Bony defects arising from tumor resection or debridement after infection, non-union or trauma present a challenging problem to orthopedic surgeons, as well as patients due to compliance issues. Current treatment options are time intensive, require more than one operation and are associated with high rate of complications. For this reason, we developed a new surgical procedure to bridge a massive long bone defect.in situ periosteal sleeve is elevated circumferentially off of healthy diaphyseal bone adjacent to the bone defect. Then, the adjacent bone is osteotomized and the transport segment is moved along an intramedullary nail, out of the periosteal sleeve and into the original diaphyseal defect, where it is docked. Vascularity is maintained through retention of the soft tissue attachments to the in situ periosteal sleeve. In addition, periosteal osteogenesis can be augmented through utilization of cancellous bone graft or in situ cortical bone adherent to the periosteal sleeve.To bridge the gap, an The proposed procedure is novel in that it exploits the osteogenic potential of the periosteum by replacing the defect arising from resection of tissue out of a pathological area with a defect in a healthy area of tissue, through transport of the adjacent bone segment. Furthermore, the proposed procedure has several advantages over the current standard of care including ease of implementation, rapid patient mobilization, and no need for specialized implants  or costly orthobiologics.e.g. the Ilizarov procedure) as well as areas of the world where surgeons have little access to expensive, complex devices and orthobiologics.The proposed procedure offers a viable and potentially preferable alternative to the current standard treatment modalities, particularly in areas of the world where few surgeons are trained for procedures such as distraction osteogenesis ( Surgical treatment modalities involving auto/allografting and bone regeneration via distraction osteogenesis are complex, time intensive procedures of inherently high risk due to vagaries of organ donation, in the case of allografts, and the complexity of soft and hard tissue salvage during the process of distraction osteogenesis. In addition, orthobiologics are costly and their dosage regimes as well as efficacy are currently the subject of much research [Replacement of bone where there is none is one of the most challenging problems facing orthopedic surgeons today. In the case of tumor resection or trauma, massive bone defects must be filled with regenerate bone as quickly as possible in order to restore function. Current standards for bridging of massive bone defects in long bones generally follow a theme of research -3.Both bone grafting and bone transport procedures are complex for the surgeon as well as for the patient. Furthermore, they are susceptible to complications such as delayed union, extensive treatment time periods, infections, and insufficient mechanical function outcomes that can result in fractures. The high complication rates of these procedures exacerbate the previously mentioned difficulties associated with these treatment modalities, from the perspective of the surgeon as well as that of the patient. In short, the inherent risk of complications increases the need for patient compliance and clinical follow-up. Despite the effort associated with these procedures, their results are often less than satisfactory. Hence, the complexity and shortcomings of current state-of-the-art surgical procedures have provided impetus to develop a new treatment modality that provides a relatively straightforward, single step procedure with a high probability of success for the bridging of massive bone defects in long bones. The procedure is straightforward and can be implemented in operating rooms across the world without the need for high-tech equipment or expensive orthobiologics. The purpose of this manuscript is to describe the novel procedure.The proposed procedure is applicable for clinical scenarios including tumor resection as well as debridement after an infection or non-union. In the case of reconstruction after tumor resection Fig. , a transThe proposed procedure depends to a large degree on bone's inherent healing strategies. Bone is a remarkably resilient tissue capable of adaptation to the most extreme biological and mechanical environments; this capacity for self-regeneration without scarring is based on bone's endogenous healing strategies. First, bone remodels itself through osteoclastic resorption and osteoblastic matrix apposition; by constantly reweaving itself, the structure is dynamic and optimal for prevailing mechanical function. Furthermore, the natural healing cascade of bone after trauma recapitulates embryonic endochondral ossification. Hence, modeling, growth and remodeling confer a means to regenerate functional tissue at any time in the life cycle of a bone. The "raw materials" necessary to replace bone are located in the environment or produced by the cells that do the work of regeneration, i.e. osteoclasts and osteoblasts. In the case of regeneration of bone in defects, further potentially key constituents to the formation of a functional regenerate in situ include a patent blood supply, chemical gradients of morphogens and/or cytokines, a template onto which the cells can anchor themselves during the rebuilding process (e.g. graft or a scaffold), and biophysical stimuli such as fluid flow and/or cell level strains. The proposed procedure essentially replaces the defect site in a pathological zone with a defect site in a healthy bed of tissue and provides for progenitor cells through the surrounding, healthy periosteum as well as many of the other key constituents for successful tissue regeneration, as defined above.proof of feasibility for the proposed procedure. An 11-year old male presented with a low grade surface osteosarcoma of the tibia. After resection of the tumor, the fibula was resected for transfer and the surrounding periosteum was left behind to serve as an osteo-inductive and -conductive sleeve  as well as where surgeons have less access to expensive, complex devices and orthobiologics.The proposed procedure is novel in that it introduces for the first time the possibility to bridge a massive defect in a long bone using a single stage procedure. Furthermore, the proposed procedure has several advantages over the current standard of care including ease of implementation, lack of requirement for specialized implants  or costly orthobiologics, and rapid patient mobilization. This makes the proposed procedure a viable and potentially preferable alternative to the current standard treatment modalities, particularly areas of the world where few surgeons are trained for procedures such as distraction osteogenesis  declare that they have no competing interests.UK conceived of the technical innovation, organized its design and coordination, and drafted the manuscript. DSS was the senior surgeon in the clinical case showing feasibility. Both authors read and approved the final manuscript.


Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV).n = 417), or EFV (n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV , while the increase in TC was lower , resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (−4.1%) and an increase for patients receiving EFV . The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV , as were the increases of triglycerides  and low-density lipoprotein cholesterol . These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs.Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (NVP-containing ART shows larger increases in HDL-c and decreases in TC:HDL-c ratio than an EFV-containing regimen. Based on these findings, protease-inhibitor-sparing regimens based on non-nucleoside reverse transcriptase inhibitor, particularly those containing NVP, may be expected to result in a reduced risk of coronary heart disease. Comparison of two commonly prescribed non-nucleoside reverse transcriptase inhibitors shows that patients on nevirapine have better blood lipid profiles Numerous large epidemiological studies have unambiguously demonstrated a strong inverse relationship between the plasma concentration of high-density lipoprotein cholesterol (HDL-c) and the incidence of coronary heart disease (CHD) ,2. RecenCombination antiretroviral therapy (ART) for the treatment of HIV-1 infection has been associated with fat redistribution, insulin resistance, and changes in plasma concentrations of lipids and lipoproteins ,8,9. EacAlthough as yet no clinical data have been generated to support this, these differences between ART regimens raise the expectation that NNRTI-based regimens, particularly in view of their effects on HDL-c, may favourably modify the CHD risk compared with many of the PI-containing regimens. With respect to the two currently commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV), no detailed comparative data have been reported concerning their effect on plasma lipids and HDL-c in particular.We prospectively analysed lipid and lipoprotein changes in a preplanned substudy of the 2NN trial in which ART-naive patients received stavudine (d4T) and lamivudine (3TC) with the randomly assigned addition of NVP, EFV, or both drugs combined.The 2NN trial was an open-label study, the main results of which have been published elsewhere . PatientThe current analyses were preplanned. Only those patients were included who used all components of their allocated treatment for at least 95% of the time during the 48 wk of follow-up (self-reported). Change of d4T and/or 3TC was allowed for reasons of toxicity. Employing such ‘on treatment’ (OT) analysis, allows the best possible assessment of lipid changes that actually result from differences in regimens. Patients in the NVP-od and NVP-bd groups were combined, given that the virologic efficacy of these treatments was comparable and no differences in risk of virologic failure were observed.Plasma samples for prospective determination of lipids and lipoproteins were collected at baseline (before start of treatment) and at weeks 2, 4, 8, 12, 24, 36, and 48. Blood was drawn after a mandatory fast of at least 3 h. The samples were analysed in local laboratories according to predefined protocols. These laboratories were selected by the Virtual Central Laboratory (Zeist, The Netherlands), which selected the laboratories, assured the quality of the analyses and data, and standardised all results. Plasma concentrations of HDL-c, TC, and TGs were assessed by standard enzymatic assays. The concentration of LDL-c was calculated using the Friedewald equation, but only when the concentration of TGs was below 4.5 mmol/l . BecauseX minus concentration at baseline divided by concentration at baseline, times 100. Study-week-specific estimates were used for the subsequent analyses.The primary study outcome was the mean percentage change of HDL-c, TC, TC:HDL-c ratio, non-HDL-c, LDL-c, and TGs between start of allocated treatment and week 48. For each patient at each specific study week we calculated this estimate as concentration at week 3) or decrease in pVL (<2.5, 2.5–3.5, or >3.5 log10), and virologic failure during follow-up. Virologic failure was defined as (1) never having obtained a pVL of less than 50 copies/ml or (2) a rebound to two consecutive pVLs of ≥50 copies/ml. A single pVL of ≥50 copies/ml at week 48 was also considered a virologic failure.Factors assessed for a possible association with the primary outcome were sex, study region , body mass index (BMI) (continuous), increase between start of therapy and week 48 in CD4+ cells  in the model were tested for significance using the Type III F-statistic. The estimates of a specific level of the fixed effect were modelled using the ‘least squared means' approach. Differences in these estimates between different levels of the variable were tested for significance using the t-statistic.Since the analyses might be biased because of the OT approach or the modelling of data, we performed two sensitivity analyses. The first was an analysis using the same modelling strategy but for an intention-to-treat population including all patients who started their randomised treatment. The second was an analysis using only available data for the OT population, without modelling of data points.p-value less than 0.15. A two-sided p-value less than 0.05 was considered statistically significant in the final analyses. The SAS statistical package was used for analyses (version 8.02, SAS Institute, Cary, North Carolina, United States).Independent risk factors were assessed by multivariable regression analyses. The multivariable analysis included the variable ‘treatment group' and all predefined variables. Interaction between treatment group and a specific variable was assumed at a Of the 1,216 patients included in the 2NN study, 607 were allocated to the NVP treatment group and 400 to the EFV treatment group. Of these, 42 (6.9%) patients in the NVP group and 25 (6.3%) patients in the EFV group did not start their treatment or were considered a ‘study entry violator’ by a (blinded-to-treatment) independent endpoint committee. These patients were excluded from the analyses. From the remaining patients (565 using NVP and 375 using EFV), only those who remained on their assigned treatment during the follow-up were included in the analyses. This resulted in a final sample size of 417 (68.7%) patients in the NVP group and 289 (72.3%) in the EFV group.All of the included patients had at least one measurement of each lipid parameter and could therefore be used in the statistical models. The baseline characteristics of the subset of patients included in the current analyses are summarised in In the NVP group, 148 of the 565 eligible patients (26.2%) were not included in the OT analyses. Of these 96 (65%) were nonadherent (including patients lost to follow-up while on randomised treatment), 30 (20%) changed their NNRTI to EFV, and 22 (15%) changed their regimen by adding a PI. In the EFV group, 76 of the 375 eligible patients (20.3%) were not included in the OT analyses. Of these 54 (71%) were nonadherent, 17 (22%) changed their NNRTI to NVP, 3 (4%) added a PI, and 2 (3%) added a third nucleoside reverse transcriptase inhibitor.All changes within the treatment groups in lipid and lipoprotein concentration, as well as in TC:HDL-c ratio were statistically significant.p = 0.036) (p = 0.073). These changes resulted in a decrease of the TC:HDL-c ratio in the NVP group (−4.1%) compared to an increase in the EFV group , and a significantly smaller increase of non-HDL-c in the NVP group .The increase of HDL-c was 8.9%  larger in the NVP treatment group (42.5%) than in the EFV treatment group (33.7%). This was statistically significant (= 0.036) . In contp < 0.001). The difference in LDL-c increase was not statistically significant .The increase of TGs was 28.9% (95% CI, −42.3 to −5.0) smaller in the NVP group (20.1%) than in the EFV group , the increases of HDL-c were slightly lower , just as for TC (26.1% for NVP group, 30.4% for EFV group) and non-HDL-c (24.3% for NVP group, 33.1% for EFV group). The TC:HDL-c ratio showed a smaller decrease for patients taking NVP (−2.6%) but a larger increase for patients taking EFV (+7.2%). The increase in TGs was larger for both patients taking NVP (24.3%) and patients taking EFV (49.3%). The LDL-c increase was somewhat smaller for patients taking NVP (33.1%) but larger for patients taking EFV (47.3%).The difference between patients taking NVP and those taking EFV for HDL-c  remained statistically significant, just as the difference in the TC:HDL-c ratio , non-HDL-c , and TGs . Additionally, the difference between NVP and EFV treatment groups became statistically significant for TC  and LDL-c  compared to the original OT analysis. The second sensitivity analysis (using only available data for the OT population) also showed comparable estimates (data not shown).p = 0.409).The increase in HDL-c for patients who started their ART when their HDL-c levels were, according to the National Cholesterol Education Program (NCEP) guidelines, low (<1.03 mmol/l), normal (1.03–1.55 mmol/l), or high (>1.55 mmol/l) is reported in Factors independently associated with changes in the lipid concentrations were analysed by a multivariable regression analysis .Men had a significantly smaller increase of HDL-c, compared to women, but a larger increase of TC. This resulted in an increased TC:HDL-c ratio for men and a decreased ratio for women, while the increase of non-HDL-c was significantly larger in men.The changes in lipid concentrations varied markedly by region. Patients from Asia/Australia and South Africa had the largest decrease in the TC:HDL-c ratio because of an increase of HDL-c that outweighed the increase of TC. Patients from South America, compared to those from other regions, had a significantly smaller HDL-c increase with a comparable TC increase, resulting in an increased TC:HDL-c ratio. Although patients from Europe showed the largest change in HDL-c, the increases in TC and TC:HDL-c ratio were intermediate. A striking finding is the much larger increase of TGs in patients from South America compared to those in patients from other regions, which to a lesser extent was also seen for non-HDL-c.10 larger decrease in pVL there was a 4.6% increase in TC (p < 0.001), a 7.8% increase in HDL-c (p < 0.001), a 10.2% increase in LDL-c (p < 0.001), and a 3.6% increase in non-HDL-c (p = 0.002), while the TC:HDL-c ratio declined with 1.6% (p = 0.051). In this analysis, there was also a clear association between pVL decline and change in TGs .For all lipid concentrations, except TGs, there was a clear pattern of larger increases of lipid levels with larger decreases of pVL over 48 wk. This was also seen when the pVL increase over 48 wk was analysed as a continuous variable. For each log3 did not show markedly different effects compared to increases of 100–250 cells/mm3. When analysed as a continuous variable, there was no statistically significant association between CD4+-cell increase and change in any of the lipid parameters.In general, a smaller CD4+-cell increase was associated with a smaller increase in lipid concentration, while increases of more than 250 cells/mmBMI was independently associated with increases in all lipid parameters, except TC. Although the increases per unit increase in BMI were statistically significant, the magnitude of increases was rather low.p = 0.005 and p = 0.075, respectively). Men had a significant increase of TGs in both the NVP group (14.1%) and the EFV group (43.3%); women using NVP had no significant TG increase (6.5%), while those using EFV had (15.9%). The effect of pVL decrease on TG increase was quite different for patients taking NVP versus those taking EFV. In the NVP group, the increase in TG concentration was 17.2% for a pVL decrease less than 2.5 log10, 16.6% for a decrease between 2.5 and 3.5 log10, and −6.1% (denoting a decrease) for a pVL decrease more than 3.5 log10. In the EFV group, these estimates were 27.4%, 37.2%, and 26.0%, respectively.All these factors exhibited a similar effect in both the NVP and the EFV treatment group (no significant interactions). There were, however two exceptions. For changes in TGs, the effect of sex and pVL decrease differed between the treatment groups  and decrease of the TC:HDL-c ratio  remained statistically significant.Also, the difference in non-HDL-c increase  and TG increase  remained statistically significant.The difference in TC increase  became statistically significant. The difference between NVP and EFV groups for the increase in LDL-c remained statistically nonsignificant .p = 0.003). The adjusted change in TC:HDL-c ratio was −4.3% for patients taking NVP and +6.6% for patients taking EFV (p < 0.001). These values were 26.6% and 31.0% for TC (p = 0.020), 24.4% and 33.9% for non-HDL-c (p < 0.001), 17.9% and 45.1% for TG (p < 0.001), and 35.5% and 41.5% for LDL-c (p = 0.168). These estimates were very similar in the two sensitivity analyses (data not shown).The adjusted increase of HDL-c was 42.3% and 32.4% for patients taking NVP and EFV, respectively  that did not show significant differences between NVP and EFV [In contrast to a small randomised study  according to NCEP guidelines. But also patients with a normal HDL-c level, who are not at an increased CHD risk, showed marked increases in HDL-c. This baseline effect can likewise be distilled from the other studies, where those with the lowest baseline value  showed p = 0.161), and the increases of HDL-c remained statistically significant even after adjustment for pVL decrease.One may postulate that the HDL-c increase merely reflects an adequate suppression of HIV-1 infection . In support, a larger decrease in pVL was associated with a larger increase of HDL-c in the present study. However, the magnitude of the HDL-c increase was only slightly different for patients experiencing virologic failure during these 48 wk (29.5%) and those with complete suppression , the concentrations of TC and LDL-c increased again to levels that did not differ significantly from before seroconversion. Such a ‘return to normal’ as a result of ART was not seen for HDL-c. The reported increases by Riddler et al. in TC (0.88 mmol/l) and LDL-c (0.41 mmol/l) were of a comparable magnitude to that found for patients taking NVP in this present study (0.97 and 0.55 mmol/l, respectively). However, the HDL-c increase was more than ten times smaller (0.03 mmol/l) in the Riddler et al. study than the 0.36 mmol/l observed in patients taking NVP in the present study, while the mean HDL-c values at which ART was started were comparable in the two studies (1.04 and 1.0 mmol/l, respectively). This indicates that although at least part of the change in TC and LDL-c may reflect a ‘return towards normal’, the magnitude of the HDL-c increase observed in our study must have occurred through additional mechanisms. Since we have no information on the antiretroviral efficacy of the regimens used in the Riddler et al. study, we have to consider that the reported differences between the Riddler et al. study and the present study might be partly due to differences in HIV-1 suppression. However, the type of PI-based regimens used in the Riddler et al. study and the long-term adequate adherence by the patients make large differences in antiretroviral efficacy unlikely.We are currently conducting studies to unravel whether NVP possibly stimulates synthesis of the most important apolipoprotein of HDL-c, apoAI, or alternatively, for instance, decreases the clearance of HDL-c particles.Several studies have convincingly shown that an HDL-c increase is associated with a significant decrease in CHD mortality independent of changes in LDL-c ,2. OveraThe data indicate that EFV might have a more detrimental effect on TG levels than NVP. That EFV indeed can be associated with an increase in TGs was shown in two studies, in which sporadical hypertriglyceridaemia was reported in patients starting an ART regimen with EFV but without d4T ,25. A diThe proportional increase in TG levels with both NVP and EFV treatment seems large, but the median absolute TG level at week 48 was still low in both treatment groups (1.2 mmol/l and 1.4 mmol/l, respectively). In the NCEP guidelines, a TG concentration below 1.69 mmol/l is still considered normal . The incThe differences between patients taking NVP and those taking EFV in changes in TC as well as TGs are unlikely to be explained by the concurrent use of d4T. In both treatment groups, the percentage of patients who used d4T as part of their regimen throughout follow-up was high (96% for the NVP treatment group and 98% for the EFV treatment group). This high rate of d4T use might, however, be responsible for the impression that the increases in TC and TGs seem to continue or even accelerate towards the end of the study period, as opposed to a somewhat declining effect of treatment on HDL-c after 24 wk. A possible explanation for this may be the gradual, progressive worsening of fat redistribution or lipodystrophy that one would expect to occur in this continuously d4T-exposed patient population. Both the incidence and severity of lipodystrophy are particularly increased with d4T-containing ART regimens, and lipodystrophy has been reported to be associated with increased TC and TG levels ,30,31,32Due to the relatively short mandatory fasting period (3 h), the measured TG concentration might be biased, possibly even more so given that HIV-1 infection may be associated with reduced TG clearance following food intake . As a coThe relationship between ART and CHD has been the subject of several studies, based on either clinical or validated surrogate endpoints  to meet the criteria for being eligible for the OT analysis. Patients replacing their assigned NNRTI by the NNRTI from the other treatment group of the study would have little effect on the lipid estimates, since both NNRTIs show changes in lipid concentrations, which go in the same direction. Another possible reason for the similarity between these two analyses could be the relatively late timing of treatment changes (mean of 75 d for patients taking NVP and 95 d for patients taking EFV). The fact that the second sensitivity analysis also showed comparable results indicates that modelling of data did not affect the lipid estimates.A limitation of the present study is the lack of data on conventional CHD risk factors like smoking. The 2NN being a randomised study, it may be expected that these and other confounding variables are equally distributed over the treatment groups. Possible residual confounding, however, cannot be excluded, and the results should therefore be interpreted cautiously.While awaiting the results of future studies, the less atherogenic lipid profile of patients taking NVP in comparison to those of patients taking EFV may be among the various factors to consider when selecting the most appropriate initial ART regimen, particularly for those patients with HIV-1 with a significant a priori CHD risk. Including such a consideration seems warranted, since treatment of the ART-induced lipid changes with currently licensed lipid-lowering agents is not without problems. Most of the available statins except pravastatin and fluvastatin, are metabolised through cytochrome isoenzyme CYP3A4, just as the PIs and NNRTIs are, providing concern for potential drug–drug interactions. Furthermore, statin therapy in patients using a PI-based regimen is in general not able to reduce the lipid concentrations to normal levels ,50. StudUse of the novel PI atazanavir may also be considered an attractive option in patients at high risk of CHD, given that it is associated with markedly smaller increases of TC, LDL-c, and TGs compared to previously available PI-based regimens ,55, but The reported increase of HDL-c concentration with NNRTI use is far greater than that seen with conventional lipid-lowering drugs and is of a similar magnitude as the HDL-c increases reported with the most powerful HDL-c-increasing drugs that are currently in clinical development ,56. AsztUnravelling the mechanism or mechanisms by which NVP and EFV raise HDL-c could contribute to the development of novel interventions aimed at increasing HDL-c and thereby ultimately to reducing CHD risk in the population at large.Drugs used to treat HIV  help patients to live longer, but they can also have some serious side effects. For example, the longer people take them, the higher the risk they'll get heart disease. Why? Part of the reason is that many—though not all—antiretroviral drugs cause changes in cholesterol levels in the bloodstream (an increase in the amount of “bad” cholesterol and a reduction in the amount of “good” cholesterol).Two of the most commonly prescribed antiretroviral drugs are nevirapine and efavirenz. Previous smaller studies showed that treatment with either of the drugs could increase the amount of “good” cholesterol. The researchers now wanted to directly compare these drugs to find out what effect they had on patients' cholesterol levels in a much larger group of patients.The scientists studied adults with HIV who had never previously taken antiretroviral drugs. All of the patients then took “triple therapy”—a combination of three antiretroviral drugs. Some of the patients took nevirapine as part of their triple therapy, whereas some took efavirenz. The researchers took blood samples regularly for almost a year and measured patients' cholesterol levels.They confirmed that both nevirapine and efavirenz indeed have a beneficial effect on patients' cholesterol levels. They both increase the amount of “good” cholesterol in the bloodstream. The increase was higher with nevirapine than with efavirenz.If your treatment includes nevirapine or efavirenz (particularly nevirapine), this can raise your level of “good” cholesterol.The results of the study may be especially important if you are already at risk for heart disease. In other words, if you have risk factors for heart disease—high blood pressure, diabetes, heart disease running in your family, being a smoker—it may be beneficial for your HIV medications to include nevirapine. If you smoke, you can lower your risk of heart disease by quitting. If you have high blood pressure or diabetes, treating these conditions can also lower your risk of heart disease.Although the researchers showed that nevirapine and efavirenz can have a beneficial effect on cholesterol levels, they haven't actually shown that this reduces patients' risk of getting heart disease.The study was funded by the company that produces nevirapine. In theory this could have affected the results (research has shown that company-sponsored studies are more likely to produce results favorable to the company than studies without sponsorship). The study, however, was carried out by a network of independent investigators who state that the company had no influence on the reporting of the results.www.tht.org.uk), AIDS.ORG (www.aids.org), and The Body (www.thebody.com).You can get more information on HIV and its treatment from the Terrence Higgins Trust (


I describe here the history leading up to and including my laboratory's discovery of the first human retrovirus, HTLV-I, and its close relative, HTLV-II. My efforts were inspired by early work showing a retroviral etiology for leukemias in various animals, including non-human primates. My two main approaches were to develop criteria for and methods for detection of viral reverse transcriptase and to identify growth factors that could support the growth of hematopoietic cells. These efforts finally yielded success following the discovery of IL-2 and its use to culture adult T cell lymphoma/leukemia cells. After arriving at NIH in 1965 I spent my first year as a young physician caring and treating (mostly unsuccessfully) acute leukemias in children: a vivid experience and one which made me absolute in a decision to be fully involved in laboratory research and not return to clinical medicine. My research interest almost from the very start was in the biology of blood cells, and I focused on comparisons of human leukemic cells with normal leukocytes. This was mainly limited to comparative biochemistry. Specifically, I studied enzymes of pyrimidine nucleoside and nucleotide metabolism, tRNA species and their corresponding amino acyl-tRNA synthetases, and finally DNA polymerases [see refs.[The main leukemia I worked on was acute lymphocytic leukemias (ALL). After all, these were the most common of the acute leukemias and gram quantities of these cells were available from my clinical colleagues at NCI. Importantly, these were the only leukemias for which reasonably similar normal control cells were available, namely, normal human lymphoblasts. Scientists in Philadelphia had just discovered that a plant lectin, phytohemagglutinin (PHA), could induce human lymphocytes to become activated and go through a mitotic cycle. These normal lymphoblasts looked like ALL cells, but these were days before most of us would or could know of the great complexity of subtypes of lumphocytes. Functional discriminatory assays were barely available and monoclonal antibodies with their capacity to provide surface markers were yet to come. Thus, we did not then sub-classify lymphocytic leukemias. Herb Cooper of NIH had learned how to purify lymphocytes from columns packed with nylon; myeloid cells would adhere, but lymphocytes passed through. Cooper generously provided this technique to me. During this period 1968–1970) I became very impressed by the studies of Leo Sachs in Israel and later also of Don Metcalf in Australia who where showing that, like some lymphocytes, myeloid cells could also be grown in the laboratory but not in liquid culture. Instead, they used the technique previously applied to virus transformed cells of cell growth on a methylcellulose solid surface in the form of cell colonies. However, growth was transient and the amount of cells quite limited, precluding many types of biochemical, molecular biological, and virological experiments. Nonetheless, from this system, Sachs and his colleagues and Metcalf and co-workers made seminal discoveries, including a growth/differentiation factor, granulocyte macrophage colony-stimulating factor (GM-CSF), which was specific for the myeloid lineage. Sachs logically believed the main production of GM-CSF would be from myeloid cells, i.e., a feedback regulation – granulopoietic progenitors proliferated and formed "dead end" granulocytes, which should produce their own granulopoietic factor [see refs. [8–1970 I Meanwhile, while comparing ALL cells to normal lymphocytes, I decided to test the conditioned medium of the PHA-stimulated normal cells for growth factor. The late Alan Wu had just joined me from the laboratories of Till and McCulloch in Toronto shortly after the publication of their famous paper describing hematopoietic stem cell assays (in mice) for the first time. Alan and Joan Prival, a post-doctoral fellow, joined me in reporting the then surprising finding that lymphocytes (T cells) made GM-CSF . This woIn this period early 1970s) I began to study animal retroviruses because in several animals these kinds of viruses caused leukemias. Thus, no matter whether human retroviruses (leukemia-causing or otherwise) existed or not, a study of animal retroviruses, especially focused on learning their mechanisms of leukemia causation, might provide insights into the mechanisms involved in human leukemias. However, my co-workers and I also decided to search for human retroviruses, an unpopular goal at this time, considering the decades of attempts and failures. I was, nonetheless, encouraged by discussions with William Jarrett, the Scottish veterinarian who discovered feline leukemia virus, and by the work of the late Howard Temin. Temin, of course, had predicted that retroviruses of animals replicated by having their RNA genome transcribed into a DNA form, which would then integrate into the DNA of the target cell. He referred to this integrated form as provirus, the name given to his theory. In 1970 Temin and his colleague Mizutani, and separately, David Baltimore, gave credence to the theory with their discovery of the DNA polymerase carried by all retroviruses, reverse transcriptase (RT)70s I beg. For me RT forms in virions only upon budding from the cell. Consequently, finding this enzyme in media of cultured cells implied release of retrovirus particles, and finding RT from extracts of cells implied the presence of a cell associated virus particles, as for example, virions associated with the cell surface membrane. We found rare cases of leukemia that scored positive in RT assays. The problem, however, was that RT might be a product of a normal cellular gene. We needed to develop the assay not only as a very sensitive one but also one that would distinguish RT from all of the then known cellular DNA polymerases . This became a major objective [see refs.  and 11--11-14 foNature New Biology in 1972 [Armed with these RT assays we did find a few cases of adult lymphocytic leukemias with RT showing all the characteristics of RT from a retrovirus . We published on the one best characterized in  in 1972 . We beliThe obvious and easiest approach to virus isolation was by using cell lines. Cell culture technology had become widely available by the 1960s, and many cell lines from different species were available. The approach is generally to co-culture the primary cells (in our case the leukemic cells) with a wide variety of such lines and hope virus will take in one or more. This, of course, would be after scoring positive in the RT assay. However, by this period, there was increasing antagonism to research directed toward the finding of human tumor viruses and especially of retroviruses. The NCI had created the heavily funded Virus Cancer Program which was under attack for failing to find clear evidence of tumor viruses. Moreover, by the mid-1970s there had been not only decades of failure to find human retroviruses, there had been many false starts by many investigators utilizing the co-culture system that involved cell lines, including one by me. The usual problem was a cross contamination with an animal retrovirus. For this reason I became convinced that we had to find ways to grow primary blood cells, but not with the systems of Sachs and Metcalf. These methylcellulose colonies of leukocytes provided too few cells and growth of these cells were limited in number and in time. When we had our next hint of an RT positive leukemic sample it turned out to be from a patient with a myeloid leukemia, so we searched for a growth factor that would maintain and promote growth of human myeloid leukemic cells in liquid suspension culture. This had not been achieved before. From an early-term (first few weeks) abortion, we obtained some human embryonic cells that produced a factor that led to the first successful routine growth of these human leukemic cells in liquid suspension(16). We called these HL (human leukemia) cells, with a given sequential number of the samples we had studied. One of these cultured cell populations became an immortalized cell line, HL-60. It was the first human leukemic myeloid cell line  and likeOne approach was to culture many different types of cells from many different tissue sources (including human embryos) for several days, collect the media (conditioned media or CM), and add it to leukocytes from normal human cord blood, samples of human bone marrow, and myeloid leukemic cells. In this period (early mid-1970s), a post-doctoral fellow, Doris Morgan, joined our group and took part in the search. As would be expected, CM from PHA-stimulated lymphocytes was one of the cell sources I asked to be screened. Doris was succeeding in growing cells from human bone marrow, and was intensely nursing them daily for months. But they were lymphocytes, not myeloid cells. It was neither unique nor interesting to grow human B cells. Even at this time Epstein-Barr virus (EBV) immortalized cell lines were well known to grow often from normal blood or a bone marrow mixed cell population. Indeed, they were the only kind of blood cells that could be routinely grown in long-term culture, but analyses of the cells revealed that they were T cells, which at that time had only recently been clearly delineated from B cells by certain functional assays (the E rosette assay, for example). The factor we had found in the PHA-CM was a new growth factor. Francis Ruscetti had then joined our group and carried out a set of experiments that demonstrated this more fully, and we reported these results in 1976–1977,19 and tIn this same period the pressure against attempts to find human retroviruses intensified. It was not only the prevailing atmosphere of failure but also reasonable scientific arguments. For examples: (1) there was little evidence for leukemia viruses in primates. (2) When retroviruses were found in animals they were not difficult to find. Extensive viremia preceded disease, therefore, if they infected humans, they would be easy to find and would have been discovered much earlier. (3) Human sera in the presence of complement lysed animal retroviruses, thereby providing a rational mechanism for the conclusion that humans were protected.Finally, there were technical difficulties such as the ability to culture primary human cells  from a pet old world Gibbon ape to a new world Wooly monkey. It was well known that retroviruses could move from one species to another, but in all cases these were very ancient events only discovered by analyses of cellular DNA of many animals. But in this case the event occurred "right before our eyes", giving rise to the virus from the Wooly monkey known as simian sarcoma virus . We feltThe first detection and isolation of HTLV-1 was in 1979, and the first detection came from the analysis of a T cell line established by J. Minna and A. Gazdar from a patient these clinicians called a cutaneous T cell lymphoma. Alternatively, such patients were also called mycosis fungoides or Sezary T cell leukemia depending upon clinical nuances. Though IL-2 was supplied by us for them to use in their initial culturing of these cells, the cells rapidly immortalized. An outstanding post-doctoral fellow, Bernard Poiesz, carried out RT assays on these cells with positive results, and we soon arranged for electron microscopic analysis of concentrated RT plus cultures and found retrovirus particles. Because putative human retroviruses viruses had been found many times before by several investigators in established cell lines, only to be subsequently shown to be accidental laboratory contaminants, by the late 1970s I was well aware that much more had to be done before this work was presentable. For instance, we had to (1) show that the same virus could be isolated from primary tissue samples of the same patient by culturing primary T cells with IL-2; (2) demonstrate that the virus was novel, i.e., not any of the known animal retroviruses; (3) show it could infect human T cells in vitro; (4) demonstrate specific antibodies to the virus in the serum of the patient; (5) demonstrate that proviral DNA could be found integrated in the DNA of the cells from which the virus was isolated; (6) provide evidence that this was not a one-time affair by showing serological evidence of specific antibodies not only in the patient but in others as well. These results were successfully obtained in 1979–1980 and available by the time we submitted and published our first report in 1980 , enablinCancer Research in November 1981 [Two events significantly catalyzed the further development of our work and of our understanding of HTLV-1 and its role in T cell malignancies. The first of these (in the summer of 1980) was information from Drs. Tom Waldmann and H. Uchiyama, who had come to NIH as a visit scientist. They brought to our attention the ATL cluster in Japan so in the fall of 1980 I contacted two Japanese friends, the late Yohei Ito, then Chair of Microbiology at Kyoto University and Tad Aoki for more information and for sera from such patients to test for antibodies to HTLV. This specific clinical entity had been described as early as 1977 by Takatsuki and his co-workers Yodoi and Uchiyama, and was called adult T cell leukemia by him. Aoki and Ito sent sera from such patients to me in 1980, and these sera scored positive for antibodies to HTLV-1. Based on these results Ito organized a small meeting at Lake Miwa outside of Kyoto attended by a few co-workers and myself from the U.S. and Aoki, Ito, and several other Japanese scientists most notably Takatsuki, Y. Hinuma, and T. Miyoshi. The meeting was held in March 1981. Several of my colleagues and I presented our results in detail. This included description of several isolates of HTLV-1, characteristics of purified HTLV-1 p24 as well as reverse transcriptase proteins, evidence of integrated HTLV-1 provirus T cell malignancies and healthy volunteers which provided clear evidence for the linkage of HTLV-1 to certain T cell malignancies, and the positive serological results in Japanese ATL patients. In organizing this meeting the intention of Ito was to foster wide collaboration in Japan with me and my co-workers on this disease. The meeting summary was published in ber 1981 .It was only at the end of the meeting when we were summarizing and planning for this collaboration with the Japanese investigators, that Dr. Yorio Hinuma "announced" he too had a retrovirus. He presented EM pictures of virus particles from a cell line established by Dr. Miyoshi by co-cultivation of ATL cells and normal human T cells. These results of Miyoshi were the first indication of the transforming capability of HTLV-l because the cell line that was immortalized was from the normal donor . Later, The second meeting of considerable importance was in London chaired by the late hematologist Sir John Dacie and attended by Dacie, Drs. Daniel Catovsky, Robin Weiss, Mel Greaves, and William Jarrett among others from Great Britain and by my collaborator in epidemiological studies, Dr. William Blattner, and myself. It was Catvosky who called for this meeting because he noted that we had found HTLV-1 mainly in African Americans and black persons in the Caribbean and he had found an unusual frequency of adult T cell malignancies in Caribbean immigrants to England. He recognized the similarities of their disease to Takatsuki's ATL. Thus, he postulated they were one and the same disease and HTLV-1 would be present in all. He was right. Promptly, Blattner accelerated his studies in the Caribbean and documented that HTLV-1 was endemic in some islands. He and Guy de Thé of France would then show that this result depended upon the particular tribes in Africa from which the individuals descended.Some of these experiences would be a precursor of a persistent pattern, i.e., HTLVs are not easy to transmit, remain within families and regions over long periods of time, and have old-world linkage. Ultimately, related viruses would be found in old-world primates and more distantly related viruses in some ungulates. The modes of transmission would soon be forthcoming as sexual contact, blood, and mother to child via breast feeding. Later in 1981 we isolated HTLV-2 from a leukemia described as "a hairy cell T cell leukemia" , but thiA companion article in Retrovirology by Kiyoshi Takatsuki recounts the events surrounding the discovery of the disease, adult T-cell leukemia .


Objective measures of hand function as individuals participate in home and community activities are needed in order to better plan and evaluate rehabilitation treatments. Traditional measures collected in the clinical setting are often not reflective of actual functional performance. Recent advances in technology, however, enable the development of a lightweight, comfortable data collection monitor to measure hand kinematics.This paper presents the design analysis of a wearable sensor glove with a specific focus on the sensors selected to measure bend. The most important requirement for the glove is easy donning and removal for individuals with significantly reduced range of motion in the hands and fingers. Additional requirements include comfort and durability, cost effectiveness, and measurement repeatability. These requirements eliminate existing measurement gloves from consideration. Glove construction is introduced, and the sensor selection and glove evaluation process are presented.Evaluation of commercial bend sensors shows that although most are not appropriate for repeatable measurements of finger flexion, one has been successfully identified. A case study for sensor glove repeatability using the final glove configuration and sensors does show a high degree of repeatability in both the gripped and flat hand positions (average coefficient of variability = 2.96% and 0.10%, respectively).Measuring functional outcomes in a portable manner can provide a wealth of information important to clinicians for the evaluation and treatment of movement disorders in the hand and fingers. This device is an important step in that direction as both a research and an evaluation method. Rehabilitation research has recently begun to emphasize the use of objective outcome measures to assess the efficacy of rehabilitation treatment or intervention . These gUnfortunately, rehabilitation researchers have very few methods available to objectively evaluate hand use and function outside the clinic, especially for individuals with moderate to severe reduction in range of motion in the hand and fingers. Joint range of motion (ROM) is a primary measure in hand rehabilitation, and is traditionally assessed using manual goniometry. Manual methods, however, are limited to static measurements. In addition, they can be adversely affected by common issues such as inter- and intra-operator error and operator experience level .In order to objectively measure hand use outside the clinic, the selected method must be both portable and capable of recording continuous streams of data over time. Automated measurement methods can meet these requirements as well as eliminate most operator-related issues. For example, 24-hour monitoring has proven useful for tracking parameters such as heart rate and blood pressure, and the same concept can be extended to other useful parameters, although currently no wearable devices are available to measure finger posture in a similar manner. Practical medical applications can include providing input for virtual reality therapy, measuring hand function in the planning of rehabilitation therapies, or evaluating the outcome of interventions under more realistic conditions.Sensor gloves have been proposed to provide automatic measurements of finger and joint position during different activities, with the virtual reality industry continuing to drive the market for sensor gloves . For exaCyberGlove (Immersion Corporation, San Jose, CA) contains 5 to 22 "patented bend-sensing technology" strain gauges to measure individual joint movements. This glove, however, is very expensive and difficult for stroke survivors to don. The Essential Reality (Mineola, NY) P5 glove also uses bend sensors, Abrams/Gentile flex sensors (wired flexion measurements), and infrared (IR) emitters (line-of-site wireless position and rotation measurements). The flex sensors are attached to each finger by rings between the proximal and distal interphalangeal joints (DIP). While price of this glove is appealing (<$200), the glove is not portable and requires the wearer to keep the top of the glove always facing a fixed antenna IR receiver.The Humanglove™  is a flexible glove with 20 Hall effect sensors to measure bend. The Humanglove was evaluated for feasibility and repeatability in finger range of motion in all joints; work continues to establish the measurement accuracy [Several research gloves have been reported with no clinical results. Karlsson et al.  determinThe existing glove systems do not meet the needs set forth in our device requirements. Although some gloves are lightweight, others such as force feedback and exoskeleton based gloves are too heavy and bulky for home use by individuals with hand impairments. Most are too expensive or require custom sizing to reduce errors; measurement errors are decreased when gloves fit more snugly . HoweverThe environment proposed for the glove use is also very challenging. A majority of the existing methods are not appropriate for wearable measurements in the home and community, and none are designed for use with clinical and rehabilitation populations who may exhibit significant range of motion restriction in the fingers.The long term goal of this project, therefore, is to design, build, and clinically evaluate a novel low-cost wireless device to measure hand and finger activity while individuals participate in normal home and community activities. It will be used to study the loss of hand function that can occur following neurological disorders such as stroke and traumatic brain injury, and to evaluate how treatments can improve an individual's ability to function in the home and community environments.This article describes the design process for the development of the glove, discussing wearability issues such as comfort, durability and weight and focusing on sensor characterization and selection. The results of an initial evaluation of measurement repeatability while wearing the glove are presented. Appropriate characterization of the glove must occur in two phases: evaluation of the sensors separately, and then evaluation of the entire glove after appropriate sensors have been identified and characterized. Full repeatability results and measurement accuracy will be reported in the future.The creation of effective custom measurement systems requires detailed attention to the requirements and design analysis phases of the development process. While it may be tempting to solve multiple problems with one system, this often leads to overly complicated devices that take too long to complete, and may not actually meet the core requirements. To avoid this scenario, the sensor glove project focused specifically on a set of core requirements presented below, and pursued a multi-step analysis of the design to ensure the requirements were being appropriately addressed. The steps include an analysis of glove construction methods, characterisation of sensors, and exploration of sensor repeatability and accuracy on the bench and during subject trials.The primary requirements fall into four categories.1) Donning and Removing: The glove must be easy to don and remove for individuals having reduced range of motion in the hand and fingers.2) Comfort and Durability: The glove must be lightweight and unobtrusive, and permit comfortable wearing for at least 24 hours. It must not restrict range of motion or represent a snag hazard during use.3) Function: The glove must detect a wide range of activities, including fine motor activities such as writing. Measurements must be accurate and repeatable. The sensors must not move around, but remain in the same position with respect to the joints and phalanges over time. The system must allow the performance of normal daily activities, although use in water is not required. Measurements must be repeatable with an error no more than 5% of full scale.4) Cost: Manufacturing cost is an important consideration for several reasons. An inexpensive device allows several to be deployed simultaneously to perform research studies more quickly. A low-cost glove can be considered disposable for sanitary reasons. Finally, wearers may unknowingly limit or modify their hand motions and activities in an attempt to protect an expensive device. A low-cost alternative ensures that more realistic and representative data are captured and recorded.As noted, a variety of sensors have been employed to measure joint angle, including strain gauges or bend sensors, fiber optics, pneumatics, or Hall effect sensors. While each has advantages and disadvantages, the requirements for our glove preclude the use of all but the bend sensors. Using fiber optics to measure bend requires a light source such as a light emitting diode and a photo detector. The amount of bend is proportional to the attenuation of detected light in specially treated sections of fiber that pass over the tops of the finger joints. Disadvantages of this method include the complexity of glove construction and price. Hall effect sensors, which detect magnetic fields, and can be configured as proximity sensors to provide a linear output proportional to distance from a magnetic source. By placing a series of sensors on the back of a glove in a predefined pattern, the joint angle can be computed from the changing field strengths measured by the sensors when the fingers bend. While these devices are small, the resulting glove can be somewhat bulky and will require a magnetic source, adding to overall weight. Interference from other electromagnetic sources is also a concern. Strain gauges detect stretch produced by joint rotation. They may have very high accuracy, but are expensive and often delicate.Bend sensors offer a lightweight and inexpensive alternative. These sensors are thin flexible membranes that change resistance when bent; increasing bend angle is generally associated with increased measured resistance. One or more layers of carbon and a conductive material are applied over a thin substrate. Depending on the sensor type, bending motion forces conductive particles further apart, increasing the resistance to current flow. These sensors are popular for detecting obstacles and measuring large changes in bend angle, and are proposed for accurate measurement of finger posture. However, most exhibit a time-varying creep behavior when held in a fixed bent position that reduces the accuracy of measurement. We sought to find bend sensors that would be feasible.®, Nylon and cotton. The material must exhibit stretch so that finger motion and bending are not restricted. While some blends resisted finger motions, most were flexible enough that the wearer could forget the glove was on. A discussion of the process and final selection of glove materials and application method can be found elsewhere [In order to explore the first two requirements, ease of donning and comfort/durability, several prototype glove systems were created in order to identify the best materials and construction methods to satisfy these requirements. Several materials were evaluated, including blends of Lycralsewhere .® / 7% Nylon blend; it is used to create thin sleeves into which the sensors are inserted. One sleeve is attached to the back of each finger in order to locate the sensor directly over each joint; the optimal adhesive is very thin, double-sided toupee tape. Applying the sensors to the back of the fingers, rather than using a traditional glove that must be donned, allows easy application and removal for individuals who cannot fully open all fingers to put on a traditional glove. Total glove cost without sensors is less than $2.50.The final glove material is a 93% LycraComfort and durability were evaluated over a 24 hour period. The glove survived intact and did not impede any activities other than showering and tucking in a shirt. Because the sensors are attached to the back of the hand, the palmar surface of the hand is uncovered and free of obstruction, leaving the sense of touch intact. While only one individual was used to narrow down the different prototype ideas, 24 individuals  are currently participating in a study to more fully evaluate the glove configuration and performance.An early decision was made to use an inexpensive bend sensor as the sensing element for its low profile, light weight, and low cost. While the first prototype glove has only 5 sensors, the design provides the flexibility to add additional sensors for all joints and for finger adduction/abduction. Sensors from several manufacturers were characterized in order to determine if measurements were repeatable and if large changes in finger posture and fine motor control could be captured. In addition, the calibration relationship between bend angle and measured resistance was evaluated.The importance of repeatability testing cannot be overemphasized. The sensors were evaluated separately before being incorporated into the sensor glove. Two types of tests were performed using a set of tubes of known diameter: 1) determination of full scale and the resistance-bend relationship (using tube diameters: 4", 3", 2", and 1.5", 1" and 0.75"), and 2) evaluation of measurement repeatability (using the 3" diameter tube). A physical guide was placed on each tube to ensure that the sensor was placed in the same location on the tube each time it was applied. From four to ten sensors from each manufacturer were evaluated. To test the sensors, each was initially placed flat on the table for several seconds, then bent over a single calibration tube for 30 to 60 seconds, and then placed flat again. Resistance readings were taken during each phase. The expected profile for this activity should look like a rectangular wave between two resistance values: a lower resistance value in the flat position, then the higher value when bent on the tube, and ending with the original lower flat value. Multiple measurements were taken to evaluate the variation in sensor outputs, and to construct a bend resistance versus tube diameter relationship that could be used for calibration purposes.Full scale is determined from the endpoints of the calibration relationship. The minimum measured resistance value corresponds to the flat position, and the maximum resistance value is represented by the resistance measured on the 0.75" calibration tube. The maximum value is an estimate of what would be observed in human subjects because the bending radius over a finger joint is not exactly replicated by bending over different diameter tubes; however, making this assumption allows the different sensors to be compared to one another for selection purposes. Full scale error is computed as the percent change in resistance measured while a sensor is fixed unmoving on a calibration tube with respect to the full scale range.A second error is also reported, and is calculated as the percent change in the peak sensor resistance with respect to the magnitude of the step function rise in resistance when the sensor is positioned on a calibration tube. This error calculation was also selected for comparison because a number of everyday activities such as grasping and moving objects find the hand in roughly this position.As discussed in the results section, additional analysis was performed to explore an unexpected time-varying behavior of the sensors. Collection of these data and of the data described in the next section was performed using a host computer with an 8 channel 16-bit A/D card. The sensors were connected to an interface box and data on all sensors was collected at 100 Hz using LabView . Analysis was performed using Microsoft Excel.A major concern in developing a measurement method is that measurements are repeatable. If the bend sensors and the configuration of these sensors on the fingers will be used for several measurements during the same session, or for measurements over several sessions, then repeatability must be established before the data can be given credence. Rigorous validation of repeatability, however, is often lacking from descriptions of various "data gloves."One method to evaluate repeatability of sensor glove-type devices has been proposed by Wise  and expaThis standardized repeatability testing protocol procedure includes four tests. We will use two, Tests A and C, which focus on repeatability of multiple measurements over a single data collection session. Tests A and C are performed here because the first focus of the glove is for single data collection sessions (which can last up to 24 hours). The protocol used here follows the modifications proposed in [Test A: A roughly cylindrical plaster mold is custom created for each subject to ensure that the fingers are flexed to the same position for each test. The participant clenches the mold for 6 seconds and then releases the mold for 6 seconds. This clench/release cycle is repeated 10 times. Repeatability measurements are taken from each sensor during the clench phases.Test C: The participant places the hand on a table top and alternately raises the hand and lightly flexes the fingers, and returns the hand to the table top for 6 second each. Repeatability of the flat hand position is explored in this test. In order to achieve repeatability in hand and finger position, and outline of the hand profile is drawn on paper and placed on the table. This cycle is also repeated 10 times.For each test above, the participant rested for at least 1 minute, and then repeated the entire test. This was done 10 times for both Test A and Test C, for a total of 100 grip/release cycles for each test. Descriptive statistics are computed (mean, standard deviation, and coefficient of variation). The percent coefficient of variation (standard deviation divided by the mean*100%) is used to compare the measurement variability among the five digits and between the two repeatability tests.Figure Performing sensor evaluation and characterization early in the design process allowed us to identify several shortcomings of commercial bend sensors and eventually select an appropriate sensor.The first sensor evaluated was the Abrams-Gentile Entertainment, Inc. (New York, NY) sensor patent #5,086,785. Attempts to measure repeatable bend resistance versus calibration tube diameter failed because the measured resistance decayed over time. The Abrams-Gentile sensor exhibits the most common behavior that we will refer to as Type A behavior, and it appears in Figure The average decay in resistance while on the tube was computed. After 30 seconds, the average error for the Abrams-Gentile sensors was 9.5% of full scale, and 24.4% of step function rise resistance Table . The AbrThe same testing was repeated using sensors from Spectra Symbol . Similarly, the step function rise in resistance measured on application to the 3" calibration ring dropped 31.8 % in the first 30 seconds . These included flex sensors with an overlaminate adhered by a pressure sensitive adhesive sensor #1), with a robust polyimide overlaminate sensor #2), with no overlamination but with a stiff backer sensor #3), and an overmolded sensor (sensor #4) for harsh environmental conditions. Representative contours for the 3" calibration test are shown in Figure , with no, and an , with a Bend sensors are used in a number of university and home projects, despite our findings that most are not repeatable for moderate to fine resolution measurements. Instead, most are appropriate for binary ON/OFF applications, or applications that do not require high resolution or highly repeatable results. Examples include using the sensor as a "whisker" to sense the proximity of an object for collision detection, for detecting large changes in bend angle, or for more unique applications such as adding effects to music . Others Repeatability testing began with the evaluation of the sensors and final sensor selection, and continues by considering the performance of the entire glove. The sensor glove repeatability testing has been performed with one participant, who is the first in a study that will include repeatability testing for 6 healthy controls. All participants complete an Institutional Review Board consent form and the required HIPAA authorization forms. The plaster mold was created as shown in Figure The results of Test A reveal the repeatability of measurement in the grip hand position. Coefficient of variability for all five digits is less than 6% (thumb: 0.55%, index: 5.37%, middle: 1.91%, ring: 4.61%, pinkie: 2.36%). Figure The results for Test C show the repeatability in the flat hand position with the sensors fully extended. Coefficient of variability for all five digits is less than 1% (thumb: 0.18%, index: 0.08%, middle: 0.05%, ring: 0.07%, pinkie: 0.15%). Figure These results are similar to  in that The glove developed in this research is unconventional, and its uniqueness owes to the appropriate attention to the core requirements during the design analysis phase. The glove provides a novel method to evaluate actual functional capacity, starting with the dynamic evaluation of ROM as individuals participate in their normal daily activities.The glove is not a generic solution, but a specific device to measure finger posture in an underserved population. Bend sensors were selected for their lightweight low profile, and for cost effectiveness. Although significant error can be introduced by using bend sensors, sensors with the appropriate repeatability characteristics have been identified. The bare Flexpoint sensors provided repeatable measurements with a 30 second error of 0.8% full scale, as compared to 9.5% for the next best solution, the Abrams-Gentile sensor. The overall glove configuration shows strong promise for providing repeatable measurements over long periods of time without undesired movement over the joints. Coefficient of variability averaged 2.96% and 0.10% across the five digits for the grip test and flat hand test, respectively. The glove is low cost; the total cost for the disposable portion of the device  is less than $40, which is significantly less than any other reported solution. The glove can be used not only to measure flexion in individuals with reduced range of motion who cannot wear traditional measurement gloves, but also to measure passive ROM and cleaning activities in individuals who cannot initiate volitional activity in their affected hand.Future directions include completion of the current study to establish repeatability and to identify calibration methods. The wireless link will be added midway through the study to provide full wearability and unencumbered movement, paving the way for extended studies in the home and community environments.The author(s) declare that they have no competing interests.LS made substantial contributions to the conception and design of the device and drafted the manuscript. DK identified a need for the device, contributed to the requirements and design of the device, and participated in revisions of the manuscript.


To determine accuracy of ultrasound (US) kidney, ureter and bladder (KUB) compared to un-enhanced helical CT (UHCT) in patients with renal failure in the diagnosis of stone and obstruction.This is a case controlled study conducted in the period from June 2000 to July 2003 at a university hospital. All patients had both US and UHCT scan. Patients with serum creatinine ≥ 1.8 mg/dl were included in the study. Only direct visualization of stone was considered as confirmatory. In both the studies, UHCT and US, presence of stone and obstruction were noted. The relevant biochemicals, radiological and clinical records of all the patients were analyzed. Data was analyzed using commercially available software.During the period of study 864 patients had UHCT for evaluation of the urinary tract in patients presenting with flank pain. Out of these 34 patients had both UHCT and US done within a span of one day and had serum creatinine of ≥1.8 mg/dl. Mean age was 48 ±15.8 years and 59% of patients were males. UHCT identified renal stones in 21 (62%), whereas 17 of these were identified on US, with a sensitivity of 81%. Of the four patients with renal stones missed on US, three were identified on plain x-ray; the mean size of stones missed was 6.3 mm. Of the 22 (65%) patients with ureteric stone on UHCT, US could only identify 10; a further 7 were identified on x-ray KUB, giving a sensitivity of 45%  and 77% (US with x-ray KUB).US is sensitive and specific for renal stones, 81% and 100% and for hydronephrosis, 93% and 100%, respectively. Its sensitivity to pick ureteric stone (46%) and to identify hydroureter (50%) is low. Addition of x-ray KUB abdomen increases the sensitivity for ureteric stones to 77%. Intravenous urography (IVU) has been the gold standard for the radiological survey of intra renal collecting system, ureter and bladder. Choice of imaging for urinary tract in patients with raised serum creatinine is limited to non-contrast enhanced studies. These considerations have led to the use of other modalities like combination of plain abdominal radiography (KUB) and gray scale ultrasound (US) kidney, ureter and bladder. More recently use of non-contrast enhanced CT (UHCT) and magnetic resonance urography (MRU) in the evaluation of flank pain has received increasing attention ,2. Work Ultrasound has many inherent advantages, which includes lack of radiation, universal availability, in expensive and non-invasive. It is useful in the diagnosis of renal and ureteric calculi. Stones on US are characteristically demonstrated as highly echogenic foci with distinct acoustic shadowing. The greatest challenge with regard to US is the identification of ureteral calculi, particularly in it's abdominal, and upper pelvic course. This limitation of US is due to its inability to scan retroperitoneum due to overlying bowel loop, and bony structures ,6Plain abdominal radiograph also lacks specificity, as phleboliths are not readily differentiated from ureteric calculi. Plain radiographs are also not sensitive to radiolucent calculi and non-calculus obstruction.In the present study we have compared the diagnostic accuracy of UHCT with US with x-ray KUB for the diagnosis of renal and ureteric stones in patients with raised serum creatinine precluding the use of contrast enhanced study.This is a case controlled study conducted in the period from June 2000 to July 2003 at a university hospital. All patients who had both US and un-enhanced helical CT (UHCT) scans performed within a span of 24 hours and a serum creatinine ≥ 1.8 mg/dl were included in the study. Serum creatinine of 1.8 mg/dl is considered as a cut off for use of intravenous contrast by our radiology department.The radiologist's reports on CT, CT films and medical records of patients for suspected renal/ureteral colic were reviewed. The UHCT were obtained on a Cti/pro single slice helical CT scanner . The exposure factors setting were KVp 130 and mAS 200–250. All scans were obtained from the upper border of T12 vertebral body to the lower border of symphysis pubis using 5–7 mm collimation, without the use of oral or intravenous contrast material. Patients were placed in supine position with full urinary bladder at the time of the UHCT. Additional prone films were taken whenever the radiologist needed a better description of suspected distal ureteric calculi. Ultrasound KUB was done using 3.75 MHz surface probe. All ultrasounds were seen and reported after being reviewed by a senior radiologist. Secondary signs of obstruction, like hydronephrosis, hydroureter, nephromegaly, perinephric and periureteric stranding were also noted but only direct visualization of stone was considered confirmatory.The relevant biochemicals, radiological and clinical records of all the patients were analyzed. In the studies, UHCT, and US presence of stone and obstruction were noted. Data was analyzed using commercially available software .During the 38-month period of study 864 patients had UHCT for evaluation of the urinary tract in patients presenting with flank pain. Out of these 34 patients had both UHCT and US done within a span of one day and had serum creatinine of ≥ 1.8 mg/dl. UHCT was considered as a reference point in the study as all stones identified on the CT were subsequently reconfirmed with interventional treatment or history of spontaneous passage.Mean age was 48 ± 15.8 years (range 20–76 years), 59% of patients were males. UHCT identified renal stones in 21 and ureteric stones in 22 patients. Forty-two (98%) of these stones were confirmed clinically (history of spontaneous passage), or during treatment with ureteroscopy, percutaneous nephrolithotomy and extracorporeal shock wave lithotripsy. Of the 21 renal stones, only 17 were identified on US, with a sensitivity of 81%, specificity and positive predictive value of 100% and negative predictive value of 77%. Of the four patients with renal stones missed on US, three were identified on x-ray KUB; the mean stone size of stones missed on US was 6.3 mm. In all cases US and x-ray KUB were performed prior to the UHCT.Of the 22 patients with ureteric stone, on UHCT, US could only identify 10. Twelve patients with ureteric stones identified on UHCT were missed on US. The mean size of stones missed was 6.1 mm (range 3–15 mm). The sensitivity, specificity, positive and negative predictive values were 46, 100, 100 and 50% respectively. A further 7 patients, missed on US, were identified on x-ray KUB. The overall sensitivity of US and x-ray KUB was 77%. The impact of location of stones missed on US is shown in table IVU has been the traditional imaging modality of choice for evaluation of patients suspected of having urolithiasis and obstruction. Choice of imaging for urinary tract in patients with renal insufficiency and renal failure is limited to non-contrast enhanced studies. Gray scale ultra sonography is the most effective way to exclude sub acute or chronic obstruction. However, regular gray scale US is not accurate in minimally dilated obstruction, such as with partially obstructing ureteric stone; in one series, 4–5% of patients with obstruction showed minimal or no upper tract dilatation . Duplex US has high sensitivity for renal stones and presence of hydronephrosis. But its sensitivity for ureteral calculi is low. In one study, where IVU was compared with US, the sensitivity of US for ureteral calculi was only 37%  and when hydronephrosis was included as positive sign for ureteral calculi the sensitivity increased to 74% .Recent studies have demonstrated that UHCT is an excellent method for demonstrating urolithiasis and obstruction in patients presenting with flank pain -3. SmithSensitivity of US is reported to be 96 % for renal stones and is 100% sensitive for stones larger than 5 mm in reported literature . In our In the present study US alone had a sensitivity of only 46% for direct visualization of ureteric stones, in combination with x-ray KUB it increased to 77%. The 12 stones missed on US had a mean size of 6.1 mm (range 3–15 mm). Majority of stones missed on US were in the middle ureter (n = 9), 2 were in the proximal ureter and one in the distal ureter. X-ray KUB identified 7 of the 12 stones missed on US. Of these 12 patients with ureteric stones missed only 2 had hydroureter. Presence of hydroureter in patients with ureterolithiasis is valuable as it allows the ureter to be traced to the level of obstruction. Majority (9 out of 12) of stones missed on US were in the middle ureter, an area often obscured by bowel gas.In summary, US is the first imaging study for evaluating the patients with previously undiagnosed renal failure. It helps the clinician to separate end stage renal disease from potentially reversible obstructive uropathy secondary to urolithiasis. US is highly sensitive and specific for renal stones in patients with renal failure, it lacks sensitivity for ureteric calculi particularly when they are in the middle ureter. Even addition of x-ray KUB to US misses about a quarter of ureteric stones; we therefore recommend using UHCT if ureterolithiasis is clinically suspected or US and x-ray KUB examinations are equivocal. Due to small sample size, findings of this study should be validated by other studies on a larger cohort of patients.None declared.MHA conceived the idea, analyzed data and drafted the manuscript.AHJ collected the data and analyzed the results.MNS analyzed results and drafted the manuscript.The pre-publication history for this paper can be accessed here:


Most studies have been done in the developed world showing benefit only for viral mild gastroenteritis. We evaluated the effect of a milk formula containing one billion  in the LGG group (247.8 ml/kg) than in the placebo group (195.0 ml/kg). No significant differences were found in duration of diarrhea (58.5 hours with LGG vs. 50.4 hours with placebo), rate of treatment failure (21.1% with LGG vs. 18.0% with placebo), and proportion of patients with unresolved diarrhea after 120 hours (12.2% with LGG vs. 12.5% with placebo). The rate of stools with reducing substances after 24 hours of treatment increased significantly in both groups (from 41.4% to 72.2% with LGG and from 45.9% to 68.0% with placebo).This study did not show a positive effect of LGG on the clinical course of acute watery diarrhea. Positive beneficial effects of LGG, as had been reported elsewhere, could have been masked in our study by worsening diarrhea due to transient lactose malabsorption. Further studies with low-lactose or non-lactose conveyors of LGG are desirable. Diarrheal diseases in the developing world continue to cause significant morbidity and mortality, especially when associated with malnutrition . DehydraLactobacillus casei strain GG (LGG) reduces both the severity and duration of acute non dehydrating rotavirus enteritis [Adjuvant therapy to ORT, based on oral administration of live probiotic bacteria aimed to improve recovery of infants from acute watery diarrhea, has been under active investigation . These snteritis . Anothernteritis . In a munteritis .Lactobacillus casei strain GG (LGG) on the duration and severity of diarrhea in children with acute watery diarrhea from our hospital. The study was conducted in the Rehydration Unit of Cayetano Heredia Hospital in Lima, Peru from September 1991 to June 1992. The study protocol and Consent Form were reviewed and approved by the Ethical Committee of Cayetano Heredia University in compliance with the Helsinki Declaration.Limited information is available on the potential role of LGG in infants living in the developing world, with more severe acute watery diarrhea , where eMale infants 3–36 months of age brought for treatment because of acute diarrhea to the Rehydration Unit of Cayetano Heredia Hospital, Lima during September 1991 to June 1992 were eligible for the study if they met the following criteria: (a) a history of three or more watery stools per day for less than 48 hours, (b) no bloody stools at the moment of first examination, (c) clinical signs of dehydration, (d) no clinical features of hypovolemic shock, (e) no clinical signs of a coexisting acute systemic illness (i.e., meningitis, sepsis, pneumonia) or a recognized chronic disease such as pulmonary tuberculosis, and (f) no history of current antibiotic or antidiarrheal medication use. Patients 3–6 months old were considered for the study only if they were not on exclusive breastfeeding. Patients were not selected if their weight for age was less than 60% of the median weight for age established by the National Center for Health and Statistics (NCHS) . Only pa9 cfu/ml of Lactobacillus casei strain GG (LGG) or a similar milk formula not containing LGG. Both formulas were of identical looking and tasting. Both milk formulas were provided by the manufacturer  as milk powder to reconstitute with water. They were given in bottles, appropriately labeled and number-coded for each child to secure the double-blind design. The actual assignment of children to their study numbers was made at the time of their enrollment into the study. Each child admitted into the study was allocated to either treatment group by restricted randomization using random permuted blocks. The codes were prepared in Finland and kept in sealed envelopes in Lima.Infants fulfilling the admission criteria were randomly assigned to a double-blind comparison of a milk formula containing 10A clinical history and physical examination was completed upon admission to identify the patient, to determine the duration, type and severity of his diarrhea, to assess associated clinical features , and to establish the nutritional status and previous dietary regimen of the subject. Blood for determination of serum sodium, potassium, chloride, glucose and bicarbonate, blood urea nitrogen, microhematocrit and plasma specific gravity was drawn from each patient before starting treatment. A routine urine analysis was also made. Fecal samples or rectal swabs taken at admission were transported in Cary-Blair transport medium to Cayetano Heredia University Microbiology Laboratory for primary isolation and identification of bacterial enteropathogens. A separate vial containing phosphate buffer saline was used to transport fecal specimens for rotavirus examination.Salmonella, Shigella, E. coli and Vibrios by standard direct and enrichment enteric media. Campylobacter was selectively cultured on sheep blood agar containing Butzler's antibiotic supplement and Aeromonas on ampicillin blood agar preceded by overnight enrichment in alkaline peptone water. Five lactose fermenting colonies of E. coli isolates per patient were serotyped according to standard methods using polyvalent sera for the recognition of enteropathogenic E. coli. Detection of Rotavirus was made by ELISA method using Rotazime®. Identification of enterotoxigenic strains of E. coli was not done. Details of the microbiologic methods used in this study are described in detail elsewhere [Specimens were cultured for lsewhere .The degree of dehydration was assessed clinically. Dehydration was corrected and then fluid balance maintained using the oral rehydration salts (ORS) in its standard WHO's recommended formulation, following the WHO Guidelines . Briefly11 cfu of LGG for those receiving the formula containing LGG. Administration of the formula was by bottle and not compulsive. If the child refused to drink the formula after reasonable attempts, no extraordinary methods, like delivery via nasogastric tubing, were used; in this situation the formula was offered again four hours later.Once dehydration was corrected, feeding, including administration of the assigned study formula was initiated. The first dose of the assigned study formula was administered as soon as rehydration was completed and subsequent doses were given every four hours until cessation of diarrhea or for a maximum of five days. The formula was prepared immediately before administration of each dose by a specially trained nurse that was exclusively working for the study. Measuring spoons provided by the manufacturer were used and the formula powder was kept refrigerated all the time once the container was opened. Before use, the sachets with the study formulas were kept in a -20°C refrigerator. The formula powder was diluted in warm boiled water as to provide 670 Kcal per liter. The amount of formula given to each child was calculated based on the child's body weight, each child being given 150 ml/kg/day to a maximum of 1000 ml/day. On average, each serving of 100 ml will supply 10ad libitum for a maximum of 1000 ml/day. Caloric requirements were completed with a blended soft baby food prepared from fresh ingredients (chicken breast, rice, carrots, squash, potatoes, and vegetable oil), by the Hospital's Nutrition Department. This soft baby food provides 1 Kcal per gram . A total of at least 100 Kcal/kg/day  were offered to these children.Patients under six months of age were fed only the randomly assigned study formula to provide a daily caloric intake of at least 100 Kcal/kg (in a volume of 150 ml/kg/day). No other foods were given for these under six months patients. Older patients were fed the assigned formula All oral intake (ORS, study formula, breast milk, plain water, soft baby food) as well as urine, stool and vomitus volume were strictly measured and recorded during hospitalization. For this purpose patients were put on metabolic beds . A urine collection bag was fitted to avoid contamination of stools with urine and to measure the urine volume. After the first 72 hours, differential weight of dry and soiled diapers was used instead the metabolic bed to determine stool weight if the previous observed purging rate was below 5 ml/kg/hour. Blood analyses taken at admission were repeated at 24 hours. Stool examination for pH, glucose, reducing substances, leukocytes and microscopic fat were performed at admission, 24, 72 hours and at discharge. Urine specific gravity was determined every 24 hours until discharge.Patients were discharged from the study 24 hours after cessation of diarrhea, or at the end of five days from admission, or at the time treatment failure occurred. At discharge each patient was categorized as have completed the trial, as a treatment failure, as an unresolved diarrhea situation, or as a withdrawal.• Rate of treatment failure: proportion of patients in each study group who have recurrence or continued presence of more than 5% dehydration, worsening electrolyte abnormalities, no weight gain since admission, developing of ileus or severe diarrhea defined as a purging rate in excess of 10 ml/Kg/hr in two consecutive 4-hour periods.• Rate of unresolved diarrhea after five days of treatment: proportion of patients in each study group with continuing diarrhea after five days of treatment.• Duration of diarrhea: time in hours from admission until cessation of diarrhea• Duration of hospitalization: time in hours from admission until discharge from hospital. Patients with treatment failure are excluded.• Total stool output: volume of diarrheic stools collected from admission until cessation of diarrhea or for a maximum of 120 hours if diarrhea continues, expressed in milliliters per kilogram of body weight.• Total intake of oral rehydration solution: volume of ORS taken from admission until cessation of diarrhea or for a maximum of 120 hours if diarrhea continues, expressed in milliliters per kilogram of body weight.• Total study formula intake: volume of study formula taken from admission until cessation of diarrhea or for a maximum of 120 hours if diarrhea continues, expressed in milliliters per kilogram of body weight.• Total energy intake: energy from all sources (ORS, formula) taken from admission until cessation of diarrhea or for a maximum of 120 hours if diarrhea continues, expressed in kilocalories per kilogram of body weight.• Total volume of vomitus: volume of vomitus collected each day from admission until cessation of vomitus or for a maximum of 120 hours, expressed in milliliters per kilogram of body weight.• Total volume of urine: volume of urine collected each day from admission until cessation of diarrhea or for a maximum of 120 hours, expressed in milliliters per kilogram of body weight.The following definitions were used for this study:• Carbohydrate malabsorption: stool sample giving a positive reaction for reducing substances (0.75 g % or above).• Cessation of diarrhea: passage of formed stool or passage of no stool for 12 consecutive hours.• Early withdrawal: patient who (a) developed a complicating illness, (b) presented bloody diarrhea after admission and before five days of treatment, (c) was prematurely discharged under request of his parent or legal guardian, or (d) had any protocol violation or non-compliance.® v. 1.02 (Dbase® compatible formats) using a data entry program with on-line checking. The data was checked again in batch mode and finally transferred to EpiInfo® for Windows® v. 3.01 (November 2003) where the tabulations and statistical analysis were performed. Letters (A or B, maintaining blindly the treatment group assignment) identified treatment groups until all statistical analysis was completed. Only after completing the analysis investigators unblinded the treatment assignment. Baseline and outcome two-way comparisons were made between the two treatment groups. A 5% level of significance for statistical tests was set in advance for all comparisons. Chi-square Yates corrected was used to compare discrete variables. One way analysis of variance was performed for continuous variables. Data from patients prematurely withdrawn from the study was included in the analysis up to the time of withdrawal .The data, initially collected in pre-coded forms, were entered in a database organized with a relational model under Fox ProA total of 179 patients were admitted into the study, 90 in the LGG group and 89 in the control group. Nineteen patients, eight from the LGG group and 11 from the control group, were prematurely withdrawn from the study  were observed in two variables that measure severity of illness: stool frequency 24 hours before admission and stool output during rehydration phase. Both were higher in the LGG group. Other indicators of severity, like clinical estimate of dehydration, percentage of weight gain after rehydration and proportion of patients with vomitus before admission, were similar between both groups. On the other hand, there were more cases  of rotavirus in the placebo group than in the LGG group. In order to make sure that the groups were in fact comparable, we perform the statistical adjustment for these variables using multiple regression analysis and found no association with the principal outcomes .Vibrio cholerae (10.1%) and Campylobacter sp. (8.4%), with an important proportion of patients having mixed infections. These findings differ considerably from those of the Finnish clinical trial in which LGG was also tested for efficacy in reducing acute infantile diarrhea [In more than 55% of patients an enteropathogen could be identified. This figure could be higher because studies for ETEC were not done. The most prevalent agents were rotavirus (30.7%), EPEC (11.7%), diarrhea . In the cholerae .1% and CThe first topic to be discussed here is the high proportion of patients that did not recovered optimally during the trial, a condition that did not depend on the assigned treatment group. About 12% of patients had an unresolved diarrhea and an additional 20% were classified as treatment failures, mostly due to severe diarrhea. In two clinical trials conducted at our unit similar rates were found. For instance, in a clinical trial designed to test the clinical efficacy of a citrate-based ORS in children with acute watery diarrhea, patients who received standard therapy (WHO-ORS) had a treatment failure rate of about 24% . This ra10–11 cfu per day [11 cfu per day, well above the threshold dose of 10 billion cfu suggested as most effective [Lactobacillus GG in the sachets while stored in Lima was not confirmed bacteriologically.Except for total stool output , no significant differences in the principal outcomes between groups were found. Duration of diarrhea, duration of hospitalization, and total ORS intake were not significantly different between the experimental and placebo group. The mean volume of formula (and of lactose) administered to children was the same for both groups. The confidence limits of the difference between the two groups indicate that a maximum reduction on duration of diarrhea of 6.7% attributable to the LGG formula could have been detected with the sample size of this study. These numbers indicate that the study does have a sample size sufficient to reject a type II error. No positive effects of treatment could be demonstrated as opposed to Isolauri's experience in Finland [ffective . ViabiliThere were slightly fewer cases of rotavirus in the LGG group than in the placebo group (24.4% vs. 39.3%), although the difference was not statistically significant. LGG appears to be more effective in viral than in bacterial diarrhea . These fOur study clearly shows that the rate of carbohydrate malabsorption raised in both treatment groups from 43.6% at admission to 70.1% 24 hours later. The amount of lactose offered to patients in this study was much higher than in the usual feeding regimen at our unit (10.5 g/kg/day vs. 3.7 g/kg/day, respectively). Although to some investigators lactose intolerance is becoming a decreasing problem , it is cBoth groups were comparable in their baseline characteristics. Marginal differences were found in variables that measured severity of illness before treatment. Total stool output was slightly higher in the LGG group reaching a marginal statistical significance. No significant differences in the other principal outcome variables were found between treatment groups. The proportion of patients with unresolved diarrhea after 120 hours was similar in both treatment groups. For those patients that ceased diarrhea during the study period the mean duration of diarrhea was similar between groups. The rate of carbohydrate malabsorption after 24 hours of treatment increased significantly in both treatment groups.None declared.ES-L participated in the design of the study, organized and coordinated the study, participated in the statistical analysis and drafted the manuscript. PM-L carried out the clinical work, participated in the statistical analysis and the drafting of the manuscript. MC-S carried out the statistical analysis. EC-W participated in the clinical work. RBS conceived of the study, and participated in its design and drafting of the manuscript. All authors read and approved the final manuscriptThe pre-publication history for this paper can be accessed here: