Recurrent Cesarean scar pregnancy: case series and literature review.

OBJECTIVES: To determine the rate of recurrent Cesarean scar pregnancy (CSP) in our clinical practices and to evaluate whether the mode of treatment of a CSP is associated with the risk of recurrent CSP, as well as to review the published literature on recurrent CSP. METHODS: We performed a retrospective search of our six obstetric and gynecological departmental ultrasound databases for all CSPs and recurrent CSPs between 2010 and 2019. We extracted various data, including number of CSPs with follow-up, number of cases attempting and number achieving pregnancy following treatment of CSP and number of recurrent CSPs, as well as details of the treatment of the original CSP. After analyzing the clinical data, we evaluated whether the mode of treatment terminating the previous CSP was associated with the risk of recurrent CSP. We also performed a PubMed search for: 'recurrent Cesarean scar pregnancy' and 'recurrent Cesarean scar ectopic pregnancy'. Articles were reviewed for year of publication, and extraction and analysis of the same data as those obtained from our departmental databases were performed. RESULTS: Our database search identified 252 cases of CSP. The overall rate of clinical follow-up ranged between 71.4% and 100%, according to treatment site (mean, 90.9%). Among these, 105 women had another pregnancy after treatment of the previous CSP. Of these, 36 (34.3%) pregnancies were recurrent CSP, with 27 women having a single recurrence and three women having multiple recurrences, one with two, one with three and one with four. We did not find any particular single or combination treatment mode terminating the previous CSP to be associated with recurrent CSP. The literature search identified 17 articles that yielded sufficient information for us to evaluate their reported prevalence of recurrent CSP. These reported 1743 primary diagnoses of CSP, of which 944 had reliable follow-up. Data were available for 489 cases that attempted to conceive again after treatment of a previous CSP, and on the 327 pregnancies achieved. Of these, 67 (20.5%) were recurrent CSP. CONCLUSIONS: On the basis of our pooled clinical data and review of the literature, recurrent CSP is apparently more common than was previously assumed based upon mostly single-case reports or series with few cases. This should be borne in mind when counseling patients undergoing treatment for CSP regarding their risk of recurrence. We found no obvious causal relationship or association between the type of treatment of the previous CSP and recurrence of CSP. Patients who become pregnant after treatment of a CSP should be encouraged to have an early (5-7-week) first-trimester transvaginal scan to determine the location of the gestation. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Optogenetic surface stimulation of the rat cervical spinal cord.

Electrical intraspinal microstimulation (ISMS) at various sites along the cervical spinal cord permits forelimb muscle activation, elicits complex limb movements and may enhance functional recovery after spinal cord injury. Here, we explore optogenetic spinal stimulation (OSS) as a less invasive and cell type-specific alternative to ISMS. To map forelimb muscle activation by OSS in rats, adeno-associated viruses (AAV) carrying the blue-light sensitive ion channels channelrhodopsin-2 (ChR2) and Chronos were injected into the cervical spinal cord at different depths and volumes. Following an AAV incubation period of several weeks, OSS-induced forelimb muscle activation and movements were assessed at 16 sites along the dorsal surface of the cervical spinal cord. Three distinct movement types were observed. We find that AAV injection volume and depth can be titrated to achieve OSS-based activation of several movements. Optical stimulation of the spinal cord is thus a promising method for dissecting the function of spinal circuitry and targeting therapies following injury. NEW & NOTEWORTHY Optogenetics in the spinal cord can be used both for therapeutic treatments and to uncover basic mechanisms of spinal cord physiology. For the first time, we describe the methodology and outcomes of optogenetic surface stimulation of the rat spinal cord. Specifically, we describe the evoked responses of forelimbs and address the effects of different adeno-associated virus injection paradigms. Additionally, we are the first to report on the limitations of light penetration through the rat spinal cord.

What studies of macaque monkeys have told us about human color vision.

Animal models are a necessary component of systems neuroscience research. Determining which animal model to use for a given study involves a complicated calculus. Some experimental manipulations are easily made in some animal models but impossible in others. Some animal models are similar to humans with respect to particular scientific questions, and others are less so. In this review, I discuss work done in my laboratory to investigate the neural mechanisms of color vision in the rhesus macaque. The emphasis is on the strengths of the macaque model, but shortcomings are also discussed.

Test offering, not additional information, may increase HIV testing uptake in a knowledgeable population.

OBJECTIVES: To evaluate patient HIV knowledge and testing experience and assess the effect of an HIV informational handout on HIV testing propensity. DESIGN: Cross sectional, descriptive techniques were employed to assess demographics, HIV knowledge and HIV testing experience. A randomized controlled trial was performed to determine if an HIV/AIDS information sheet influenced testing propensity. SETTING: Blantyre Adventist Hospital Outpatient Clinic. SUBJECTS: Non-emergency patients over 18 years old attending during consulting hours. INTERVENTIONS: All subjects answered a questionnaire. For the randomized controlled trial component, half received an HIV information handout. MAIN OUTCOME MEASURES: Proportions were calculated to evaluate testing experience. Logistic regression was used to assess impact of written information and demographics on HIV testing propensity. RESULTS: 490 participants were recruited, of whom 57% had never been tested for HIV. Of the untested, 88% had never been offered an HIV test. Of those that had never been offered a test, 46% desired one. The sample was highly knowledgeable about HIV. Reading an information sheet had no impact on HIV knowledge (p=0.736 to 0.788) or desire for testing (p=0.387). However, age (OR=0.97, 95%CI (0.95,0.99)) and gender (OR=1.85, 95%CI (1.06, 3.23)) significantly correlated with testing propensity. CONCLUSIONS: A large percentage of patients who have never been offered HIV testing desire testing. More frequent HIV test offering by clinicians could improve testing rates. Clinician education programmes should be developed to increase test offering. Furthermore, written health information in a setting of high HIV/AIDS knowledge may not change behaviour. Alternative methods should be employed to encourage HIV testing uptake.

Target selection for saccadic eye movements: direction-selective visual responses in the superior colliculus.

We investigated the role of the superior colliculus (SC) in saccade target selection in rhesus monkeys who were trained to perform a direction-discrimination task. In this task, the monkey discriminated between opposed directions of visual motion and indicated its judgment by making a saccadic eye movement to one of two visual targets that were spatially aligned with the two possible directions of motion in the display. Thus the neural circuits that implement target selection in this task are likely to receive directionally selective visual inputs and be closely linked to the saccadic system. We therefore studied prelude neurons in the intermediate and deep layers of the SC that can discharge up to several seconds before an impending saccade, indicating a relatively high-level role in saccade planning. We used the direction-discrimination task to identify neurons whose prelude activity "predicted" the impending perceptual report several seconds before the animal actually executed the operant eye movement; these "choice predicting" cells comprised approximately 30% of the neurons we encountered in the intermediate and deep layers of the SC. Surprisingly, about half of these prelude cells yielded direction-selective responses to our motion stimulus during a passive fixation task. In general, these neurons responded to motion stimuli in many locations around the visual field including the center of gaze where the visual discriminanda were positioned during the direction-discrimination task. Preferred directions generally pointed toward the location of the movement field of the SC neuron in accordance with the sensorimotor demands of the discrimination task. Control experiments indicate that the directional responses do not simply reflect covertly planned saccades. Our results indicate that a small population of SC prelude neurons exhibits properties appropriate for linking stimulus cues to saccade target selection in the context of a visual discrimination task.

Target selection for saccadic eye movements: prelude activity in the superior colliculus during a direction-discrimination task.

We investigated the role of the superior colliculus (SC) in saccade target selection while macaque monkeys performed a direction-discrimination task. The monkeys selected one of two possible saccade targets based on the direction of motion in a stochastic random-dot display; the difficulty of the task was varied by adjusting the strength of the motion signal in the display. One of the two saccade targets was positioned within the movement field of the SC neuron under study while the other target was positioned well outside the movement field. Approximately 30% of the neurons in the intermediate and deep layers of the SC discharged target-specific preludes of activity that "predicted" target choices well before execution of the saccadic eye movement. Across the population of neurons, the strength of the motion signal in the display influenced the intensity of this "predictive" prelude activity: SC activity signaled the impending saccade more reliably when the motion signal was strong than when it was weak. The dependence of neural activity on motion strength could not be explained by small variations in the metrics of the saccadic eye movements. Predictive activity was particularly strong in a subpopulation of neurons with directional visual responses that we have described previously. For a subset of SC neurons, therefore, prelude activity reflects the difficulty of the direction discrimination in addition to the target of the impending saccade. These results are consistent with the notion that a restricted network of SC neurons plays a role in the process of saccade target selection.

Transforming events in thyroid tumorigenesis and their association with follicular lesions.

Thyroid tumors comprise a broad spectrum of neoplastic phenotypes, and distinct molecular events have been implicated in their pathogenesis. Pituitary tumor transforming gene, originally isolated from GH(4) pituitary cells, is tumorigenic in vivo, regulates basic fibroblast growth factor secretion, and is homologous to a securin inhibitor of chromatid separation. Pituitary tumor transforming gene 1 is expressed at low levels in several normal human tissues and is abundantly expressed in neoplasms, including colorectal carcinoma, where pituitary tumor transforming gene expression correlated highly with tumor invasiveness. As pituitary tumor transforming gene is regulated by E and as thyroid cancer shows a strong female preponderance, we examined pituitary tumor transforming gene 1 expression and action in human thyroid tumors and in normal human and rat thyroid cells. Increased pituitary tumor transforming gene 1 expression was evident early in thyroid tumors and was most abundantly expressed in a subset of thyroid hyperplasia, follicular adenomas, and follicular carcinomas (1.8-fold; P < 0.0001). Pituitary tumor transforming gene 1 overexpression in rat FRTL5 thyroid cells and in primary human thyroid cell cultures causes in vitro transformation and produces a dedifferentiated neoplastic phenotype. As pituitary tumor transforming gene 1 was abundantly overexpressed in follicular adenoma and follicular carcinoma, we propose that pituitary tumor transforming gene overexpression may play a role in the early molecular events leading to divergent development of follicular and papillary carcinoma.

Human pituitary tumor-transforming gene induces angiogenesis.

Angiogenesis is a key determinant and rate-limiting step in tumor progression and metastatic spread. As pituitary tumor-transforming gene (PTTG) induces basic fibroblast growth factor (bFGF), we tested angiogenesis induced by conditioned medium (CM) derived from NIH-3T3 transfectants overexpressing wild-type human PTTG (WT-hPTTG-CM). We also examined the relationship between PTTG expression and tumor vascularity in a series of human tumors. CM from Wt-hPTTG transfectants induced proliferation, migration, and tube formation of human umbilical vein endothelial cells in vitro. The bFGF concentration in WT-hPTTG-CM was elevated (10.5 +/- 0.56) compared with CM from nontransfected NIH-3T3 cells (3.3 +/- 0.56 pg/mL), and addition of anti-bFGF antibody to CM abrogated these angiogenesis markers (P < 0.01). In vivo, concentrated WT-hPTTG-CM induced chick chorioallantoic membrane spoke-wheel-like appearances. Moreover, CM derived from hPTTG transfectants harboring a point mutation on the C-terminus proline-rich region of PTTG induced weaker angiogenic activity than WT-hPTTG-CM (P < 0.01). Thus, human PTTG induces an angiogenic phenotype in both in vitro and in vivo angiogenesis models, and high PTTG messenger ribonucleic acid is associated with an angiogenic phenotype in human tumors. These PTTG-directed angiogenic actions may be mediated through bFGF, which also contributes to tumor growth.

Pituitary tumor transforming gene (PTTG) regulates placental JEG-3 cell division and survival: evidence from live cell imaging.

The pituitary transforming gene, PTTG, is abundantly expressed in endocrine neoplasms. PTTG has recently been recognized as a mammalian securin based on its biochemical homology to Pds1p. PTTG expression and intracellular localization were therefore studied during the cell cycle in human placental JEG-3 cells. PTTG mRNA and protein expressions were low at the G1/S border, gradually increased during S phase, and peaked at G2/M, but PTTG levels were attenuated as cells entered G1. In interphase cells, wild-type PTTG, an epitope-tagged PTTG, and a PTTG-EGFP conjugate all localized to both the nucleus and cytoplasm, but in mitotic cells, PTTG was not observed in the chromosome region. PTTG-EGFP colocalized with mitotic spindles in early mitosis and was degraded in anaphase. Intracellular fates of PTTG-EGFP and a conjugate of EGFP and a mutant inactivated PTTG devoid of an SH3-binding domain were observed by real-time visualization of the EGFP conjugates in live cells. The same cells were continuously observed as they progressed from G1/S border to S, G2/M, and G1. Most cells (67%) expressing PTTG-EGFP died by apoptosis, and few cells (4%) expressing PTTG-EGFP divided, whereas those expressing mutant PTTG-EGFP divided. PTTG-EGFP, as well as the mutant PTTG-EGFP, disappeared after cells divided. The results show that PTTG expression and localization are cell cycle-dependent and demonstrate that PTTG regulates endocrine tumor cell division and survival.

Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis.

Pituitary tumors are commonly encountered, and result from clonal expansion of a single mutated cell. Hypothalamic hormones, local growth factors and circulating sex steroid hormones promote pituitary tumor growth and expansion into large invasive tumors. Estrogen acting directly through its receptor and by stimulation of fibroblast growth factor regulates prolactin synthesis and secretion. Fibroblast growth factor-2 (bFGF) modulates angiogenesis, tumor formation and progression in many tissues, including the anterior pituitary. A pituitary tumor-derived transforming gene (PTTG) has been isolated, which is tumorigenic in vivo, regulates bFGF secretion, and inhibits chromatid separation. The human PTTG family consists of at least three homologous genes, of which PTTG1 is located on chromosome 5q33 and is expressed at low levels in most normal human tissues but is highly expressed in malignant human cell lines and in pituitary tumors. We report here that pituitary pttg is regulated in vivo and in vitro by estrogen. Maximal induction of rat pituitary pttg mRNA in vivo occurred early in pituitary transformation (normal cell to hypertrophic/hyperplastic cell), coincident with bFGF and vascular endothelial growth factor induction and pituitary angiogenesis. We also demonstrate that pttg expression is induced by bFGF, and show concordant pttg and bFGF expression in experimental and human pituitary adenomas. As bFGF and estrogen both induce pttg, and pttg expression coincides with the early lactotrophic hyperplastic response, angiogenesis and prolactinoma development, we propose a previously unknown paracrine growth factor-mediated mechanism for pituitary tumor pathogenesis and potentially other estrogen-regulated tumors.

Separate signals for target selection and movement specification in the superior colliculus.

At any given instant, multiple potential targets for saccades are present in the visual world, implying that a "selection process" within the brain determines the target of the next eye movement. Some superior colliculus (SC) neurons begin discharging seconds before saccade initiation, suggesting involvement in target selection or, alternatively, in postselectional saccade preparation. SC neurons were recorded in monkeys who selected saccade targets on the basis of motion direction in a visual display. Some neurons carried a direction-selective visual signal, consistent with a role in target selection in this task, whereas other SC neurons appeared to be more involved in postselection specification of saccade parameters.

Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas.

We recently cloned a novel pituitary tumor transforming gene (PTTG). Here we report PTTG expression in human pituitary adenomas and in normal pituitary tissue. In situ hybridization revealed PTTG expression in nonfunctioning and in GH-secreting adenomas but not in normal pituitary tissue. Using a more sensitive detection method, RT-PCR, low level PTTG expression was detected in normal pituitary. However, when expression levels in normal pituitary tissue were compared with those in 54 pituitary tumors using comparative reverse transcription polymerase chain reaction (RT-PCR), we found that most tumor samples expressed higher levels of PTTG. More than 50% PTTG increases were observed in 23 of 30 nonfunctioning pituitary tumors, all 13 GH-producing tumors, 9 of 10 prolactinomas, and 1 ACTH-secreting tumor, with more than 10-fold increases evident in some tumors. Furthermore, higher PTTG expression (P = 0.03) was observed in hormone-secreting tumors that had invaded the sphenoid bone (stages III and IV; 95% CI 3.118-9.715) compared with hormone-secreting tumors that were confined to the pituitary fossa (stages I and II; 95% CI 1.681-3.051). Therefore, PTTG abundance is a molecular marker for invasiveness in hormone-secreting pituitary tumors. The ubiquitous and prevalent expression of pituitary adenoma PTTG suggests that PTTG plays a role in pituitary tumorigenesis and invasiveness.

Structure, expression, and function of human pituitary tumor-transforming gene (PTTG).

Despite advances in characterizing the pathophysiology and genetics of pituitary tumors, molecular mechanisms of their pathogenesis are poorly understood. Recently, we isolated a transforming gene [pituitary tumor-transforming gene (PTTG)] from rat pituitary tumor cells. Here we describe the cloning of human PTTG, which is located on chromosome 5q33 and shares striking sequence homology with its rat counterpart. Northern analysis revealed PTTG expression in normal adult testis, thymus, colon, small intestine, brain, lung, and fetal liver, but most abundant levels of PTTG mRNA were observed in several carcinoma cell lines. Stable transfection of NIH 3T3 cells with human PTTG cDNA caused anchorage-independent transformation in vitro and induced in vivo tumor formation when transfectants were injected into athymic mice. Overexpression of PTTG in transfected NIH 3T3 cells also stimulated expression and secretion of basic fibroblast growth factor, a human pituitary tumor growth-regulating factor. A proline-rich region, which contains two PXXP motifs for the SH3 domain-binding site, was detected in the PTTG protein sequence. When these proline residues were changed by site-directed mutagenesis, PTTG in vitro transforming and in vivo tumor-inducing activity, as well as stimulation of basic fibroblast growth factor, was abrogated. These results indicate that human PTTG, a novel oncogene, may function through SH3-mediated signal transduction pathways and activation of growth factor(s).

Neurophysiology: sensing and categorizing.

Objects differ along many stimulus dimensions, but observers typically group them into fewer 'categories' according to their potential use or behavioral relevance. New experiments in awake, behaving monkeys open a window onto the process of stimulus categorization within the central nervous system.

Protease-resistant form of insulin-like growth factor-binding protein 5 is an inhibitor of insulin-like growth factor-I actions on porcine smooth muscle cells in culture.

IGFs are pleiotrophic mitogens for porcine smooth muscle cells (pSMC) in culture. The effects of IGFs on cells are modulated by various insulin-like growth factor-binding proteins (IGFBP). IGFBP-5 is synthesized by pSMC and binds to the extracellular matrix. However, IGFBP-5 is also secreted into conditioned medium of cultured cells and is cleaved into fragments by a concomitantly produced protease. These fragments have reduced affinity for the IGFs and cleavage makes it difficult to assess the role of intact IGFBP-5. To study the consequence of accumulation of intact IGFBP-5 in medium, we determined the cleavage site in IGFBP-5 and prepared a protease resistant mutant. Amino acid sequencing of purified IGFBP-5 fragments suggested Arg138-Arg139 as the primary cleavage site. Arg138-Arg139-->Asn138-Asn139 mutations were introduced to create protease-resistant IGFBP-5, which has the same affinity for IGF-I as the native protein. This mutant IGFBP-5 remained intact even after 24 h of incubation and it inhibited several IGF-I actions when added to pSMC culture medium. The mutant IGFBP-5 (500 ng/ml) decreased IGF-I stimulated cellular DNA synthesis by 84%, protein synthesis by 77%, and it inhibited IGF-I stimulated migration of pSMC by 77%. It also inhibited IGF-I stimulation of IRS-1 phosphorylation. In contrast, the same amount of native IGFBP-5 did not inhibit IGF-I actions. The significance of inhibitory effects of the protease resistant IGFBP-5 was further demonstrated in pSMC transfected with mutant or native IGFBP-5 cDNAs. The mutant IGFBP-5 accumulated in culture medium of transfected cells, while native IGFBP-5 was degraded into fragments, PSMC overexpressing the mutant IGFBP-5 also responded poorly to IGF-I compared with mock transfected cells. IGF-I (5 ng/ml) increased [35S]methionine incorporation into control cells by 36% above the basal level, but it did not significantly change (4%) in pSMC cultures that were producing the mutant IGFBP-5. In conclusion, the accumulation of protease-resistant IGFBP-5 in the medium was inhibitory to IGF-I actions on pSMC. This suggests that proteolysis can prevent IGFBP-5 from acting as an inhibitor of IGF-I-stimulated effects and that it serves as an important mechanism for regulating cellular responsiveness to IGF-I.

Two types of image generation: evidence for left and right hemisphere processes.

The results from seven experiments provide evidence that visual mental images can be generated by either the left or right cerebral hemisphere, but in different ways. Subjects were cued to form images within a grid or within a set of four corner brackets; a single X mark was enclosed within each stimulus, and the subjects were to determine whether the X mark was enclosed within each stimulus, and the subjects were to determine whether the X mark would have fallen on an imaged pattern. When subjects memorized descriptions of how parts were arranged, they could later form images of the composite pattern when cued in the right visual field (left hemisphere) more accurately than when they were cued in the left visual field (right hemisphere). In contrast, when subjects memorized individual segments on a screen, and 'mentally glued' them into a single pattern, they later could form images more accurately, at least in some circumstances, when cued in the left visual field. These results were predicted by the theory that images are built up by arranging parts, and that two different processes can be used to arrange them. One process uses stored descriptions to arrange parts, and is more effective in the left cerebral hemisphere; the other process uses stored memories of metric positions to arrange parts, and is more effective in the right cerebral hemisphere. Convergent evidence was obtained by having subjects memorize letters in grids (which are easily encoded using descriptions of the positions of segments) or within a space delineated by four brackets (which require memorizing the precise positions of the segments). Subjects were relatively more accurate when cued in the left visual field with bracket stimuli, but tended to be relatively more accurate when cued in the right visual field with grids stimuli. Control experiments showed that this finding was not due to hemispheric differences in the ease of forming images at different sizes or differences in the ease of perceptually encoding the probes.

Modulation of associative memory function in a biophysical simulation of rat piriform cortex.

1. Associative memory function was analyzed in a realistic biophysical simulation of rat piriform (olfactory) cortex containing 240 pyramidal cells and 58 each of two types of inhibitory interneurons. Pyramidal cell simulations incorporated six different intrinsic currents and three different synaptic currents. We investigated the hypothesis that acetylcholine sets the appropriate dynamics for learning within the network, whereas removal of cholinergic modulation sets the appropriate dynamics for recall. The associative memory function of the network was tested during recall after simulation of the cholinergic suppression of intrinsic fiber synaptic transmission and the cholinergic suppression of neuronal adaptation during learning. 2. Hebbian modification of excitatory synaptic connections between pyramidal cells during learning of patterns of afferent activity allowed the model to show the basic associative memory property of completion during recall in response to degraded versions of those patterns, as evaluated by a performance measure based on normalized dot products. 3. During learning of multiple overlapping patterns of afferent activity, recall of previously learned patterns interfered with the learning of new patterns. As more patterns were stored this interference could lead to the exponential growth of a large number of excitatory synaptic connections within the network. This runaway synaptic modification during learning led to excessive excitatory activity during recall, preventing the accurate recall of individual patterns. 4. Runaway synaptic modification of excitatory intrinsic connections could be prevented by selective suppression of synaptic transmission at these synapses during learning. This allowed effective recall of single learned afferent patterns in response to degraded versions of those patterns, without interference from other learned patterns. 5. During learning, cholinergic suppression of neuronal adaptation enhanced the activity of cortical pyramidal cells in response to afferent input, compensating for decreased activity due to suppression of intrinsic fiber synaptic transmission. This modulation of adaptation led to more rapid learning of afferent input patterns, as demonstrated by higher values of the performance measure. 6. During recall, when suppression of excitatory intrinsic synaptic transmission was removed, continued cholinergic suppression of neuronal adaptation led to the spread of excessive activity. More stable activity patterns during recall could be obtained when the cholinergic suppression of neuronal adaptation was removed at the same time as the cholinergic suppression of synaptic transmission. 7. A realistic biophysical simulation of the effects of acetylcholine on synaptic transmission and neuronal adaptation in the piriform cortex shows that these effects act together to set the appropriate dynamics for learning, whereas removal of both effects sets the appropriate dynamics for recall.

Increased intestinal vitamin D receptor in genetic hypercalciuric rats. A cause of intestinal calcium hyperabsorption.

In humans, familial or idiopathic hypercalciuria (IH) is a common cause of hypercalciuria and predisposes to calcium oxalate nephrolithiasis. Intestinal calcium hyperabsorption is a constant feature of IH and may be due to either a vitamin D-independent process in the intestine, a primary overproduction of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or a defect in renal tubular calcium reabsorption. Selective breeding of spontaneously hypercalciuric male and female Sprague-Dawley rats resulted in offspring with hypercalciuria, increased intestinal calcium absorption, and normal serum 1,25(OH)2D3 levels. The role of the vitamin D receptor (VDR) in the regulation of intestinal calcium absorption was explored in 10th generation male genetic IH rats and normocalciuric controls. Urine calcium excretion was greater in IH rats than controls (2.9 +/- 0.3 vs. 0.7 +/- 0.2 mg/24 h, P < 0.001). IH rat intestine contained twice the abundance of VDR compared with normocalciuric controls (536 +/- 73 vs. 243 +/- 42 nmol/mg protein, P < 0.001), with no difference in the affinity of the receptor for its ligand. Comparable migration of IH and normal intestinal VDR on Western blots and of intestinal VDR mRNA by Northern analysis suggests that the VDR in IH rat intestine is not due to large deletion or addition mutations of the wild-type VDR. IH rat intestine contained greater concentrations of vitamin D-dependent calbindin 9-kD protein. The present studies strongly suggest that increased intestinal VDR number and normal levels of circulating 1,25(OH)2D3 result in increased functional VDR-1,25(OH)2D3 complexes, which exert biological actions in enterocytes to increase intestinal calcium transport. Intestinal calcium hyperabsorption in the IH rat may be the first example of a genetic disorder resulting from a pathologic increase in VDR.