Explanatory models of medically unexplained symptoms: a qualitative analysis of the literature

Background Medically unexplained symptoms (MUS) are common in primary health care. Both patients and doctors are burdened with the symptoms that negatively affect patients' quality of life. General practitioners (GPs) often face difficulties when giving patients legitimate and convincing explanations for their symptoms. This explanation is important for reassuring patients and for maintaining a good doctor-patient communication and relationship.Objective To provide an overview of explanatory models for MUS.Study design We performed a systematic search of reviews in PsycINFO and PubMed about explanatory models of MUS. We performed a qualitative analysis of the data according to the principles of constant comparative analysis to identify specific explanatory models.Results We distinguished nine specific explanatory models of MUS in the literature: somatosensory amplification, sensitisation, sensitivity, immune system sensitisation, endocrine dysregulation, signal filter model, illness behaviour model, autonomous nervous system dysfunction and abnormal proprioception. The nine different explanatory models focus on different domains, including somatic causes, perception, illness behaviour and predisposition. We also found one meta-model, which incorporates these four domains: the cognitive behavioural therapy model.Conclusion Although GPs often face difficulties when providing explanations to patients with MUS, there are multiple explanatory models in the scientific literature that may be of use in daily medical practice.     

Epistasis analysis between homologous recombination genes in Saccharomyces cerevisiae identifies multiple repair pathways for Sgs1, Mus81-Mms4 and RNase H2

The DNA repair genes SGS1 and MUS81 of Saccharomyces cerevisiae are thought to control alternative pathways for the repair of toxic recombination intermediates based on the fact that sgs1Δ mus81Δ synthetic lethality is suppressed in the absence of homologous recombination (HR). Although these genes appear to functionally overlap in yeast and other model systems, the specific pathways controlled by SGS1 and MUS81 are poorly defined. Epistasis analyses based on DNA damage sensitivity previously indicated that SGS1 functioned primarily downstream of RAD51, and that MUS81 was independent of RAD51. To further define these genetic pathways, we carried out a systematic epistasis analysis between the RAD52-epistasis group genes and SGS1, MUS81, and RNH202, which encodes a subunit of RNase H2. Based on synthetic-fitness interactions and DNA damage sensitivities, we find that RAD52 is epistatic to MUS81 but not SGS1. In contrast, RAD54, RAD55 and RAD57 are epistatic to SGS1, MUS81 and RNH202. As expected, SHU2 is epistatic to SGS1, while both SHU1 and SHU2 are epistatic to MUS81. Importantly, loss of any RNase H2 subunit on its own resulted in increased recombination using a simple marker-excision assay. RNase H2 is thus needed to maintain genome stability consistent with the sgs1Δ rnh202Δ synthetic fitness defect. We conclude that SGS1 and MUS81 act in parallel pathways downstream of RAD51 and RAD52, respectively. The data further indicate these pathways share common components and display complex interactions.     

Phylogeographic origin of Hokkaido house mice (Mus musculus) as indicated by genetic markers with maternal, paternal and biparental inheritance

We examined intraspecies genetic variation in house mice (Mus musculus molossinus) from the northern third of the Japanese Islands, in order to obtain evidence of the history of mouse colonization that might have shaped the current genetic diversity. We extended the previous sampling of mitochondrial cytochrome b sequence and added information from the Y-linked Sry gene and ribosomal RNA gene surveys. We distinguish mitochondrial haplotypes characteristic of the North Asian musculus subspecies group (involving M. m. musculus and M. m. molossinus) as 'MUS', and that of the Southeast Asian castaneus subspecies group as 'CAS' (although the mice resemble MUS morphologically). There was a clear geographic partition of MUS and CAS types into southern and northern Hokkaido, respectively. Conversely, on Tohoku, the MUS and CAS types were interspersed without clear geographic subdivision. In contrast to the mtDNA data, all Hokkaido and Tohoku mice examined were found to possess a unique type for the Y-linked Sry gene, specific to Korea and Japan. Restriction site analysis of nuclear rDNA probe showed a consistent distribution of MUS and CAS types, as major and minor components, respectively, in the Hokkaido and Tohoku mice. These data support the previous notion that the Hokkaido and Tohoku mice experienced genetic hybridization between primary residents of CAS origin and MUS newcomers arriving via a southern route. The invasion of the MUS type could correspond with the evidence for arrival of prehistoric peoples. There are, however, alternative interpretations, including genetic admixture between MUS arriving by a southern route and CAS from a northern route.     

Cost-Effectiveness of Collaborative Care for the Treatment of Depressive Disorders in Primary Care: A Systematic Review

BackgroundFor the treatment of depressive disorders, the framework of collaborative care has been recommended, which showed improved outcomes in the primary care sector. Yet, an earlier literature review did not find sufficient evidence to draw robust conclusions on the cost-effectiveness of collaborative care.PurposeTo systematically review studies on the cost-effectiveness of collaborative care, compared with usual care for the treatment of patients with depressive disorders in primary care.MethodsA systematic literature search in major databases was conducted. Risk of bias was assessed using the Cochrane Collaboration’s tool. Methodological quality of the articles was assessed using the Consensus on Health Economic Criteria (CHEC) list. To ensure comparability across studies, cost data were inflated to the year 2012 using country-specific gross domestic product inflation rates, and were adjusted to international dollars using purchasing power parities (PPP).ResultsIn total, 19 cost-effectiveness analyses were reviewed. The included studies had sample sizes between n = 65 to n = 1,801, and time horizons between six to 24 months. Between 42% and 89% of the CHEC quality criteria were fulfilled, and in only one study no risk of bias was identified. A societal perspective was used by five studies. Incremental costs per depression-free day ranged from dominance to US$PPP 64.89, and incremental costs per QALY from dominance to US$PPP 874,562.ConclusionDespite our review improved the comparability of study results, cost-effectiveness of collaborative care compared with usual care for the treatment of patients with depressive disorders in primary care is ambiguous depending on willingness to pay. A still considerable uncertainty, due to inconsistent methodological quality and results among included studies, suggests further cost-effectiveness analyses using QALYs as effect measures and a time horizon of at least 1 year.     

Identification and characterization of MUS81 point mutations that abolish interaction with the SLX4 scaffold protein

MUS81-EME1 is a conserved structure-selective endonuclease with a preference for branched DNA substrates in vitro that correspond to intermediates of DNA repair. Cells lacking MUS81 or EME1 show defects in the repair of DNA interstrand crosslinks (ICL) resulting in hypersensitivity to agents such as mitomycin C. In metazoans, a proportion of cellular MUS81-EME1 binds the SLX4 scaffold protein, which is itself instrumental for ICL repair. It was previously reported that mutations in SLX4 that abolished interaction with MUS81 affected ICL repair in human cells but not in murine cells. In this study we looked the other way around by pinpointing amino acid residues in MUS81 that when mutated abolish the interaction with SLX4. These mutations fully rescued the mitomycin C hypersensitivity of MUS81 knockout murine cells, but they were unable to rescue the sensitivity of two different human cell lines defective in MUS81. These data support an SLX4-dependent role for MUS81 in the repair, but not the induction of ICL-induced double-strand breaks. This study sheds light on the extent to which MUS81 function in ICL repair requires interaction with SLX4.     

Substrate specificity of the MUS81-EME2 structure selective endonuclease

MUS81 plays important cellular roles in the restart of stalled replication forks, the resolution of recombination intermediates and in telomere length maintenance. Although the actions of MUS81-EME1 have been extensively investigated, MUS81 is the catalytic subunit of two human structure-selective endonucleases, MUS81-EME1 and MUS81-EME2. Little is presently known about the activities of MUS81-EME2. Here, we have purified MUS81-EME2 and compared its activities with MUS81-EME1. We find that MUS81-EME2 is a more active endonuclease than MUS81-EME1 and exhibits broader substrate specificity. Like MUS81-EME1, MUS81-EME2 cleaves 3′-flaps, replication forks and nicked Holliday junctions, and exhibits limited endonuclease activity with intact Holliday junctions. In contrast to MUS81-EME1, however, MUS81-EME2 cuts D-loop recombination intermediates and in so doing disengages the D-loop structure by cleaving the 3′-invading strand. Additionally, MUS81-EME2 acts on 5′-flap structures to cleave off a duplex arm, in reactions that cannot be promoted by MUS81-EME1. These studies suggest that MUS81-EME1 and MUS81-EME2 exhibit similar and yet distinct DNA structure selectivity, indicating that the two MUS81 complexes may promote different nucleolytic cleavage reactions in vivo.     

A winged helix domain in human MUS81 binds DNA and modulates the endonuclease activity of MUS81 complexes

The MUS81-EME1 endonuclease maintains metazoan genomic integrity by cleaving branched DNA structures that arise during the resolution of recombination intermediates. In humans, MUS81 also forms a poorly characterized complex with EME2. Here, we identify and determine the structure of a winged helix (WH) domain from human MUS81, which binds DNA. WH domain mutations greatly reduce binding of the isolated domain to DNA and impact on incision activity of MUS81-EME1/EME2 complexes. Deletion of the WH domain reduces the endonuclease activity of both MUS81-EME1 and MUS81-EME2 complexes, and incisions made by MUS81-EME2 are made closer to the junction on substrates containing a downstream duplex, such as fork structures and nicked Holliday junctions. WH domain mutation or deletion in Schizosaccharomyces pombe phenocopies the DNA-damage sensitivity of strains deleted for mus81. Our results indicate an important role for the WH domain in both yeast and human MUS81 complexes.     

Survival of the Replication Checkpoint Deficient Cells Requires MUS81-RAD52 Function

In checkpoint-deficient cells, DNA double-strand breaks (DSBs) are produced during replication by the structure-specific endonuclease MUS81. The mechanism underlying MUS81-dependent cleavage, and the effect on chromosome integrity and viability of checkpoint deficient cells is only partly understood, especially in human cells. Here, we show that MUS81-induced DSBs are specifically triggered by CHK1 inhibition in a manner that is unrelated to the loss of RAD51, and does not involve formation of a RAD51 substrate. Indeed, CHK1 deficiency results in the formation of a RAD52-dependent structure that is cleaved by MUS81. Moreover, in CHK1-deficient cells depletion of RAD52, but not of MUS81, rescues chromosome instability observed after replication fork stalling. However, when RAD52 is down-regulated, recovery from replication stress requires MUS81, and loss of both these proteins results in massive cell death that can be suppressed by RAD51 depletion. Our findings reveal a novel RAD52/MUS81-dependent mechanism that promotes cell viability and genome integrity in checkpoint-deficient cells, and disclose the involvement of MUS81 to multiple processes after replication stress.     

Economic Burden of Hypoglycemia in Patients with Type 2 Diabetes Mellitus from Korea

Background

Hypoglycemia is a very serious complication in patients with type 2 diabetes mellitus (T2DM) and affects the economic burden of treatment. This study aims to create models of the cost of treating hypoglycemia in patients with T2DM based upon physician estimates of medical resource usage.

Methods

Using a literature review and personal advice from endocrinologists and emergency physicians, we developed several models for managing patients with hypoglycemia. The final model was approved by the consulting experts. We also developed 3 unique surveys to allow endocrinologists, emergency room (ER) physicians, and primary care physicians to evaluate the resource usage of patients with hypoglycemia. Medical costs were calculated by multiplying the estimated medical resource usage by the corresponding health insurance medical care costs reported in 2014.

Results

In total, 40 endocrinologists, 20 ER physicians, and 30 primary care physicians completed the survey. We identified 12 types of standard medical models for secondary or tertiary hospitals and 4 for primary care clinics based on the use of ER, general ward, or intensive care unit (ICU) and patients’ status of consciousness and self-respiration. Estimated medical costs per person per hypoglycemic event ranged from $17.28 to $1,857.09 for secondary and tertiary hospitals. These costs were higher for patients who were unconscious and for those requiring ICU admission.

Conclusion

Hypoglycemia has a substantial impact on the medical costs and its prevention will result in economic benefits for T2DM patients and society.     

Medically Unexplained and Explained Physical Symptoms in the General Population: Association with Prevalent and Incident Mental Disorders

Background

Clinical studies have shown that Medically Unexplained Symptoms (MUS) are related to common mental disorders. It is unknown how often common mental disorders occur in subjects who have explained physical symptoms (PHY), MUS or both, in the general population, what the incidence rates are, and whether there is a difference between PHY and MUS in this respect.

Aim

To study the prevalence and incidence rates of mood, anxiety and substance use disorders in groups with PHY, MUS and combined MUS and PHY compared to a no-symptoms reference group in the general population.

Method

Data were derived from the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2), a nationally representative face-to-face survey of the general population aged 18-64 years. We selected subjects with explained physical symptoms only (n=1952), with MUS only (n=177), with both MUS and PHY (n=209), and a reference group with no physical symptoms (n=4168). The assessment of common mental disorders was through the Composite International Diagnostic Interview 3.0. Multivariate logistic regression analyses were used to examine the association between group membership and the prevalence and first-incidence rates of comorbid mental disorders, adjusted for socio-demographic characteristics.

Results

MUS were associated with the highest prevalence rates of mood and anxiety disorders, and combined MUS and PHY with the highest prevalence rates of substance disorder. Combined MUS and PHY were associated with a higher incidence rate of mood disorder only (OR 2.9 (95%CI:1.27,6.74)).

Conclusion

In the general population, PHY, MUS and the combination of both are related to mood and anxiety disorder, but odds are highest for combined MUS and PHY in relation to substance use disorder. Combined MUS and PHY are related to a greater incidence of mood disorder. These findings warrant further research into possibilities to improve recognition and early intervention in subjects with combined MUS and PHY.     

Damage-dependent regulation of MUS81-EME1 by Fanconi anemia complementation group A protein

MUS81-EME1 is a DNA endonuclease involved in replication-coupled repair of DNA interstrand cross-links (ICLs). A prevalent hypothetical role of MUS81-EME1 in ICL repair is to unhook the damage by incising the leading strand at the 3′ side of an ICL lesion. In this study, we report that purified MUS81-EME1 incises DNA at the 5′ side of a psoralen ICL residing in fork structures. Intriguingly, ICL repair protein, Fanconi anemia complementation group A protein (FANCA), greatly enhances MUS81-EME1-mediated ICL incision. On the contrary, FANCA exhibits a two-phase incision regulation when DNA is undamaged or the damage affects only one DNA strand. Studies using truncated FANCA proteins indicate that both the N- and C-moieties of the protein are required for the incision regulation. Using laser-induced psoralen ICL formation in cells, we find that FANCA interacts with and recruits MUS81 to ICL lesions. This report clarifies the incision specificity of MUS81-EME1 on ICL damage and establishes that FANCA regulates the incision activity of MUS81-EME1 in a damage-dependent manner.     

Human MUS81 complexes stimulate flap endonuclease 1

The yeast heterodimeric Mus81-Mms4 complex possesses a structure-specific endonuclease activity that is critical for the restart of stalled replication forks and removal of toxic recombination intermediates. Previously, we reported that Mus81-Mms4 and Rad27 (yeast FEN1, another structure-specific endonuclease) showed mutual stimulation of nuclease activity. In this study, we investigated the interactions between human FEN1 and MUS81-EME1 or MUS81-EME2, the human homologs of the yeast Mus81-Mms4 complex. We found that both MUS81-EME1 and MUS81-EME2 increased the activity of FEN1, but FEN1 did not stimulate the activity of MUS81-EME1/EME2. The MUS81 subunit alone and its N-terminal half were able to bind to FEN1 and stimulate its endonuclease activity. A truncated FEN1 fragment lacking the C-terminal region that retained catalytic activity was not stimulated by MUS81. Michaelis-Menten kinetic analysis revealed that MUS81 increased the interaction between FEN1 and its substrates, resulting in increased turnover. We also showed that, after DNA damage in human cells, FEN1 co-localizes with MUS81. These findings indicate that the human proteins and yeast homologs act similarly, except that the human FEN1 does not stimulate the nuclease activities of MUS81-EME1 or MUS81-EME2. Thus, the mammalian MUS81 complexes and FEN1 collaborate to remove the various flap structures that arise during many DNA transactions, including Okazaki fragment processing.     

Urologic syndrome associated with wire caging in AKR mice

Individually housed male AKR/NCrlBR mice used in a chronic inhalation experiment were noted to develop a severe obstructive genitourinary condition. The mouse urologic syndrome (MUS) had one or more of the following features: bladder distension; peripreputial urine staining, alopecia, and edema; paraphimosis; urethral blockage; ulcerative balanophosthitis; hydronephrosis; pyelonephritis; rectal prolapse; and perineal ulcerative dermatitis. MUS was less severe and less prevalent in similarly housed B6C3F1/CrlBR and NIH-Swiss mice used in the same experiment. Epidemiologic evidence within the animal facility restricted the syndrome to the inhalation toxicology area. The effects of intermittent water deprivation as well as wire caging on the development of MUS were studied because these conditions were only utilized in the inhalation facility. Male AKR/NCrlBR mice, caged individually in suspended wire caging or kept isolated in polystyrene shoebox style cages containing wire floorwalk bottoms, all developed MUS within 16 weeks. Mice which were housed directly on hardwood bedding in identical plastic caging remained free of the syndrome, as did castrated males which were kept in suspended wire cages. Water deprivation was not found to be a major contributing factor to the development of the condition, but was found to augment its severity. We concluded that although MUS is probably multifactorial in etiology, housing susceptible animals on wire bottom caging may exacerbate the incidence and severity of the condition in certain strains of male mice.     

Determination of muscimol and ibotenic acid in Amanita mushrooms by high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry

A reliable analytical method was developed for the quantification and identification of muscimol (MUS) and ibotenic acid (IBO), the toxic constituents of Amanita muscaria and Amanita pantherina. MUS and IBO were extracted from mushrooms by aqueous methanol and derivatized with dansyl chloride (DNS-Cl). After extraction with ethyl acetate and evaporation of the solvent, the residue was ethylated with 1.25 M hydrogen chloride in ethanol. The resulting derivatives were quantified by high-performance liquid chromatography with UV detection and identified by liquid chromatography electrospray ionization tandem mass spectrometry. Calibration curves were linear in the range of 25-2500 ppm for MUS and 40-2500 ppm for IBO, respectively. This method was successfully applied to identify and quantify MUS and IBO in Amanita mushrooms naturally grown and circulated in the drug market.     

The Incidence of First Venous Thromboembolism in and around Pregnancy Using Linked Primary and Secondary Care Data: A Population Based Cohort Study from England and Comparative Meta-Analysis

Background

Recent linkage between primary and secondary care data has provided valuable information for studying heath outcomes that may initially present in different health care settings. The aim of this study was therefore, twofold: to use linked primary and secondary care data to determine an optimum definition for estimating the incidence of first VTE in and around pregnancy; and secondly to conduct a systematic literature review of studies on perinatal VTE incidence with the purpose of comparing our estimates.

Methods

We used primary care data from the Clinical Practice Research Datalink (CPRD), which incorporates linkages to secondary care contained within Hospital Episode Statistics (HES) between 1997 and 2010 to estimate the incidence rate of VTE in the antepartum and postpartum period. We systematically searched the literature on the incidence of VTE during antepartum and postpartum periods and performed a meta-analysis to provide comparison.

Findings

Using combined CPRD and HES data and a restrictive VTE definition, the absolute rate during the antepartum period and first six weeks postpartum (early postpartum) were 99 (95%CI 85–116) and 468 (95%CI 391–561) per 100,000 person-years respectively. These were comparable to the pooled estimates from our meta-analysis (using studies after 2005) during the antepartum period (118/100,000 person-years) and early postpartum (424/100,000 person-years). When we used only secondary care data to identify VTE events, incidence was lower during the early postpartum period (308/100,000 person-years), whereas relying only on primary care data lead to lower incidence during the time around delivery, but higher rates during the postpartum period (558/100,000 person-years).

Conclusion

Using combined CPRD and HES data gives estimates of the risk of VTE in and around pregnancy that are comparable to the existing literature. It also provides more accurate estimation of the date of VTE diagnosis which will allow risk stratification during specific pregnancy and postpartum periods.     

A GABA-neuropeptide Y (NPY) interplay in LH release

Neuropeptide Y (NPY) stimulates and gamma-amino butyric acid (GABA) inhibits LH release in the rat. Since a sub-population of NPY-producing neurons in the arcuate nucleus (ARC) of the hypothalamus co-express GABA, the possibility of an interplay between NPY and GABA in the release of LH was investigated in two ways. First by employing light and electron microscopic double staining for NPY and GABA, using pre and post-immunolabeling on rat brain sections, we detected GABA in NPY immunoreactive axon terminals in the MPOA, one of the primary sites of action of these neurotransmitters/neuromodulators in the regulation of LH release. These morphological findings raised the possibility that inhibitory GABA co-released with NPY may act to restrain the excitatory effects of NPY on LH release. Muscimol (MUS, 0.44 or 1.76 nmol/rat), a GABA(A) receptor agonist, administered intracerebroventricularly (icv), alone failed to affect LH release, but NPY (0.47 nmol/rat icv) alone stimulated LH release in ovarian steroid-primed ovariectomized rats. On the other hand, administration of MUS blocked the NPY-induced stimulation of LH release in a dose-dependent manner. Similarly, administration of MUS abolished the excitatory effects on LH release of 1229U91, a selective NPY Y4 receptor agonist. These results support the possibility that in the event of co-release of these neurotransmitters/neuromodulators, GABA may act to restrain stimulation of LH release by NPY during the basal episodic and cyclic release of LH in vivo.     

Best Practice Updates for Multidisciplinary Care in Weight Loss Surgery

The objective of this study is to update evidence‐based best practice guidelines for multidisciplinary care of weight loss surgery (WLS) patients. We performed systematic search of English‐language literature on WLS, patient selection, and medical, multidisciplinary, and nutritional care published between April 2004 and May 2007 in MEDLINE and the Cochrane Library. Key words were used to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence‐based models. A total of 150 papers were retrieved from the literature search and 112 were reviewed in detail. We made evidence‐based best practice recommendations from the most recent literature on multidisciplinary care of WLS patients. New recommendations were developed in the areas of patient selection, medical evaluation, and treatment. Regular updates of evidence‐based recommendations for best practices in multidisciplinary care are required to address changes in patient demographics and levels of obesity. Key factors in patient safety include comprehensive preoperative medical evaluation, patient education, appropriate perioperative care, and long‐term follow‐up.     

Developing a register of randomised controlled trials in primary care.

OBJECTIVE--To determine the number, nature, site of publication, and feasibility of identifying randomised controlled trials relevant to primary care. DESIGN--Review of literature using three strategies: approaching journal editors, Medline search, and manual search of individual journals. SETTING--Journals containing publications of studies based in primary care. MAIN OUTCOME MEASURES--The number, site of publication, and subject of trials identified. RESULTS--No journal had a system which enabled identification of all the randomised controlled trials it published. 266 trials relevant to primary care were identified from 110 different journals during 1987-91 by Medline. Of these, only 62 trials were published in primary care journals. Hand searching of seven major primary care research journals showed that between 13% and 38% of the trials had been missed by the Medline search. Of the trials identified, 47 (18%) were concerned with mental disease (including neuroses, tobacco misuse and alcohol misuse) and 43 (16%) were concerned with hypertension. CONCLUSION--Given the diversity of publication sources and topics, this supports the need for a centrally based register of randomised controlled trials that may be relevant to primary care overviews in the future.     

What will a primary care led NHS mean for GP workload? The problem of the lack of an evidence base.

Ongoing negotiations on the general practitioner contract raise the question of remunerating general practitioners for increased workload resulting from the shift from secondary to primary care. A review of the literature shows that there is little evidence on whether a shift of services from secondary to primary care is responsible for general practitioners'' increased workload, and scope for making generalisations is limited. The implication is that general practitioners have little more than anecdotal evidence to support their claims of greatly increased workloads, and there is insufficient evidence to make informed decisions about remunerating general practitioners for the extra work resulting from the changes. Lack of evidence does not, however, mean that there is no problem with workload. It will be increasingly important to identify mechanisms for ensuring that resources follow workload.     

Incidence of obstructive uropathy in male B6C3F1 mice on a 24-month carcinogenicity study and its apparent prevention by ochratoxin A

A 24-month study assessed the carcinogenic potential of the nephrotoxic mycotoxin ochratoxin A (OA) in B6C3F1 mice. Three groups of 50 males and 50 females were fed 0.1 or 40 ppm OA in the diet. Obstructive urinary tract disease (mouse urological syndrome [MUS]) accounted for the greatest number of spontaneous deaths in the male mice of control (12/50) and 1 ppm (13/50) dose groups, but the disease was not observed in the males fed 40 ppm OA. The earliest age of onset of clinical signs of MUS was 4 months and the average age of onset was 10.1 months. The first death from MUS was observed at 5 months and average age at death was 12.2 months. The mice were caged in groups of five mice per cage and clustering of cases of MUS was observed. Properties of OA which may be important to its preventive effect include inhibition of growth of gram positive bacteria and the production of polyuria as a result of renal proximal tubular damage.