Tratamiento farmacológico de la litiasis renal: medicamentos actuales y monitorización del pH urinario / Pharmacologic treatment of kidney stones: Current medication and pH monitoring

La nefrolitiasis es una enfermedad urológica de prevalencia mundial asociada a una importante morbilidad y malestar para el paciente. El tratamiento actual de los cálculos renales se basa en intervenciones quirúrgicas y farmacológicas. Aunque la cirugía puede ser necesaria en casos determinados, el tratamiento farmacológico es una opción más asequible, fácilmente disponible y menos invasiva para el paciente. Se realizó una revisión exhaustiva para resumir la bibliografía disponible sobre las estrategias de manejo farmacológico de los principales tipos de litiasis: oxalato cálcico, fosfato cálcico, ácido úrico, estruvita y cistina. La regulación de factores como el pH urinario, la cristalización de los cálculos y los trastornos metabólicos del paciente que precipitan el desarrollo y el crecimiento de los cálculos es fundamental para estos enfoques terapéuticos. Esta revisión hace hincapié en las opciones farmacológicas disponibles para el tratamiento según el tipo de litiasis y destaca la importancia de un tratamiento médico personalizado para cada paciente, aspecto que debe ser tenido en cuenta por todos los médicos. (AU)

Nephrolithiasis is a globally prevalent urologic condition associated with significant morbidity and patient discomfort. Current management of kidney stones includes both surgical and pharmacologic interventions. Though surgery may be necessary under certain circumstances, pharmacologic treatment is a more affordable, readily available, and a less invasive option for patients. A comprehensive scoping review was conducted to summarize the available literature on the pharmacologic strategies for managing the predominant stone types including calcium oxalate, calcium phosphate, uric acid, struvite, and cystine stones. Central to these therapeutic approaches is the regulation of factors such as urine pH, stone crystallization, and patient metabolics that precipitate stone development and growth. This review highlights the pharmacological options available for treating each kidney stone type, emphasizing the importance of patient tailored medical management that should be considered by every physician. (AU)

Pharmacologic treatment of kidney stones: Current medication and pH monitoring.

Nephrolithiasis is a globally prevalent urologic condition associated with significant morbidity and patient discomfort. Current management of kidney stones includes both surgical and pharmacologic interventions. Though surgery may be necessary under certain circumstances, pharmacologic treatment is a more affordable, readily available, and a less invasive option for patients. A comprehensive scoping review was conducted to summarize the available literature on the pharmacologic strategies for managing the predominant stone types including calcium oxalate, calcium phosphate, uric acid, struvite, and cystine stones. Central to these therapeutic approaches is the regulation of factors such as urine pH, stone crystallization, and patient metabolics that precipitate stone development and growth. This review highlights the pharmacological options available for treating each kidney stone type, emphasizing the importance of patient tailored medical management that should be considered by every physician.

Imputation of Assay Bioactivity Data Using Deep Learning.

We describe a novel deep learning neural network method and its application to impute assay pIC50 values. Unlike conventional machine learning approaches, this method is trained on sparse bioactivity data as input, typical of that found in public and commercial databases, enabling it to learn directly from correlations between activities measured in different assays. In two case studies on public domain data sets we show that the neural network method outperforms traditional quantitative structure-activity relationship (QSAR) models and other leading approaches. Furthermore, by focusing on only the most confident predictions the accuracy is increased to R2 > 0.9 using our method, as compared to R2 = 0.44 when reporting all predictions.

Accidental bowel leakage in the mature women's health study: prevalence and predictors.

BACKGROUND: The 2007 National Institutes of Health incontinence consensus panel emphasised the need for classification and identification of persons at risk for faecal incontinence (FI). OBJECTIVES: To explore the prevalence of FI; to characterise severity and 'bother'; and to identify factors associated with FI in a large sample of community-dwelling women. DESIGN, SETTING, AND PARTICIPANTS: A cohort of US women ≥ 45 years old was surveyed via an internet-based questionnaire between September 2009 and April 2010. MAIN OUTCOME MEASURE: Accidental leakage of liquid or solid stool at least once in the last 12 months. KEY RESULTS: Eighty-five per cent of those surveyed (5817/6873) participated and were predominantly white, well educated and insured. The prevalence of FI at least once in the past year was 18.8% (1096/5817; 95% CI: 17.8-19.9%) and 97% of these women were bothered by this frequency of leakage. Among 938 respondents with FI, 71.1% (667) preferred the term 'accidental bowel leakage' (ABL) over faecal or bowel incontinence. Bowel disorders, urinary incontinence, stroke, age 55-64, diabetes mellitus and prior vaginal delivery were associated with an increased odds of FI, whereas being married, Black or American Indian/Alaska Native race/ethnicity, and income ≥ $40,000 per year were associated with a decreased odds of FI. CONCLUSIONS: Nearly one-fifth of mature US women suffer from bothersome leakage of stool at least yearly and the overwhelming majority prefer the term 'Accidental Bowel Leakage.' Those with bowel disorders and urinary incontinence are most likely to experience ABL. Incorporating questions regarding ABL or bowel and bladder disorders into routine screening may aid in identifying silent sufferers of ABL.

Quality of life impact in women with accidental bowel leakage.

BACKGROUND: Accidental bowel leakage (ABL) is associated with negative impact on quality of life (QoL) and many women do not seek care. OBJECTIVES: To assess current perspectives and QoL among women with ABL; to identify factors associated with severe impact on condition-specific QoL; and to describe care-seeking for ABL. DESIGN, SETTING AND PARTICIPANTS: Sub-analysis of 1096 women with ABL identified through an internet-based, self-administered survey of 5817 US women ≥ 45 years old. MAIN OUTCOME MEASURE: Severe impact on QoL was defined as response of 'affects very much' or 'greatly' to any of seven domains within Pelvic Floor Impact Questionnaire. RESULTS: QoL data were available for 85.6% (938/1096) of women with ABL. Domains relating to frustration, emotional health and participation in social activities demonstrated the greatest negative impact, with 39.2% (95% CI 36.1-42.4%) having overall severe impact. More frequent ABL, faecal urgency, nocturnal bowel movements, FI without warning, stress FI, weekly urinary incontinence and underlying bowel disorder were associated with severe impact on QoL. Of the 28.6% (268/938) of women who spoke to a physician about their ABL, the majority did so with a general practitioner or family physician (56.0%, 150/268). Only 19.0% (51/268) consulted an internist or gastroenterologist [27.2% (73/268)]. CONCLUSIONS: Nearly 40% of adult women with ABL have severe negative impact on QoL, but less than one-third seek care. More than half of those who seek care do so with their primary care provider. Improved awareness of the prevalence and impact of FI by these providers may decrease barriers and improve QoL.

Economic transition should come with a health warning: the case of Vietnam.

STUDY OBJECTIVE: s: To assess the affordability of health care to poor rural households in Vietnam under conditions of transition from a planned to a market economy and, in light of other transitional experience, inform policy on increasing access of the poor to affordable care of acceptable quality. DESIGN: Observational study by cross sectional socioeconomic survey, longitudinal healthcare seeking survey, and qualitative semi-structured interviews and focus group discussions; qualitative follow up over six years. SETTING: Four rural communes in north of Vietnam between 1992 and 1998. SURVEY PARTICIPANTS: 656 households (2995 people) selected by systematic random sampling. MAIN RESULTS: Compared with non-poor households, poor households had significantly lower average per capita rates of healthcare consultation and expenditure (p<0.01 in both cases). Poor households delayed and minimised healthcare seeking, especially of expensive hospital services. Two thirds of average healthcare spending by poor households was on relatively inexpensive but frequent acts of local ambulatory care. The poor restrained their healthcare seeking but not in proportion to income: for households reporting illness, the average proportion of income devoted to health care was 21.9% for the poor compared with 8.2% for the non-poor (p<0.01). To meet healthcare costs, many poor households reduced essential consumption, sold assets and incurred debt, threatening their future livelihood. CONCLUSIONS: In the short-term the poor need exemption from public sector user fees in both primary and hospital care. In the longer run the government budget and prepayment schemes should replace direct user charges in healthcare finance. Transitional economies like Vietnam should preserve the public health services built up under the planned economy. Market reforms that stimulate growth in the economy appear inappropriate to reform of social sectors.

Three new DP alleles identified in a study of 800 unrelated bone marrow donor-recipient pairs.

HLA-DP genotyping of 800 unrelated donor-recipient pairs in phase 5 of a retrospective analysis of unrelated bone marrow transplantation, sponsored by the National Marrow Donor Program (NMDP), has identified two new DPB1 alleles (DPB1*8701 and DBP1*8801) and one new DPA1 (DPA1*0108) allele. Sequencing confirmed that all three of these new alleles represent novel combinations of previously described sequence motifs, reinforcing the notion that "gene conversion-like" events play an important role in generating HLA allelic diversity. The identification of these new alleles brings the total number of DPA1 alleles to 20 and the total number of DPB1 alleles to 94.

Differences in stability among the human apolipoprotein E isoforms determined by the amino-terminal domain.

Denaturation by guanidine-HCl, urea, or heating was performed on the common isoforms of human apolipoprotein (apo) E (apoE2, apoE3, and apoE4) and their 22-kDa and 10-kDa fragments in order to investigate the effects of the cysteine/arginine interchanges at residues 112 and 158. Previous physical characterization of apoE3 established that apoE contains two domains, the 10-kDa carboxyl-terminal and 22-kDa amino-terminal domains, which unfold independently and exhibit large differences in stability. However, the physical properties of apoE2, apoE3, and apoE4 have not been compared before. Analysis by circular dichroism showed that the different isoforms have identical alpha-helical contents and guanidine-HCl denaturation confirmed that the two domains unfold independently in all three isoforms. However, guanidine-HCl, urea, and thermal denaturation showed differences in stability among the 22-kDa amino-terminal fragments of the apoE isoforms (apoE4 < apoE3 < apoE2). Furthermore, guanidine-HCl denaturation monitored by circular dichroism and fluorescence suggested the presence of a folding intermediate in apoE, most prominently in apoE4. Thus, these studies reveal that the major isoforms of apoE, which are associated with different pathological consequences, exhibit significant differences in stability.

From cooperation to competition in national health systems--and back?: impact on professional ethics and quality of care.

Ethical behaviour in health workers is the jewel in the crown of health services. Health system policies need to nurture a professional service ethic. The primary health care policy envisioned a national health system led by the public sector and based on a philosophy of cooperation. A common theme of 'health sector reform' in OECD countries, introduced in the context of neoliberalism, has been the use of 'managed competition' to increase efficiency. Some countries that flirted with health system competition have returned to cooperation. Market relationships tend to be oppositional and to stimulate self-seeking behaviour. Health system relationships should encourage patient and community centred behaviour. The World Bank and bilateral donors have exported health sector reform theories from the north to the south, involving privatization and marketization policies. This is despite the lack of evidence on their desirability or feasibility of implementing them. Private health care has increased in many developing countries, more as a result of economic crisis and liberalization than specific health sector reforms. Much of this private practice is unlicensed and unregulated, and informal privatization has had a damaging effect on health worker ethics. The lead policy should be reconstruction of the public health system, involving decentralization, democratization and improved management. Commonsense contracting of an existing private sector is different from a policy of proactive privatization and marketization. Underlying the two approaches is whether health care should be viewed as a human right best served by socialized provision or a private good requiring governments only to correct market failures and ensure basic care for the poor. It is a matter of politics, not economics.

Apolipoprotein E;-low density lipoprotein receptor interaction. Influences of basic residue and amphipathic alpha-helix organization in the ligand.

Conserved lysines and arginines within amino acids 140-150 of apolipoprotein (apo) E are crucial for the interaction between apoE and the low density lipoprotein receptor (LDLR). To explore the roles of amphipathic alpha-helix and basic residue organization in the binding process, we performed site-directed mutagenesis on the 22-kDa fragment of apoE (amino acids 1-191). Exchange of lysine and arginine at positions 143, 146, and 147 demonstrated that a positive charge rather than a specific basic residue is required at these positions. Consistent with this finding, substitution of neutral amino acids for the lysines at positions 143 and 146 reduced the binding affinity to about 30% of the wild-type value. This reduction corresponds to a decrease in free energy of binding of approximately 600 cal/mol, consistent with the elimination of a hydrogen-bonded ion pair (salt bridge) between a lysine on apoE and an acidic residue on the LDLR. Binding activity was similarly reduced when K143 and K146 were both mutated to arginine (K143R + K146R), indicating that more than the side-chain positive charge can be important.Exchanging lysines and leucines indicated that the amphipathic alpha-helical structure of amino acids 140-150 is critical for normal binding to the low density lipoprotein receptor.

Structure and function of procollagen C-proteinase (mTolloid) domains determined by protease digestion, circular dichroism, binding to procollagen type I, and computer modeling.

Procollagen C-proteinase-2 (pCP-2, mTld) is derived from the longest splicing variant of the gene encoding bone morphogenetic protein 1 (BMP-1). The variants have identical amino terminal signal peptides, prodomains and astacin-like protease domains. However, they differ in the length of their carboxy terminal part, which in pCP-2 has the composition CUB1, CUB2, EGF-like1, CUB3, EGF-like2, CUB4, CUB5, and C-tail. In the shorter form, pCP-1 (i.e., BMP-1), the sequence ends after the CUB3-domain. Using a combination of mutagenesis and structural approaches, we have investigated the structure and function of subfragments of pCP-2. The full-length latent recombinant enzyme and its N-terminally truncated form lacking the prodomain were tested for their enzymic activity. The intact protein showed only partial processing of procollagen type I, whereas the truncated form expressed enzymic activity indistinguishable from its native counterpart purified from chick embryo tendons. These results clearly demonstrated that the prodomain is required for the latency of the enzyme but not for its correct folding. Limited proteolysis of the recombinant protein with alpha-chymotrypsin produced four discrete fragments revealing the location of cleavage sites between the repetitive CUB/EGF domains. The results provide evidence that the CUB sequences form independently folded modules that are stabilized by two pairs of internal disulfide bridges. The modules are linked to each other by more flexible, hinge-like peptides. Solid-phase binding assays with isolated CUB domains and immobilized procollagen type I demonstrated that the first three but not the last two CUB domains specifically bound to the substrate. To define putative sites for CUB-CUB or CUB-substrate interactions, we generated molecular models for pCP-2 CUB domains. The models were obtained using as a template the structure of CUB domain in zona pellucida adhesion protein PSP-I/PSP-II from porcine sperm. The predicted conformations for homology models were, subsequently, confirmed by circular dichroism spectroscopy of polypeptide domains isolated following limited proteolysis with alpha-chymotrypsin.

Recipient tumor necrosis factor-alpha and interleukin-10 gene polymorphisms associate with early mortality and acute graft-versus-host disease severity in HLA-matched sibling bone marrow transplants.

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is strongly implicated in graft-versus-host disease (GVHD) and other acute bone marrow transplant (BMT) complications. The antiinflammatory interleukin-10 (IL-10) antagonizes TNF-alpha and reduces GVHD. We previously showed association of recipient TNF (TNFd) and IL-10 (IL-10(-1064)) gene polymorphisms with acute GVHD severity in matched sibling BMT using only cyclosporin A monotherapy. The current study tested association of GVHD with TNFd and IL-10(-1064/-1082) polymorphisms in a large cohort (144 matched sibling donor/recipient pairs) given both cyclosporine A (CyA) and methotrexate (MTX) prophylaxis. Genotype results were correlated with acute and chronic GVHD and mortality. Patients homozygous for the TNFd microsatellite allele 3 had higher early mortality: 23.7% of TNFd3/d3 homozygotes died before day 30, compared with 6.80% of non-d3/d3 recipients (P =.013). Recipients possessing longer IL-10(-1064) microsatellite alleles developed more severe acute GVHD: 22.3% of recipients possessing alleles 12 to 15 developed grade III to IV GVHD, versus 3.92% of those with smaller alleles (P <.01). Other recipient or donor genotypes tested did not significantly affect GVHD or mortality. We conclude that recipient TNFd and IL-10(-1064) polymorphisms associate with early mortality and severe acute GVHD in matched sibling BMT with dual prophylaxis. This supports the hypothesis of genetic predisposition towards GVHD and other BMT complications other than histocompatibility antigen disparity.

First principles investigation of singly reduced cytochrome P450.

1. The application of novel ab initio quantum mechanical methods to the states in the catalytic cycle of cytochrome P450 following the first reduction step is described. 2. A good correlation was found between the calculated energy of reduction and the experimentally determined redox potential for a range of substrate- and substrate analogue-bound systems. 3. On reduction of the haem system, the ground state of Fe remains Fe3+. On binding of a CO molecule, Fe adopts a low-spin Fe2+ state, in agreement with experiment. However, on binding of an O2 molecule, calculations indicate that the system adopts a ferric superoxide ground state, in which the Fe is in a low-spin Fe3+ state.

Four new DP alleles identified in a study of 500 unrelated bone marrow donor-recipient pairs.

HLA-DP genotyping of 500 donor recipient pairs in a retrospective analysis sponsored by the National Marrow Donor Program (NMDP) identified four new DP alleles, two DPB1 and two DPA1. DNA sequencing confirmed that DPB1*8001 and *8101, each found in a single individual, are novel combinations of previously described sequence motifs in the six variable regions of DPB1. DPA1*02014, found in two individuals, is identical to DPA1*02011 except for a novel silent substitution, a G to A transition at the third position of codon 14. DPA1*01032, found in one individual, is identical to DPB1*01031 except for a silent G to A transition at the third position of codon 20. The identification of these novel alleles brings the total number of reported DPB1 alleles to 85 and DPA1 alleles to 15.

Evidence for stabilization of the low-spin state of cytochrome P450 due to shortening of the proximal heme bond.

The cytochrome P450 superfamily of enzymes is ubiquitous, being responsible for the metabolism of a wide range of endogenous and xenobiotic compounds. However, the detailed mechanism of the catalytic cycle of these enzymes is still not fully understood. We describe results, obtained from first principles molecular simulations, which indicate that the low-spin state of the Fe3+ ion, present in the heme moiety at the active site of a cytochrome P450 enzyme, may be stabilized by shortening of the proximal bond of the heme. Calculations indicate that a bond length of less than approximately 2.05 A between the heme Fe3+ ion and the cysteine S, which forms the proximal ligand, would result in the stabilization of the low-spin state of the Fe3+, inhibiting the progress of the P450 catalytic cycle. Our investigation uses novel first principles modeling techniques which treat the entire system quantum-mechanically.

Familial ureteral abnormalities syndrome: genomic mapping, clinical findings.

Abnormal development of the ureter during embryogenesis, when occurring in multiple family members, appears to be a genetically determined defect with autosomal dominant inheritance and high penetrance, which can lead to significant kidney damage, renal failure, and death. We have studied 48 individuals within a large kindred in which ureteral-related abnormalities (including vesicoureteral reflux, ureteropelvic junction obstruction, duplicated ureters, and medullary sponge kidney) were segregated. Family members who had not had previous diagnostic studies were evaluated for presence or absence of ureteral abnormalities and we attempted to map the locus for this familial ureteral abnormalities syndrome (FUAS). These studies identified 11 asymptomatic individuals, previously assumed to be unaffected, with minor abnormalities. When linkage analysis between the inheritance of ureteral abnormalities and six marker loci glyoxalase I (GLO- ), major histocompatibility antigens (HLA-A, B, and DR/DQ), D6S288, and factor XIII antigen (F13A1) on the short arm of chromosome 6 was performed, the lod scores significantly rejected linkage over a 77.1-cM distance. These findings are in contrast to previous data suggesting linkage between the presence of ureteral abnormalities and HLA, and indicate the possibility of genetic heterogeneity of FUAS.