Microbiota induces tonic CCL2 systemic levels that control pDC trafficking in steady state.

Plasmacytoid dendritic cells (pDCs) detect viruses initiating antiviral type I interferon responses. The microbiota is known to shape immune responses, but whether it influences pDC homeostasis and/or function is poorly understood. By comparing pDCs in germ-free and specific pathogen-free mice, we found that the microbiota supports homeostatic trafficking by eliciting constitutive levels of the chemokine CCL2 that engages CCR2. Mononuclear phagocytes were required for tonic CCL2 levels. CCL2 was particularly important for trafficking of a CCR2hi subset of pDCs that produced proinflammatory cytokines and was prone to apoptosis. We further demonstrated that CCR2 was also essential for pDC migration during inflammation. Wild-type (WT):Ccr2-/- mixed bone marrow chimeras revealed that CCR2 promotes pDC migration in a cell-intrinsic manner. Overall, we identify a novel role for the microbiota in shaping immunity, which includes induction of CCL2 levels that control homeostatic trafficking of pDCs.

CD154 blockade abrogates allospecific responses and enhances CD4(+) regulatory T-cells in mouse orthotopic lung transplant.

Acute cellular rejection (ACR) is a common and important clinical complication following lung transplantation. While there is a clinical need for the development of novel therapies to prevent ACR, the regulation of allospecific effector T-cells in this process remains incompletely understood. Using the MHC-mismatched mouse orthotopic lung transplant model, we investigated the short-term role of anti-CD154 mAb therapy alone on allograft pathology and alloimmune T-cell effector responses. Untreated C57BL/6 recipients of BALB/c left lung allografts had high-grade rejection and diminished CD4(+) : CD8(+) graft ratios, marked by predominantly CD8(+) >CD4(+) IFN-γ(+) allospecific effector responses at day 10, compared to isograft controls. Anti-CD154 mAb therapy strikingly abrogated both CD8(+) and CD4(+) alloeffector responses and significantly increased lung allograft CD4(+) : CD8(+) ratios. Examination of graft CD4(+) T-cells revealed significantly increased frequencies of CD4(+) CD25(+) Foxp3(+) regulatory T-cells in the lung allografts of anti-CD154-treated mice and was associated with significant attenuation of ACR compared to untreated controls. Together, these data show that CD154/CD40 costimulation blockade alone is sufficient to abrogate allospecific effector T-cell responses and significantly shifts the lung allograft toward an environment predominated by CD4(+) T regulatory cells in association with an attenuation of ACR.

Noradrenergic function and clinical outcome in antidepressant pharmacotherapy.

Controversy remains regarding the role of noradrenergic systems in determining clinical response to antidepressant pharmacotherapy. Pineal gland production of melatonin can serve as a physiologic index of noradrenergic function. The aim of this study was to examine the effects of antidepressant treatment on 24-hour urinary excretion of the principle metabolite of melatonin, 6-sulfatoxymelatonin in treatment responders and nonresponders. Twenty-four outpatients meeting DSM-III-R criteria for Major Depression received treatment with either fluvoxamine or imipramine for 6 weeks while participating in a placebo-controlled double-blind clinical trial. Twenty-four hour excretion of 6-sulfatoxymelatonin was measured at baseline and at the conclusion of the treatment trial. Changes in urinary excretion of 6-sulfatoxymelatonin distinguished antidepressant responders from nonresponders, with a significant increase observed in the former group and a significant decrease in the latter. The degree of clinical response was correlated with the change in 6-sulfatoxymelatonin excretion. These results suggest that enhanced noradrenergic function may play an important role in determining clinical response to antidepressant pharmacotherapy.

HOX genes in human lung: altered expression in primary pulmonary hypertension and emphysema.

HOX genes belong to the large family of homeodomain genes that function as transcription factors. Animal studies indicate that they play an essential role in lung development. We investigated the expression pattern of HOX genes in human lung tissue by using microarray and degenerate reverse transcriptase-polymerase chain reaction survey techniques. HOX genes predominantly from the 3' end of clusters A and B were expressed in normal human adult lung and among them HOXA5 was the most abundant, followed by HOXB2 and HOXB6. In fetal (12 weeks old) and diseased lung specimens (emphysema, primary pulmonary hypertension) additional HOX genes from clusters C and D were expressed. Using in situ hybridization, transcripts for HOXA5 were predominantly found in alveolar septal and epithelial cells, both in normal and diseased lungs. A 2.5-fold increase in HOXA5 mRNA expression was demonstrated by quantitative reverse transcriptase-polymerase chain reaction in primary pulmonary hypertension lung specimens when compared to normal lung tissue. In conclusion, we demonstrate that HOX genes are selectively expressed in the human lung. Differences in the pattern of HOX gene expression exist among fetal, adult, and diseased lung specimens. The altered pattern of HOX gene expression may contribute to the development of pulmonary diseases.

Carpal tunnel syndrome in women undergoing reduction mammaplasty.

Women with mammary hypertrophy who present for reduction mammaplasty have several well-described musculoskeletal complaints, but a high prevalence of carpal tunnel syndrome has not been reported. We identified 151 patients from a plastic surgery practice who underwent reduction mammaplasty from 1994 to 1996. To this group we added a convenience sample of 64 women volunteers with relatively smaller breasts (brassiere cup size B or smaller). We questioned the entire group about specific symptoms and examined them using standard provocative tests. Carpal tunnel syndrome was defined as the coexistence of symptoms and at least two physical examination findings. We examined its association with breast size, age, race, and body mass index. Stepwise logistic regression was used to determine which physical characteristics were predictive of the condition. Carpal tunnel syndrome was found in 30 patients (19.9 percent) (95 percent confidence interval, 13.8 to 27.1) and in none of the women in the convenience sample. Breast size and, to a lesser degree, body mass index were found to be highly significant predictors of carpal tunnel syndrome. After controlling for breast size, race was also significant. Breast size displayed an independent risk ratio of 6.67 when comparing the upper quartile of size to the lower quartiles. There is a markedly higher prevalence of carpal tunnel syndrome in women who present for reduction mammaplasty than in those with smaller breasts. Breast size was a significant predictor of carpal tunnel syndrome.

Hippocampal volume reduction in major depression.

OBJECTIVE: Elevated levels of glucocorticoids in depression have been hypothesized to be associated with damage to the hippocampus, a brain area involved in learning and memory. The purpose of this study was to measure hippocampal volume in patients with depression. METHOD: Magnetic resonance imaging was used to measure the volume of the hippocampus in 16 patients with major depression in remission and 16 case-matched nondepressed comparison subjects. RESULTS: Patients with depression had a statistically significant 19% smaller left hippocampal volume than comparison subjects, without smaller volumes of comparison regions (amygdala, caudate, frontal lobe, and temporal lobe) or whole brain volume. The findings were significant after brain size, alcohol exposure, age, and education were controlled for. CONCLUSIONS: These findings are consistent with smaller left hippocampal volume in depression.

Interaction of procedural factors in human performance on yoked schedules.

The differential effects of reinforcement contingencies and contextual variables on human performance were investigated in two experiments. In Experiment 1, adult human subjects operated a joystick in a video game in which the destruction of targets was arranged according to a yoked variable-ratio variable-interval schedule of reinforcement. Three variables were examined across 12 conditions: verbal instructions, shaping, and the use of a consummatory response following reinforcement (i.e., depositing a coin into a bank). Behavior was most responsive to the reinforcement contingencies when the consummatory response was available, responding was established by shaping, and subjects received minimal verbal instructions about their task. The responsiveness of variable-interval subjects' behavior varied more than that of variable-ratio subjects when these contextual factors were altered. Experiment 2 examined resistance to instructional control under the same yoked-schedules design. Conditions varied in terms of the validity of instructions. Performance on variable-ratio schedules was more resistant to instructional control than that on variable-interval schedules.

Issues in balancing teenage clients' confidentiality and reporting statutory rape among Kansas Title X clinic staff.

Through Federal welfare reform, Congress directed states to aggressively enforce statutory rape laws. Family planning professionals deal with many adolescent clients, and their support for such enforcement or willingness to report is unclear. The authors of this study examined current attitudes and practices of family planning program managers (FPPMs) about statutory rape law enforcement, including current reporting practices. In 1997, all 77 local Kansas Title X FPPMs were surveyed. Structured telephone interviews were conducted with 10 FPPMs to add detail to quantitative responses. Sixty-eight FPPMs responded to the written survey (88%). Of these, 79% supported aggressive enforcement, and 43% thought enforcement would reduce adolescent pregnancy rates. With increased enforcement, 38% believed teenagers would be discouraged from seeking reproductive health care, compared to 41% who believed they would not. Among key informants, all of whom were FPPMs, willingness to report cases was mixed, with those who would report wanting the flexibility to judge on a case-by-case basis. For those not reporting cases, confidentiality concerns overrode beliefs in any positive outcome of enforcement. Kansas Title X FPPMs strongly supported aggressive enforcement, but had mixed beliefs about negative consequences. Among those interviewed, there were also mixed beliefs and practices about reporting. Reporting from FPPMs will be sporadic and arbitrary unless protocols are developed and laws are clarified.

Interlaboratory comparison of ultrasonic backscatter, attenuation, and speed measurements.

In a study involving 10 different sites, independent results of measurements of ultrasonic properties on equivalent tissue-mimicking samples are reported and compared. The properties measured were propagation speed, attenuation coefficients, and backscatter coefficients. Reasonably good agreement exists for attenuation coefficients, but less satisfactory results were found for propagation speeds. As anticipated, agreement was not impressive in the case of backscatter coefficients. Results for four sites agreed rather well in both absolute values and frequency dependence, and results from other sites were lower by as much as an order of magnitude. The study is valuable for laboratories doing quantitative studies.

Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action.

BACKGROUND: Brain serotonin (5-HT) content is dependent on plasma levels of the essential amino acid, tryptophan (TRP). We have previously reported that rapid TRP depletion more frequently reversed the antidepressant response to monoamine oxidase inhibitors and 5-HT reuptake inhibitors than to desipramine (DMI). This study further investigates the relationship of relapse during TRP depletion to antidepressant type in nonrefractory, depressed patients randomly assigned to treatment with either DMI or fluoxetine (FLU). METHODS: Fifty-five drug-free depressed (DSM-III-R) patients were randomly assigned to antidepressant treatment with either DMI or FLU. All patients were either treatment naive (n = 34) or had previously received successful antidepressant treatment (n = 21). During the treatment phase, 35 patients had therapeutic responses by predetermined criteria (DMI 18/25; FLU 17/23) and 30 of these (15 DMI responders and 15 FLU responders) went on to TRP depletion testing. Patients received two 2-day test sessions involving administration of similar amino acid drinks. One session led to rapid TRP depletion and the other did not. Behavioral ratings [Hamilton Depression Scale (HDRS)] and plasma for TRP levels were obtained prior to, during, and after testing. Relapse was defined as a 50% increase in HDRS with total < or = 17. RESULTS: Total and free TRP decreased 70% to 80% 5 hours after the TRP-free drink. While 8/15 FLU responders relapsed, only 1/15 of the DMI responders relapsed. No patient experienced significant depressive symptoms during control testing. CONCLUSIONS: Rapid depletion of plasma TRP transiently reverses the antidepressant response in many patients on FLU but not DMI. Depressive relapse during TRP depletion appears to be more related to antidepressant type than to patient variables since patients were randomly assigned to the two treatments. Antidepressant response to FLU appears to be more dependent on 5-HT availability than that of DMI, suggesting that antidepressants mediate their therapeutic effects through different mechanisms.

Effect of catecholamine depletion on lithium-induced long-term remission of bipolar disorder.

BACKGROUND: This study investigated the effects of catecholamine depletion with alpha-methylparatyrosine (AMPT) on mood indices in patients with bipolar disorder who were in long-term remission with lithium therapy. METHODS: Eight subjects with DSM-IV bipolar disorder currently in remission for > 3 months on lithium were included in the study. Subjects were given either AMPT or placebo, in a randomized double-blind manner, in two test sessions of 4 days each. RESULTS: Subjects did not have any significant changes in mood during AMPT or placebo administration; however, 24-48 hours after the last active AMPT dose subjects had a transient relapse of hypomanic symptoms. Relapse of hypomanic symptoms did not correlate with increases in serum levels of homovanillic acid or 3-methoxy-4-hydroxyphenylglycol. CONCLUSIONS: These findings suggest that the mechanism of prevention of manic relapse by long-term lithium therapy may be dependent on stability of the catecholamine system.

The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial.

BACKGROUND: Preliminary reports have suggested that concomitant institution of pindolol and serotonin reuptake inhibitors robustly hastens clinical response; however, contradictory evidence from a randomized double-blind, controlled trial was recently reported by this group in a population of depressed patients who were prescribed fluoxetine and pindolol. Herein, we report final results from an extended sample size. METHODS: Drug-free outpatients with a major depressive episode were randomized in a double-blind manner to one of two treatment conditions: fluoxetine (20 mg daily) with pindolol (7.5 to 10 mg daily) or fluoxetine (20 mg daily) with placebo. After 6 weeks, patients were followed for 3 more weeks in a single-blind manner, on fluoxetine and placebo pindolol. RESULTS: Eighty-six patients completed at least 1 or more weeks on protocol, with 45 and 41 patients randomized to the pindolol and placebo groups respectively. After 2 weeks on protocol, partial remission (i.e., at least 50% decrease in depression rating scores from baseline) rates for pindolol (16%) and placebo (19%) groups were comparable. By the study's end, a partial remission was achieved, at least transiently, for 67% of the pindolol group and 80% of the placebo group. Pindolol treatment was associated with statistically significant reduction in blood pressure and pulse as compared to the control group. The two groups did not have overall differences in rates of attrition, time to response, and side effects. CONCLUSIONS: In accord with our previously published findings, these extended results do not support the efficacy of pindolol in hastening clinical response to fluoxetine in a patient population with predominantly chronic and recurrent depression.

Transient depressive relapse induced by catecholamine depletion: potential phenotypic vulnerability marker?

BACKGROUND: Although state-related alterations in catecholamine function have been well-described in depressed subjects, enduring abnormalities have been less reliably identified. In our study, medication-free subjects with fully remitted major depression underwent a paradigm of catecholamine depletion, via use of the tyrosine hydroxylase inhibitor alpha-methylparatyrosine. METHOD: Subjects underwent 2 sets of testing conditions in a double-blind, random-ordered, crossover design, approximately 1 week apart. They underwent active catecholamine depletion (via oral administration of 5 g alpha-methylparatyrosine) or sedation-controlled, sham catecholamine depletion (via oral administration of 250 mg diphenhydramine hydrochloride), during a 2-day observation. Serial mood ratings and blood samples were obtained. RESULTS: Fourteen subjects completed the active testing condition; 13 completed sham testing. Subjects experienced marked, transient increases in core depressive and anxiety symptoms, as demonstrated by a mean 21-point increase on Hamilton Depression Rating Scale scores. Furthermore, 10 (71%) of 14 subjects fulfilled relapse criteria during active testing, whereas 1 (8%) of 13 subjects did so during sham testing. The severity of the depressive reaction correlated with baseline plasma cortisol levels (r = 0.59; P =.04). CONCLUSIONS: Euthymic, medication-free subjects with a history of major depression demonstrate significant depressive symptoms when undergoing testing with alpha-methylparatyrosine. This depressive reaction may represent a reliable marker for a history of depression. Further work is needed to clarify the significance of this finding.

Issues in statutory rape law enforcement: the views of district attorneys in Kansas.

CONTEXT: The 1996 federal welfare reform law calls for the reduction of adolescent pregnancy rates through aggressive enforcement of statutory rape laws at the local and state level. Yet there are few quantitative data on district attorneys' attitudes toward enforcement and related issues. METHODS: Anonymous surveys were mailed to all 105 Kansas district attorneys in 1997; 92 surveys were returned. In-depth telephone interviews were conducted with seven of the attorneys. RESULTS: Most of the respondents (74%) favored aggressive enforcement, but just 37% believed the public would support aggressive enforcement. Only 24% believed enforcement would reduce adolescent pregnancy. Fifty-seven percent supported the current legal age of consent in Kansas (16 years). Fifty-three percent thought the law should not specify age differences between the partners. Most (77%) believed the law should protect sexually active minors, and that paternity acknowledgments should be admissible evidence in prosecutions (78%). Only 17% believed that enforcement would discourage adolescents from seeking health care. CONCLUSIONS: The potential impact of statutory rape prosecution on reproductive and psychological health should be considered in each case. Educating law enforcement officials about adolescent health care issues and encouraging them to consult with professionals in health and psychological fields may help to minimize the potentially negative effects of enforcement on adolescents' reproductive health.

PIP: Because there are few qualitative data on the attitudes of district attorneys towards the local enforcement of statutory rape laws called for by the 1996 federal welfare reform law, anonymous surveys were sent to all 105 Kansas district attorneys in 1997. Data were gathered from the 92 returned surveys and from in-depth telephone interviews with seven of the respondents. It was found that 74% of the respondents favored aggressive enforcement, but only 37% believed the public would support such action, and only 24% thought enforcement would reduce the incidence of adolescent pregnancy. While 57% supported the legal age of consent in Kansas (16 years), 53% thought the law should not specify age differences between the partners, but prosecutions are the exception when the age difference is less than 3 years unless the victim was mentally disabled or the case involved force. Most of the district attorneys (77%) rejected the view that a minor who is already sexually active does not merit the protection of statutory rape laws, and 78% felt that paternity acknowledgements should be admissible evidence in prosecutions. Only 17% expressed the opinion that enforcement would discourage adolescents from seeking health care. It was concluded that the impact of statutory rape prosecution on reproductive and psychological health should be considered on a case-by-case basis and that potentially negative impacts can be minimized by educating law enforcement officials about adolescent health care issues.

An epidemic of Malassezia pachydermatis in an intensive care nursery associated with colonization of health care workers' pet dogs.

BACKGROUND: Malassezia species are lipophilic yeasts that are emerging as nosocomial pathogens, particularly in low-birth-weight neonates who receive lipid emulsions. When a cluster of patients with Malassezia pachydermatis infection was identified in an intensive care nursery, we initiated an investigation. METHODS: A case patient was defined as any infant in the intensive care nursery who had a positive culture for M. pachydermatis between October 17, 1993, and January 18, 1995. We conducted a cohort study to identify risk factors for colonization and infection with M. pachydermatis. We collected cultures from the infants and the health care workers and from the health care workers' pets, since this organism has been associated with otitis externa in dogs. RESULTS: Fifteen infants met the case definition: eight with bloodstream infections, two with urinary tract infections, one with meningitis, and four with asymptomatic colonization. The case patients were significantly more likely than the other infants to weigh 1300 g or less (15 of 65 vs. 0 of 419, P<0.001). In a multivariate analysis of infants weighing 1300 g or less, the independent risk factors for colonization or infection with M. pachydermatis were a greater severity of concomitant illness (odds ratio, 19.7; P=0.001), arterial catheterization for nine or more days (odds ratio, 29.5; P=0.027), and exposure to Nurse A (odds ratio, 74.7; P=0.004). In a point-prevalence survey, 9 additional infants, 1 health care worker, and 12 of the health care workers' pet dogs had positive cultures for M. pachydermatis. The isolates from all 15 case patients, the 9 additional colonized infants, 1 health care worker, and 3 of the 12 dogs had identical patterns of restriction-fragment-length polymorphisms. CONCLUSIONS: In this outbreak, it is likely that M. pachydermatis was introduced into the intensive care nursery on health care workers' hands after being colonized from pet dogs at home. The organism persisted in the nursery through patient-to-patient transmission.

Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse.

BACKGROUND: Short-term depletion of plasma tryptophan has been shown to result in depressive relapse in patients with remission of major depression. Positron emission tomography and single photon emission computed tomography studies implicated the dorsolateral prefrontal cortex, orbitofrontal cortex, thalamus, and caudate nucleus in the pathogenesis of depression. The purpose of this study was to measure cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. METHODS: Patients diagnosed as having major depression (N = 21) who clinically improved with serotonin reuptake inhibitors underwent 2 test days involving tryptophan depletion or placebo, followed 6 hours later by positron emission tomography scanning with fludeoxy-glucose F18. Brain metabolism was compared in patients with (n = 7) and without (n = 14) a tryptophan depletion-induced depressive relapse. RESULTS: Tryptophan depletion resulted in a decrease in brain metabolism in the middle frontal gyrus (dorsolateral prefrontal cortex), thalamus, and orbitofrontal cortex in patients with a depletion-induced depressive relapse (but not in patients without depletion-induced relapse). Decreased brain metabolism in these regions correlated with increased depressive symptoms. Baseline metabolism was increased in prefrontal and limbic regions in relapse-prone patients. CONCLUSION: Specific brain regions, including the middle frontal gyrus, thalamus, and orbitofrontal cortex, may mediate the symptoms of patients with major depression.

Effect of pindolol in hastening response to fluoxetine in the treatment of major depression: a double-blind, placebo-controlled trial.

OBJECTIVE: In two preliminary studies, pindolol produced robust results in hastening clinical response to antidepressant drugs in depressed patients. Validity of those pilot studies was limited by use of an open-label, unblinded study design, and so the authors conducted a double-blind, placebo-controlled trial to assess the effectiveness of pindolol in hastening response to fluoxetine. METHOD: Drug-free outpatients with major depression were concurrently treated with fluoxetine (20 mg/day) and either placebo or pindolol (5.0 mg b.i.d. or 2.5 mg t.i.d.), for 6 weeks, in a randomized, double-blind manner. After 6 weeks, all patients received fluoxetine and placebo and were followed for 3 further weeks in a single-blind manner. RESULTS: Forty-three patients completed at least 1 week of the protocol. Rates of partial remission after 2 weeks of treatment with fluoxetine and either pindolol or placebo were 17% (four of 23 patients) and 20% (four of 20 patients), respectively. At study completion, 65% of the patients (N = 28) demonstrated at least a partial remission, and there was no difference between treatment groups. The pindolol group, but not the placebo group, demonstrated significant reductions in blood pressure and pulse rate. The average time to remission and the rates of attrition, overall response, and side effects were similar in the two groups. CONCLUSIONS: These findings do not support the efficacy of pindolol in hastening clinical response in patients treated with fluoxetine.