Facial expressivity in dominant macaques is linked to group cohesion.

Social living affords primates (including humans) many benefits. Communication has been proposed to be the key mechanism used to bond social connections, which could explain why primates have evolved such expressive faces. We assessed whether the facial expressivity of the dominant male (quantified from the coding of anatomically based facial movement) was related to social network properties (based on social proximity and grooming) in nine groups of captive rhesus macaques (Macaca mulatta) housed in uniform physical and social environments. More facially expressive dominant male macaques were more socially connected and had more cohesive social groups. These findings show that inter-individual differences in facial expressivity are related to differential social outcomes at both an individual and group level. More expressive individuals occupy more beneficial social positions, which could help explain the selection for complex facial communication in primates.

Managing loneliness: a qualitative study of older people's views.

Engaging with older people who self-identify as lonely may help professionals in mental health and other services understand how they deal with loneliness. The evidence-base for effective interventions to address loneliness is inconclusive. This study aimed to explore how community-dwelling lonely older people in England manage their experiences of loneliness. Twenty eight community-dwelling older people identifying as lonely, based on responses to two loneliness measures (self-report and a standardised instrument), participated in in-depth interviews between 2013 and 2014. Fifteen lived alone. Thematic analysis of transcribed interviews was conducted by a multidisciplinary team including older people.Participants drew on a range of strategies to ameliorate their distress which had been developed over their lives and shaped according to individual coping styles and contexts. Strategies included physical engagement with the world beyond their home, using technologies, planning, and engagement with purpose in an 'outside world', and acceptance, endurance, revealing and hiding, positive attitude and motivation, and distraction within an 'inside world'. Strategies of interests and hobbies, comparative thinking, religion and spirituality and use of alcohol straddled both the inside and outside worlds. Participants conveyed a personal responsibility for managing feelings of loneliness rather than relying on others. This study includes the experiences of those living with loneliness whilst also living with other people. When developing policy and practice responses to loneliness it is important to listen attentively to the views of those who may not be engaging with services designed for 'the lonely' and to consider their own strategies for managing it.

The diagnosis and management of respiratory tract fungal infection in cystic fibrosis: A UK survey of current practice.

Aspergillus fumigatus is commonly found in the airways of patients with cystic fibrosis (CF), and allergic bronchopulmonary aspergillosis (ABPA) is the most recognized associated clinical condition. However, accurate diagnosis remains challenging, and there is a paucity of clinical trials to guide clinical management of fungal disease. The aim of this survey was to assess the variability in current practice across the UK in diagnosis and management of fungal lung disease in CF patients. A 21 question anonymous online survey was sent to 94 paediatric and adult CF consultants in the UK. The response rate was 60.6% (32 adult physicians, 25 pediatricians) with 55 full and 2 partially completed surveys. For a first diagnosis of ABPA 20 (35.1%) treat with prednisolone alone, 38 (66.7%) use prednisolone with itraconazole and 2 (3.5%) choose voriconazole. Only 5 (8.8%) treat with prednisolone alone for a 1st relapse, 33 (58%) used prednisolone with itraconazole. To reduce treatment, 21 (36.8%) decrease steroids to zero over time and maintain azole therapy, 18 (31.6%) stop the azole and steroid after a fixed time, and 5 (8.8%) stop the azole after a fixed time and maintain a small steroid dose. Thirty-eight (66.7%) respondents believe Aspergillus colonization of the airway can cause clinical deterioration, and 37 (66.1%) would treat this. Scedosporium apiospermum infection has been diagnosed and treated by 35 (61.4%) of respondents. Results of this survey highlight the variance in clinical practice and the limited evidence available to guide management of fungal infection in CF.

Width Scaling of an Interface Constrained by a Membrane.

We investigate the shape of a growing interface in the presence of an impenetrable moving membrane. The two distinct geometrical arrangements of the interface and membrane, obtained by placing the membrane behind or ahead of the interface, are not symmetrically related. On the basis of numerical results and an exact calculation, we argue that these two arrangements represent two distinct universality classes for interfacial growth: while the well-established Kardar-Parisi-Zhang (KPZ) growth is obtained in the "ahead" arrangement, we find an arrested KPZ growth with a smaller roughness exponent in the "behind" arrangement. This suggests that the surface properties of growing cell membranes and expanding bacterial colonies, for example, are fundamentally distinct.

Children, but not chimpanzees, have facial correlates of determination.

Facial expressions have long been proposed to be important agents in forming and maintaining cooperative interactions in social groups. Human beings are inordinately cooperative when compared with their closest-living relatives, the great apes, and hence one might expect species differences in facial expressivity in contexts in which cooperation could be advantageous. Here, human children and chimpanzees were given an identical task designed to induce an element of frustration (it was impossible to solve). In children, but not chimpanzees, facial expressions associated with effort and determination positively correlated with persistence at the task. By contrast, bodily indicators of stress (self-directed behaviour) negatively correlated with task persistence in chimpanzees. Thus, children exhibited more behaviour as they persisted, and chimpanzees exhibited less. The facial expressions produced by children, could, therefore, function to solicit prosocial assistance from others.

Body mass index and nutritional intake following Elexacaftor/Tezacaftor/Ivacaftor modulator therapy in adults with cystic fibrosis.

BACKGROUND: Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy is often associated with increased body mass index (BMI) in people with cystic fibrosis (CF). This is thought to reflect improved clinical stability and increased appetite and nutritional intake. We explored the change in BMI and nutritional intake following ETI modulator therapy in adults with CF. METHODS: Dietary intake, measured with myfood24®, and BMI were collected from adults with CF at baseline and follow-up as part of an observational study. Changes in BMI and nutritional intake in participants who commenced ETI therapy between time points were assessed. To contextualize findings, we also assessed changes in BMI and nutritional intake between study points in a group on no modulators. RESULTS: In the pre and post ETI threapy group (n = 40), BMI significantly increased from 23.0 kg/m2 (IQR 21.4, 25.3) at baseline to 24.6 kg/m2 (IQR 23.0, 26.7) at follow-up (p<0.001), with a median of 68 weeks between time points (range 20-94 weeks) and median duration of ETI therapy was 23 weeks (range 7-72 weeks). There was a significant decrease in energy intake from 2551 kcal/day (IQR 2107, 3115) to 2153 kcal/day (IQR 1648, 2606), p<0.001. In the no modulator group (n = 10), BMI and energy intake did not significantly change between time points (p>0.05), a median of 28 weeks apart (range 20-76 weeks). CONCLUSIONS: These findings tentatively suggest that the increase in BMI with ETI therapy may not simply be attributable to an increase in oral intake. Further exploration into the underlying aetiology of weight gain with ETI therapy is needed.

Diabetes is associated with increased burden of gastrointestinal symptoms in adults with cystic fibrosis.

BACKGROUND: Individuals with diabetes mellitus (DM) are known to frequently experience gastrointestinal (GI) symptoms. In contrast, the impact of cystic fibrosis-related diabetes (CFRD) on accentuating GI symptoms in people with cystic fibrosis (pwCF) is unknown. We sought to examine this. METHODS: Abdominal symptoms were measured using the validated CF-specific GI symptom questionnaire - CFAbd-Score© - as part of a multicentre cohort study in pancreatic insufficient adults with CF, not on cystic fibrosis transmembrane conductance regulator (CFTR) modulators. The CFAbd-Score total score (0-100pts), its 5 domains, alongside nine specific GI symptoms associated with DM, were compared between the CFRD and non-CFRD groups. RESULTS: 27 (31%) and 61 (69%) participants with CF were recruited in the CFRD and non-CFRD groups respectively. Total CFAbd-Score and the two domains: gastroesophageal reflux disease and disorders of appetite were significantly higher in the CFRD group compared to the non-CFRD group (p<0.05), with the mean total CFAbd-Score being 25.4 ± 2.5 and 18.4 ± 1.5 in the CFRD and non-CFRD groups respectively. Among the nine GI symptoms commonly reported as elevated in DM, bloating and nausea were significantly more common in individuals with CFRD compared to those without (p<0.05). CONCLUSIONS: Individuals with CFRD overall, have a higher GI symptom burden, according to CFAbd-Scores. Specifically, they experience significantly more bloating and nausea. Close monitoring and further research is needed to better understand and manage GI symptoms in this group.

Long-term impact of liver transplantation on respiratory function and nutritional status in children and adults with cystic fibrosis.

Early liver transplant (LT) has been advocated for patients with cystic fibrosis liver disease (CFLD) and evidence of deterioration in nutritional state and respiratory function to prevent further decline. However, the impact of single LT on long-term respiratory function and nutritional status has not been adequately addressed. We performed a retrospective analysis of the outcomes of 40 (21 adult/19 pediatric) patients with CFLD transplanted between 1987 and 2009 with median follow-up of 47.8 months (range 4-180). One and five-year actuarial survival rates were 85%/64% for adult and 90%/85% for pediatric LT cohorts, respectively. Lung function remained stable until 4 years (FEV(1) % predicted; pretransplant 48.4% vs. 45.9%, 4 years posttransplant) but declined by 5 years (42.4%). Up to 4 years posttransplant mean annual decline in FEV(1) % was lower (0.74%; p = 0.04) compared with the predicted 3% annual decline in CF patients with comorbidity including diabetes. Number of courses of intravenous antibiotics was reduced following LT, from 3.9/year pretransplant to 1.1/year, 5 years posttransplant. Body mass index was preserved posttransplant; 18.0 kg/m(2) (range 15-24.3) pretransplant versus 19.6 kg/m(2) (range 16.4-22.7) 5 years posttransplant. In conclusion, LT is an effective treatment for selected patients with cirrhosis due to CFLD, stabilizing aspects of long-term lung function and preserving nutritional status.

Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis.

Investigation of events committing cells to death revealed that a concealed NH2-terminal epitope of the pro-apoptotic protein Bak became exposed in vivo before apoptosis. This occurred after treatment of human Jurkat or CEM-C7A T-lymphoma cells with the mechanistically disparate agents staurosporine, etoposide or dexamethasone. The rapid, up to 10-fold increase in Bak-associated immunofluorescence was measured with epitope-specific monoclonal antibodies using flow cytometry and microscopy. In contrast, using a polyclonal antibody to Bak, immunofluorescence was detected both before and after treatment. There were no differences in Bak protein content nor in subcellular location before or after treatment. Immunofluorescence showed Bcl-xL and Bak were largely associated with mitochondria and in untreated cells they coimmunoprecipitated in the presence of nonioinic detergent. This association was significantly decreased after cell perturbation suggesting that Bcl-xL dissociation from Bak occurred on exposure of Bak's NH2 terminus. Multiple forms of Bak protein were observed by two dimensional electrophoresis but these were unchanged by inducers of apoptosis. This indicated that integration of cellular damage signals did not take place directly on the Bak protein. Release of proteins, including Bcl-xL, from Bak is suggested to be an important event in commitment to death.

A cell cycle-specific requirement for the XRCC1 BRCT II domain during mammalian DNA strand break repair.

XRCC1 protein is essential for viability in mammals and is required for efficient DNA single-strand break repair and genetic stability following DNA base damage. We report here that XRCC1-dependent strand break repair in G(1) phase of the cell cycle is abolished by mutations created within the XRCC1 BRCT domain that interact with DNA ligase III. In contrast, XRCC1-dependent DNA strand break repair in S phase is largely unaffected by these mutations. These data describe a cell cycle-specific role for a BRCT domain, and we conclude that the XRCC1-DNA ligase III complex is required for DNA strand break repair in G(1) phase of the cell cycle but is dispensable for this process in S phase. The S-phase DNA repair process can remove both strand breaks induced in S phase and those that persist from G(1) and can in part compensate for lack of repair in G(1). This process correlates with the appearance of XRCC1 nuclear foci that colocalize with Rad51 and may thus function in concert with homologous recombination.

Intensive weekly combination chemotherapy for patients with intermediate-grade and high-grade non-Hodgkin's lymphoma.

High response and overall survival rates have been reported for second- and third-generation combination chemotherapy regimens used in the treatment of advanced intermediate- and high-grade non-Hodgkin's lymphoma (NHL). Results with methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) chemotherapy have been particularly impressive, although this regimen produces considerable toxicity. We have devised a similar regimen, which differs from previously reported weekly regimens in that it includes etoposide given at 14-day intervals. The doses of methotrexate and prednisolone were lower in our regimen than those used in MACOP-B. Alternating cycles of cyclophosphamide, doxorubicin, and etoposide (week 1) and methotrexate, bleomycin, and vincristine (week 2) were given for a total of 12 weeks, with continuous oral prednisolone and prophylactic antibiotics. We report here the first 61 patients entered onto this study. The overall response rate is 84% (57% complete remission [CR], 27% partial remission [PR]). With a median follow-up of 32 months for surviving patients, the actuarial overall survival at 3 years is 47%, and the failure-free survival is 45%. The dose-limiting toxicity of this regimen was mucositis. Five deaths occurred during chemotherapy, two of which were due to sepsis. The dose intensities of cyclophosphamide and doxorubicin in this regimen are considerably lower than those in MACOP-B. However, because of the inclusion of etoposide, the projected average relative dose intensity for our regimen is higher than that for MACOP-B. Our regimen has produced inferior results to those reported for MACOP-B. This may be because the addition of etoposide has failed to compensate for the lower doses of doxorubicin and cyclophosphamide. Alternatively, it may reflect differences in the presenting features of the patient populations.

Surgery after initial chemotherapy for localized small-cell carcinoma of the lung.

Despite the high response rates induced by chemotherapy, many patients with limited small-cell lung cancer (SCLC) relapse at the site of primary disease. Failure of radiotherapy to overcome this has led to the use of surgery as part of a combined modality approach. Between December 1981 and December 1985, 189 patients with SCLC were assessed for suitability for surgery after an initial three cycles of chemotherapy (doxorubicin, cyclophosphamide, and etoposide). Fifty-seven were found to have limited disease, and of these, 19 were ineligible or unfit for surgery. Of the 38 eligible patients, 84% had an objective response to three cycles of chemotherapy and 25 were deemed suitable for surgery after restaging. At thoracotomy, four were inoperable, nine had a lobectomy, and 12 had a pneumonectomy. There was no evidence of viable SCLC in four resection specimens (one stage 1, two stage 2, one stage 3 at presentation), no viable SCLC but an entirely separate focus of viable poorly differentiated squamous carcinoma (SqLC) in one, and the remaining specimens contained viable SCLC. Survival of patients selected to undergo tumor resection was excellent (median survival, 33 months; plateau phase, 48% alive at 3 to 5 years), but survival of the entire group with limited SCLC was not dissimilar from that reported in previous series of limited-stage tumor treated with chemotherapy alone. Long-term survival appeared to be largely restricted to those with no evidence of viable SCLC at surgery (no viable SCLC, zero of five relapsed; viable SCLC, 13 of 16 relapsed and/or died). This prospective study confirms the feasibility of the combined modality approach, but suggests that any improvement in overall survival is likely to be small. Until the results from multicenter randomized trials are available, surgery, as part of a combined modality program, should be regarded as experimental.

Cisplatin combination chemotherapy versus chlorambucil in advanced ovarian carcinoma: mature results of a randomized trial.

A randomized study to compare the efficacy of combination chemotherapy (cisplatin, doxorubicin, cyclophosphamide: PACe) with chlorambucil (CB) in International Federation of Gynecology and Obstetrics (FIGO) stage III and IV ovarian carcinoma was conducted between May 1979 and October 1983. Patients failing initial CB were subsequently eligible for treatment with PACe. Eighty-nine patients were randomized and 85 were eligible for analysis; as of date, 72 of these patients have died. The majority of patients in this study had bulky residual disease after their initial laparotomy (76%). Complete response (CR) was documented by a second laparotomy after five cycles of combination therapy or 6 to 12 months alkylating agent therapy. The overall response rate (CR plus partial response [PR]) for the combination (PACe, 68%) was significantly higher (P = .0004) than that for the chlorambucil (CB, 26%). However, the median survival was not improved (PACe, 13 months; CB, 11 months) and the survival curves were not significantly different (log rank test P = .25). The results of this study are comparable to preliminary data reported from other similar randomized studies. PACe, as administered in this study, is not indicated as routine therapy in patients with bulky residual ovarian carcinoma.

Cranial computed tomography before lumbar puncture: a prospective clinical evaluation.

OBJECTIVE: To prospectively identify which patients can safely undergo lumbar puncture (LP) without screening cranial computed tomography (CT). METHODS: Emergency department physicians examined patients before CT. Examiners recorded the presence or absence of 10 clinical findings and answered 8 additional questions. The criterion standard was noncontrast cranial CT interpreted by staff radiologists. Clinical findings were prospectively compared with those of CT. RESULTS: One hundred thirteen consecutive adults with the urgent need for LP (median age, 42 years) were studied. Fifteen percent of patients meeting entrance criteria had new CT-documented lesions, with 2.7% having lesions that contraindicated LP. Sensitivity, specificity, and likelihood ratios (LRs) were measured for the clinical findings. Three statistically significant predictors of new intracranial lesions were identified: altered mentation (positive LR, 2.2; 95% confidence interval [CI], 1.5-3.2), focal neurologic examination (positive LR, 4.3; 95% CI, 1.9-10), and papilledema (positive LR, 11.1; 95% CI, 1.1-115). No single item adequately predicted the absence of CT abnormalities, but the clinical screening items in aggregate significantly predicted the results (negative LR, 0; upper 95% confidence limit, 0.6). The overall clinical impression had the highest predictive value in identifying patients with CT-defined contraindications to LP (positive LR, 18.8; 95% CI, 4.8-43). CONCLUSIONS: Because of the low prevalence of lesions that contraindicate LP, screening cranial CT solely to establish the safety of performing an LP typically provides limited additional information. Physicians can use their overall clinical impression and 3 clinical predictors to identify patients with the greatest risk of having intracranial lesions that may contraindicate LP.

Immuno-, lectin-, and enzyme-histochemical characterization of human bone marrow endothelium.

"Homing" of hematopoietic progenitor cells to the bone marrow occurs during the clinical practice of bone marrow transplantation. Its mechanism is unknown, although adhesive interactions between hematopoietic cells and sinusoidal endothelium in the bone marrow may be implicated. Studies of human bone marrow endothelial cells have previously been limited by the lack of markers for these cells. In this report, we describe positive staining of bone marrow endothelial cells from human bone marrow trephine biopsies with antibody to factor VIII-related antigen (FVIIIR-Ag) (Dako, High Wycombe, UK), the plant lectin Ulex europaeus agglutinin-I (UEA-I), and two mouse monoclonal antibodies, BMA120 and QBEND/10. In addition, alkaline phosphatase could be demonstrated in the majority of marrow endothelial cells using a novel enzyme histochemical technique. These studies defined the marker profile of human marrow endothelium. The results of this study will facilitate the isolation and culture of human marrow endothelial cells for in vitro studies of their roles in hematopoietic stem cell homing.

Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine. Pediatric AIDS Clinical Trials Group 185 Team.

OBJECTIVE: To evaluate independent contributions of maternal factors to adverse pregnancy outcomes (APO) in HIV-infected women receiving antiretroviral therapy (ART). DESIGN: Risk factors for preterm birth (< 37 weeks gestation), low birth weight (LBW) (< 2500 g), and intrauterine growth retardation (IUGR) (birth weight < 10th percentile for gestational age) examined in 497 HIV-infected pregnant women enrolled in PACTG 185, a perinatal clinical trial. METHODS: HIV RNA copy number, culture titer, and CD4 lymphocyte counts were measured during pregnancy. Information collected included antenatal use of cigarettes, alcohol, illicit drugs; ART; obstetric history and complications. RESULTS: Eighty-six percent were minority race/ethnicity; 86% received antenatal monotherapy, predominantly zidovudine (ZDV), and 14% received combination antiretrovirals. Preterm birth occurred in 17%, LBW in 13%, IUGR in 6%. Risk of preterm birth was independently associated with prior preterm birth [odds ratio (OR) 3.34; P < 0.001], multiple gestation (OR, 6.02; P = 0.011), antenatal alcohol use (OR, 1.91; P = 0.038), and antenatal diagnosis of genital herpes (OR, 0.24; P = 0.022) or pre-eclampsia (OR, 6.36; P = 0.025). LBW was associated with antenatal diagnosis of genital herpes (OR, 0.08; P = 0.014) and pre-eclampsia (OR, 5.25; P = 0.049), and baseline HIV culture titer (OR, 1.41; P = 0.037). IUGR was associated with multiple gestation (OR, 8.20; P = 0.010), antenatal cigarette use (OR, 3.60; P = 0.008), and pre-eclampsia (OR, 12.90; P = 0.007). Maternal immune status and HIV RNA copy number were not associated with APO. CONCLUSIONS: Risk factors for APO in antiretroviral treated HIV-infected women are similar to those reported for uninfected women. These data suggest that provision of prenatal care and ART may reduce APO.

Prednisolone, cytosine arabinoside, lomustine (CCNU), etoposide and thioguanine (PACET) combination chemotherapy for relapsed or refractory non-Hodgkin lymphoma.

27 patients with relapsed/refractory non-Hodgkin lymphoma (NHL) received combination chemotherapy with prednisolone, cytosine arabinoside, lomustine (CCNU), etoposide and thioguanine (PACET). 25 patients are evaluable for response. 7 (26%) obtained a complete response and one (4%) a partial response. The median survival for the entire group was 6 months. 2 patients are currently alive without disease, 1 of whom has received further therapy. The regimen was intensely myelosuppressive, but was well tolerated. The complete response rate and median survival figures are comparable to previous studies of salvage therapy confirming the poor prognosis for relapsed NHL and emphasising the need for prospective randomised studies.

Measurement of antibodies to tubulin by radioimmunoassay.

A solid-phase double antibody radioimmunoassay capable of measuring antibody to tubulin, the principal component of microtubules, is described. This assay is simple, combining sensitivity with specificity and also allowing determination of antibody subclasses.