Absence Of Therapeutic Intervention Research Articles

Clinical Impact of Radiologist’s Alert System on Patient Care for High-risk Incidental CT Findings: A Machine Learning-Based Risk Factor Analysis

Rationale and ObjectivesEfficient communication between radiologists and clinicians ordering computed tomography (CT) examinations is crucial for managing high-risk incidental CT findings (ICTFs). Herein, we introduced a Radiologist’s Alert and Patient Care Follow-up System (APCFS) for high-risk ICTFs. This study aimed to analyze the ICTFs detected by this system and the factors associated with them. Materials and MethodsThis retrospective study was approved by the institutional review board. We analyzed 52,331 CT examinations conducted between 2019 and 2021. In cases where high-risk ICTFs were identified, radiologists utilized APCFS to prompt ordering clinicians for further patient care. We assessed the frequency, affected body organs, presence or absence of therapeutic interventions, and diagnoses of high-risk ICTFs. An automated machine learning platform was employed to analyze the factors associated with high-risk ICTFs. ResultsAmong the 52,331 CT examinations, 507 (0.96%) revealed high-risk ICTFs, primarily affecting the lung (18.0%). Of these 507 high-risk ICTFs, 117 (23.1%) underwent therapeutic interventions, while 362 (71.4%) required only follow-up. Of the 117 cases undergoing interventions, 61 (52.1%) required surgery. Of the 219 high-risk ICTFs leading to a confirmed diagnosis, 146 (66.7%) were neoplastic lesions, including 88 (60.3%) malignancies, and 73 (33.3%) were non-neoplastic lesions. The top three risk factors associated with high-risk ICTFs in the regularized logistic regression model were the imaging protocol (especially aortic valve implantation planning protocol), imaging area (especially whole-body imaging), and clinical department (especially cardiology). ConclusionUtilizing APCFS, high-risk ICTFs were detected in approximately 1% of all CT examinations, likely associated with specific imaging protocols, areas, and clinical departments.

Risk factors for clinical relapse in patients with ulcerative colitis who are in clinical remission but with endoscopic activity.

The treatment strategy for patients with ulcerative colitis (UC) in clinical remission who have not achieved mucosal healing is unclear. This study aimed to determine the risk factors of relapse in patients in clinical remission with endoscopic activity. This retrospective, single-center study included patients with UC who underwent colonoscopy (CS) and were in clinical remission with endoscopic activity. Characteristics were compared between patients who relapsed within 2 years after CS and those who did not. A Cox proportional hazards regression model was used to identify risk factors contributing to clinical relapse. Recent worsening in bowel symptoms was defined as increase in bowel frequency and/or increase in abdominal pain within approximately 1 month based on the descriptions in the medical charts. This study regarded 142 patients in clinical remission with an endoscopic activity of Mayo endoscopic subscore (MES) of ≥1 as eligible, and 33 (23%) patients relapsed during the observation period. Recent worsening of bowel symptoms was a significant risk factor for clinical relapse (hazard ratio [HR]: 3.02, 95% confidence interval [CI]: 1.34-6.84). This was particularly evident in patients with MES of 2 (HR: 5.16, 95% CI: 1.48-18.04), whereas no risk factors were identified in patients with MES of 1. The presence or absence of therapeutic intervention just after CS did not significantly affect clinical relapse. Recent worsening in bowel symptoms was a significant risk factor for clinical relapse in patients with UC who were in clinical remission with endoscopic activity.

The phenomenon of spontaneous tumor regression in breast cancer

Abstract Spontaneous tumor regression is an increasingly prevalent phenomenon of partial or complete disappearance of primary tumor tissue or associated metastases in the absence of therapeutic intervention. Cases of spontaneous regression have been established in malignant tumors, such as testicular germ cell tumor, renal cell cancer, melanoma, basal cell carcinoma, neuroblastoma, colon cancer, breast cancer, as well as metastases. Breast cancer has increasingly been reported to have a higher rate of spontaneous regression than previously thought. Immunologic response is cited as the forefront of spontaneous regression phenomenon, with the focus on immunologic cell death. This report brings awareness to a case of spontaneous regression observed in invasive ductal carcinoma of the breast and how disruption of the tumor microenvironment can take a variable course even in malignant disease.

Analysis Of Nursing Care In Schizophrenic Patients With Chronic Low Self-Esteem Through Hortikultural Therapy At Rsj Prof. Dr. Soerodjo Magelang

Background : Schizophrenia is a severe mental disorder that is chronic and requires antipsychotic treatment for a long time or even a lifetime (Julacha et al. 2022). One of the nursing problems in Schizophrenic patients encountered is low self-esteem. Low self-esteem is a personal assessment of the results achieved by analyzing how far the behavior meets the ideal self. Long-lasting low self-esteem in the absence of therapeutic intervention can lead to identity chaos and eventually personalization. So it is necessary to make a promotive effort.Purpose : To explain the application of horticultural therapy to improve self-esteem in schizophrenic patients with chronic low self-esteem.Method : Using a case study of the application of horticultural therapy in 3 patients with chronic low self-esteem. The location of the case study was carried out at Wisma Dwarawati RSJ Prof. Dr. Soedjono Magelang. Selection of case study subjects according to inclusion criteria. Data collection was carried out through a therapeutic approach to patients, observation, and measurement of low self-esteem levels using the Rosenberg Self Esteem Scale (RSES) instrument. Implementation was carried out for three meetings for 60 minutes.Discussion : Based on research by Krissanti et al. (2019) revealed that occupational gardening therapy can reduce the level of low self-esteem disorders. Recommendations : Efforts in implementing low self-esteem patients with horticultural therapy can affect the level of self-esteem in patients to fall. So that it can be used as a guideline for health workers to provide implementation of structural activity therapy with horticultural therapy in patients with intense chronic low self-esteem.Keywords : Schizophrenia, Low Self-Esteem, Horticultural Therapy

Neurocognitive profile of a cohort of SMA type 1 pediatric patients and emotional aspects, resilience and coping strategies of their caregivers.

Spinal muscular atrophy (SMA) type 1 represents the most severe condition of the spectrum of SMA 5q. In the absence of therapeutic interventions, patients do not achieve any motor milestone and their life expectancy does not exceed two years of age. To date, three disease-modifying drugs have been approved for SMA type I. These treatments have radically changed the natural history of the disease, improving motor, respiratory and bulbar functions. In recent years huge amount of data have been collected worldwide related to motor, respiratory and swallowing function outcome in treated patients, whereas the neurocognitive profile of treated patients has been poorly explored. Here we report the neurocognitive development profile of a cohort of SMA type I children treated with a disease modifying therapy. We also describe the burden and resilience as well as the coping strategies of their caregivers. Our finding show a global developmental delay in most patients and defects in gross motor functions contribute most to lower the general development quotient of Griffiths III, whereas the scores obtained on evaluating learning and language abilities scales suggest a positive trend in the developmental trajectory of general neurocognitive abilities. Some parents reported anxiety and stress but overall they were resilient (and had good coping strategies towards the burden of care for their child. These results reinforce the importance of routinely assessing the neurocognitive aspects in SMA type I patients and to offer an early intervention to favor the psychosocial development of these children.

Molecular Aspects of COVID-19 Differential Pathogenesis.

In the absence of therapeutic interventions, and a possible vaccine candidate, the spread of COVID-19 disease and associated fatalities are on the rise. The high mutation frequency in the genomic material of these viruses supports their ability to adapt to new environments, resulting in an efficient alteration in tissue tropism and host range. Therefore, the coronavirus’ health threats could be relevant for the long-term. The epidemiological data indicate that age, sex, and cardio-metabolic disease have a significant impact on the spread and severity of COVID-19. In this review, we highlight recent updates on the pathogenesis of SARS-CoV-2 among men and women, including children. We also discuss the role of the cellular receptors and coreceptors used by the virus to enter host cells on differential infection among men, women, and cardio-metabolic patients.

Molecular MRD Monitoring Is Feasible in the Majority of Children with AML and Is Highly Predictive of Outcome: Results from the International MyeChild01 Study

Introduction Most children with acute myeloid leukaemia (AML) harbour fusion genes which are ideal targets for molecular minimal residual disease (MRD) monitoring. However, evidence of prognostic significance is currently lacking and consequently most current paediatric AML treatment protocols rely on flow cytometric (FCM) evaluation to allocate treatment. Molecular MRD techniques provide significantly greater sensitivity and specificity and could allow more accurate outcome prediction, and consequently more personalised therapy, which is highly relevant in a disease where treatment related mortality, morbidity and relapse remain significant. Methods Between June 2016 and February 2019, MyeChild01 enrolled 170 children aged 0-18y with newly diagnosed AML who were randomly assigned to induction therapy with liposomal daunorubicin or mitoxantrone with cytarabine with or without gemtuzumab ozogamicin. Consolidation treatment was determined by karyotype, mutational profile and MRD status. Comprehensive centralised diagnostic assessment consisted of: Karyotype and fluorescence in-situ hybridisation (FISH) using a custom panel of probes to detect paediatric AML-associated gene fusions.PCR based screening for mutations in FLT3, NPM1 and CEPBA.Targeted capture of known fusion loci and paired end sequencing.RNA-seq using the Illumina TruSight fusion panel. Where a fusion gene was identified, RT-qPCR assays were designed and optimised for each patient. NPM1 mutation was also used as an MRD target if present. Paired PB and BM samples were requested after each cycle of treatment. Patients could have sequential monitoring after completion of therapy although this was not mandated. For this analysis, patients with core-binding factor (CBF) leukaemias i.e. inv(16)(p13q22) or t(8;21)(q22q22) with transcript levels above previously defined thresholds (Yin et al, 2012) were considered MRD positive. For all other targets, amplification in at least 2/3 replicates at <40 PCR cycles in either PB or BM was considered MRD positive. For patients with CBF or NPM1 mutation, both molecular and FCM MRD status contributed to treatment allocation. Otherwise, FCM MRD was used unless there was no FCM target. Allogeneic stem cell transplantation (HSCT) was recommended for all patients with poor risk cytogenetics, those with intermediate risk cytogenetics who were MRD positive after cycle 2, and those with favourable risk cytogenetics who were MRD positive at the end of cycle 3. After completion of treatment, no specific advice was given regarding management of positive MRD results. Results We identified fusion genes in 126/170 patients (74%). We designed 55 unique RT-qPCR assays to specifically amplify 27 fusions with calculated sensitivity between 1:104 and 1:106. 62/126 children provided a complete set of samples: 31 (60%) with favourable, 18 (29%) with intermediate and 13 (21%) with high risk cytogenetic / molecular profiles. We analysed the effect of molecular MRD status at the end of protocol specified treatment, which included SCT in 17/62 (27%). One year event-free survival from diagnosis was 70% (95% confidence interval 52-82%) in patients who tested MRD negative compared to 11% (1-39%) in patients who tested MRD positive at the end of treatment (p<0.0001, figure 1a). Estimated cumulative incidence of relapse was 17% (7-30%) in patients who tested MRD negative vs 78% (28-95%) in those testing positive (p<0.0001 figure 1b). MRD status at earlier time points had less impact, possibly due to treatment intensification for MRD positivity. Four patients received non-protocol specified SCT due to physician / family preference based on persistently positive or serially rising transcript levels after completion of treatment. At last follow up 4/4 were alive in complete remission. Rising transcript levels were observed in a further 8 patients to whom no pre-emptive treatment was given due to individual preference or lack of appropriate therapy. Haematological relapse subsequently occurred in 8/8. Conclusion Molecular MRD monitoring is feasible in the majority of children with AML, permitting refinement of response-adapted therapy. Molecular MRD status at the end of treatment is highly predictive of outcome, identifying molecular complete remission as a treatment goal for these children. Serially rising MRD levels reliably predict relapse in the absence of therapeutic intervention. Disclosures Dillon: Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TEVA: Consultancy, Honoraria. Vyas:Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Forty Seven, Inc.: Research Funding; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau. Amrolia:UCLB: Patents & Royalties. Baruchel:Bellicum: Consultancy; Servier: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Moderate Traumatic Brain Injury Alters the Gastrointestinal Microbiome in a Time-Dependent Manner.

The microbiome is defined as the collective genomes of the microbes (composed of bacteria, bacteriophage, fungi, protozoa, and viruses) that colonize the human body, and alterations have been associated with a number of disease states. Changes in gut commensals can influence the neurologic system via the brain-gut axis, and systemic insults such as trauma or traumatic brain injury (TBI) may alter the gut microbiome. The objective of this study was to evaluate the gut microbiome in a preclinical TBI cortical impact model. Male rats underwent craniotomy and randomized to a sham group (n = 4), or a moderate TBI (n = 10) using a pneumatic impactor. MRI and behavioral assessments were performed pre-TBI and on days 2, 7, and 14 days thereafter. Microbiome composition was determined with 16s rRNA sequencing from fecal sample DNA pre-TBI and 2 hrs, 1, 3, and 7 days afterward. Alpha- and β-bacterial diversity, as well as organizational taxonomic units (OTUs), were determined. Significant changes in the gut microbiome were evident as early as 2 h after TBI as compared with pre-injured samples and sham rats. While there were varying trends among the phylogenetic families across time, some changes persisted through 7 days in the absence of therapeutic intervention. While large structural lesions and behavioral deficits were apparent post-TBI, there were modest but significant decreases in α-diversity. Moreover, both changes in representative phyla and α-diversity measures were significantly correlated with MRI-determined lesion volume. These results suggest that changes in the microbiome may represent a novel biomarker to stage TBI severity and predict functional outcome.

Efficacy of Therapeutic Intervention for Patients With an Ulcerative Colitis Mayo Endoscopic Score of 1.

Mucosal healing (MH) is proposed as a therapeutic target for ulcerative colitis (UC). Recent studies have indicated that the rate of clinical relapse in patients with a Mayo endoscopic score (MES) of 1 is higher than that of patients with an MES of 0. However, no study has yet investigated whether therapeutic intervention prevents clinical relapse in patients with an MES of 1. Patients with UC with an MES of 1 and partial Mayo score ≤2 were included in this study. All patients were followed from first colonoscopy (CS) until follow-up CS. Differences in the rate of clinical relapse (requiring additional treatment for UC) or endoscopic exacerbation (MES ≥2 and proximal extension) were compared between the therapeutic intervention (immediately after first CS) group and the nontherapeutic intervention group; risk factors for relapse were also assessed. Among 1523 patients with UC who underwent CS between 2013 and 2016, 220 patients were included in this study. The rate of clinical relapse (P = 0.005) and endoscopic exacerbation (P = 0.11) in patients with therapeutic intervention was lower than that in patients without therapeutic intervention. Multivariable analysis indicated that absence of therapeutic intervention (P = 0.001 for clinical relapse, P = 0.050 for endoscopic exacerbation) and a higher Ulcerative Colitis Endoscopic Index of Severity vascular pattern score immediately after first CS (P = 0.021 for clinical relapse, P = 0.019 for endoscopic exacerbation) were risk factors for both clinical relapse and endoscopic exacerbation. Therapeutic intervention for patients with UC with an MES of 1 might prevent disease relapse.

The microenvironment in primary cutaneous melanoma with associated spontaneous tumor regression: evaluation for T-regulatory cells and the presence of an immunosuppressive microenvironment.

Spontaneous tumor regression, regression in the absence of therapeutic intervention, can be identified histologically in over 25% of primary cutaneous melanomas at initial diagnosis. A unique subset of T lymphocytes found in areas of regression can be histologically distinguished from tumor-infiltrating T lymphocytes (TIL) found in areas of tumor progression. We call this unique subset of T lymphocytes regression-associated T lymphocytes (RATs). The aim of this study is to determine the phenotype of lymphocytes and the density of specific cell types linked to immunosuppression in areas of tumor progression compared with areas of tumor regression. These specific cell types include T-regulatory cells (Tregs) and S100A9 cells. A total of 14 primary cutaneous melanomas with areas of progression and regression were used. Immunohistochemistry staining was used to identify CD4 cells, CD8 cells, Tregs, and S100A9 cells. Two independent observers manually counted three high-powered ×40 fields. There was no predominance of CD4 or CD8 T lymphocytes in either RATs or TIL. We identified a lower density of Tregs in RATs compared with TIL when using the FOXP3/CD4 Treg marker (P=0.04) and a marginal difference when using our second, confirmatory Treg marker, FOXP3/CD25 (P=0.11). We observed a lower density of S100A9 cells in RATs compared with TIL (P=0.002). There was an observable difference in the tumor microenvironments of RATs and TIL, with RATs having a significantly lower density of Tregs and S100A9 cells. We deduce that the absence of immunosuppression in areas of regression allows for a more robust immune response and thus effective eradication of tumor cells.

Glomerular hyperfiltration: a marker of early renal damage in pre-diabetes and pre-hypertension

Glomerular hyperfiltration is a characteristic functional abnormality in insulin-dependent diabetes mellitus and occurs in the large majority of young Type 1 diabetic patients. Hyperfiltration is hypothesized to be a precursor of intraglomerular hypertension leading to albuminuria. Glomerular filtration rate (GFR) then falls progressively in parallel with a further rise in albuminuria which may lead, in the long run, to end-stage renal failure. Experimental and clinical studies have shown that glomerular hyperfiltration can occur also in hypertension. However, whether hyperfiltration occurs also in early stages of hyperglycaemia and high blood pressure, such as in pre-diabetes and pre-hypertension, is not well known. In this issue of the Journal, Okada and Coll studied a large Japanese population showing that in pre-diabetic and pre-hypertensive subjects, the prevalence of hyperfiltration is proportional to the level of glucose and blood pressure, respectively. One main problem with the diagnosis of hyperfiltration is that no generally accepted definition is available due to the strong inverse correlation of GFR with age. To overcome this limitation, Okada et al. calculated the upper normal limit of GFR in a large healthy Japanese sample divided into 10-year age groups, providing ageand sex-specific reference values. For hyperfiltration to develop, the concomitant action of a variety of pathogenetic factors are needed including increased body mass index, hyperinsulinaemia, activation of the sympathetic nervous system, hyperleptinaemia, increased oxidative stress, inflammatory cytokines, etc. Another mechanism accounting for increased GFR in obese persons is increased NaCl intake. In addition, a significant role of increased Na reabsorption in the pathophysiology of glomerular hyperfiltration in obesity and hypertension has been described. Pharmacological agents with action on the renin–angiotensin system are effective in reducing glomerular hypertension which accounts for their efficacy in preventing progression of microalbuminuria in diabetes and hypertension. According to current guidelines, only low GFR and microalbuminuria or proteinuria should be considered as markers of renal dysfunction. Due to the strong association between hyperfiltration and risk of microalbuminuria found in diabetes and hypertension, hyperfiltration should be regarded as a precursor of nephropathy in these clinical conditions. More extensive use of markers of early organ damage may help clinicians to reach a more timely decision about the initiation of treatment and thus delay cardiovascular complications. Hyperglycaemia and high blood pressure in people with hyperfiltration should be treated earlier to prevent the progression of renal dysfunction to chronic kidney disease. Increased GFR, also called hyperfiltration, is a proposed mechanism for renal injury in several clinical conditions. According to the Brenner theory [1], low nephron number at birth explains why some individuals are prone to developing progressive renal damage later in life when other risk factors become operative. At the single-nephron level, hyperfiltration is hypothesized to be a precursor of intraglomerular hypertension leading to albuminuria. Increased glomerular capillary hydraulic pressure may be due to changes in systemic arterial pressure and/or changes in efferent and afferent arteriolar resistances. In the absence of therapeutic interventions, GFR then falls progressively in parallel with a further rise in albuminuria which may lead, in the long run, to end-stage renal failure (Figure 1). Human models of renal injury are in keeping with this pathogenetic view. Glomerular hyperfiltration has been observed in patients with unilateral renal agenesis [2], congenitally reduced nephron number [3] and acquired reduction in renal mass [4]. These individuals are prone to developing proteinuria early in life in association with glomerular sclerosis. It is suggested that this model of renal injury may apply to the early diabetic or hypertensive kidney.

WE‐G‐214‐09: Validation of 4D‐CT Pulmonary Ventilation Imaging: Characterization of the Reproducibility

Purpose: A novel ventilation imaging method based on 4D‐CT has been applied to functional radiotherapy planning and assessing radiation‐induced ventilation changes. Understanding of its reproducibility is a prerequisite for such applications, however it has not been studied to date. The purpose of this study is to develop a method for validating 4D‐CT ventilation imaging through characterizing its reproducibility and show preliminary results. Methods: 4D‐CT ventilation images were created for three patients from repeat 4D‐CT scans at different time points, including two pre‐treatment (pre‐RT1 and pre‐RT2), one mid‐treatment (mid‐RT) and/or one post‐treatment (post‐RT). The reference (pre‐RT1) was compared with pre‐RT2 to quantify the temporal change in the absence of therapeutic intervention. Pre‐RT1 was also compared with mid‐RT and/or post‐RT to quantify the temporal change in the presence of therapeutic intervention. Finally, the Spearmanˈs voxel‐based correlations between pre‐RT1 and pre‐RT2 were compared to those between pre‐RT1 and mid‐RT or post‐RT to investigate the hypothesis: the temporal change in the absence of therapeutic intervention is smaller than that in the presence of therapeutic intervention. Results: Differences between the temporal changes in the absence and presence of therapeutic intervention were inconsistent. Regions of both agreement and disagreement were identified throughout the lung between pre‐RT1 and pre‐RT2, mid‐RT or post‐RT. The correlations with pre‐RT2 (absence) (range, 0.41–0.64) were slightly higher than or comparable to those with mid‐RT or post‐RT (presence) (range, 0.42–0.62). In general, the ventilation variations between pre‐RT1 and pre‐RT2 increased with increasing respiratory variations during the 4D‐CT acquisition. Conclusions: Preliminary results from a 3‐patient study suggest inconsistent differences between the temporal changes of 4D‐CT ventilation in the absence and presence of therapeutic intervention. Respiratory variations have been found to contribute to deteriorate the reproducibility. Ongoing studies focus on investigating more patients and spatial characteristics of the temporal changes.SK, JB and CL are employees of Philips Research Europe.

Intraarterial Treatment of GEP NET: 68Ga-DOTATOC SUV Cannot Predict 90Y-DOTATOC Uptake

Kratochwil and colleagues (1) demonstrate in their very elegant study that selective intraarterial (i.a.) application of 68Ga-DOTATOC into the feeding artery of liver metastases from neuroendocrine tumors leads to a significantly higher SUV compared with intravenous (i.v.) application. An advantage of their study is the absence of therapeutic interventions as a confounding factor. This is a limitation in other studies comparing different therapeutic approaches as it commonly restricts recruitment of suitably large, homogeneous patient groups.However, we do not believe that these data can be extrapolated to suggest a higher tumor uptake or a greater therapeutic efficacy of 90Y- or 177Lu-DOTATOC following i.a. application.Following our previously reported experience with i.a. application of 131I-MIBG (2), we have so far treated 5 patients with 90Y-DOTATOC intravenously, followed by i.a. treatment 6 months later. We could not observe a consistently higher tumor uptake following i.a. application. Intraarterial-to-intravenous uptake ratios varied widely in our patients, from 0.45 to 2.74.We are aware that ours is a very small group of patients, but due to the markedly different receptor affinities of 68Ga-DOTATOC and 90Y-DOTATOC we do not expect a significantly greater tumor uptake following i.a. application of 90Y-DOTATOC.Heppeler and colleagues (3) showed that SSR2 receptor affinity of 67Ga-DOTATOC was 4 to 5 times higher than that of 90Y- and 111In-DOTATOC, respectively. In their study, 67Ga-DOTATOC showed a significantly higher tumor and lower renal uptake than the other 2 compounds. These data lead us to conclude that, in contrast to 68Ga-DOTATOC, a significantly higher tumor uptake after i.a. application cannot be expected for 90Y-DOTATOC.No potential conflicts of interest were disclosed.

Prognostic factors in the palliation of pancreatic cancer

Aim: Few patients with pancreatic cancer are eligible for resection. In the remainder, estimation of prognosis is important to optimise various aspects of care, including palliation of biliary obstruction and trial of chemotherapy.The aim is to evaluate the prognostic significance of clinical and laboratory variables in patients with unresectable pancreatic cancer.Methods: Information was gathered retrospectively for 325 patients with unresectable pancreatic cancer who underwent palliative interventions, including surgical bypass, endoscopic or percutaneous stenting or who received supportive care only.Results: Histological proof was obtained in 182 patients (56%). Median survival was 5.7 months. Absence of therapeutic intervention, leukocytosis (WCC≥11×109/l), gamma glutamyl transferase (γGT)>165U/L, prothrombin time ratio ≥1.1, and C-reactive protein (CRP) ≥5mg/dL were associated with shorter survival on univariate analysis. Only absence of therapeutic intervention, leukocytosis, and γGT>165U/L reached significance on multivariate analysis. In the 51 patients in whom serum CRP was available, CRP was the only significant predictor of survival on multivariate analysis.Conclusions: Leukocytosis, elevated γGT and raised CRP predict shorter survival and may help to guide the choice of palliative intervention for patients with unresectable pancreatic cancer.

HIV strategically targets HIV-specific T cells

HIV enters cells by binding to CD4 and a chemokine coreceptor. As a result, the majority of HIV-infected cells in HIV-positive individuals are CD4+ T helper cells. CD4+ T cells recognise foreign peptide antigens, which are processed predominantly from extracellular proteins, and are bound to MHC class II molecules on the surface of antigen-presenting cells (APCs). CD4+ T cells perform a central role in the coordination of humoral and cellular immune responses. HIV infection is characterised by the progressive loss of CD4+ T cells. The gradual decline of these key immune orchestrators is followed, almost inevitably, by AIDS and death. It is known that CD4+ T-cell responses to HIV are generally lost early after infection (in the absence of therapeutic intervention), whereas responses specific for other antigens are preserved throughout the asymptomatic phase until the eventual collapse of the immune system. This led to the hypothesis that HIV might preferentially infect CD4+ T cells that respond to HIV antigens, resulting in their dysfunction or destruction.

Three mouse models of muscular dystrophy: the natural history of strength and fatigue in dystrophin-, dystrophin/utrophin-, and laminin alpha2-deficient mice.

To optimize and evaluate treatments for muscular dystrophy, it is important to know the natural history of the disease in the absence of therapeutic intervention. Here we characterized disease progression of three mutant mouse strains of muscular dystrophy: mdx mice, which lack dystrophin; mdx:utrn-/- mice, which also lack utrophin; and dy/dy mice, which are deficient in laminin alpha2. Normal mice show a marked increase in forelimb strength over the first 10 weeks of life and little fatigue (<5%) over five consecutive strength trials. Mdx and mdx:utrn-/- mice demonstrate less strength then normal mice and approximately 40% fatigue at each age. Mdx mice become obese but mdx:utrn-/- mice do not. Dy/dy mice remain small and are much weaker than mdx and mdx:utrn-/- mice at all ages even when normalized to weight; however, they show only minimal fatigue (10%). This work demonstrates a distinct pattern of disease progression in each model and provides a foundation for assessing strategies for improving strength in each model.

Spontaneous central retinal artery occlusion in hemoglobin sickle cell disease

PURPOSE: To describe a case of spontaneous central retinal artery occlusion in a young man with hemoglobin sickle cell disease. METHOD: Case report. RESULTS: A 31-year-old African-American man with a history of hemoglobin sickle cell disease developed sudden painless loss of vision in the right eye. Medical history was remarkable for the recent history of a mild painful crisis, but no other systemic illness or contributing factors. Central retinal artery occlusion was diagnosed with retinal whitening, cherry red spot, and delayed arteriovenous transit on fluorescein angiography. Over the ensuing week, the patient had visual recovery to 20/60 in the absence of therapeutic intervention. CONCLUSION: Central retinal artery occlusion has been reported in sickle cell hemoglobinopathies (ie, SS, S-thal, sickle trait, and sickle cell), but the association with sickle cell disease is rare. Most reports have described additional contributing factors, such as trauma or concomitant systemic illness, to help account for the central retinal artery occlusion. The present case suggests that sickle cell disease alone is sufficient for the development of central retinal artery occlusion.

Keynote address: variations in the natural history of HIV infection.

In general, the natural history of HIV infection as revealed by prospective cohort studies such as the Multicenter AIDS Cohort Study (MACS) is consistent with our current understanding of the immunopathogenesis of HIV disease. Although the limitations of CD4+ T cell counts as a predictor of response to therapy are now recognized, enumeration of these cells remains an important predictor of outcome. Additional information regarding prognosis can be obtained using other immunological and virological information. Analysis of data from cohort studies has revealed varying patterns of CD4+ lymphocyte count decline associated with differing evidence of immune activation, specific antibody responses, CD8+ T cell responses, and level of viral burden. Of interest, some asymptomatic HIV-infected persons appear to show immune stability in the absence of therapeutic interventions. In addition, the combination of antiretroviral therapy and prophylaxis for Pneumocystis carinii pneumonia (but apparently not prophylaxis for fungal or Mycobacterium avium-intracellulare infections) has prolonged survival in patients with AIDS.

Prospective analysis of sperm-oocyte fusion and reactive oxygen species generation as criteria for the diagnosis of infertility

We have undertaken a prospective analysis of the diagnostic significance of three different criteria of human sperm function including the conventional semen profile, measurements of hamster-oocyte fusion, and determinations of reactive oxygen species generation in 139 couples. The latter, who were characterized by a lack of detectable abnormalities in the female partner, were followed up for a maximum of 4 years to determine the incidence of spontaneous pregnancy in the absence of therapeutic intervention. Assessments of monthly fecundity with life table analysis techniques revealed a highly significant, positive relationship between fertility and hamster-oocyte fusion rates that were measured in the presence of the ionophore, A23187. Conversely, reactive oxygen species generation was shown to be negatively associated with both the outcome of the sperm-oocyte fusion assay and fertility in vivo. The clinical significance of these diagnostic techniques was emphasized by the fact that within the same data set, the conventional semen profile was of no significant diagnostic value.

Reproducibility and persistence of abnormal transmitral flow velocity patterns detected by pulsed Doppler ultrasound

This prospective study examines the reproducibility and persistence of abnormal transmitral flow detected using pulsed Doppler ultrasound on 2 separate occasions between 2 days and 6 weeks apart. The 22 patients included were accepted consecutively from those having an abnormal diastolic flow pattern at initial examination. Abnormal flow velocity patterns were defined as those exhibiting reversal of the ratio of the passive filling velocity (E) and active atrial transport velocity (A). There was no significant difference between the separately recorded values for the ratio of the peak E and A velocities or of the ratio of the planimetered areas beneath each of the velocity waves, with positive correlations for both sets of values ( r = 0.68, r = 0.67). Significant positive correlation also existed between the mean rates of acceleration to each of the E and A velocity peaks of the transmitral waveform recorded on separate occasions ( r = 0.68, r = 0.95). Interobserver variation for the analysis of hard-copy pulsed Doppler recordings between two trained observers was less than 5% and intraobserver error for recording analysis was less than 2% for both observers. Abnormal transmitral flow velocity patterns persist unchanged in the absence of therapeutic intervention and the acceptably small observer error in the recording and analysis of such flow patterns allows consistent and clinically reliable data to be obtained.