Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia

Objective

Ataxia telangiectasia (AT) is a rare genetic, multi-system disorder characterized by neurodegeneration, chromosome instability, B and T cell immunodeficiency and a predisposition to cancer. We examined immunologic parameters reflecting cell development and proliferation and their relevancy to the clinical phenotype in affected individuals.

Patients and Methods

AT patients from the AT National Clinic in Israel underwent immunological investigation. Their T and B cell workup included lymphocyte subset counts, immunoglobulin levels, responses to mitogenic stimulations, TCR-Vβ families and BCR immunoglobulin heavy chain spectratyping, TCR rearrangement excision circles (TRECs) and Kappa-deleting recombination excision circles (KRECs).

Results

Thirty-seven AT patients (median age 12.7 years, range 4.2–25.1) were evaluated. CD20 B and CD3 T lymphocytes were decreased in 67 % and 64 % of the patients, respectively, while only 33 % of the patients had reduced lymphoproliferative responses. Almost all AT patients displayed extremely low TRECs and KRECs levels, irrespective of their age. Those levels were correlated to one another and to the amounts of CD3+ and CD20+ cells, respectively. Abnormal TCR-Vβ repertoires were found with different degrees of clonality or reduced expression in these AT patients. There was no clear clustering of expansions to specific TCR-Vβ genes. PCR spectratyping analysis of the FR2 IgH BCR gene rearrangements in peripheral blood was abnormal in 50 % of the patients.

Conclusion

The immunodeficiency associated with AT is combined, remains low over time and not progressive. It is characterized by low TREC and KREC copies suggestive of abnormal T and B cell neogenesis.     

Sex Differences in Hierarchical Stability in a Formation of a Mixed-sex Group of Rhesus Macaques

Forming groups of captive rhesus macaques (Macaca mulatta) is a common management practice. New formations of unfamiliar macaques can be costly, with high levels of trauma, particularly as intense aggression is used to establish a dominance hierarchy. Combining previous subgroups into one new group may be beneficial, as some individuals already have established dominance relationships. We tested this hypothesis by forming a new mixed-sex group of rhesus macaques that combined an established group of females with an established group of males. Prior to the mixed-sex group formation, both the female and male hierarchies had been stable for 3 y; after mixed-sex group formation these hierarchies were maintained by the females and were initially maintained by the males for 3 wks. However, the temporary hospitalization (due to a laceration caused by aggression) of the alpha male destabilized the male hierarchy. Age and weight then predicted male rank. Temporary hospitalizations resulted in rank changes for the males, evidenced by reversals in subordination signals. This study indicates that using established groups of familiar individuals may maintain female hierarchical stability in a mixed-sex group formation, but further research is needed to understand how to maintain and predict male hierarchical stability to reduce trauma. Improved knowledge of hierarchical stability would be invaluable to managers of large rhesus macaque groups and would help improve the welfare of captive rhesus macaques.

Social group formations of captive nonhuman primates (NHPs) occur frequently for a variety of reasons (for example, breeding, research purposes, permanent housing arrangements). Rhesus macaques are the most used NHP in biomedical research.¹⁵ Classified as highly despotic, rhesus macaques rely on a heavy use of aggression to maintain and reinforce their dominance hierarchy,⁴⁷ which ultimately governs access to resources and mates.⁵⁰ Extensive aggression can result in significant traumas and even death.^12,51 Reducing trauma is therefore an important goal both to maintain the animals’ welfare and to minimize the associated cost of care. Thus, this research is aimed at improving the success of forming groups with minimal trauma.One strategy to potentially improve the success of group formations and decrease aggression is to mix familiar individuals with an already established dominance relationship.^18,53 However, dominance ranks are not static and can change if aspects of the social environment change,^1,11,17 such as the loss of keystone individuals³⁴ or addition of new allies.¹⁷ As many NHPs are housed in pairs or small social groups, substantial research has been aimed at understanding pairing success,^14,31,38 but less is known about factors that contribute to successful formations of large, naturalistic social groups. Because high levels of aggression and trauma can occur even in well-established groups,^8,45 gauging social stability in large group formations of rhesus macaques is difficult, as aggression does not necessarily equate to incompatibility or trauma.^8,31,38 Understanding whether individuals maintain their previous hierarchies is critical information for behavioral managers as they form new social groups.Wild female rhesus macaques remain in their natal groups and acquire adjacent ranks to their mothers through coalitionary support.¹⁰ Males also retain their ranks near their mothers while in their natal groups,¹⁶ but after dispersal at sexual maturity and entry into a new breeding group, males mainly enter the group at the bottom of the hierarchy and move up after dispersals or deaths (see²⁶ for general background information and an unusual case of rank acquisition). Because males emigrate from multiple natal groups, many of them will be unfamiliar to one another. Whether male dominance relationships in their natal groups affect their rank in subsequent groups as adults is uncertain, although some research suggests that postnatal nepotism occurs in long-tailed macaques (Macaca fascicularis), with males maintaining a high dominance rank longer in non-natal groups when other male kin are present.²⁵ In many groups in which males originate from multiple natal groups, tenure in the new social group often dictates male dominance rank.²⁶The current research sought to determine whether female and male rhesus macaques would maintain their established same-sex hierarchies during a group formation in which an established group of females was introduced to an established group of males. If previous relationships are maintained, this could indicate that using established groups of familiar same-sex individuals could lessen the trauma and associated costs of a group formation, as individuals would not need to use high levels of aggression to sort out their hierarchy. We predicted that previous social rank, rather than individual attributes, would predict social rank in the new mixed-sex social group.     

JC Virus T-Antigen DNA in Gastrointestinal Mucosa of Immunosuppressed Patients: A Prospective,Controlled Study

Background  

JC virus (JCV), a polyoma virus, is the etiological agent of progressive multifocal leukoencephalopathy in immunosuppressed patients. JCV T-Ag has proven oncogenic potential and is expressed in colonic polyps and carcinomas. We proposed that the prevalence of JCV T-Ag DNA is higher in the normal gastrointestinal (GI) mucosa of immunosuppressed patients compared with their immunocompetent counterparts.     

Norms for disproportionate loss in speech intelligibility

The audiometric records of 324 subjects with sensorineural hearing loss, presumed to be cochlear, were analyzed in order to develop norms for "disproportionate loss" in speech intelligibility. From the scatterplot relating PBmax to PTA2 (average of HTLs at 1,000, 2,000, and 4,000 Hz), and the scatterplot relating SSImax to PTA1 (average of HTLs at 500, 1,000, and 2,000 Hz), linear boundaries were constructed encompassing approximately 98% of observed values. A speech intelligibility score (PB or SSI) may be considered "disproportionately poor" if it falls below this empirically derived boundary.     

Use of a metal detector in the location of a swallowed razor blade in the oesophagus

A case describing the use of a metal detector to locate a metallic foreign body swallowed by a prisoner. Initial work up included plain thoracic X-rays and a gastrografin swallow which were negative. A metal detector was used to confirm the presence of a metal body in the oesophagus which was verified by a barium swallow.     

Superior vena cava syndrome associated with lymphoma.

OBJECTIVE--To evaluate the workup and treatment of children with lymphoma and superior vena cava syndrome. DESIGN--A retrospective survey. SETTING--State hospital serving as a secondary and tertiary referral center for pediatric oncology and pediatric cardiac surgery. PARTICIPANTS--Eleven children aged 11 months to 12 years diagnosed as having lymphoma or T-cell acute lymphoblastic leukemia who presented with superior vena cava syndrome during an 11-year period. INTERVENTIONS--Lymph node biopsy (two patients), thoracenthesis (five patients), bone marrow aspiration (two patients), and thoracenthesis in addition to bone marrow aspiration (two patients). All aspirates were evaluated with immunohistochemical studies. Chemotherapy was the only management intervention. RESULTS--T-cell lymphoma or leukemia accounted for nine cases and Hodgkin's disease for two cases. Respiratory symptoms occurred in 10 patients, including tracheal compression in six patients (compression was life-threatening in one patient). Diagnosis of superior vena cava syndrome was achieved in eight patients using surface-marker analysis of aspirates. The syndrome disappeared within 2 to 10 days. Seven of nine children whose conditions were diagnosed more than 1 year before this writing were alive and free of disease after mean follow-up of 37 months. CONCLUSIONS--(1) A specific diagnosis can be achieved in most children with superior vena cava syndrome and lymphoma; (2) Thoracic computed tomographic scans are essential, identifying minute pleural effusions that can aid diagnosis; (3) Anesthetic hazard is related only to severe tracheal compression; (4) Chemotherapy achieves excellent symptomatic relief; and (5) Long-term survival, without disease, is achievable.     

Maternal and fetal serum prolactin levels in cases of premature rupture of membranes

Serum prolactin levels were measured in maternal and fetal sera immediately post delivery in 20 cases of premature rupture of the membranes and in 20 controls. Fetal serum prolactin levels were 781 +/- 265 ng/ml in cases of PRM and 737 +/- 314 ng/ml in controls. Maternal serum prolactin levels were 504 +/- 264 ng/ml in cases of PRM and 731 +/- 361 ng/ml in controls. This difference is statistically significant (t = 1.81, p less than 0.05). A probable role of prolactin in maintaining fetal membrane integrity and the probable effect of the difference in maternal serum prolactin concentration in the two groups on the membranes' viscoelastic properties is discussed.     

Pharmacological,morphological and behavioral analysis of motor impairment in experimentally vitamin C deficient guinea pigs

The scurvy shows an inflammatory disease and gingival bleeding. Nevertheless, in an animal model for guinea pigs, described by Den Hartog Jager in 1985, scurvy was associated with a motor neuron disease with demyelinization of the pyramidal tract, provoking neurogenic atrophy of muscles. Aiming at searching the protective role of vitamin C in nervous system, a pharmacological, morphological and behavioral study was conducted. Three experimental groups were used: A100, animals receiving 100 mg/ vitamin C/ day; A5.0, animals receiving 5.0 mg/vitamin C/ day; and A0, animals without vitamin C. We analyzed the weight gain, muscular diameter and behavioral tests. In all tests examined, we found significant differences between the supplemented groups in comparison with scorbutic group (p<0.05). Thereafter, the animals were killed for histopathology of gastrocnemius muscle, spinal cord and tooth tissues. In addition, a morphometric study of periodontal thickness and alpha-motor neuron cell body diameter were done. The vitamin C-diet free regimen seemed to induce a disruption in spinal cord morphology, involving the lower motor neuron, as confirmed by a significant reduction in neuron perycaria diameter and muscular atrophy, complicated by increased nutritional deficit.     

Diaphragm plication following phrenic nerve injury: a comparison of paediatric and adult patients

BACKGROUND: A study was undertaken to evaluate whether adults differ from children in the indications and outcome of diaphragmatic plication following phrenic nerve injury. METHODS: A retrospective study was performed of 21 patients, 10 below the age of 5 and 11 older than 37 years. The indication for surgery for all the children was failure to wean from ventilatory support. The indications for surgery in the adult group were ventilator dependency (n=4) and symptomatic dyspnoea (n=7). All patients had at least one imaging study confirming diaphragmatic paralysis. The American Thoracic Society (ATS) dyspnoea scale, pulmonary function tests, and quantitative pulmonary perfusion scans were used as evaluation parameters. At surgery the diaphragm was centrally plicated. RESULTS: One child died immediately after surgery due to irreversible heart failure and two children died within 2 months of surgery from ongoing complications of their original condition. These three patients were considered as selection failures. Seven children were weaned from ventilatory support within a median of 4 days (range 2-140). Only one of four ventilated adults was successfully weaned. Seven adults who underwent surgery for chronic symptoms had a marked subjective improvement of 2-3 levels in the ATS dyspnoea scale. Pulmonary function studies in the seven symptomatic adults showed a 40% improvement above baseline. Severely asymmetrical perfusion scans reverted to a normal pattern after plication. CONCLUSIONS: Diaphragmatic plication offers a significant benefit to children with diaphragmatic paralysis and should be performed early to facilitate weaning from mechanical ventilation. While plication is of limited benefit in weaning ventilated adults, it results in significant subjective and objective lifetime improvement in non-ventilated symptomatic adults.     

Resection and perfusion thermochemotherapy: a new approach for the treatment of thymic malignancies with pleural spread

BACKGROUND: Thymoma and thymic carcinoma with pleural spread have a high rate of locoregional recurrence and poor prognosis. Maximal debulking coupled with aggressive local treatment could offer a chance for cure. This study evaluates the early and midterm results of operation and hyperthermic pleural perfusion with cisplatinum for thymic malignancies. METHODS: Fifteen patients (11 men), 20 to 67 years old (10 thymoma, 4 thymic carcinoma, 1 carcinoma in thymic cyst) underwent resection and hyperthermic pleural perfusion between 1995 to 2000. All had pleural spread proven before or intraoperatively. Six of the thymoma cases were recurrent. Current operation included resection without pleurectomy (9 patients), resection with pleurectomy (5), and extrapleural pneumonectomy (1 patient) with intraoperative hyperthermic pleural perfusion in all. Intrapleural temperature reached 40.3 degrees C to 43 degrees C. The total dose of cisplatinum was 150 mg or more in 14 patients. RESULTS: Complete resection (R0) was achieved in 10 patients, subtotal (R1) in 3, and partial (R2) in 2. There was no operative mortality, no hemodynamic or respiratory disturbances during perfusion, and no hematologic, neurologic, or renal complications. Complications consisted of significant bleeding (2 patients), fever (2), and air leak (1 patient). Two patients with thymic carcinoma died after 27 and 34 months, and 1 is alive with no evidence of disease at 54 months. Two patients with thymoma died after 7 and 36 months. Eight are alive after 9 to 70 months. Four patients (all R0) are alive without local recurrence more than 60 months after operation and hyperthermic pleural perfusion. CONCLUSIONS: Operation and thermochemotherpy is feasible and safe in patients with thymic tumors. This method seems to offer excellent local control for patients with stage IV-a thymic malignancies. Midterm results suggest that operation plus hyperthermic pleural perfusion may lengthen survival in stage IV-a thymoma.