Morphologic and functional effects of renal cryoinjury

Wilms' tumor presents with bilateral renal involvement in 10% of patients. With the current treatment protocols for Wilms' tumor emphasizing maximal preservation of renal parenchyma, cryosurgery may offer an alternative to bilateral tumor resections in these patients. This study was designed to examine the effects of profound cryotherapy on a significant portion of the renal parenchyma, simulating the clinical application of this technique. Eighteen New Zealand white rabbits underwent unilateral nephrectomy, with four serving as controls. The contralateral kidney in the experimental animals was subjected to cryoinjury with a liquid nitrogen probe. Needle thermocouples monitored surface temperature 1/2 cm from the margin of the probe tip and renal "core" temperature 1 cm within the renal parenchyma directly beneath the tip. The kidney was cooled until the "core" temperature reached -40 degrees C, and this was achieved with a probe temperature of -180 degrees C for an average of 11.8 min. All animals tolerated the cryoinjury well and were sacrificed in pairs at 24 and 72 hr, and 1, 2, 3, 4, and 8 weeks. Transient gross hematuria was noted in 25% of the animals and microscopic hematuria in 50%. Serum blood urea nitrogen and creatinine levels reached maximum levels at 72 hr (BUN, 92 +/- 28 mg%; Creatinine, 7.2 +/- 1 mg%) and gradually returned toward normal thereafter. The cryolesion at 24 hr resembled a hemorrhagic infarct involving 40% of the kidney. By 8 weeks this lesion had contracted to a fibrotic lesion involving 20% of the kidney by weight. The surrounding uninjured renal parenchyma underwent compensatory hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spontaneous rupture of a renal artery aneurysm presenting as gross hematuria

Renal artery aneurysms (RAAs) are localized dilations of the renal artery and/or its branches. They are being found with increasing frequency as a result of unrelated abdominal imaging or on workup for hypertension. They are rarely symptomatic; however, they can be a cause of life-threatening hematuria. Discussed is the case of a previously healthy 46-year-old man presenting with flank pain and gross hematuria. It is imperative for the practicing urologist to be aware of the appropriate evaluation and management of RAAs.     

Expression of miRNA-223 and NLRP3 gene in IgA patients and intervention of traditional Chinese medicine

ObjectiveThe purpose of this study was to investigate the expression of miRNA-223 and NLRP3 in IgA patients and the intervention of traditional Chinese medicine (TCM), so as to realize the basic pathological changes of IgA patients, the expression of miRNA-223 and NLRP3 in IgA patients and the changes of patients' body indexes before and after the treatment of TCM.MethodsFirstly, according to the clinical data, patients with IgA nephropathy were divided into different groups according to their pathological changes. After that, the chemical sections and staining steps of the immune kidney were carried out. Immunohistochemical pv-9000 two-step method was used to stain it. By this method, miRNA-223 and NLRP3 genes in kidney were determined. After that, the image analysis method was used for semi quantitative experiment. Finally, the intervention of TCM was used to study the changes of indicators before and after treatment.ResultsmiRNA-223 and NLRP3 genes could be found mainly in the cytoplasm of renal tubular epithelial cells and the interstitium of monocyte in renal tissue, and there were significant differences between miRNA-223 and NLRP3 genes in the expression levels of proteinuria alone, hematuria albuminuria alone and hematuria alone. There was a positive correlation between miRNA-223 and NLRP3 expression and 24-hour urinary protein in IgA nephropathy. In addition, it also had positive correlation with MCP-1 and IL-18.ConclusionThis study could provide some direction and guidance for clinical diagnosis and treatment of IgA nephropathy.     

Bladder Tumor Diagnosis—Improved Excretory Cystograms

The correct precystoscopic diagnosis of bladder tumor was made in 20 of 23 patients with this disease, among more than 1,000 persons studied by double-dose excretory urography. There was no increase in the incidence of untoward effects. Double-dose excretory urography with delayed bladder films is recommended as the primary urographic procedure in all patients with gross or microscopic hematuria in whom bladder tumor is suspected.     

Use of alternative medicine by patients attending a gastroenterology clinic.

We carried out a study to determine the proportion of patients attending a university-based gastroenterology outpatient clinic who sought alternative medical care for the same health problem that had prompted them to see a gastroenterologist. After the patients completed a self-administered questionnaire, the gastroenterologist gave a diagnosis and assigned a functional rating. Of the 395 patients 287 (73%) had not used alternative medicine, and 36 (9%) had sought alternative medical care for the problem that had prompted them to see a gastroenterologist. There were no significant differences between alternative medicine users and nonusers in sociodemographic characteristics, use of health care services or general health status. Patients with a functional disease were more likely to seek alternative medical care than those with organic disease (33% v. 7%) (p less than 0.0001). Fewer alternative medicine users (54%) than nonusers (85%) were satisfied with conventional medicine (p less than 0.001), and more alternative medicine users (49%) than nonusers (13%) were very sceptical of conventional medicine (p less than 0.0001).     

Cytologic detection of Wuchereria bancrofti microfilariae in urine collected during a routine workup for hematuria

A 23-year-old Guyanese man experienced intermittent, total, painless, gross hematuria for a month for which he sought medical attention at the Kings County Hospital Center in Brooklyn. Hematuria was accompanied by weakness but not by frequency of urination or burning on urination. Catheterized urine at the time of cystoscopy and each of two subsequent voided specimens examined cytologically contained sheathed microfilariae. Distinguishing features of the microfilariae were well demonstrated with the Papanicolaou stain. The well-stained nuclei, which did not extend into the clear zone, and the distinct, pale-stained sheath led to the positive identification of the microfilariae as Wuchereria bancrofti. The Papanicolaou stain may well be the stain of choice for the identification of microfilariae in the blood. The excellent detail obtained with this routine cytologic stain is as good as that with Giemsa, which does not stain the sheath.     

An economic perspective on personalized medicine

The concept of personalized medicine not only promises to enhance the life of patients and increase the quality of clinical practice and targeted care pathways, but also to lower overall healthcare costs through early-detection, prevention, accurate risk assessments and efficiencies in care delivery. Current inefficiencies are widely regarded as substantial enough to have a significant impact on the economies of major nations like the US and China, and, therefore the world economy. A recent OECD report estimates healthcare expenditure for some of the developed western and eastern nations to be anywhere from 10% to 18%, and growing (with the US at the highest). Personalized medicine aims to use state-of-the-art genomic technologies, rich medical record data, tissue and blood banks and clinical knowledge that will allow clinicians and payors to tailor treatments to individuals, thereby greatly reducing the costs of ineffective therapies incurred through the current trial and error clinical paradigm. Pivotal to the field are drugs that have been designed to target a specific molecular pathway that has gone wrong and results in a diseased condition and the diagnostic tests that allow clinicians to separate responders from non-responders. However, the truly personalized approach in medicine faces two major problems: complex biology and complex economics; the pathways involved in diseases are quite often not well understood, and most targeted drugs are very expensive. As a result of all current efforts to translate the concepts of personalized healthcare into the clinic, personalized medicine becomes participatory and this implies patient decisions about their own health. Such a new paradigm requires powerful tools to handle significant amounts of personal information with the approach to be known as “P4 medicine”, that is predictive, preventive, personalized and participatory. P4 medicine promises to increase the quality of clinical care and treatments and will ultimately save costs. The greatest challenges are economic, not scientific.     

Evidence-based medicine,opinion-based medicine,and real-world medicine

The freedom of a doctor to treat an individual patient in the way he believes best has been markedly limited by the concept of evidence-based medicine. Clearly all would wish to practice according to the best available evidence, but it has become accepted that "evidence-based" means that which is derived from randomized, and preferably double-blind, clinical trials. The history of clinical trial development, which can be traced to the use of oranges and lemons for the treatment of scurvy in 1747, has reflected a progressive need to establish whether smaller and smaller effects of treatment are real. It has led to difficult concepts such as "equivalence" and aberrations such as "meta-analysis." An examination of evidence-based practice shows that it has usually been filtered through the opinions of experts and journal editors, and "opinion-based medicine" would be a more appropriate term. In the real world of individual patients with multiple diseases who are receiving a number of different drugs, the practice of evidence-based (or even opinion-based) medicine is extremely difficult. For each patient a judgment has to be made by the clinician of the likely balance of risks and benefits of any therapy. Good practice still requires clinical freedom for doctors.     

Behavioral convergence and institutional separation: An analysis of plural medicine in Sri Lanka

In Sri Lanka, as in India, two formally structured systems of medical service exist side-by-side. While Western-style biomedicine is believed to be useful, Ayurvedic medicine is also well established and commonly used. Underlying one explanation for the existence of plural medical systems is the idea that traditional and Western systems of medicine provide unique treatments for distinct problems, and patients having certain characteristics select them accordingly. A brief review of several studies in Sri Lanka suggests, however, that Western and Ayurvedic physicians practice medicine in similar ways, are selected for treatment of very similar symptoms, and from the patient's point of view are aften indistinguishable from each other. A second structural explanation rests on the fact that, as institutions, Western and Ayurvedic medicine have effectively divided up territory and jobs to the satisfaction of each; this division allows for upward mobility, through medicine, for young people from different segments of society. Thus these medical systems persist, not because each provides something unique for patients, but because they provide access to status and power for the physicians themselves.     

Urinary schistosomiasis: a report of four cases and a review.

Urinary schistosomiasis is a common cause of hematuria in tropical regions, where it most often affects teenage boys. Children presenting with hematuria in the developed world are usually considered to have bacterial cystitis or a structural lesion and are investigated and treated accordingly. The authors report on a family recently returned to Canada from Nigeria in which all four children had urinary schistosomiasis. Nocturnal enuresis was the presenting symptom in the index case; this patient also had hematuria and dysuria. Nocturia occurred in a second child, and the other two children were asymptomatic. All four were cured by a single dose of praziquantel, a new schistosomicide. The life cycle of the causative organism, the clinical manifestations of schistosomiasis, the host response and treatment with praziquantel are reviewed.     

Prospects for translational regenerative medicine

Translational medicine is an evolutional concept that encompasses the rapid translation of basic research for use in clinical disease diagnosis, prevention and treatment. It follows the idea "from bench to bedside and back", and hence relies on cooperation between laboratory research and clinical care. In the past decade, translational medicine has received unprecedented attention from scientists and clinicians and its fundamental principles have penetrated throughout biomedicine, offering a sign post that guides modern medical research toward a patient-centered focus. Translational regenerative medicine is still in its infancy, and significant basic research investment has not yet achieved satisfactory clinical outcomes for patients. In particular, there are many challenges associated with the use of cell- and tissue-based products for clinical therapies. This review summarizes the transformation and global progress in translational medicine over the past decade. The current obstacles and opportunities in translational regenerative medicine are outlined in the context of stem cell therapy and tissue engineering for the safe and effective regeneration of functional tissue. This review highlights the requirement for multi-disciplinary and inter-disciplinary cooperation to ensure the development of the best possible regenerative therapies within the shortest timeframe possible for the greatest patient benefit.     

Medicalization as a moral problem for preventative medicine

Preventive medicine is sometimes criticised as it contributes to medicalization of normal life. The concept ‘medicalization’ has been introduced by Zola to refer to processes in which the labels ‘healthy’ and ‘ill’ are made relevant for more and more aspects of human life. If preventive medicine contributes to medicalization, would that be morally problematic? My thesis is that such a contribution is indeed morally problematic. The concept is sometimes used to express moral intuitions regarding the practice of prevention and health promotion. Through analysis of these intuitions as well as some other moral concerns, I give an explication of the moral problems of medicalization within the context of preventive medicine.     

Moving towards personalized medicine in rheumatoid arthritis

To develop personalized medicine strategies for improvement of patient management in rheumatoid arthritis, the clinical and molecular properties of the individual patients need to be well characterized. A crucial step in this approach is to discover subgroups of patients that are characterized by a good or poor treatment outcome. Dennis and colleagues have identified distinct pretreatment gene expression profiles in affected synovial tissue specimens and a tissue type-related systemic protein pattern which are associated with a positive or negative clinical outcome to monotherapy with adalumimab (anti-TNFα) and tocilizumab (anti-IL-6 receptor). These observations assign biological pathways associated with response outcome and provide evidence for the existence of systemic, easy-to-measure predictive biomarkers for clinical benefit of these biologics.     

Sex and gender in medicine

Gender specific medicine is a part of gender-research, which has been insufficiently considered up to the present in medicine, sanitation and politics. Part of the scientific medicine simply ignores the knowledge that men and women are different in feeling, thinking and social acting without any question. Doctors often incline to treat all their patients as if there was just one gender: i.e. the male one. It is without dispute that men and women vastly suffer from the same diseases, but they often go through them quite differently. The female body seems to work differently from the male one in nearly all respects--starting with the brain, going on with the heart, cardiovascular, lungs, stomach and intestines and ending up with the skin and immune order. Identical cases of illnesses bring about different symptoms on both sides. Therapeutics therefore have to be appropriate for the specific gender. This however demands complete thinking in preventive measures, therapy, development of one's education and research. Exactly for this reason the new "gender-model" is absolutely important and necessary in medicine as a new pattern of thinking. Only in this way one can realize a comprehensive revaluation of health and disease of both sexes. Pre-eminently one has to convince people that the embedding of "gender" both in medicine and the surrounding area is much more useful than costly from the scientific, political and individual point oft view.     

Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements

Most genetic disruptions underlying human disease are microlesions, whereas gross lesions are rare with gross deletions being most frequently found (6%). Similar observations have been made in primary immunodeficiency genes, such as BTK, but for unknown reasons the IGHM and DCLRE1C (Artemis) gene defects frequently represent gross deletions ( approximately 60%). We characterized the gross deletion breakpoints in IGHM-, BTK-, and Artemis-deficient patients. The IGHM deletion breakpoints did not show involvement of recombination signal sequences or immunoglobulin switch regions. Instead, five IGHM, eight BTK, and five unique Artemis breakpoints were located in or near sequences derived from transposable elements (TE). The breakpoints of four out of five disrupted Artemis alleles were located in highly homologous regions, similar to Ig subclass deficiencies and Vh deletion polymorphisms. Nevertheless, these observations suggest a role for TEs in mediating gross deletions. The identified gross deletion breakpoints were mostly located in TE subclasses that were specifically overrepresented in the involved gene as compared to the average in the human genome. This concerned both long (LINE1) and short (Alu, MIR) interspersed elements, as well as LTR retrotransposons (ERV). Furthermore, a high total TE content (>40%) was associated with an increased frequency of gross deletions. Both findings were further investigated and confirmed in a total set of 20 genes disrupted in human disease. Thus, to our knowledge for the first time, we provide evidence that a high TE content, irrespective of the type of element, results in the increased incidence of gross deletions as gene disruption underlying human disease.     

NXX-066 in patients with Alzheimer's disease: a bridging study

Reduced cholinergic transmission is a key neurotransmitter dysfunction in Alzheimer's Disease (AD). NXX-066, a physostigmine analog and acetylcholinesterase (AChE) inhibitor, has demonstrated activity in animal models of memory function, and was well tolerated in healthy subjects up to a single dose of 64 mg and multiple doses of 60 mg QD for seven days. Since AChE inhibitors are often tolerated differently in AD patients than in healthy volunteers, a randomized, placebo-controlled, double-blind, single-center, inpatient bridging study was conducted to determine the maximum tolerated dose (MTD) of NXX-066 in the target patient population. Seven consecutive panels of eight AD patients each (6 active, 2 placebo) received fixed oral doses of NXX-066 (20, 30, 40, 50, 60, 70, or 80 mg BID) for seven days. Initiation of each subsequent panel (dose group) was contingent upon the tolerability of lower dose levels. The MTD was determined to be 70 mg BID when four of six patients receiving 80 mg BID were prematurely discontinued from the study due to nausea and/or vomiting, accompanied in some patients by mild to moderate dizziness, headache, asthenia, and gastric symptoms. Wide variability in plasma levels of NXX-066 was observed in all dose panels. AChE inhibition in whole blood correlated with both maximum plasma concentration and dose; however, AChE inhibition was not predictive of adverse events. In this study, AD patients tolerated larger daily doses of NXX-066 on a BID regimen than healthy normal subjects had tolerated with QD dosing. Further studies are warranted to examine whether differing tolerability between patients and healthy subjects or the reduced dosing interval explains these findings.     

MTP-PE in liposomes as a biological response modifier in the treatment of cancer: Current status

MTP-PE in liposomes is a BRM which can be given relatively safely to patients with cancer. The maximum tolerated dose appears to be higher than the optimal dose inducing immunomodulatory effects such as cytokine induction and monocyte/macrophage activation. The most consistently induced cytokines measured in the plasma of patients a few hours after MTP-PE are TNF and IL-6. Indirect evidence supports the assumption that increased levels of TNF and IL-6 are signs of macrophage activation occurringin situ in tissues taking up liposomal MTP-PE shortly after injection. These tissues are mainly lungs, liver and spleen, as shown in 4 patients injected with radiolabelled liposomes containing MTP-PE. Assuming that activated monocytes and macrophages cannot eliminate gross tumor load, the main targets for MTP-PE are micrometastases after removal of the primary tumor. Thus, adjuvant treatment using liposomal MTP-PE in combination with chemotherapy is a major goal for the future.