic exclusion).

Expression of murine Lm-1 locus. Lm-1 determinants on lymphocytes and macrophages, and effects of Lm-1 incompatibility on bone marrow grafts.

Lm-1 is an Igh-linked locus that codes for cell surface alloantigens (Lm-1 determinants) recognized by T lymphocytes. Using Lm-1 congenic strains and cold-target inhibition of anti-Lm-1-specific lysis by cytotoxic T lymphocytes, we were able to demonstrate differential expression of two distinct Lm-1 antigenic determinants. One determinant is expressed on the surface of T cell blasts, the other on a number of pre-B cell lines. Both determinants are present on B cell blasts. Macrophages also bear Lm-1 determinants, and possibly express a determinant not found on lymphocytes. Fibroblasts, (unstimulated) thymocytes, and immature T cells lack detectable Lm-1 determinants. These data indicate that expression of the Lm-1 locus is dependent on cell lineage and the stage of cell differentiation or activation. We propose that Lm-1 is a lymphocyte-macrophage differentiation locus containing a number of structurally and functionally related genes. Evidence was presented that Lm-1 may also serve as a histocompatibility locus of major importance for bone marrow transplantation. Specifically, when Lm-1-incompatible bone marrow cells and spleen cells (from normal or anti-Lm-1 immune mice) were transplanted into X-irradiated recipients, the maturation and/or function of bone marrow-derived donor B cells was delayed or inhibited.

Unexpected rearrangement and expression of the immunoglobulin lambda1 locus in scid mice.

In severe combined immunodeficient (scid) mice, V(D)J recombination is severely impaired due to a recessive mutation (scid). Thus, we were surprised to find in this study that Vlambda1-Jlambda1 rearrangement is routinely detectable in scid fetal liver, adult bone marrow, and spleen in the apparent absence of completed VH-DJH and Vkappa-Jkappa rearrangements. Particularly surprising, we found the level of Vlambda1-Jlambda1 rearrangement in scid fetal liver to be comparable to that in fetal liver of wild-type mice. The majority of scid Vlambda1-Jlambda1 rearrangements contained abnormal deletions at the VJ junction, consistent with the known effect of scid. However, approximately 15% of Vlambda1-Jlambda1 rearrangements lacked abnormal deletions. Productive lambda1 transcripts resulting from in-frame rearrangements were readily detectable in scid adult bone marrow and spleen, consistent with our ability to detect lambda1-expressing cells by flow cytometry in the spleens of bcl-2-transgenic scid mice. Strikingly, lambda1 transcripts from individual scid mice often showed VJ junctional sequences with the same recurring palindromic (P) additions of three, four, or five nucleotides. To account for these findings, we suggest that (a) nonhomologous end joining of Vlambda1 and Jlambda1 coding ends in fetal B lineage cells may not be (severely) impaired by scid; (b) recurring P additions in scid lambda1 transcripts may reflect certain molecular constraints imposed by scid on the resolution of Vlambda1 and Jlambda1 hairpin coding ends; and (c), scid lymphocytes with productively rearranged Vlambda1 and Jlambda1 elements may differentiate into recombinase-inactive cells and emigrate from bone marrow to spleen.

Serological distinciton of heavy chain variable regions (VH subgroups) of mouse immunoglobulins. I. Common VH determinants on the heavy chains of mouse myeloma proteins having different binding sites.

16 of more than 100 mouse myeloma proteins, including 3 proteins of the IgG2a class and 13 of the IgA class, were shown to have a similar heavy chain variable region (VH) antigen(s) (U10-173). The proteins bearing these antigenic determinants (U10-173+ proteins) represented at least five different ligand-binding specificities. These findings, taken togeter with available sequence data for VH regions of U10-173+ proteins, have led us to conclude that U10-173 defines a small number of related VH subgroups. The ability to detect VH subgroups in mice by serological means, as has been done in humans also, promises new and useful kinds of VH markers for immunologic study.

T lymphocytes specific for immunoglobulin allotype. I. Igh-1b-specific T cells demonstrated by suppression in vivo and cytotoxicity in vitro.

We show that determinants of IgG(2a) of C57BL/6 mice (Igh-1(b)) stimulate allotypespecific T cells in BALB/c mice. Such cells are detected in two different functional assays; chronic allotype suppression and T cell-mediated cytotoxicity. A population of suppressor T cells capable of inducing chronic Igh-1(b) suppression was demonstrated by rosetting procedures to possess Igh-1(b)-specific receptors, a result interpreted as indicating that suppressor T cells may act directly upon allotype-bearing B cells. From similar populations we were also able to demonstrate Igh-1(b)-specific cytotoxic T cells. Such cells were lytic for target myeloma cells expressing the Igh-1(b) allotype of IgG28, and were ineffective against a variant cell line failing to express Igh-1(b), and other target cell lines expressing different allotypes or isotypes. The similar specificity of suppressor T cells and cytotoxic T lymphocytes for Igh-1(b) allotype raises the possibility that the target in allotype suppression is a B cell, and that allotype-specific cytotoxic T cells may play some role in regulation of allotype expression in the suppressed state.

T lymphocytes specific for immunoglobulin allotype. II. Cloned Igh-1b-specific cytotoxic T cells.

This study describes long-term-cultured lines and clones of cytotoxic T cells (Tc) with specificity for determinants of the Igh-1(b) immunoglobulin allotype. These Tc clones were initiated by repeated stimulation of immune spleen cells from BALB/c mice with an Igh-1(b)-producing myeloma, and then they were maintained in medium supplemented with mitogen-induced growth factors in the absence offurther antigenic stimulation . The lytic potency of these clones was 30-100-fold greater than the primary cultures from which they were derived, and specificity studies showed them to be lytic for Igh-1(b) targets and not for targets expressing Igh-1(a) or Igh-4(b), nor the lipopolysaccharide blasts . Finally, soluble preparations of Ig were tested for their ability to block lysis of labeled Igh-1(b)-expressing targets. The results showed that Igh-1(b) and not other immunoglobulin allotypes or isotypes could block lysis, and that the mechanism of lytic inhibition is due to Igh-1(b)-induced autolysis of the killer cells.

V(D)J recombination in peritoneal B cells of leaky scid mice.

Developing lymphocytes in immune-deficient severe combined immunodeficient (scid) mice express a defective recombinase activity and rarely succeed in making an antigen receptor; those cells that do succeed account for the known B and T cell leakiness in this mutant mouse strain. To gain more insight into the nature of the scid defect, we assessed the status of heavy (H) and light (L)k, chain genes in immunoglobulin (Ig)Mk-secreting B cells from the peritoneal cavity of old leaky scid mice, the only lymphoid site where scid B cells have been routinely detected. We found these cells to be unusual in that their nonexpressed H chain alleles were either abnormally rearranged or in germline configuration (wild-type B cells generally show normal rearrangements at both H chain alleles). The VDJH junctions of the expressed alleles showed little or no nontemplated (N) addition, similar to neonatal B cells from wild-type mice. About half of the V(D)J junctions lacking N additions contained nucleotides that could have been encoded by either of the participating coding elements (VDH, DJH, or VJk), indicating that the recombination occurred between short stretches of homology. Unusually long templated (P) additions were seen in both VDJH and VJK junctions, and many recombinations appeared to involve P-based homologies. These findings suggest that: (a) B cell leakiness results from a low frequency of coding joint formation in cells expressing the defective scid recombinase activity; (b) joining of scid coding ends is facilitated when the ends contain short stretches of sequence homology, where in many cases, one of the homologous sequences results from a P addition; and (c) scid peritoneal B cells may arise early in ontogeny.

Evidence of functional lymphocytes in some (leaky) scid mice.

Although the majority of severe combined immune deficiency (scid) mice lack functional lymphocytes, some (2-23%) appear to develop a limited number of B and T cells between 3 and 9 mo old. Most of these leaky scid mice were shown to contain very few clones (less than or equal to 3) of Ig-producing plasmacytes. Clonal progeny were distributed unevenly in the lymphatic tissues and appeared as discrete plasmacytic foci. In many cases, individual clones persisted for several months and produced abnormally high concentrations of Ig that included multiple isotypes. Functional T cells were inferred from the ability of leaky mice to reject allogeneic skin grafts, a T cell-dependent reaction. Interestingly, approximately 40% of leaky mice developed thymic lymphomas. In other respects, leaky mice resembled regular scid mice; e.g., their splenic cells failed to express common lymphocyte antigens (Ly-5[B220], Ly-1) and to proliferate in response to lymphocyte mitogens. Histologically, their lymphoid tissues retained the same general pattern of severe lymphocytic deficiency as scid mice.