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Biomedical subjects

A B Shah

Publications and source records attributed to A B Shah.

At least 19 recordsLinked to original sources

Meningiomas: report of a hospital-based registry.

This is a hospital-based epidemiologic study of meningiomas. Of 1321 central nervous system tumours, meningiomas constituted 21% of the cases, being the second largest category of a single histologic type after astrocytomas. Of the 267 meningiomas studied, 247 were intra-cranial (92.5%). The age of the patients varied between 6 to 84 years. Histological subclassification is presented and treatment schedules discussed. 261 (98%) meningiomas were histologically benign and 5 were malignant meningiomas (1.9%). A 5-year follow-up was available in most cases, with the help of which it was possible to understand the biological behaviour of various sub-types and the influence of other parameters such as location and treatment schedules. Of note was the fact, that out of 261 patients with benign meningiomas, 11 succumbed in the immediate post-operative period and in 8 of these cases, the tumour was located at the base of the skull.

Adolescent↗

Elastase controls the binding of the vitamin D-binding protein (Gc-globulin) to neutrophils: a potential role in the regulation of C5a co-chemotactic activity.

The vitamin D-binding protein (DBP) binds to the plasma membranes of numerous cell types and mediates a diverse array of cellular functions. DBP bound to the surface of leukocytes serves as a co-chemotactic factor for C5a, significantly enhancing the chemotactic activity of pM concentrations of C5a. This study investigated the regulation of DBP binding to neutrophils as a possible key step in the process of chemotaxis enhancement to C5a. Using radioiodinated DBP as a probe, neutrophils released 70% of previously bound DBP into the extracellular media during a 60-min incubation at 37 degrees C. This was suppressed by serine protease inhibitors (PMSF, Pefabloc SC), but not by metallo- or thiol-protease inhibitors. DBP shed from neutrophils had no detectable alteration in its m.w., suggesting that a serine protease probably cleaves the DBP binding site, releasing DBP in an unaltered form. Cells treated with PMSF accumulate DBP vs time with over 90% of the protein localized to the plasma membrane. Purified neutrophil plasma membranes were used to screen a panel of protease inhibitors for their ability to suppress shedding of the DBP binding site. Only inhibitors to neutrophil elastase prevented the loss of membrane DBP-binding capacity. Moreover, treatment of intact neutrophils with elastase inhibitors prevented the generation of C5a co-chemotactic activity from DBP. These results indicate that steady state binding of DBP is essential for co-chemotactic activity, and further suggest that neutrophil elastase may play a critical role in the C5a co-chemotactic mechanism.

Cell Membrane↗

Utilization of oral hypoglycemic agents in a drug-insured U.S. population.

OBJECTIVE: Clinical trials provide information regarding the safety and efficacy of medications used to manage type 2 diabetes but do not elucidate drug effectiveness in a typical managed care environment. The aim of this study was to characterize "real-world" drug utilization patterns from both a prescriber and a patient perspective. RESEARCH DESIGN AND METHODS: We conducted a retrospective analysis of a large administrative pharmacy claims database, using data on continuously pharmacy benefit-eligible members prescribed oral hypoglycemic agents (OHAs). RESULTS: The 12-month persistence rate for the OHA cohort was low, ranging from 31% for alpha-glucosidase inhibitors to 60% for metformin; compliance rates varied between 70 and 80%. During the first 12 months of therapy, 36% of the patients remaining on therapy at 12 months had one or more therapy modifications. The mean number of therapy changes increased with the length of patient follow-up, with more than half of all patients experiencing at least one therapy change over the duration of follow-up. CONCLUSIONS: These findings document the wide variation in utilization patterns associated with pharmacological management of type 2 diabetes, suggesting that opportunity exists to optimize its pharmacological management.

Carbamates↗

Cutaneous and subcutaneous Ewing's sarcoma: an indolent disease.

PURPOSE: The occurrence of extraosseous Ewing's sarcoma (ES) in deep soft tissues has been well described, but cases in which this tumor occurs in a primary cutaneous or subcutaneous site have rarely been reported. The superficial variant may be less aggressive than are the more common bony and deep soft tissue counterparts with an apparently favorable outcome. A retrospective review of patients with cutaneous or subcutaneous ES was conducted to analyze outcome and patterns of failure. METHODS AND MATERIALS: Between July 1985 and March 1997, 14 patients with cutaneous or subcutaneous ES were treated at St. Jude Children's Research Hospital. The median age at presentation was 16 years (range 7-21 years). Anatomic locations included trunk and pelvis (7), upper or lower extremity (4), and head and neck (3). The median size of the lesion was 3 cm (range, 1-12 cm). Thirteen had definitive surgical resections, and one had biopsy of the mass at the time of referral. They were enrolled on institutional (12) or cooperative group (2) protocols. All patients received chemotherapy, composed of vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, and dactinomycin. Patients on institutional protocols received radiation (36 Gy) to the operative bed (150-180 cGy/fraction/day). Postoperative radiotherapy was omitted for 2 patients who had complete resection on the cooperative group study. RESULTS: No patients had metastatic disease at presentation. Thirteen patients had wide local excision of the primary tumors prior to enrollment on chemotherapy; surgical margins were negative (10), microscopically positive (2), and indeterminate (1). Eleven patients received radiotherapy to the tumor bed; 2 with clear surgical margins were treated without irradiation. The patient who had biopsy only received induction chemotherapy followed by definitive surgical resection and postoperative radiotherapy. The median follow-up was 77 months (range 17-111 months). None of the patients has developed local recurrence or distant metastasis. Several of the patients developed treatment-related sequelae, including veno-occlusive disease of the lung and hemorrhagic cystitis (1), myelodysplastic syndrome (1), chemotherapy-induced ovarian failure (1), moist desquamation (1), and dermatofibroma within the radiotherapy volumes (1). CONCLUSIONS: Cutaneous and subcutaneous ES are associated with an indolent course and a favorable prognosis when treated with combined modality therapy. Elimination of radiation therapy following complete resection has been tested in the POG 9354 trial. The high rate of local control, low rate of metastatic disease, and excellent overall outcome may suggest a role for less intensive chemotherapy, as well as tailoring to diminish or avoid radiation therapy in completely resected cases, with a goal to minimize toxicity while maintaining a high cure rate.

Adolescent↗

Traumatic diaphragmatic rupture: associated injuries and outcome.

A retrospective case note analysis was performed on all patients treated for traumatic diaphragmatic rupture (TDR) at a major teaching hospital between January 1990 and August 1998. Patients were identified from the prospectively maintained UK Trauma and Research Network Database. Of the 480 cases of torso trauma admitted during the study period, 16 (3.3%) had TDR. Blunt trauma accounted for 13 (81%) of the injuries. A radiological pre-operative diagnosis was made in 10 (62.5%) patients. Seven of these were made on initial chest radiography, two on ultrasound scan and one on computed tomography. All patients underwent a midline laparotomy and TDR was subsequently diagnosed at operation in 6 patients. The left hemidiaphragm was ruptured in 14 (87.5%) patients and there was visceral herniation in 8 (50%). Twelve patients with blunt trauma had associated abdominal and extra-abdominal injuries, but only one of the three patients with penetrating trauma had other injuries. The median Injury Severity Score (range) was 21 (9-50). The median time (range) spent on the intensive care unit was 2 days (0-35 days). Pulmonary complications occurred in 7 (44%) patients. Two (12.5%) patients died from associated head injuries. TDR results from blunt and penetrating torso trauma, is uncommon, rarely occurs in isolation and is associated with a high morbidity and mortality. A high index of suspicion makes early diagnosis more likely as initial physical and radiological signs may be lacking.

Adolescent↗

Long-term follow-up of patients treated with primary radiotherapy for supradiaphragmatic Hodgkin's disease at St. Jude Children's Research Hospital.

OBJECTIVE: To assess disease control, patterns of relapse, factors predictive of relapse, and late effects of treatment, we reviewed all cases of supradiaphragmatic (SD) Hodgkin's disease (HD) treated with primary radiation therapy (RT) at our institution. METHODS: We retrospectively reviewed the disease characteristics, treatment history, and long-term outcome of the 106 patients with Stage I and II supradiaphragmatic HD who received definitive irradiation at St. Jude Children's Research Hospital between 1970 and 1995. As of the date of analysis, 95 patients are alive, with a median follow-up of 13.3 years (range, 1.9-24.2 years). RESULTS: The median age at diagnosis was 14.7 years (range, 3.7-22.7). Involved-field RT was given to 13 patients (12%), whereas 37 (35%) had mantle RT, 51 patients (48%) had subtotal nodal irradiation, and 5 (5%) had total nodal irradiation. Relapsed disease developed in 26 patients at a median of 1.8 years (range, 0.2-9.3 years). The 5- and 10-year estimated cumulative incidences of relapse were 20.9% +/- 4.0% and 25.1% +/- 4.3%, respectively. With a median dose of 36 Gy (range, 32-40), in-field failure rate was 6.2%, whereas subdiaphragmatic relapse in sites irradiated prophylactically was 1.5%. There was a trend toward an increased incidence of relapse with higher ESR (p = 0.088) and greater number of sites of disease (p = 0.087). Age, stage, histology, nodal disease > or = 6 cm, the presence of bulky mediastinal disease, and the method of staging did not affect the incidence of relapse. The pattern of failure could not be predicted based on the stage of disease, the extent of subdiaphragmatic staging, the extent of radiation therapy, or the sequence of RT fields-"ping pong" vs. sequential. Subset analysis of Stage II patients revealed significantly more relapses in clinically staged patients. Excluding Stage IA patients with high cervical disease or peripheral nodal disease, nodal extension failures were more common for patients undergoing limited-volume RT, whereas extranodal relapses were likely after STNI or TNI. The estimated 10- and 15-year cumulative incidences of second malignancies were 2.9% +/- 1.6% and 7.9% +/- 3.3%, respectively. Our patients are at increased risk of second malignancies (11-fold), and fatal cardiac (68-fold) and infectious (33-fold) complications. Overall survival at 10 years was 90.8% +/- 3.2%; event-free survival was 72.1% +/- 5.0%. CONCLUSIONS: The current analysis confirms the curative potential of RT for HD in children and adolescents. Despite successful salvage therapy, relapsed disease remained the principal cause of death in our cohort. Excess risk of septic death in asplenic patients, fatal heart disease, and second malignancies may further compromise the ultimate cure of HD in long-term survivors.

Adolescent↗

Pediatric choroid plexus neoplasms.

PURPOSE: Choroid plexus tumors (CPT) are rare childhood neoplasms. The relatively small number of reported cases and the controversies surrounding the clinical and pathological classification of these tumors have made it difficult to define a standard of care for these patients. Our intention is to contribute to the body of knowledge of these tumors and further define the role of adjuvant therapy. METHODS AND MATERIALS: We performed a retrospective review of 14 children with choroid plexus neoplasms referred to St. Jude Children's Research Hospital between October 1985 and December 1987. Ten patients had choroid plexus carcinoma (CPC) based on pathologic criteria and evidence of brain invasion at surgery or leptomeningeal disease (M+); 4 patients had choroid plexus papilloma (CPP). Patients with CPP were initially treated with surgery alone whereas patients with CPC were generally treated with postoperative therapy that included chemotherapy (CT) and/or craniospinal irradiation (CSI) with a focal boost to the primary site. For most patients CT consisted of combinations of cyclophosphamide, etoposide, vincristine, and a platinum agent. The median CSI dose was 35.2 Gy (range 24-46.2 Gy). The median primary site dose was 55.2 Gy (range 49.6-64 Gy). RESULTS: Seven of the 10 CPC cases presented with leptomeningeal dissemination; two of these patients have succumbed to disease. Of the 3 patients with M0 status, all are alive with no evidence of disease (NED). The medial time to relapse from the time of surgery was 5.3 mo (range 3-25 mo). Seven CPC patients were treated with gross total resection (GTR). Three of these patients (2 M0, 1 M+) received CT without CSI and are currently NED (27, 69, and 60 mo respectively). One M+ patient progressed on CT and has stable disease after CSI (6 mo), one (M0) received CT and CSI and is NED (120 mo), one (M+) is currently on CT with objective response (3 mo) and one (M+) died of progressive disease (24.5 mo) despite CT and CSI. Three patients with CPC had subtotal resection (STR). One of these patients (M+) received CT and CSI and is NED (23 mo), one (M0) had an elective second resection GTR alone and is currently NED (153 mo), and one (M+) developed progressive disease (13.5 mo) while on CT and died despite CSI. Among the 4 CPP patients, GTR was performed in two; both were NED at 54 and 81 mo. Two patients with CPP (one with focal atypia) were treated with STR initially; both transformed to CPC at 7 and 27 mo, respectively. Both were currently NED following salvage with (1) GTR and CSI alone (98 mo) or (2) STR, CT, and CSI (62 mo). Six of the 12 survivors in this series had significant neuropsychological sequelae. CONCLUSION: The prognosis of CPP is good for patients treated with GTR. Malignant transformation occurred in 2 CPP patients with less than GTR. Patients with localized CPC who undergo GTR have had a favorable outcome with the addition of chemotherapy or irradiation. CSI may not be routinely indicated in M0 children following GTR. There is evidence that salvage with radiation therapy may be successful following progression on chemotherapy. For patients treated with STR, the use of CT and CSI appears to be necessary.

Adolescent↗

Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses.

Wilson disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver and subsequently in the brain and other organs. On the basis of sequence homology to known genes, the WD gene (ATP7B) appears to be a copper-transporting P-type ATPase. A search for ATP7B mutations in WD patients from five population samples, including 109 North American patients, revealed 27 distinct mutations, 18 of which are novel. A composite of published findings shows missense mutations in all exons-except in exons 1-5, which encode the six copper-binding motifs, and in exon 21, which spans the carboxy-terminus and the poly(A) tail. Over one-half of all WD mutations occur only rarely in any population sample. A splice-site mutation in exon 12 accounts for 3% of the WD mutations in our sample and produces an in-frame, 39-bp insertion in mRNA of patients homozygous, but not heterozygous, for the mutation. The most common WD mutation (His1069Glu) was represented in approximately 38% of all the WD chromosomes from the North American, Russian, and Swedish samples. In several population cohorts, this mutation deviated from Hardy-Weinberg equilibrium, with an overrepresentation of homozygotes. We did not find a significant correlation between His1069Glu homozygosity and several clinical indices, including age of onset, clinical manifestation, ceruloplasmin activity, hepatic copper levels, and the presence of Kayser-Fleischer rings. Finally, lymphoblast cell lines from individuals homozygous for His1069Glu and 4 other mutations all demonstrated significantly decreased copper-stimulated ATPase activity.

Adenosine Triphosphatases↗

Patterns of failure following bone marrow transplantation for metastatic breast cancer: the role of consolidative local therapy.

PURPOSE: The purpose of this analysis is to evaluate the patterns of failure and the role of local therapy in conjunction with bone marrow transplantation (BMT) for metastatic or recurrent breast cancer. METHODS AND MATERIALS: Between June 1986 and November 1991, 46 patients with hormone unresponsive metastatic or recurrent breast cancer underwent high dose chemotherapy (HDC) with hematopoietic stem cell support. The most commonly used preparative regimen consisted of thiotepa (750 mg/m2), cisplatin (150 mg/m2), and cyclophosphamide (120 mg/kg) followed by autologous BMT. Consolidative surgery or irradiation was considered in patients whose cancer responded to BMT and had localized sites of disease. RESULTS: Six patients (13%) died of BMT-related complications. Of the remaining 40 patients, 22 were candidates for consolidative therapy, and 18 of those patients received consolidative irradiation (17 patients) or surgery (1 patient) to one or more sites. At median follow-up of 27 months (range, 20-78), 12 of 18 (67%) patients have continuous local control at the 22 consolidated sites (1 of 4 controlled at chest wall sites, 7 of 8 at regional nodal sites, 7 of 7 at localized bone sites, and 1 of 3 at lung/mediastinal sites). Toxicity of consolidative irradiation was mainly limited to myelosuppression in 6 of 17 patients. Two patients did not complete the consolidative local therapy, one because of hematologic toxicity and one because of rapid systemic tumor progression during treatment. CONCLUSION: In patients with localized areas of extravisceral metastases, consolidative irradiation is feasible with acceptable hematologic toxicity. Consolidative irradiation can result in continuous local control, especially in isolated bone metastases and in regional nodal sites; however, the advantage is less clear in patients undergoing consolidative irradiation for chest wall failures. Because distant visceral metastases still remain a major site of failure after this HDC regimen, a more effective systemic therapy is needed. Consolidative local treatment should be considered in future HDC/BMT protocols for metastatic breast cancer, especially in localized nodal and osseous sites.

Actuarial Analysis↗

Diagnosis and treatment of Clostridium difficile colitis.

Pseudomembranous colitis associated with antibiotic therapy is almost always due to an overgrowth of Clostridium difficile. If untreated, pseudomembranous colitis can lead to severe diarrhea, hypovolemic shock, toxic dilatation of the colon, cecal perforation, hemorrhage, and death. However, C difficile-associated colitis can mimic the more common "benign" antibiotic-associated diarrhea that is not caused by C difficile. An algorithm for diagnosis management of hospitalized patients with antibiotic diarrhea and C difficile colitis is presented in this review. Diagnosis depends on sigmoidoscopy and/or stool tests for C difficile toxins in all patients with antibiotic-associated diarrhea. If the results of these tests are positive, either metronidazole or vancomycin is recommended for treatment of mild illness, and vancomycin is recommended for treatment of severe illness. Oral therapy is always preferred because it is more reliable. In patients with recurrent or relapsing colitis, treatment with either metronidazole or vancomycin is effective for that episode, but novel approaches, such as the oral or rectal introduction of competing nonpathogenic organisms, may prove to be more successful in prevention of relapses.

Anti-Bacterial Agents↗

The microstructure of cortical neuropil before and after decompression in experimental infantile hydrocephalus.

Hydrocephalus is a common clinical disorder and responsible for many pediatric neurological deficits. Relatively little is known about the cellular mechanisms of this disorder and less is known about reconstitution of connectivity following ventricular shunt procedures. In the present studies experimental infantile hydrocephalus produced by kaolin injection was studied in a neonate kitten model. The neuropil of the cerebral cortex was examined in hydrocephalic animals and animals which received a ventriculoperitoneal shunt to reduce ventriculomegaly. The brains were processed for Golgi silver impregnation and electron microscopy to study the detailed dendritic and synaptic architecture. The periventricular region of the hydrocephalic animals exhibited increased extracellular space and signs of neuronal degeneration. Components of the deep neuropil (laminae V-VI) were in disarray and surrounded by edematous extracellular spaces. The superficial neuropil (laminae I-IV), in contrast, appeared intact, but detailed examination showed indications of dendritic degeneration. Shunt procedures successfully restored the cortical mantle to near normal thickness. However, Golgi light microscopy and electron microscopy revealed that dendritic appendage morphology was altered. The results are discussed in regard to development of neuronal connectivity following shunt procedures.

Animals↗

Effects of risk-associated human dietary macrocomponents on processes related to carcinogenesis in human-flora-associated (HFA) rats.

Dietary fat, protein and fibre have been shown to modulate cancer risk in humans and the present study examined the biological effects in human-flora-associated (HFA) rats of altering intake levels within the normal human range. Two control groups, one HFA and the other germfree (GF), consumed a human diet low in fat, fibre and beef for 4 weeks; three other groups consumed human diets similar except for independent 3-fold increases in fat, beef protein or fibre. After 2 weeks on the diets, magnetically recoverable microcapsules were given orally to the rats and subsequently recovered from the faeces to assess endogenous cross-linking agents. After 4 weeks, measurements were made of gut microfloral enzyme activities, hepatic activation of dietary mutagens and hepatic DNA adducts by 32P-postlabelling. Activation in vitro of the dietary mutagens 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by hepatic S9, formation of endogenous hepatic DNA adducts in vivo and the beta-glucuronidase activity of caecal contents were all increased in the sequence high fat > high fibre > high beef = control. Of the two DNA adducts found in all HFA rats, only one was present in GF controls, indicating that the human gut microflora (subject to human dietary modulation) either releases a DNA-adducting product able to act outside the gastrointestinal tract, or stimulates the generation of such a product by mammalian processes. Caecal nitrate reductase activity was highest in rats fed the high beef diet, whilst entrapment of cross-linking agents was highest in those fed the high fibre diet. These results show that risk-related components of human diets interact with human gut microflora to modulate the production of endogenous DNA-adducting and cross-linking substances.

Animals↗

Magnetic microcapsules as novel biomonitors of cross-linking agents and diet-dependent reactive oxygen species in the human gastrointestinal tract.

Six healthy, scientifically informed human volunteers were given 14C-labeled polyethyleneimine (PEI) microcapsules by mouth. Fecal 14C recovery was inversely related to mean gut transit time (r = -0.66), and the extent of cross-linking between the membrane and core PEI was inversely related to total fecal output (r = -0.81). Cross-linking of PEI microcapsules may be a biomonitor of endogenous cross-linking agents within the human gastrointestinal tract. Extensive loss of [14C]CH3 label occurred from the microcapsules during human transit and in in vitro fermentations with human fecal flora. A mechanism whereby reactive oxygen species could arise in the iron-rich core of these microcapsules, leading to loss of [14C]CH3 label, is proposed.

Adult↗

Interaction with microsomal lipid as a major factor responsible for S9-mediated inhibition of 1,8-dinitropyrene mutagenicity.

1,8-Dinitropyrene (1,8-DNP), present in polluted air, is a rodent carcinogen and a potent, direct-acting mutagen in salmonella typhimurium TA98. This mutagenicity is markedly reduced in the presence of mammalian hepatic S9 or microsomes. We demonstrate that at least a substantial part of this effect is attributable to non-enzymatic processes. The microsomal-dependent inhibition was unaffected by omission of an NADPH-generating system or when the cytochrome P-450 inhibitor, SKF-525A, or the cytochrome P-448 inhibitor, ellipticine, was incorporated in the metabolic activation system, suggesting that mixed function oxidases are not involved. Heat inactivation partially decreased the ability of induced S9 to reduce DNP mutagenicity. Substitution of S9 with a similar concentration of bovine serum albumin did not affect DNP activity. Thus non-specific binding to microsomal protein is not involved. However, when lipids, derived from uninduced microsomes, were added to incubations of DNP and S. typhimurium TA98, mutagenicity was decreased. Furthermore, substitution of microsomal lipids with a suspension of phosphatidylcholine (PC), a major lipid constituent of microsomes, affected DNP mutagenicity similarly. An increase in PC concentration resulted in a greater inhibitory effect. The reduction in DNP mutagenicity observed with microsomal lipids or with PC was less than that detected with uninduced S9, whilst the mutagenicity of 2-nitrofluorene was reduced to an approximately equal extent by lipids and S9. This phenomenon may be responsible for the S9-mediated detoxification of other mutagenic nitroaromatic compounds and may have important implications for mutagenicity testing.

Air Pollutants↗

Inhibition of dinitropyrene mutagenicity in vitro and in vivo using Salmonella typhimurium and the intrasanguinous host-mediated assay.

Dinitropyrenes (DNP), present in polluted air, are potent direct-acting mutagens in Salmonella typhimurium TA98. This mutagenicity is markedly reduced in the presence of rat-liver S9 or microsomes. This has now been confirmed using mouse hepatic fractions. Since most in vitro test systems do not adequately simulate conditions encountered in the intact animal, we have investigated dinitropyrene mutagenicity to Salmonella in the host-mediated assay. 1,8-Dinitropyrene (1,8-DNP) given p.o. to BALB/c mice induced a weak mutagenic effect in S. typhimurium TA98 recovered from the liver 1 h after i.v. administration (optimum time). Over the entire dose range tested no toxicity to bacterial cells was detected. Mutation induction in vivo was dose-related with maximum response at 1 mg DNP/kg body weight. This optimum dose, however, was non-mutagenic to strains TA98/1,8-DNP6 (O-transacetylase-deficient) or TA98NR/1,8-DNP6 (nitroreductase- and O-transacetylase-deficient). 1,3-Dinitropyrene and 1,6-dinitropyrene were weakly mutagenic to TA98 at doses similar to 1,8-DNP. Studies with [14C]1,8-DNP showed that 1 h after oral dosing (1 mg/kg), over 100 ng of 1,8-DNP equivalents were present in the liver (= 0.73% dose). However, only about 5.5 ng were present in the bacterial pellet, suggesting that hepatic components in vivo, as in vitro, bind to DNP, thus interfering with its interaction with Salmonella.

Administration, Oral↗