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Motility abnormalities in gastroesophageal reflux disease.

Esophageal dysmotility occurs in association with GERD; however, the cause of these motility abnormalities is not known. It is also not clear whether injury results from the presence of acid itself, inflammatory change or fibrosisin the esophageal wall. It is also unclear if reversal of these abnormalities takes place, and if so, to what degree. There are, however, a subset of patients who seem to have improvement with effective medical or surgical therapy, parodoxically, the same patients in whom a fundoplication, particularly a complete wrap, would lead to severe postoperative dysphagia secondary to preoperative dysmotility. What does all this mean for the individual patient? It is likely that most will not have any important change in esophageal motility abnormalities with standard medical or surgical therapy. Fundoplication might be safely performed in patients with minimal motility abnormalities, but those with severe abnormalities should be approached with caution. The conservative approach is to perform a partial fundoplication (Toupet) in those with ineffective motility (> 30% low-amplitude or nontransmitted contractions). It is hoped that future investigations will aid in understanding the pathogenesis of these abnormalities and how they can be used more precisely to guide antireflux therapy.

Esophageal Motility Disorders↗

Cell immortalization as a key, rate-limiting event in malignant transformation: approaches toward a molecular genetic analysis.

Recent advances using somatic cell genetic approaches have provided a convincing body of evidence that the senescence of mammalian cells in culture is controlled by a small group of genes, one or more of which are functionally deleted in the process of immortalization. Microcell-mediated mono-chromosomal transfer methods should permit precise mapping of these genes to specific chromosomal regions. Cloning of senescence genes, using either conventional 'positional cloning' techniques or retroviral insertion mutagenesis, is now a realistic possibility. The leap in our understanding of the molecular genetic events driving the alternative cellular states of limited proliferative capacity and immortality, which such advances should precipitate, will finally permit the question of the role of cell immortalization in cancer to be addressed, and may open the door to the design of new modes of cancer therapy. In addition, the precise mechanism underlying the wide difference in transformability between human and rodent cells, which should also emerge from these investigations, is likely to make a significant contribution towards resolving the key issue of the relevance of rodent tumour induction assays in assessing the potential carcinogenicity of environmental chemicals.

Animals↗

Full or partial seroreversion in patients infected by hepatitis C virus.

Cases of partial seroreversion have been reported in hemodialyzed or immunodepressed patients, but spontaneous clearance of viremia associated with a disappearance of specific antibodies or clearance while receiving therapy has not been precisely documented in immunocompetent hepatitis C virus (HCV)-infected persons. A longitudinal study of markers of HCV infection in a cohort of 178 multitransfused patients followed over an 8-year period was done to establish well-documented cases of partial or full seroreversion. Thirty (16.8%) of 178 patients were HCV-infected; among them, 5 had partial or full seroreversion. Seroreversion to an anti-HCV-negative state is characterized by a quantitative decrease in antibody. A seroreversion may be observed in three circumstances: spontaneously, induced by therapy, and in conjunction with human immunodeficiency virus infection. Long-term follow-up of seroreverters will establish whether they have definitively eradicated HCV from their systems.

Alanine Transaminase↗

Decompressive laparotomy to treat intractable intracranial hypertension after traumatic brain injury.

INTRODUCTION: Increases in intra-abdominal pressure (IAP) can cause increases in intracranial pressure (ICP). Recently, we noticed that abdominal fascial release could be useful in treating intracranial hypertension (ICH) after traumatic brain injury (TBI). We added this as an option in our treatment of TBI. METHODS: In our institution, ICH is treated with an algorithm using osmolar therapy, CSF drainage and barbiturates. Patients with refractory ICH have routine measurement of IAP. If elevated, consideration is given to decompressive laparotomy. We retrospectively reviewed all patients admitted from January 2000 through July 2003 who had abdominal decompression to treat refractory ICH. RESULTS: From 1/00 to 7/03, 17 patients underwent decompressive laparotomy for intractable ICH. Thirteen male and 4 females all sustained blunt injury. All had failed maximal therapy including 14 who had had decompressive craniectomy. Mean ICP was 30 +/- 8.1 mmHg (range 20-40 mmHg) before decompression. No patients had evidence of abdominal compartment syndrome (ACS). Before decompression mean IAP was 27.5 (+/- 5.2) mmHg (range 21-35 mmHg). After abdominal decompression ICP dropped precipitously by at least 10 mmHg to a mean of 17.5 (+/- 3.2) mmHg (range 10-25 mmHg). In 6 patients the decrease in ICP was transient. All died. The remaining 11 had sustained decreases in ICP. All survived, made neurologic recovery and were discharged to a rehabilitation facility. CONCLUSION: Decompressive laparotomy can be a useful adjunct in the treatment of ICH failing maximal therapy following TBI. More work will need to be done to precise the exact indications for this therapy.

Adolescent↗

The changes in quantitative HCV RNA titers during interferon alpha 2B therapy in patients with chronic hepatitis C infection.

OBJECTIVE: Our aim was to analyze the outcomes and the patterns of response to interferon treatment in patients with chronic hepatitis C using serum HCV RNA as the primary endpoint of therapy. METHODS: Seventy anti-HCV-positive patients were treated with 3 million U of interferon-alpha-2b thrice weekly for 24 wk and followed for an additional 24 wk after cessation of therapy (wk 48). Serum HCV RNA was measured by a reverse transcriptase-polymerase chain reaction method that has a sensitivity of < 100 viral copies per ml. RESULTS: The mean pretreatment HCV RNA was 2.8 +/- 2.2 x 10(6) viral copies per ml. Genotype 1 patients had significantly higher mean baseline viral titers than those with genotype 2 (p = 0.03). At wk 48, 12 (17%) patients were HCV RNA negative and considered virological complete responders (CR) to treatment. The remaining patients were HCV RNA positive at wk 48 and were considered nonresponders to therapy. There were two types of virological nonresponder patients, responder relapse (RR) and no response (NR). The mean baseline HCV RNA level was significantly lower in the virological CR patients (p = 0.0004). At wk 12 and 24 of interferon treatment, both the virological CR and RR patients had lower serum HCV RNA concentrations than the patients in the NR category (p = 0.0001), while at wk 48, only. the virological CR patients had undetectable HCV RNA when compared to the RR and NR patients (p = 0.04). Transient decreases in the HCV RNA titers of > or = 1 log in magnitude were observed in 49% of the NR patients, which rose to pretreatment levels either during or after interferon therapy. CONCLUSIONS: Our findings indicate that measurement of serum HCV RNA precisely defined the responses to interferon therapy. Because the goal is to eliminate virus in patients with chronic hepatitis C infection, then HCV RNA should be used as the primary endpoint of treatment.

Adolescent↗

The role of stem cells in physiology, pathophysiology, and therapy of the liver.

The objectives of the present review is to update readers with the rapidly changing concepts in liver stem cell biology and related clinical applications. The liver has adapted to the inflow of ingested toxins by the evolutionary development of unique regenerative properties and responds to injury or tissue loss by rapid division of the mature cells, hepatocytes, and bile duct epithelial cells. Proliferation of the parenchymal cells is regulated by numerous cytokine/growth factor-mediated pathways and is timely synchronized with extracellular matrix degradation and the restoration of the vasculature. The putative role of stem cells in physiology, pathophysiology, and therapy is not yet precisely known but currently is under intensive investigation. Resident hepatic stem/ progenitor cells have been identified in small numbers and implicated in liver tissue repair, when hepatocyte and bile duct replication capacity is exhausted or experimentally inhibited. Several independent reports have suggested that bone marrow cells can give rise to different hepatic epithelial cells types, including hepatic stem cells, hepatocytes, and bile duct epithelium. These observations have resulted in the hypothesis that extrahepatic stem cells, specifically bone marrow-derived stem cells, are an important source for liver epithelial cell replacement, particularly during chronic injury. Most of published data, however, now suggest that they do not play a relevant role in replacement of epithelial cells in any known form of hepatic injury. In vitro differentiation protocols for various adult extrahepatic stem cells might eventually provide valuable sources of cells for transplantation and therapy. Amniotic epithelial stem cells, fetal liver progenitor cells as well as embryonic stem cells currently emerge as alternative stem cell sources and open new possibilities for cellular therapies of liver disease.

Cell Differentiation↗

Head and neck nodal station images: guidance for three-dimensional radiation therapy treatment planning.

When we use radiation to treat cancer patients, the irradiated volume usually encloses the detectable tumor and any metastatic areas that are thought to be at risk. Usually, in three-dimensional (3D) radiation therapy, we need to define the clinical target volume (CTV), which identifies the areas suspected of containing microscopic metastasis. We can use a set of computed tomographic (CT) images to define these suspected areas, which we relate to nodal station distributions. The traditional method uses special anatomic landmarks for such definition. This lymph node image guidance method uses a set of CT images to show the relevant nodal stations and find the correlation between the suspected areas and the lymphatic pathways. First, we used CT images from head and neck cancer patients. Then, we designed a program to delineate the regional lymphatic areas in order to distinguish the position of all the major lymph nodes in the head and neck region. These lymph nodes were then used to assist the oncologist in developing treatment references. Finally, we established a database management system to determine the relationships between different lesions and lymph nodes, as well as correlations, with metastatic pathways. Defining these relationships on the CT images provided oncologists specific information that could be used to define the CTV more precisely for 3D radiation therapy.

Head and Neck Neoplasms↗

Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia.

Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.

Leukemia, Myeloid, Acute↗

Clinical response to chemotherapy and hormone therapy as first treatment after therapeutic ovariectomy in advanced breast cancer patients.

The results of chemotherapy and hormone therapy, administered after relapse of the disease, were evaluated in 106 patients with homogeneous clinical characteristics who were subjected to bilateral ovariectomy for advanced breast cancer, whether the response to castration was favorable or not. In spite of an unfavorable response to the ovariectomy, 40.0% of the patients responded to hormone therapy, whereas 32.5% of the cases did not benefit from the successive hormone therapy, although they had responded to ovariectomy. The contrast, 65%, after favorably responding to ovariectomy, showed regression of the neoplasm after chemotherapy for the relapse. This apparent discordance of the results could be due to the fact that response to castration is not the only valid parameter to identify hormone dependence of a breast cancer and/or that the breast cancer is composed, in various proportions, of hormone-sensitive and chemo-sensitive cells. The predominance of one of these 2 components could determine the response of the neoplasm to therapy. The authors conclude that a more extensive and accurate hormone typing of the patient could give more precise indications for the appropriate therapy.

Adult↗

p53 expression, proliferation marker Ki-S5, DNA content and serum PSA: possible biopotential markers in human prostatic cancer.

OBJECTIVES: The biology of prostate cancer is poorly understood. Despite established prognostic criteria, a confident prediction of the clinical outcome is not always possible. Therefore, additional and more precise information is highly desirable. In the present study, we compared potential biologic markers with the laboratory, clinical, and histopathologic parameters of prostate-specific antigen (PSA) level, tumor stage, and tumor grade. METHODS: Paraffin-embedded material from 62 radical prostatectomies for prostate carcinoma was examined immunohistochemically using monoclonal antibody Ki-S5 to determine the tumor growth fraction and antibody DO-1 to assess p53 protein overexpression. Deoxyribonucleic acid-ploidy was analyzed by flow and image cytometry. Preoperative PSA levels were assessed by standard method. The tumors were categorized according to the Gleason grading system and staged postsurgery after the TNM classification. RESULTS: The p53 expression, proliferation rate (Ki-S5), and rate of aneuploidy correlated closely with stage (P < 0.05) and Gleason score (P < 0.01). However, divergences were occasionally observed. The ploidy status correlated closely with proliferative activity and p53 expression. Conversely, no correlation was seen between these parameters and serum PSA content, the latter being significantly associated with the tumor stage alone. CONCLUSIONS: The results characterize proliferation marker Ki-S5, p53 expression, and ploidy status as tumor biopotential markers, whereas PSA provides diagnostic information. Use of these investigative methods promises to provide additional information relevant in prognosis and therapy selection. Nonetheless, their precise prognostic value will have to be established in further studies.

Aged↗

Helicobacter pylori infection status in relation to antibiotic and non-steroidal prescribing in patients on maintenance treatment for chronic duodenal ulcer.

UNLABELLED: It has been suggested that establishing Helicobacter pylori infection status is irrelevant prior to H. pylori eradication treatment in chronic duodenal ulcer, as virtually all may benefit from therapy. OBJECTIVE: The aim of the present study was (i) to determine the prevalence of active H. pylori infection in patients with proven chronic duodenal ulcer on long-term H2-antagonist prophylactic treatment and whether knowledge of this would influence the use of eradication therapy and (ii) to assess other factors which might influence the clinical diagnosis or H. pylori status, such as non-steroidal and antibiotic use. METHODS: One hundred and forty-five patients receiving long-term H2-antagonists for chronic duodenal ulcer were recruited. Their case records and a prescribing database were reviewed. Patients underwent endoscopy with biopsies for rapid urease test, histology and H. pylori culture. Serum was immunoblotted and an enzyme-linked immunosorbent assay for H. pylori was performed. RESULTS: Of the 145 patients, 128 (88%) were H. pylori biopsy positive. Twelve of the 17 H. pylori biopsy-negative patients had anti-H. pylori immunoglobulin G (IgG) antibodies and 10 of the 17 H. pylori-negative patients had previously received antibiotics for other indications. Nine patients were exposed to non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) and one had additional aspirin exposure. CONCLUSION: Only 11.7% of patients on maintenance treatment for chronic duodenal ulcer had no current infection with H. pylori, although more than 70% of these had serological evidence of previous infection. Confirmation of active infection may be indicated where there is a history of NSAID or antibiotic exposure and may result in more precise targeting of eradication therapy, thus avoiding unnecessary and potentially hazardous treatment.

Adult↗

Plasma Proteomics Identifies Thousand-and-One-Amino Acid Kinase 3 as a Potential Biomarker of Rheumatoid Arthritis Activity and a Novel Therapeutic Target.

OBJECTIVE: Bone destruction associated with active rheumatoid arthritis (RA) remains a major therapeutic challenge, with a lack of reliable molecular markers reflecting bone injury. This study aims to identify novel biomarkers linked to bone destruction in active RA through proteomic analysis, providing new strategies for precise monitoring and targeted therapy. METHODS: Data-independent acquisition mass spectrometry was used for proteomic quantification and bioinformatic analysis on plasma samples from 160 patients with RA and 40 healthy controls. Key proteins associated with bone destruction were screened by integrating Sharp scores with synovial single-cell RNA sequencing data and subsequently validated in two independent cohorts (N1 = 50 and N2 = 10) using enzyme-linked immunosorbent assay and multiplex immunohistochemistry. Functional studies were conducted using fibroblast-like synoviocytes (FLSs) in vitro and a collagen-induced arthritis (CIA) mouse model in vivo. RESULTS: A total of 4,998 plasma proteins were identified, with 506 showing significant differential expression between active and remitted RA. Thousand-and-one-amino acid kinase 3 (TAOK3) levels were positively associated with Sharp scores and markedly elevated in patients with active RA. Combining TAOK3 with C-reactive protein improved diagnostic accuracy for active RA (area under the curve = 0.915). High TAOK3 expression was also associated with increased relapse frequency. Functional studies showed that TAOK3 knockdown suppressed the tumor-like phenotype of FLSs and down-regulated matrix metalloproteinase 1/2/3 and cathepsin K, whereas TAOK3 overexpression promoted pannus cell-mediated bone erosion, mitigated by TAOK3-targeted inhibitor. In vivo, its inhibition showed therapeutic effects in CIA mice. CONCLUSION: TAOK3 serves as a potential biomarker for bone destruction in active RA and as a therapeutic target for precision monitoring and intervention.

Arthritis, Rheumatoid↗

Mesorectal excision for rectal cancer.

Concern about world wide local recurrence rates for rectal cancer of 20-45%, together with anxiety at the recent proliferation of adjuvant therapies, led us to review the efficacy of total mesorectal excision (TME) with which no adjuvant therapy had been combined. Precise, sharp dissection is undertaken around the integral mesentery of the hind gut, which envelopes the entire mid rectum. This procedure adds to operative time and complications but has been claimed to eliminate virtually all locally recurrent disease after "curative" surgery. Independent analysis (J. K. M.) of prospective follow-up data extended over a 13-year interval (1978-91; mean 7.5 years). The actuarial local recurrence rate after curative anterior resection at 5 years is 4% (95% Cl 0-7.5%) and the overall recurrence rate is 18% (10-25%). 10-year figures are 4% (0-11%) and 19% (7-32%). In view of the high-risk classification used for the North Central Cancer Treatment Group (NCCTG), which has led to a trend to chemoradiotherapy, a similar group of high-risk Basingstoke cases was constructed for comparison purposes. This group included 135 consecutive Dukes' B (B2) and Dukes' C cancer operations, both anterior resection and abdominal-perineal excision, for tumours below 12 cm from the anal verge. Results from TME alone are substantially superior to the best reported (NCCTG) from conventional surgery plus radiotherapy or combination chemoradiotherapy: 5% local recurrence at 5 years compared with 25% and 13.5%, respectively; and 22% overall recurrence compared with 62.7% and 41.5%, respectively (Dukes' B cases [B2], 15%; Dukes' C cases, 32%). Meticulous TME, which encompasses the whole field of tumour spread, can improve cure rates and reduce the variability of outcomes between surgeons. Far more genuine "cures" of rectal cancer are possible by surgery alone than have generally been believed or are currently accepted. Better surgical results are an essential background for the more selective use of adjuvant therapy in the future.

Aged↗

Preliminary observations on an intervention program for heavy smokers.

Each of 571 smokers selected one of three methods of smoking cessation: group therapy, individual counseling, and hypnosis. One-year results suggest little difference between the three methods in producing ex-smokers. All methods produced an average success rate of approximately 20%. It should be noted, however, that with all types of verbal or verbally related therapy it is not known precisely how these techniques work or whether the outcomes are really a function of what is put into the therapy by the treatment agent and/or the recipient. It was generally found that younger, more educated smokers chose hypnosis; older, more educated smokers chose group therapy; and older, less-formally educated smokers chose individual counseling while the youngest and generally less educated smokers chose to become nonattenders and not take part in therapy. These results have important implications for designing optimal treatment programs which will be acceptable and effective for the greatest number of smokers.

Adult↗

Human cytomegalovirus (HCMV)-specific CD4+ T lymphocyte response in AIDS patients with no past or current HCMV disease following HAART.

BACKGROUND: The incidence of Human Cytomegalovirus (HCMV) end-organ disease has dramatically decreased since the implementation of highly active antiretroviral therapies (HAARTs), but the precise immune mechanism whereby HCMV is controlled remains to be elucidated. OBJECTIVES: To investigate the effect of (HAART) on CD4+ T-cell immunity to HCMV in AIDS patients with no past or current HCMV disease. STUDY DESIGN: Seventeen patients were prospectively examined for CD4+ (CD45RO+ and CD45 RA+) T-cell counts (flow cytometry), HIV RNA load (Amplicor HIV test), HCMV leukoDNAemia and HCMV DNA in urine (nested PCR), lymphoproliferative response (LPR) to HCMV, phytohemagglutinin (PHA) and purified protein derived from Mycobacterium tuberculosis (PPD) by measurement of 5-bromo-2'-deoxyuridine incorporation to DNA (ELISA) and cytokine secretion (IFN-gamma, IL-4 and IL-10) by HCMV-stimulated peripheral blood mononuclear cell (PBMC) cultures (ELISA). RESULTS: Fifteen patients responded favorably to HAART (virologically, immunologically, or both). Of these, six patients presented LPR to HCMV at least once during follow-up, whereas most displayed detectable LPRs to PHA. IFN-gamma was detected at least once in supernatants of HCMV-stimulated PBMC cultures from 14 of the 17 patients. All but one patient tested negative for HCMV leukoDNAemia and HCMV DNA in urine, and none developed HCMV disease during the observation period. CONCLUSIONS: Control of HCMV replication and the absence of HCMV disease are not consistently associated with recovery and/or maintenance of LPR to HCMV in AIDS patients under HAART and with no prior HCMV disease. Whether detection of IFN-gamma by PBMCs upon HCMV antigenic stimulation may serve as a surrogate marker for protection against HCMV disease requires further investigation.

AIDS-Related Opportunistic Infections↗

Frequency of neoplasia in systemic lupus erythematosus and rheumatoid arthritis.

A patient population admitted to the hospital for either SLE or RA was surveyed for the subsequent development of neoplasms. The frequency of neoplasm in SLE patients appeared to be exaggerated, whereas the frequency of subsequent neoplasm in rheumatoid patients was unexpectedly low. A paucity of nephritis in the SLE group was noted. Further reports are encouraged so that the magnitude of the risk of malignancy developing with immunosuppressive therapy can be more precisely ascertained.

Adult↗

Development of allogeneic hematopoietic stem cell transplantation (HSCT).

The field of BMT has entered a new phase based on insights into basic molecular and cellular biology. The mechanism of cure mediated by allogeneic HSCT is now believed to be at least partially mediated by cellular attack against tumor-associated antigens. Better understanding of these cellular targets and the means of targeting them specifically will allow a more precise application of cellular therapy than is currently possible. This in turn may make it possible to design therapies that are increasingly selective without the collateral toxicities of GVHD, infection, and direct organ damage that currently are the limiting features of allogeneic HSCT as practiced until recently. However, it remains a challenge to demonstrate that disease-control using reduced intensity preparative regimens is at least comparable to that achieved by traditional myeloablative HSCT. This will require carefully controlled studies in each the major diseases that have shown sensitivity to the immune-mediated effects of HSCT. The chapters below will highlight progress towards the goals of elucidating the role of NST.

Animals↗

Severe preeclampsia. I. Peripartum hemodynamic observations.

With the use of peripheral and pulmonary arterial catheters, the peripartum hemodynamic patterns of 10 patients with severe preeclampsia were studied. At the time of line placement, our results demonstrated elevated cardiac outputs (9.3 +/- 1.3 L/min), high systemic vascular resistances (1,042 +/- 160 dynes . sec . cm-5), and hyperdynamic ventricular function. Immediately post partum (less than 30 minutes), a transient decline in left ventricular function in association with a rise in central venous and wedge pressures was observed. By 1 hour after delivery, ventricular function had returned to its hyperdynamic state. Swan-Ganz catheterization and cardiac output data were most helpful in the monitoring of patients with severe preeclampsia. Ventricular function in these patients appears to operate in the hyperdynamic zone or a "normal" ventricular function zone that is different from that in the nonpregnant patient. At the same time, as shown by our data and a review of the literature, severe preeclampsia appears to be a continuum, as determined by cardiac output and systemic vascular resistance measurements, which range from a high-output--low-resistance system to a low-output--high-resistance one. Therefore, in the evaluation of the patient with severe preeclampsia, a complete hemodynamic profile would be helpful in determining the "phase" of the disease and the status of ventricular function. This would be useful information with which one could theoretically direct therapy in a more precise fashion.

Adolescent↗