Differentiation stage of myeloma plasma cells: biological and clinical significance.

The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.

Insemination timing affects pregnancy rates in beef cows treated with CO-Synch protocol including an intravaginal progesterone insert.

Our objective was to determine the optimal time to artificially inseminate lactating beef cows (Bos taurus typicus) after using the standard CO-Synch protocol that also included a progesterone-releasing, intravaginal controlled internal drug release (CIDR) insert. Cows (N=605) at three locations were inseminated at four different times after CIDR insert removal and the prostaglandin F(2alpha) administration of the CO-Synch+CIDR protocol: 48, 56, 64, or 72h. Blood samples were collected 9 to 10 d before and on the day of CIDR insertion. Based on elevated (>1 ng/mL) serum progesterone concentrations, 60% of 605 cows had previously ovulated (were cycling) at the initiation of the study, with a range of 39.6% to 67.9% among locations (P<0.05). Age of cow, body condition score, and days postpartum affected (P< or =0.05) cycling status before ovulation was synchronized. Averaged across treatments, pregnancy rate to artificial insemination (AI) at Day 32 was affected (P< or =0.05) by pretreatment cycling status and body condition. Younger cows (< or =3 yr) tended to have greater AI pregnancy rates when inseminated at 56h, whereas older cows had similar pregnancy rates when inseminated at 56h or later (timing of AI by age interaction; P=0.085). Pregnancy loss between Days 32 and 63 was greatest (quadratic effect; P<0.05) when cows were inseminated at 48 and 72h. In summary, insemination times at or after 56h improved AI pregnancy rates when using the CO-Synch+CIDR program. Further work is warranted to examine age effects on timing of AI in the CO-Synch+CIDR program.

Synchronization of estrus and artificial insemination in replacement beef heifers using gonadotropin-releasing hormone, prostaglandin F2alpha, and progesterone.

We evaluated whether a fixed-time AI (TAI) protocol could yield pregnancy rates similar to a protocol requiring detection of estrus, or detection of estrus and AI plus a clean-up TAI for heifers not detected in estrus, and whether adding an injection of GnRH at controlled internal drug release (CIDR) insertion would enhance fertility in CIDR-based protocols. Estrus in 2,075 replacement beef heifers at 12 locations was synchronized, and AI was preceded by 1 of 4 treatments arranged as a 2 x 2 factorial design: 1) Estrus detection + TAI (ETAI) (n = 516): CIDR for 7 d plus 25 mg of prostaglandin F2alpha (PG) at CIDR insert removal, followed by detection of estrus for 72 h and AI for 84 h after PG (heifers not detected in estrus by 84 h received 100 microg of GnRH and TAI); 2) G+ETAI (n = 503): ETAI plus 100 microg GnRH at CIDR insertion; 3) Fixed-time AI (FTAI) (n = 525): CIDR for 7 d plus 25 mg of PG at CIDR removal, followed in 60 h by a second injection of GnRH and TAI; 4) G+FTAI (n = 531): FTAI plus 100 microg of GnRH at CIDR insertion. Blood samples were collected (d -17 and -7, relative to PG) to determine ovarian status. For heifers in ETAI and G+ETAI treatments, a minimum of twice daily observations for estrus began on d 0 and continued for at least 72 h. Inseminations were performed according to the a.m.-p.m. rule. Pregnancy was diagnosed by transrectal ultrasonography. The percentage of heifers exhibiting ovarian cyclic activity at the initiation of treatments was 89%. Pregnancy rates among locations across treatments ranged from 38 to 74%. Pregnancy rates were 54.7, 57.5, 49.3, and 53.1% for ETAI, G+ETAI, FTAI, and G+FTAI treatments, respectively. Although pregnancy rates were similar among treatments, a tendency (P = 0.065) occurred for pregnancy rates in the G+ETAI treatment to be greater than in the FTAI treatment. We concluded that the G+FTAI protocol yielded pregnancy rates similar to protocols that combine estrus detection and TAI. Further, the G+FTAI protocol produced the most consistent pregnancy rates among locations and eliminated the necessity for detection of estrus when inseminating replacement beef heifers.

Synchronization of estrus in suckled beef cows for detected estrus and artificial insemination and timed artificial insemination using gonadotropin-releasing hormone, prostaglandin F2alpha, and progesterone.

We determined whether a fixed-time AI (TAI) protocol could yield pregnancy rates similar to a protocol requiring detection of estrus, or estrous detection plus TAI, and whether adding a controlled internal device release (CIDR) to GnRH-based protocols would enhance fertility. Estrus was synchronized in 2,598 suckled beef cows at 14 locations, and AI was preceded by 1 of 5 treatments: 1) a CIDR for 7 d with 25 mg of PG F(2alpha) (PGF) at CIDR removal, followed by detection of estrus and AI during the 84 h after PGF; cows not detected in estrus by 84 h received 100 mug of GnRH and TAI at 84 h (control; n = 506); 2) GnRH administration, followed in 7 d with PGF, followed in 60 h by a second injection of GnRH and TAI (CO-Synch; n = 548); 3) CO-Synch plus a CIDR during the 7 d between the first injection of GnRH and PGF (CO-Synch + CIDR; n = 539); 4) GnRH administration, followed in 7 d with PGF, followed by detection of estrus and AI during the 84 h after PGF; cows not detected in estrus by 84 h received GnRH and TAI at 84 h (Select Synch & TAI; n = 507); and 5) Select Synch & TAI plus a CIDR during the 7 d between the first injection of GnRH and PGF (Select Synch + CIDR & TAI; n = 498). Blood samples were collected (d -17 and -7, relative to PGF) to determine estrous cycle status. For the control, Select Synch & TAI, and Select Synch + CIDR & TAI treatments, a minimum of twice daily observations for estrus began on d 0 and continued for at least 72 h. Inseminations were performed using the AM/PM rule. Pregnancy was diagnosed by transrectal ultrasonography. Percentage of cows cycling at the initiation of treatments was 66%. Pregnancy rates (proportion of cows pregnant to AI of all cows synchronized during the synchronization period) among locations across treatments ranged from 37% to 67%. Pregnancy rates were greater (P < 0.05) for the Select Synch + CIDR & TAI (58%), CO-Synch + CIDR (54%), Select Synch & TAI (53%), or control (53%) treatments than the CO-Synch (44%) treatment. Among the 3 protocols in which estrus was detected, conception rates (proportion of cows that became pregnant to AI of those exhibiting estrus during the synchronization period) were greater (P < 0.05) for Select Synch & TAI (70%; 217 of 309) and Select Synch + CIDR & TAI (67%; 230 of 345) cows than for control cows (61%; 197 of 325). We conclude that the CO-Synch + CIDR protocol yielded similar pregnancy rates to estrous detection protocols and is a reliable TAI protocol that eliminates detection of estrus when inseminating beef cows.

Methods to reduce or eliminate detection of estrus in a melengestrol acetate-PGF2alpha protocol for synchronization of estrus in beef heifers.

Three experiments were conducted to evaluate methods to decrease or eliminate the detection of estrus inherent to a melengestrol acetate (MGA)-PGF2alpha (PGF) protocol for synchronization of estrus in heifers. In each experiment, all heifers received 0.5 mg of MGA x animal(-1) x d(-1) for 14 d (d -32 to -19) and PGF (25 mg, i.m.; d 0, 0 h) 19 d after the last feeding of MGA (MGA-PGF protocol). In Exp. 1, heifers (n = 709) were assigned to each of the following protocols: 1) the MGA-PGF protocol with AI 6 to 12 h after detection of estrus (estrus AI; MGA-PGF); 2) MGA-PGF plus 100 microg, i.m. of GnRH on d -7 (1x GnRH) and estrus AI; or 3) MGA-PGF, GnRH on d -7, and GnRH (100 microg, i.m.) at 48 h after PGF, coincident with insemination (2x GnRH-TB48). In Exp. 2, heifers (n = 559) received the MGA-PGF protocol and were inseminated by either estrus AI or fixed-time AI (TAI) at 60 h, coincident with an injection of GnRH (GnRH-TB60). In Exp. 3, all heifers (n = 460) received the MGA-PGF protocol and were inseminated by estrus AI when detected up to 73 h. Heifers not observed in estrus by 73 h received TAI between 76 and 80 h. Half the heifers inseminated by TAI received no further treatment (TB80), and the remaining half was injected with GnRH at insemination (GnRH-TB80). Variance associated with the interval to estrus and the proportion in estrus from d 0 to 5 was similar for 1x GnRH and MGA-PGF treatments in Exp. 1. Pregnancy rate (d 0 to 5) did not differ for the MGA-PGF and 1x GnRH treatments (62.5 and 60.4%, respectively), and both were greater (P < 0.05) than TAI pregnancy rate in the 2x GnRH-TB48 treatment (42.3%). In Exp. 2, the peak estrous response occurred 60 h after PGF. Pregnancy rate during the synchrony period was greater (P < 0.05) for the MGA-PGF (255/401; 63.6%) than the GnRH-TB60 (74/158; 46.6%) treatment. In Exp. 3, 75.7% of heifers (348/460) were detected in estrus by 73 h and were inseminated, with a conception rate of 74.4%. Pregnancy rates after TAI did not differ between TB80 and GnRH-TB80 (14/56 = 25% and 19/ 56 = 33.9%, respectively). Total pregnancy rate was 63.5% for heifers inseminated after detected estrus and by TAI. Collectively, these data indicate that the exclusive use of TAI for heifers treated with the MGA-PGF protocol resulted in lower pregnancy rates than when AI was performed after detection of estrus. However, estrus AI for 3 d and TAI at the end of d 3 could result in pregnancy rates similar to those achieved after a 5-d period of detecting estrus.

Resynchronization of estrus in cattle of unknown pregnancy status using estrogen, progesterone, or both.

Our objective was to develop treatments applied to cattle of unknown pregnancy status that would resynchronize the repeat estrus of nonpregnant females. In Exp. 1, previously inseminated dairy and beef heifers were assigned randomly to each of three treatments 13 d after AI: 1) no treatment (controls; n = 44); 2) 0.5 mg of estradiol cypionate (ECP) i.m. on d 13 and 20 at the time of insertion and removal of a used intravaginal progesterone (P4)-releasing insert (CIDR; P4 + ECP; n = 44); and 3) same as P4 + ECP without injections of ECP (P4; n = 42). The P4 + ECP (>90%) and P4 (>75%) protocols effectively synchronized repeat periods of estrus to 2 d and did not harm established pregnancies. In Exp. 2, treatments similar to those in Exp. 1 were applied to previously inseminated beef heifers (n = 439). Feeding 0.5 mg of melengestrol acetate (MGA) from d 13 to 19 after AI replaced the CIDR as a source of progestin. Of those heifers not pregnant (n = 65) after the initial AI, more than 86% were reinseminated, but conception was decreased (P < 0.05) by 28 to 39% compared with controls. In Exp. 3, previously inseminated lactating beef cows at four locations were assigned within herd to each of three treatments: 1) no treatment (control; n = 307); 2) same as in Exp. 1, but with P4 + 1 mg of estradiol benzoate on d 13 and 20 (P4 + EB; n = 153); and 3) same as in Exp. 1, P4 + ECP (n = 149). Treatments with P4 plus estrogen did not decrease conception rates in pregnant cows at any location, but increased (P < 0.05) the percentage of nonpregnant cows returning to estrus between 19 and 23 d after timed AI from 29% in controls to 86% in P4 + EB and 65% in P4 + ECP cows. Conception rates at the return estrus were not decreased when treatments occurred between d 13 and 20. In Exp. 4, lactating beef cows were assigned as in Exp. 3 to each of three treatments: 1) no treatment (controls; n = 51); 2) P4 + ECP (n = 47), as in Exp. 1; and 3) a single injection of ECP on d 13 (n = 48). Previously established pregnancies were not harmed (P = 0.70), and return rates of nonpregnant cows did not differ (P = 0.78) among treatments. In summary, in both heifers and lactating beef cows, the P4-based resynchronization treatments increased synchronized return rates when estrus detection rates were low, had no negative effects on established pregnancies, and decreased or tended to decrease conception rates at the resynchronized estrus.

Supplemental norgestomet, progesterone, or melengestrol acetate increases pregnancy rates in suckled beef cows after timed inseminations.

In Exp. 1, 187 lactating beef cows were treated with injections of GnRH 7 d before and 48 h after prostaglandin F2alpha (PGF2alpha; Cosynch) or with Cosynch plus a 7-d treatment with an intravaginal progesterone (P4)-releasing insert (CIDR-B; Cosynch + CIDR). In Exp. 2, 183 lactating beef cows were treated with the Cosynch protocol or with Cosynch plus a 7-d treatment with norgestomet (Cosynch + NORG). In Exp. 1 and 2, blood samples for later P4 analyses were collected on d -17, -7 (first GnRH injection), 0 (PGF2alpha injection), and at timed artificial insemination (TAI; 48 h after PGF2alpha). In Exp. 3, 609 lactating beef cows were treated with the Cosynch + CIDR protocol or were fed 0.5 mg of melengestrol acetate (MGA) per day for 14 d before initiating the Cosynch protocol 12 d after the 14th d of MGA feeding (MGA + Cosynch). Blood samples were collected as in Exp. 1 and 2, plus additional samples on d -33 and -19 before PGF2alpha. In Exp. 4, 360 lactating beef cows were treated with a Cosynch + CIDR protocol, with TAI occurring at either 48 or 60 h after PGF2alpha, while receiving either GnRH or saline to form four treatments. Blood samples were collected as in Exp. 1 and 2. In Exp. 1, addition of P4 reduced the ability of the first GnRH injection to induce ovulation in anestrous cows with low P4 before PGF2alpha but improved (P = 0.06) pregnancy rates (61 vs 66%). In Exp. 2, the addition of NORG mimicked P4 by likewise increasing (P < 0.01) pregnancy rates (31 vs 51%) beyond those after Cosynch. In Exp. 3, the Cosynch + CIDR protocol increased (P < 0.001) pregnancy rates from 46 to 55% compared to the MGA + Cosynch protocol. In Exp. 4, administration of GnRH at TAI improved (P < 0.05) pregnancy outcomes (50 vs 42%), whereas timing of TAI had limited effects. We conclude that a progestin treatment concurrent with the Cosynch protocol improved pregnancy outcomes in all experiments, but pretreatment of cows with MGA was not as effective as the CIDR insert or NORG implants in this Cosynch-TAI model. Most of the improvement in pregnancy rates was associated with the increase in pregnancy rates of anestrous cows, regardless of whether ovulation was successfully induced in response to GnRH 7 d before PGF2alpha. Injection of GnRH at TAI following the Cosynch + CIDR protocol increased pregnancy rates in cycling cows with high P4 before the PGF2alpha injection and in anestrous cows with low P4 before PGF2alpha injection.

Characteristics of estrus before and after first insemination and fertility of heifers after synchronized estrus using GnRH, PGF2alpha, and progesterone.

Our objectives were to determine fertility of heifers after synchronization of estrus using PGF2alpha, preceded by progesterone (P4), GnRH, or both, and to examine the variability of estrual characteristics in heifers before first and second AI. Dairy (n = 247) and beef (n = 193) heifers were assigned randomly to each of three treatments: 1) 50 microg of GnRH (injected i.m.) administered on d -7 followed by 25 mg of PGF2alpha (i.m.) on d -1 (GnRH + PGF; modified Select Synch protocol); 2) placement of an intravaginal progesterone (P4)-releasing insert on d -7, PGF2alpha on d -1, and insert removal on d 0 (P4+PGF); and 3) 50 microg of GnRH plus a P4 insert on d -7, followed by 25 mg of PGF2alpha on d -1, and insert removal on d 0 (P4+GnRH+PGF). Characteristics of estrus were examined before first AI and before the next eligible AI (18 to 26 d later), including duration of estrus, number of standing events, and total and individual duration of standing events. In addition, all heifers were checked visually at least twice daily for estrus. Blood samples were collected on d -7, -1, and 0 for determination of P4, and pregnancy status was diagnosed by ultrasonography 27 to 34 d after AI. Rates of detected estrus were less (P < 0.05) in dairy than in beef heifers, and greater (P < 0.05) in heifers treated with P4. Pattern of conception and pregnancy rates among treatments differed between beef and dairy heifers (treatment x group interaction; P < 0.05). In dairy heifers, conception and pregnancy rates were greatest with P4+PGF, followed by P4+GnRH+PGF and GnRH+PGF, respectively. The opposite was observed among treatments in beef heifers. Administration of P4 without the preceding injection of GnRH produced the lowest pregnancy rates in beefheifers. Ofthe quantified sexual behavioral characteristics during the synchronized estrus, the number of standing events and total duration of standing events were greater (P < 0.01) than those observed during the next eligible estrus before second AI, whereas duration of estrus was unaffected.

Longitudinal assessment of neuropsychological functioning, psychiatric status, functional disability and employment status in chronic fatigue syndrome.

The longitudinal course of subjective and objective neuropsychological functioning, psychological functioning, disability level, and employment status in chronic fatigue syndrome (CFS) was examined. The relations among several key outcomes at follow-up, as well as the baseline characteristics that predict change (e.g., improvement), were also evaluated. The study sample consisted of 35 individuals who met the 1988 and 1994 CFS case definition criteria of the Centers for Disease Control (CDC) at intake. Participants were evaluated a mean of 41.9 (SEM = 1.7) months following their initial visit (range = 24-63 months). Results indicated that objective and subjective attention abilities, mood, level of fatigue, and disability improve over time in individuals with CFS. Moreover, improvements in these areas were found to be interrelated at follow-up. Finally, psychiatric status, age, and between-test duration were significant predictors of outcome. Overall, the prognosis for CFS appears to be poor, as the majority of participants remained functionally impaired over time and were unemployed at follow-up, despite the noted improvements.

Immune cell infiltrates and prognosis in primary carcinoma of the lung.

The prognostic significance of immune cell infiltrates in surgically resected human lung cancer was investigated in 710 patients. Lymphoid infiltrates were quantified on both standard H&E stained sections and, in a subset of 95 cases, using immunohistochemistry and antibodies to CD3, CD8, CD57, CD68, CD79a and S100 to identify various immune cell types. Subjective grading (low, moderate, high) of lymphoid cell infiltrates on H&E sections of tumour and measurement, using image analysis, of overall level of tumour infiltration by any of the immunohistochemically labelled specific immune cell types of the stained sections showed no prognostic significance. However, when a distinction between peritumoural and intratumoural infiltration by particular cell types was made, intratumoural infiltration by high levels of CD3+ and S100+ cells was associated with longer post-operative survival (P = 0.02 and P = 0.045, respectively). In lung cancer, subjective assessment of tumour lymphoid infiltration and overall levels of infiltration by particular immune cell types carries no prognostic significance. Intratumoural infiltration by relatively high numbers of CD3+ T-lymphocytes and Langerhans cells (S100+) is associated with a better patient outcome.

DnaB helicase stimulates primer synthesis activity on short oligonucleotide templates.

DnaB helicase stimulated the second-order RNA primer synthesis activity of primase by over 5000-fold on DNA templates that were 23 nucleotides long. This template length is the same as the DnaB helicase thermodynamic binding site size [Jezewska, M. J., and Bujalowski, W. (1996) Biochemistry 35, 2117-2128]. This phenomenal stimulation was achieved by increasing the template affinity of primase by over 300-fold and increasing the catalytic rate by over 15-fold. It was necessary to determine the optimal amount of DnaB helicase to achieve this stimulation because helicase stimulation was cooperative at low concentration and inhibitory at high helicase concentration. The cooperative stimulation at low concentration indicated the presence of a time-dependent assembly step that preceded the active state. Besides stimulating primase activity, DnaB helicase also prevented primase from synthesizing RNA primers that were longer than the template sequence. In the absence of DnaB helicase, the majority of primers synthesized by primase were longer than the template and were named "overlong primers" [Swart, J. R., and Griep, M. A. (1995) Biochemistry 34, 16097-16106]. In contrast, the helicase-stimulated RNA primers were from 10 to 14 nucleotides in length with the 12-mer representing the majority of the total RNA primers produced. It was shown that DnaB helicase stabilized the open or single-stranded conformation of the template, which favored the synthesis of the template-length-dependent primers. In contrast, when primase acted alone, it stabilized the 3'-end hairpin conformation of the template so that the template's 3'-hydroxyl served as a "DNA primer" from which primase elongated to create the overlong primers.

Transcriptional regulation of the human ADP-ribosylation factor 5 (ARF5) gene.

Hybridization of a blot containing 50 human RNAs with an ADP-ribosylation factor 5-specific (ARF5) oligonucleotide probe revealed that the ARF5 gene is expressed in all tissues; however, the level of expression varies significantly with highest levels in pancreas, pituitary gland, and placenta. The 5'-flanking region of the human ARF5 gene lacks a TATA or CAAT box and is highly GC-rich. Primer extension analysis indicates that transcription initiates at a discrete site 62 bp 5' to the start of translation; however, the sequence surrounding the transcription initiation site does not resemble the initiator elements described for other TATA-less genes. Transient transfection of ARF5/luciferase deletion constructs into human IMR-32 neuroblastoma cells revealed that sequences within 169 bp of the transcription initiation site were necessary for full expression. Two GC boxes within this region were modified by site-directed mutagenesis and found to be critical for expression of the reporter constructs. Electrophoretic mobility-shift assays demonstrated specific DNA/protein complexes could be formed with oligonucleotides containing each of the GC boxes and these complexes could be effectively competed by oligonucleotides containing either ARF5 Sp1 site or by an oligonucleotide containing a previously characterized Sp1-binding sequence. The level of ARF5 gene expression, therefore, is dependent upon Sp1 or an Sp1-like factor but does not rely upon a canonical initiator element for accurate transcription initiation.

Examination of Cloninger's basic dimensions of personality in fatiguing illness: chronic fatigue syndrome and multiple sclerosis.

Relatively few studies have examined the personality characteristics of patients with chronic fatigue syndrome (CFS). The personality profiles of 38 CFS subjects were compared with 40 healthy controls and 40 subjects with multiple sclerosis (MS), a chronic illness that shares many symptoms with CFS (e.g., fatigue), but has a known neurological substrate. Subjects were examined within Cloninger's biosocial theory of personality, which delineates basic dimensions of temperament. Both illness groups displayed similarly elevated levels of Harm Avoidance, and lower levels of Reward Dependence as compared with healthy controls. The MS group showed a lower level of Persistence than controls and CFS subjects. Implications for the relationship between chronic illness and personality are discussed.

Chronic fatigue syndrome: reviewing the research findings.

This article reviews the current state of research in chronic fatigue syndrome (CFS). The evolving definition, prevalence, and prognosis of this controversial illness are presented. We review studies examining psychiatric, personality, and psychosocial etiology for CFS. The evidence for pathophysiology in CFS is also presented, and studies investigating viral, immune, neuroimaging, neuroendocrine, and central and autonomic nervous system abnormalities in CFS are assessed. Current evidence indicates that CFS is multi-determined and heterogeneous and that subgrouping patients according to factors such as psychiatric state and symptom onset may be fruitful. The current state of treatment for CFS is reviewed, and the challenges for research aimed at resolving this prototypical mind/body problem are discussed.

Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome.

The purpose of this study was to determine the effect of exhaustive exercise on cognitive performance of patients with chronic fatigue syndrome (CFS) and sedentary healthy controls (CON). Subjects were 19 women with CFS and 20 CON. A test battery consisting of 4 cognitive tests (CTB) was given pre-, immediately post-, and 24 hours post-treadmill exercise to exhaustion. No differences were seen on the CTB pre-exercise. CFS patients improved at a slower rate than CON on the Symbol Digit Modalities Test (SDMT), Stroop Word Test (SWT), and Stroop Color Test (SCT). When compared with CON, a lower number of correct responses was seen for the CFS immediately postexercise on the SDMT (61 +/- 3 vs 66 +/- 2), SWT (137 +/- 6 vs 146 +/- 6), and SCT (99 +/- 4 vs 107 +/- 3), and 24 hours postexercise on the SDMT (64 +/- 3 vs 69 +/- 2), SWT (134 +/- 7 vs 148 +/- 5), and SCT (101 +/- 4 vs 106 +/- 3). We conclude that after physically demanding exercise, CFS subjects demonstrated impaired cognitive processing compared with healthy individuals.

Partial regression in primary carcinoma of the lung: does it occur?

AIMS: To study immunohistochemically a group of 28 primary lung cancers which demonstrated histological features reminiscent of those characteristic of regression in malignant melanoma, to determine the phenotype of their immune cell infiltrates. METHODS AND RESULTS: Using a standard s-ABC immunoperoxidase method then quantification by the Leica Q500 MC image analyser, the cellular infiltrate in these tumours, when compared to 67 control cases, showed excess CD3 + T lymphocytes (P < 0.007), with an increase in CD4:CD8 ratio and increased CD68 + macrophages (P = 0.00001). CD57 + natural killer cells and S100 + Langerhans cells were also increased, but not quite significantly (P = 0.048 and P = 0.072, respectively). CONCLUSIONS: This immunophenotype resembles that shown in regressing skin malignancies and suggests a similar process occurring in lung cancer. Regressing lung cancers are associated with a better prognosis than matched controls (P = 0.0034), some showed radiological evidence of growth retardation and the group had an excess of the large cell undifferentiated histological type.

Relation between neuropsychological impairment and functional disability in patients with chronic fatigue syndrome.

OBJECTIVES: To examine the relation between neuropsychological impairment and functional disability in patients with chronic fatigue syndrome, and determine whether the relation is independent of psychiatric factors. METHODS: The subjects were 53 patients with chronic fatigue syndrome and 32 healthy controls who did not exercise regularly. Subjects were administered a structured psychiatric interview and completed questionnaires focusing on depression and functional disability. They also completed a battery of standardised neuropsychological tasks focusing on the cognitive domains that patients with chronic fatigue syndrome experience as particularly difficult: memory (verbal and visual), and attention/concentration. A test score was defined as failing when it was > or =2 SD below the mean of the healthy controls after controlling for demographic factors. RESULTS: Those patients with chronic fatigue syndrome with higher numbers of failing neuropsychological test scores reported significantly more days of general inactivity in the past month than those with fewer failing scores. This result remained significant even after partialling out the contribution of the presence of a comorbid axis I psychiatric episode and the overall level of depressive symptomology. Patients with failing verbal memory scores were particularly functionally disabled compared with those with passing scores. CONCLUSION: A relation was found between cognitive impairment and functional disability which could not be explained entirely on the basis of psychiatric factors.

Luteal function and estrus in peripubertal beef heifers treated with an intravaginal progesterone releasing device with or without a subsequent injection of estradiol.

The objectives of this experiment were to determine if treatment of beef heifers with progesterone (P4) using an intravaginal device alone or in combination with estradiol benzoate (EB) would induce estrus and cause development of corpora lutea (CL) with a typical life span. Peripubertal heifers (n = 311) were used when about 40% of the heifers had a functional CL. The heifers were assigned to receive one of the following treatments on Day 0: 1) a sham device for 7 d (C, n = 108); 2) an intravaginal device containing P4 for 7 d (P, n = 102); or 3) an intravaginal device containing P4 for 7 d plus an injection of 1 mg EB 24 to 30 h after device removal (PE, n = 101). Serum concentrations of P4 were determined on Days -7, 0, 8, 15 and 22. Weight and age of the heifers at the start of the trial averaged 292 +/- 45 kg and 365 +/- 38 d, respectively. A greater (P < 0.0001) proportion of the heifers from the PE than P group was in standing estrus (81 vs 37%) and formed normal CL (68 vs 44%) after device removal. Of the heifers exhibiting estrus, a greater (P < 0.05) proportion of PE (94%) than P (80%) heifers was active 1 to 3 d after implant removal. Short-term progesterone treatment increased the proportion of heifers in estrus and those forming normal CL, and adding EB to the progesterone treatment further enhanced these responses.