Acute TMS/fMRI response explains offline TMS network effects - An interleaved TMS-fMRI study.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an FDA-approved therapeutic option for treatment resistant depression. However, exact mechanisms-of-action are not fully understood and individual responses are variable. Moreover, although previously suggested, the exact network effects underlying TMS' efficacy are poorly understood as of today. Although, it is supposed that DLPFC stimulation indirectly modulates the sgACC, recent evidence is sparse. METHODS: Here, we used concurrent interleaved TMS/fMRI and state-of-the-science purpose-designed MRI head coils to delineate networks and downstream regions activated by DLPFC-TMS. RESULTS: We show that regions of increased acute BOLD signal activation during TMS resemble a resting-state brain network previously shown to be modulated by offline TMS. There was a topographical overlap in wide spread cortical and sub-cortical areas within this specific RSN#17 derived from the 1000 functional connectomes project. CONCLUSION: These data imply a causal relation between DLPFC-TMS and activation of the ACC and a broader network that has been implicated in MDD. In the broader context of our recent work, these data imply a direct relation between initial changes in BOLD activity mediated by connectivity to the DLPFC target site, and later consolidation of connectivity between these regions. These insights advance our understanding of the mechanistic targets of DLPFC-TMS and may provide novel opportunities to characterize and optimize TMS therapy in other neurological and psychiatric disorders.

Efficacy and safety of two fixed doses of ibalizumab plus optimized background regimen in treatment-experienced HIV-positive individuals.

BACKGROUND: Sustained viral suppression in patients with multidrug-resistant (MDR) human immunodeficiency virus (HIV) infection remains difficult; accordingly, agents targeting different steps in the HIV life cycle are needed. Ibalizumab, a humanized immunoglobulin G4 monoclonal antibody, is a cluster of differentiation (CD4)-directed post-attachment inhibitor. METHODS: In this Phase IIb study, 113 individuals with MDR HIV-1 and limited treatment options were assigned an optimized background regimen (OBR) and randomized to either 800 mg ibalizumab every two weeks (q2wk; n=59) or 2,000 mg ibalizumab every four weeks (q4wk; n=54) up to Week 24. RESULTS: Viral loads (VL) below the detection limit were achieved in 44% and 28% of patients in the 800 mg q2wk and 2,000 mg q4wk groups, respectively, at Week 24. Mean (standard deviation) VL (log10 copies/mL) decreased from Baseline (4.6(0.8), 800 mg q2wk; 4.7(0.7), 2,000 mg q4wk) to Week 2, with the reduction maintained through Week 24 (2.9(1.5), 800 mg q2wk; 3.2(1.4), 2,000 mg q4wk). Baseline CD4+ counts were 80.5 and 54.0 cells/µL in the 800 mg q2wk and 2,000 mg q4wk groups, respectively. Mean CD4+ T-cell count was increased at Week 24 in both groups. No serious adverse events were related to ibalizumab. CONCLUSION: In heavily treatment-experienced patients with HIV (PWH) at a more advanced baseline disease severity, clinically significant response rates at Week 24 were achieved with ibalizumab plus OBR. Ibalizumab's unique mechanism of action and lack of cross-resistance to other antiretroviral agents make it an important component of combination treatment regimens for PWH with limited treatment options.

Evidence for high-fidelity timing-dependent synaptic plasticity of human motor cortex.

A single transcranial magnetic stimulation (TMS) pulse typically evokes a short series of spikes in corticospinal neurons [known as indirect (I)-waves] which are thought to arise from transynaptic input. Delivering a second pulse at inter-pulse intervals (IPIs) corresponding to the timing of these I-waves leads to a facilitation of the response, and if stimulus pairs are delivered repeatedly, a persistent LTP-like increase in excitability can occur. This has been demonstrated at an IPI of 1.5 ms, which corresponds to the first I-wave interval, in an intervention referred to as ITMS (I-wave TMS), and it has been argued that this may have similarities with timing-dependent plasticity models. Consequently, we hypothesized that if the second stimulus is delivered so as not to coincide with I-wave timing, it should lead to LTD. We performed a crossover study in 10 subjects in which TMS doublets were timed to coincide (1.5-ms IPI, ITMS(1.5)) or not coincide (2-ms IPI, ITMS(2)) with I-wave firing. Single pulse motor-evoked potential (MEP) amplitude, resting motor threshold (RMT), and short-interval cortical inhibition (SICI) were measured from the first dorsal interosseous (FDI) muscle. After ITMS(1.5) corticomotor excitability was increased by ~60% for 15 min (P < 0.05) and returned to baseline by 20 min. Increasing the IPI by just 500 µs to 2 ms reversed the aftereffect, and MEP amplitude was significantly reduced (~35%, P < 0.05) for 15 min before returning to baseline. This reduction was not associated with an increase in SICI, suggesting a reduction in excitatory transmission rather than an increase in inhibitory efficacy. RMT also remained unchanged, suggesting that these changes were not due to changes in membrane excitability. Amplitude-matching ITMS(2) did not modulate excitability. The results are consistent with timing-dependent synaptic LTP/D-like effects and suggest that there are plasticity mechanisms operating in the human motor cortex with a temporal resolution of the order of a few hundreds of microseconds.

Inhibitory and disinhibitory effects on I-wave facilitation in motor cortex.

A suprathreshold pulse of transcranial magnetic stimulation (TMS) delivered to human motor cortex results in a period of long-interval intracortical inhibition (LICI) followed by a briefer period of disinhibition (late cortical disinhibition [LCD]). Short-interval intracortical facilitation (SICF) is mediated by excitatory networks in the motor cortex responsible for the generation of the indirect (I-) wave volleys that are evoked by TMS at a periodicity of about 1.5 ms. Because the excitatory synaptic network responsible for SICF undergoes inhibitory regulation, we hypothesized that SICF will be modulated during periods of inhibition and disinhibition. In particular we were interested to know whether SICF was up-regulated during disinhibition, implying an increase in excitatory synaptic efficacy. We measured SICF, at a paired-pulse interval of 1.5 ms, at various times (100-300 ms) after a suprathreshold priming stimulus (PS) of sufficient strength to evoke LICI and LCD. We found that the strength of SICF was normal during LICI, but was increased during LCD by an average of 64%. SICF onset latency was reduced by one I-wave interval during LCD and was delayed by one I-wave interval during LICI. We conclude that disinhibition, rather than inhibition, modulates the excitatory neuronal networks that underlie SICF, whereas the I-wave targeted is modified by the presence of both inhibition and disinhibition and that there is therefore a dissociation between the strength and site of SICF interaction. The increase in SICF during disinhibition further indicates that this is a promising period to investigate or modulate excitatory synaptic networks while they are less constrained by ongoing levels of inhibition.

Modulation of corticomotor excitability by an I-wave intervention delivered during low-level voluntary contraction.

Transcranial magnetic stimulation (TMS) interventions that modulate cortical plasticity may achieve a more functional benefit if combined with neuro-rehabilitation therapies. With a TMS protocol targeting I-wave dynamics, it is possible to deliver stimuli while a subject performs a motor task, and this may more effectively target functional networks related to the task. However, the efficacy of this intervention during a simple task such as a low-level voluntary contraction is not known. We delivered paired-pulse TMS at an inter-pulse interval (IPI) of 1.5 ms for 15 min while subjects performed a 10 ± 2.5% voluntary contraction of the first dorsal interosseous (FDI) muscle and made motor evoked potential (MEP) amplitude and short-interval intracortical facilitation (SICF) curve measurements. Pre-intervention SICF curves showed only a single peak at 1.3-1.5 ms IPI. During the intervention, MEP amplitude steadily increased (P < 0.001) to 137 ± 13% of its initial value. After the intervention, SICF curves were increased in amplitude (P < 0.001) and later peaks emerged at 2.8 and 4.3 ms IPIs. A control experiment, replacing paired-pulse stimulation with single-pulse stimulation showed no effect on MEP amplitude (P = 0.951). We conclude that the I-wave intervention can be administered concurrently with a simple motor task and that it acts by increasing trans-synaptic efficacy across a number of I-waves. The ability to perform a motor task simultaneously with a TMS intervention could confer a degree of specificity to the induced excitability changes and may be beneficial for functional neuro-rehabilitation programs built around motor learning and retraining.

Influence of BDNF Val66Met polymorphism on excitatory-inhibitory balance and plasticity in human motor cortex.

OBJECTIVE: While previous studies showed that the single nucleotide polymorphism (Val66Met) of brain-derived neurotrophic factor (BDNF) can impact neuroplasticity, the influence of BDNF genotype on cortical circuitry and relationship to neuroplasticity remain relatively unexplored in human. METHODS: Using individualised transcranial magnetic stimulation (TMS) parameters, we explored the influence of the BDNF Val66Met polymorphism on excitatory and inhibitory neural circuitry, its relation to I-wave TMS (ITMS) plasticity and effect on the excitatory/inhibitory (E/I) balance in 18 healthy individuals. RESULTS: Excitatory and inhibitory indexes of neurotransmission were reduced in Met allele carriers. An E/I balance was evident, which was influenced by BDNF with higher E/I ratios in Val/Val homozygotes. Both long-term potentiation (LTP-) and depression (LTD-) like ITMS plasticity were greater in Val/Val homozygotes. LTP- but not LTD-like effects were restored in Met allele carriers by increasing stimulus intensity to compensate for reduced excitatory transmission. CONCLUSIONS: The influence of BDNF genotype may extend beyond neuroplasticity to neurotransmission. The E/I balance was evident in human motor cortex, modulated by BDNF and measurable using TMS. Given the limited sample, these preliminary findings warrant further investigation. SIGNIFICANCE: These novel findings suggest a broader role of BDNF genotype on neurocircuitry in human motor cortex.

Late cortical disinhibition in human motor cortex: a triple-pulse transcranial magnetic stimulation study.

In human motor cortex transcranial magnetic stimulation (TMS) has been used to identify short-interval intracortical inhibition (SICI) corresponding to gamma-aminobutyric acid type A (GABA(A)) effects and long-interval intracortical inhibition (LICI) and the cortical silent period (SP) corresponding to postsynaptic GABA(B) effects. Presynaptic GABA(B) effects, corresponding to disinhibition, can also be identified with TMS and have been shown to be acting during LICI by measuring SICI after a suprathreshold priming stimulus (PS). The duration of disinhibition is not certain and, guided by studies in experimental preparations, we hypothesized that it may be longer-lasting than postsynaptic inhibition, leading to a period of late cortical disinhibition and consequently a net increase in corticospinal excitability. We tested this first by measuring the motor-evoked potential (MEP) to a test stimulus (TS), delivered after a PS at interpulse intervals (IPIs) < or =300 ms that encompassed the period of PS-induced LICI and its aftermath. MEP amplitude was initially decreased, but then increased at IPIs of 190-210 ms, reaching 160 +/- 17% of baseline 200 ms after PS (P < 0.05). SP duration was 181 +/- 5 ms. A second experiment established that the onset of the later period of increased excitability correlated with PS intensity (r(2) = 0.99) and with the duration of the SP (r(2) = 0.99). The third and main experiment demonstrated that SICI was significantly reduced in strength at all IPIs < or =220 ms after PS. We conclude that TMS-induced LICI is associated with a period of disinhibition that is at first masked by LICI, but that outlasts LICI and gives rise to a period during which disinhibition predominates and net excitability is raised. Identification of this late period of disinhibition in human motor cortex may provide an opportunity to explore or modulate the behavior of excitatory networks at a time when inhibitory effects are restrained.

Neuromodulation by paired-pulse TMS at an I-wave interval facilitates multiple I-waves.

Corticospinal excitability can be increased by a transcranial magnetic stimulation (TMS) intervention that delivers repeated paired TMS pulses at an I (indirect)-wave interval of 1.5 ms. This is thought to target excitatory synaptic events by reinforcing facilitatory I-wave interaction, however, it remains to be determined what effect this intervention has on the various I-wave components. In the present study we compared I-wave facilitation curves over a range of inter-pulse intervals (IPIs) encompassing the first three I-waves, before and after 15 min of a paired-pulse TMS intervention with an IPI of 1.5 ms. The three peaks in the I-wave facilitation curves occurred at the same IPIs pre- and post-intervention (1.3, 2.5 and 4.3 ms). The facilitation curves were increased in amplitude for all three I-wave peaks post-intervention (mean increase 33%), and the mean increase across all IPIs correlated with the post-intervention increase in single-pulse MEP amplitude (r = 0.77). Modelling showed that the changes in the post-intervention curves were consistent with an increase in amplitude and broadening of the individual I-wave peaks. We conclude that an iTMS intervention with an IPI of 1.5 ms is able to target multiple I-waves. The findings are consistent with existing models of I-wave generation and suggest that the intervention increases the efficacy of synaptic events associated with the generation of descending I-wave volleys.

An investigation into the suitability of a commercial real-time PCR assay to screen for Taylorella equigenitalis in routine prebreeding equine genital swabs.

REASONS FOR PERFORMING STUDY: Standard bacteriological methods for identifying Taylorella equigenitalis in cervical smears are time consuming. Therefore, a more rapid real-time PCR assay was evaluated for its suitability in screening swabs. OBJECTIVE: To compare the results of a commercially available real-time PCR assay with routine microbiological culture for the identification of T. equigenitalis, the causative organism of contagious equine metritis, in equine genital swab samples, under 'field trial' conditions. MATERIALS AND METHODS: Routine prebreeding genital swabs (n=2072) collected from Thoroughbred mares and stallions during 2009 were examined together with stored T. equigenitalis positive material. Swabs were cultured for T. equigenitalis using standard microbiological techniques. Bacterial lysates were isolated from the swabs and examined for the presence of a 16S DNA fragment of T. equigenitalis, using a commercial multiplex real-time PCR assay system. RESULTS: There was complete concordance between positive and negative results obtained by the 2 methods. Real-time PCR also detected T. equigenitalis DNA from swabs that were negative using standard microbiological culture after 6 months' storage at +4 degrees C but from which T. equigenitalis had been isolated following collection. The sensitivities of real-time PCR and bacterial culture were both 10(-3) (equivalent to 3 colony-forming units). CONCLUSION AND CLINICAL RELEVANCE: Routine bacterial culture of T. equigenitalis requires an incubation period of not less than 7 days before a conclusive negative result can be obtained, whereas bacterial extraction and real-time PCR assay can be completed in less than 6 h. The commercially-available PCR assay tested provided a rapid and reliable method for the identification of T. equigenitalis from equine genital swabs and could be usefully employed for the screening of mares and stallions for preseason Horserace Betting Levy Board (HBLB) Code of Practice and in other situations such as for bloodstock sales screening requirements, overcoming the current delays imposed by bacterial culture requirements. Its use could be quality assured by the existing HBLB biannual testing scheme for designated laboratories.

Serum cardiac troponin I concentrations in cattle with cardiac and noncardiac disorders.

BACKGROUND: Making a clinical diagnosis of pericarditis in cattle is difficult and additional diagnostic tests are needed to evaluate cattle with suspected pericarditis. Serum cardiac troponin I (cTnI) concentrations are increased in cattle with pericarditis, but the utility of measuring serum cTnI concentrations in cattle with suspected pericarditis in cattle remains unclear. OBJECTIVES: To determine if serum cTnI concentrations in cattle can be used to differentiate pericarditis from other cardiac disorders and noncardiac thoracic diseases. ANIMALS: Seventy-seven clinically diseased cattle and 19 healthy control cattle. METHODS: Serum cTnI concentrations were measured using an Immunlite Troponin I immunometric chemiluminescent assay in consecutive cases of postmortem-confirmed pericarditis (n=18), endocarditis (n=15), chronic suppurative pneumonia (n=13), congenital heart disease (n=10), reticulitis (n=3), mediastinal abscess (n=7), thymic lymphoma (n=6), and caudal vena cava thrombosis (n=5). Serum cTnI concentrations were measured in 19 healthy cattle. RESULTS: Although serum cTnI concentrations were significantly higher in cattle with pericarditis compared with healthy cattle, they were not significantly different from concentrations in cattle with endocarditis, congenital cardiac disease, mediastinal abscess, reticulitis, caudal vena cava thrombosis, or chronic suppurative pneumonia. CONCLUSIONS: Serum cTnI cannot be used to distinguish cattle with pericarditis from cattle with other primary cardiac diseases. In addition, serum cTnI concentrations cannot distinguish between cattle with primary cardiac diseases and those with other noncardiac, intrathoracic disorders.

Protein Supplementation During or Following a Marathon Run Influences Post-Exercise Recovery.

The effects of protein supplementation on the ratings of energy/fatigue, muscle soreness [ascending (A) and descending (D) stairs], and serum creatine kinase levels following a marathon run were examined. Variables were compared between recreational male and female runners ingesting carbohydrate + protein (CP) during the run (CPDuring, n = 8) versus those that were consuming carbohydrate (CHODuring,n = 8). In a second study, outcomes were compared between subjects who consumed CP or CHO immediately following exercise [CPPost (n = 4) versus CHOPost (n = 4)]. Magnitude-based inferences revealed no meaningful differences between treatments 24 h post-marathon. At 72 h, recovery [Δ(72 hr-Pre)] was likely improved with CPDuring versus CHODuring, respectively, for Physical Energy (+14 ± 64 vs -74 ± 70 mm), Mental Fatigue (-52 ± 59 vs +1 ± 11 mm), and Soreness-D (+15 ± 9 vs +21 ± 70 mm). In addition, recovery at 72 h was likely-very likely improved with CPPost versus CHOPost for Physical Fatigue, Mental Energy, and Soreness-A. Thus, protein supplementation did not meaningfully alter recovery during the initial 24 h following a marathon. However, ratings of energy/fatigue and muscle soreness were improved over 72 h when CP was consumed during exercise, or immediately following the marathon.

Compliance with DOTS diagnosis and treatment recommendations by private practitioners in Kerala, India.

The Indian government has a national tuberculosis (TB) plan based on DOTS recommendations. The private health sector plays an increasing role in health care provision in India, and a public-private mix (PPM) project has been introduced to standardise TB diagnosis and treatment methods in Kerala, India. This study interviewed 45 private practitioners (PPs) to evaluate diagnostic, treatment and reporting practices, of whom 80% diagnose with sputum microscopy and 43% treat all of their patients according to the treatment regimens recommended by the DOTS strategy. This study demonstrates that the current management of TB by private practitioners in Kerala is still in need of improvement.

Modulation of the Direction and Magnitude of Hebbian Plasticity in Human Motor Cortex by Stimulus Intensity and Concurrent Inhibition.

BACKGROUND: The mechanisms mediating the efficacy and variability of paired associative stimulation (PAS), thought to be mediated by Hebbian plasticity, remain incompletely understood. The magnitude and direction of Hebbian plasticity may be modulated by the level of neural depolarisation, which is influenced by stimulation intensity and interactions with cortical circuits. HYPOTHESIS: PAS effects would be influenced by the intensity of transcranial magnetic stimulation (TMS) and interaction with other circuits. In particular, PAS would be inhibited by concurrent inhibitory input following median nerve stimulation, known as short latency afferent inhibition (SAI). METHODS: PAS was tested at an interstimulus interval (ISI) 2 ms or 6 ms longer than the N20 peak of the median nerve somatosensory-evoked potential (PASN20+2, PASN20+6). PASN20+2 was tested at three different TMS intensities. Short interval intracortical facilitation and inhibition were tested in the presence of SAI (SICFSAI, SICISAI). RESULTS: The propensity for long term potentiation like effects increased with higher PASN20+2 TMS stimulus intensity, whereas long term depression like effects ensued at subthreshold intensity. Stronger SAI correlated with weaker PAS LTP-like effects across individuals. PASN20+2 (maximal SAI) was less effective than PASN20+6 (weak SAI). SICFSAI or SICISAI did not influence PAS response. CONCLUSION: Inter-individual differences in SAI contribute to the variability in PAS efficacy. The magnitude and direction of PAS effects is modulated by TMS intensity. Together, these findings indicate that the level of neural activity induced by stimulation likely plays a crucial role in determining the direction and magnitude of Hebbian plastic effects evoked by PAS in human cortex.

Serum cardiac troponin I concentrations decrease following treatment of primary immune-mediated haemolytic anaemia.

OBJECTIVES: The measurement of serum cardiac troponin I concentrations in dogs with a range of non-primary cardiac illnesses suggests that cardiac myocyte damage is commonplace. Dogs with primary immune-mediated haemolytic anaemia have increased serum cardiac troponin I concentrations at the time of diagnosis. However, it is unclear whether biochemical evidence of cardiac myocyte damage improves following successful treatment of anaemia. METHODS: A haematology profile was performed and serum cardiac troponin I concentrations were measured in 19 dogs with primary immune-mediated haemolytic anaemia before and after treatment. RESULTS: The haematocrit increased significantly (P = 0 · 0001) following treatment of primary IMHA (median pre: 0 · 13 L/L, median post: 0 · 33 L/L). The serum cardiac troponin I concentrations decreased significantly (P < 0 · 05) after treatment (median pre: 0 · 26 ng/mL, median post: 0 · 16 ng/mL). CLINICAL SIGNIFICANCE: Serum cardiac troponin I concentration decreases following successful treatment of primary immune-mediated haemolytic anaemia. The clinical and prognostic significance of serum cardiac troponin I concentrations before and after treatment in dogs with primary immune-mediated haemolytic anaemia merits further investigation.

Energy density of food, gastric emptying, and obesity.

Certain receptors in the duodenal mucosa respond to the osomotic effects of the digestion products of dietary carbohydrates and proteins with a resultant slowing of gastric emptying. Other receptors respond to the soaps formed during the digestion of fats. The relative effectiveness of these two sets of receptors is such that foods with equal energy produce equal slowing of gastric emptying. Thus the rate of delivery of energy to the duodenum, and hence to the blood, can be regulated without the energy having been directly measured. The results in the literature that we have examined are consistent with this duodenal system playing some part in the regulation of food intake.

Vitamin A status of children in Sri Lanka.

A representative country-wide rural nutrition status survey determined the extent and distribution of vitamin A deficiency in Sri Lanka in children 6 through 71 months of age. Trained paramedical personnel recorded the presence or absence of selected ophthalmological signs and symptoms associated with vitamin A deficiency in 13,450 children. The results of the country-wide clinical survey indicate that a vitamin A deficiency problem of public health importance may exist in two of 15 health areas. Serum vitamin A levels were determined on 346 survey children from two of 15 health areas and compared with clinical findings for these areas. The lowest mean serum vitamin A, 26.3 microgram/100 ml, occurred in children with clinical eye findings. A high prevalence of clinical eye findings, 34%, and the low mean serum vitamin A value, 28.2 microgram/100 ml, were found in the group of chronically undernourished children--children who are less than 90% of their expected height for age. The survey results enabled planned redirection of the distribution of vitamin A capsules to preschool children in Sri Lanka to areas shown to have the highest prevalences of ophthalmological signs and symptoms and/or the highest prevalence of chronic undernutrition.

Parkinson's disease: decreased density of 3H-imipramine and 3H-paroxetine binding sites in putamen.

The density of high-affinity 3H-imipramine and 3H-paroxetine binding sites (two serotonin-uptake blockers) was decreased in the putamen of parkinsonian patients. The correlation between serotonin levels and the number of 3H-imipramine and 3H-paroxetine binding sites suggests that they are located on serotoninergic nerve terminals and could be used to study serotoninergic innervation in the human brain. Since imipramine and paroxetine are powerful antidepressants, these results furthermore suggest that decreased serotoninergic transmission may be implicated in the pathophysiology of depression in Parkinson's disease.

Parkinson's disease and dementia: norepinephrine and dopamine in locus ceruleus.

Norepinephrine, 3-methoxy 4-hydroxyphenylethyleneglycol and homovanillic acid levels were similar in the locus ceruleus of 13 controls and 8 parkinsonian patients with no intellectual deterioration, but were decreased in 7 demented patients. The concentration of dopamine was similarly diminished in non-demented and demented parkinsonians, and binding of 3H-desmethylimipramine and 3H-rauwolscine was not abnormal in parkinsonians. These data indicate that norepinephrine metabolism in the locus ceruleus is subnormal only in demented parkinsonians.

Attempted prevention of diarrheal disease in Apache children with a non-absorbable broad-spectrum antimicrobial.

A double-blind study was conducted to test the prophylactic effect of a non-absorbable broad-spectrum antimicrobial (oral colistin sulfate) against acute diarrhea in Apache children. Children 1 to 6 months old had over twice the morbidity from diarrhea if assigned to the antimicrobial group as compared to placebo, while the toddler group (7-30 months) taking the antimicrobial had somewhat less diarrhea. Enteropathogenic E. coli were significantly more often isolated from the antimicrobial group (but only in well children). No special effect on the children's growth by the antimicrobial was discerned.

History of the development of oral rehydration therapy.

Humans have often used oral fluids to replace perceived losses of water, either instinctively or with a therapeutic orientation in the form of folk remedies. Replacement therapy with intravenous (IV) fluids was formally introduced in the last century for the treatment of patients with cholera. The modern implementation of oral replacement therapy was begun by pediatricians in the 1940s who used electrolyte solutions as maintenance therapy in mildly purging children with diarrhea. However, the scientific development of oral rehydration therapy (ORT) has occurred only in the last 30 years. Basic physiologic research in the 1950s demonstrated the cotransport mechanism of sodium and organic solutes (sugars and amino acids) in the intestinal cells, thereby establishing the scientific basis for ORT. The use of ORT based on scientific observations was first reported in 1964 from the Philippines by Phillips and coworkers. Research laboratories in Dhaka and Calcutta subsequently demonstrated that the mechanism of sodium and glucose cotransport remains intact in cholera patients and that oral solutions can successfully rehydrate and maintain hydration in these patients. Clinical studies carried out in Dhaka and Calcutta confirmed the efficacy of oral rehydration solutions (ORS) and showed that nearly 80% of IV fluid could be saved if patients were hydrated by the oral route. Further studies demonstrated the safety and efficacy of ORT in patients of all ages suffering from acute diarrhea of any cause. The use of ORT has substantially reduced morbidity and mortality from acute diarrhea, particularly after the World Health Organization adopted and promoted ORT on a worldwide scale. Researchers continue to search for better ORS formulations in terms of safety, efficacy, availability, and cost. Food-based ORS are a promising area of research. The use of a sound scientific method, the establishment of a close link between basic and clinical science, and the use of field studies have proved to be major assets in the development of ORT.