Current concepts of pain pathways: a brief review of anatomy, physiology, and medical imaging.

BACKGROUND: Although the essential components of pain pathways have been identified, a thorough comprehension of the interactions necessary for creating focused treatments is still lacking. Such include more standardised methods for measuring pain in clinical and preclinical studies and more representative study populations. OBJECTIVE: This review describes the essential neuroanatomy and neurophysiology of pain nociception and its relation with currently available neuroimaging methods focused on health professionals responsible for treating pain. METHODS: Conduct a PubMed search of pain pathways using pain-related search terms, selecting the most relevant and updated information. RESULTS: Current reviews of pain highlight the importance of their study in different areas from the cellular level, pain types, neuronal plasticity, ascending, descending, and integration pathways to their clinical evaluation and neuroimaging. Advanced neuroimaging techniques such as fMRI, PET, and MEG are used to better understand the neural mechanisms underlying pain processing and identify potential targets for pain therapy. CONCLUSIONS: The study of pain pathways and neuroimaging methods allows physicians to evaluate and facilitate decision-making related to the pathologies that cause chronic pain. Some identifiable issues include a better understanding of the relationship between pain and mental health, developing more effective interventions for chronic pain's psychological and emotional aspects, and better integrating data from different neuroimaging modalities for the clinical efficacy of new pain therapies.

Current MRI Methods for the Assessment of Pathologic Prostate: A Brief Review for Clinicians.

The application of Magnetic Resonance Imaging (MRI) have helped in different modalities for prostate cancer management, from early detection to treatment planning and follow-up, the evolution of MRI techniques allows to obtain not only anatomical but also functional information to take advantage of prostate cancer detection and staging while supplying prognostic and predictive biomarkers. This review presents conventional and advanced MRI techniques (known as multiparametric MRI) that allow functional and quantitative assessment of the normal prostate gland and its correlation with prostate cancer. Additional topics include the epidemiology of prostate cancer following the Global Burden Diseases Cancer Collaboration 2018, the clinical anatomy of the prostate gland, and the lower urinary tract; we also mention some aspects of the diagnosis performance in ultrasound. We end the review with a brief explanation about the anatomical foundation of external-beam planning radiotherapy.

Imaging Assessment of the Postoperative Spine: An Updated Pictorial Review of Selected Complications.

Imaging of the postoperative spine requires the identification of several critical points by the radiologist to be written in the medical report: condition of the underlying cortical and cancellous bone, intervertebral disc, and musculoskeletal tissues; location and integrity of surgical implants; evaluation of the success of decompression procedures; delineation of fusion status; and identification of complications. This article presents a pictorial narrative review of the most common findings observed in noninstrumented and instrumented postoperative spines. Complications in the noninstrumented spine were grouped in early (hematomas, pseudomeningocele, and postoperative spine infection) and late findings (arachnoiditis, radiculitis, recurrent disc herniation, spinal stenosis, and textiloma). Complications in the instrumented spine were also sorted in early (hardware fractures) and late findings (adjacent segment disease, hardware loosening, and implant migration). This review also includes a short description of the most used diagnostic techniques in postoperative spine imaging: plain radiography, ultrasound (US), computed tomography (CT), magnetic resonance (MR), and nuclear medicine. Imaging of the postoperative spine remained a challenging task in the early identification of complications and abnormal healing process. It is crucial to consider the advantages and disadvantages of the imaging modalities to choose those that provide more accurate spinal status information during the follow-up. Our review is directed to all health professionals dealing with the assessment and care of the postoperative spine.

Free Area of the Spinal Canal and Torg's Ratio in Acute Cervical Trauma and Degenerative Disease: MANCOVA and Correlational Analyses.

BACKGROUND: The two of the most common indications for magnetic resonance (MR) imaging of the cervical spine include acute spine trauma and degenerative disease. OBJECTIVE: We aimed to correlate the measurements of the free area of the spinal canal (FASC), a new approach to the cervical spinal canal compromise, with the Torg´s ratio quantification of the cervical spine. METHODS: A cross-sectional study including 50 cervical-spine MR evaluations of patients with acute cervical trauma or degenerative disease was performed. We used multivariate analysis of covariance (MANCOVA) to identify the type of lesion, intervertebral level and gender differences between FASC and Torg´s ratio quantification of the cervical spine; age was the controlled covariate. Correlates between FASC and Torg´s ratio were obtained at each intervertebral level. RESULTS: There was a non-significant interaction between the type of lesion, gender and intervertebral levels between FASC and Torg´s ratio measurements, F (8, 456) 0.260, p = .978; Wilks' Lambda 0.991; with a small effect size (partial η2 = .005). Among the main effects, only the gender was statistically significant: F (2, 228) = 3.682, p = .027. The age (controlled covariate) was non-significantly related to FASC and Torg´s ratio quantification: F (2, 228) = .098, p = .907. The Pearson´s correlation coefficient depicted a poor, non-significant agreement between FASC and Torg´s ratio. CONCLUSION: FASC provides an integrative evaluation of the cervical spinal canal compromise in acute, cervical spine trauma and degenerative disease. Further observations and correlation with specific neurological symptoms, surgical findings and clinical outcomes are necessary to assess the usefulness of FASC in clinical settings.

Chemotherapy-induced posterior reversible encephalopathy syndrome: Three case reports.

RATIONALE: Posterior reversible encephalopathy syndrome (PRES) has been associated with the use of several medications, including chemotherapeutic agents. PATIENT CONCERNS: A 65-year-old woman was diagnosed with adenocarcinoma of the ovary, after sixth-line treatment with topotecan, at the beginning of the fourth cycle, she was admitted to the emergency room for presenting tonic-clonic seizures, visual disturbance, and hypertension. A 66-year-old woman was diagnosed with bilateral breast cancer; due to disease progression, treatment with paclitaxel and gemcitabine was started, 1 month after the last dose of chemotherapy, she was admitted to the emergency room for suffering severe headache, altered mental status, tonic-clonic seizures, and hypertension. A 60-year-old patient diagnosed with breast cancer on the left side, underwent second-line chemotherapy with gemcitabine, carboplatin, and bevacizumab, and 1 month after the last dose of chemotherapy, she was also admitted to the emergency room due to altered mental status, vomiting, tonic-clonic seizures, and hypertension. DIAGNOSIS: They were diagnosed as PRES based on physical examination, laboratory findings, and imaging techniques that revealed diffuse lesions and edema within the parieto-occipital regions. INTERVENTIONS: They received support treatment with blood pressure (BP) control, seizures were controlled with a single anti-epileptic agent, and chemotherapeutic agents from the onset of PRES to its resolution were discontinued. OUTCOMES: All these patients improved after medical treatment was started. LESSONS: Medical personnel and therapeutic establishments need to be made aware about this chemotherapy-induced neurologic complication.

Communicating Segment Aneurysm of Internal Carotid Artery Associated with Saltzman's Type III Persistent Trigeminal Artery: A Case Report.

Persistent trigeminal artery (PTA), also called primitive trigeminal artery, represents the most common embryonic remnant of fetal circulation in adulthood, (only after fetal pattern of posterior communicating artery [PComA]) with an estimated incidence of between 0.1% and 0.76%. The permanence of this fetal pattern constitutes an incidental finding in most cases, however, may be associated with aneurysms, arteriovenous malformations, trigeminal neuralgia, and other types of fetal circulation persistency. A patient with giant aneurysm in the communicating segment of the right internal carotid artery, associated with the presence of PTA and fetal pattern of PComA, also on the right side is reported.

Portal vein thrombosis with protein C-S deficiency in a non-cirrhotic patient.

There are several conditions that can lead to portal vein thrombosis (PVT), including including infection, malignancies, and coagulation disorders. Anew condition of interest is protein C and S deficiencies, associated with hypercoagulation and recurrent venous thromboembolism. We report the case of a non-cirrhotic 63-year-old male diagnosed with acute superior mesenteric vein thrombosis and PVT and combined deficiencies in proteins C and S, recanalized by short-term low molecular heparin plus oral warfarin therapy.

3T MRI and 128-slice dual-source CT cisternography images of the cranial nerves a brief pictorial review for clinicians.

There is a broad community of health sciences professionals interested in the anatomy of the cranial nerves (CNs): specialists in neurology, neurosurgery, radiology, otolaryngology, ophthalmology, maxillofacial surgery, radiation oncology, and emergency medicine, as well as other related fields. Advances in neuroimaging using high-resolution images from computed tomography (CT) and magnetic resonance (MR) have made highly-detailed visualization of brain structures possible, allowing normal findings to be routinely assessed and nervous system pathology to be detected. In this article we present an integrated perspective of the normal anatomy of the CNs established by radiologists and neurosurgeons in order to provide a practical imaging review, which combines 128-slice dual-source multiplanar images from CT cisternography and 3T MR curved reconstructed images. The information about the CNs includes their origin, course (with emphasis on the cisternal segments and location of the orifices at the skull base transmitting them), function, and a brief listing of the most common pathologies affecting them. The scope of the article is clinical anatomy; readers will find specialized texts presenting detailed information about particular topics. Our aim in this article is to provide a helpful reference for understanding the complex anatomy of the cranial nerves.

Neurocysticercosis: radiologic-pathologic correlation.

Neurocysticercosis is a neurologic parasitic disease caused by the encysted larva of the tapeworm Taenia solium and is the most important parasitic disease of the human central nervous system. It is the most common cause of acquired epilepsy in endemic settings and constitutes a public health challenge for most of the developing world. Nowadays, however, as a result of globalization, neurocysticercosis is being seen more frequently in developed countries as well. Neurocysticercosis is acquired through fecal-oral contamination, and the disease course is complex, with two intermediate hosts (ie, pigs and humans) and a definitive host (humans). Traditionally, it has been classified into active and nonactive forms according to disease location. Radiologists must be aware of its imaging appearance, which is quite variable, as is the differential diagnosis. Imaging findings depend on several factors, including the stage of the life cycle of T solium at presentation; the number and location (ie, subarachnoid, cisternal, or intraventricular) of parasites; and associated complications such as vascular involvement (ie, arteritis with or without infarction), inflammatory response (ie, edema, gliosis, or arachnoiditis), and, in ventricular forms, degree of obstruction. Thus, the diagnostic approach, management, and prognosis for neurocysticercosis differ widely depending on the type of infection.

Esclerosis temporal mesial en epilepsia del lóbulo temporal: evaluación cuantitativa con resonancia magnética 3.0 Tesla / Mesial temporal sclerosis in temporal lobe epilepsy: quantitative magnetic resonance imaging assesment with 3.0 Tesla

Se estima que hasta 70% de los pacientes con epilepsia del lóbulo temporal tienen una alteración morfológica del hipocampo, la esclerosis hipocampal mesial, también llamada esclerosis temporal mesial que se caracteriza por pérdida de neuronas y gliosis responsable del foco epiléptico. En la resonancia magnética convencional la esclerosis temporal mesial se define por la presencia de una atrofia del hipocampo más una señal hiperintensa en las secuencias con tiempo de repetición largo específicas para el hipocampo (FLAIR y T2 coronal). La resonancia magnética 3.0 Tesla permite actualmente estudiar la anatomía y fisiología cerebral o cambiar el mecanismo de adquisición de la imagen y los parámetros posproceso. La volumetría proporciona actualmente un volumen preciso y junto con la espectroscopia hace posible una evaluación cuantitativa del hipocampo. Ambas técnicas se suman a los hallazgos de la resonancia magnética convencional para identificar las lesiones cerebrales que participan en un foco epiléptico. Presentamos un caso de esclerosis temporal mesial con análisis cuantitativo del hipocampo y una breve revisión de la literatura.

Recent studies show that up to 70% of patients with temporal lobe epilepsy (TLE) have a hippocampal deficit known as temporal mesial sclerosis (TME) characterized by neuron loss and gliosis, and considered the main epileptogenic focus among this type of patients. The magnetic resonance imaging (MRI) features of TME include atrophy and hippocampus hyperintensitY in the long TR sequences (Flair and T2). The 3.0 Tesla MRI allows the study of the brain's anatomy and physiology using different sequences and post processing mechanisms. Volumetry can determine the accurate volume and, together with spectroscopy, makes possible a quantitative assessment of the hyppocampus. Both techniques help to locate cerebral areas with epileptogenic activity. We describe the imaging findings from spectroscopy and volumetry in a patient with TLE and briefly review the related literature.

Síndrome de Wallenberg: hallazgos en resonancia magnética con correlación clínica / Wallenberg syndrome: magnetic imaging findings and clinical correlation

El síndrome de Wallenberg es una de las entidades clínicas más frecuentemente reconocidas como parte de la patología vascular del tallo cerebral. En la actualidad puede ser identificada con rapidez gracias a las modernas técnicas en neuroimagen. Presentamos un paciente con cuadro clínico de miosis, disfonía, disfagia, seguido de ataxia. Se efectuó evaluación con resonancia magnética utilizando técnicas de difusión, coeficiente aparente de difusión, FLAIR (fast fluid-attenuated inversion recovery) y perfusión. Se describe la correlación clínica de los síntomas con la localización anatómica de la lesión, y se discuten los hallazgos de imagen. La descripción de este caso enfatiza la utilidad de la resonancia magnética para una adecuada evaluación y correlación clínica de los hallazgos en imagen con la exploración neurológica.

Wallenberg's syndrome is one of the most common clinically recognized conditions due to brain stem infarct, which can nowadays be identified by modern neuro-imaging techniques. We describe a patient complaining of miosis, dysphonia, and dysphagia followed by ataxia. An MRI evaluation was performed including diffusion-weighted imaging, apparent diffusion coefficient, T2-weighted images, fluid attenuated inversion recovery (FLAIR) and perfusion. A brief discussion of imaging findings is presented as well as a clinical correlation of the symptoms with the anatomic location of the lesion. This case report emphasizes the importance of imaging findings and their clinical correlation with neurological examination.

Molecular modeling of some 1H-benzimidazole derivatives with biological activity against Entamoeba histolytica: a comparative molecular field analysis study.

Comparative molecular field analysis (CoMFA) was performed on a set of 1H-benzimidazole derivatives. Molecular modeling and 3D-QSAR were employed to determine the tautomeric form that would probably fit a target receptor in Entamoeba histolytica. CoMFA results suggest that the antiamoebic activity is favored with steric bulk at position 5 of the benzimidazole ring and low electron density on the group at position 2. To the best of our knowledge this is the first 3D-QSAR study performed for benzimidazoles as antiamoebic agents. The CoMFA models derived will be very valuable to design new and more potent compounds against E. histolytica.

[Mesial temporal sclerosis in temporal lobe epilepsy: quantitative magnetic resonance imaging assesment with 3.0 Tesla]. / Esclerosis temporal mesial en epilepsia del lóbulo temporal: evaluación cuantitativa con resonancia magnética 3.0 Tesla.

Recent studies show that up to 70% of patients with temporal lobe epilepsy (TLE) have a hippocampal deficit known as temporal mesial sclerosis (TME) characterized by neuron loss and gliosis, and considered the main epileptogenic focus among this type of patients. The magnetic resonance imaging (MRI) features of TME include atrophy and hippocampus hyperintensitY in the long TR sequences (Flair and T2). The 3.0 Tesla MRI allows the study of the brain's anatomy and physiology using different sequences and post processing mechanisms. Volumetry can determine the accurate volume and, together with spectroscopy, makes possible a quantitative assessment of the hyppocampus. Both techniques help to locate cerebral areas with epileptogenic activity. We describe the imaging findings from spectroscopy and volumetry in a patient with TLE and briefly review the related literature.

[Wallenberg syndrome: magnetic imaging findings and clinical correlation]. / Síndrome de Wallenberg: hallazgos en resonancia magnética con correlación clínica.

Wallenberg's syndrome is one of the most common clinically recognized conditions due to brain stem infarct, which can nowadays be identified by modern neuro-imaging techniques. We describe a patient complaining of miosis, dysphonia, and dysphagia followed by ataxia. An MRI evaluation was performed including diffusion-weighted imaging, apparent diffusion coefficient, T2-weighted images, fluid attenuated inversion recovery (FLAIR) and perfusion. A brief discussion of imaging findings is presented as well as a clinical correlation of the symptoms with the anatomic location of the lesion. This case report emphasizes the importance of imaging findings and their clinical correlation with neurological examination.

[Traumatic dissection of extracranial internal carotid artery with middle cerebral artery stroke: imaging diagnosis]. / Disección traumática de la arteria carótida interna extracraneal con infarto en el territorio de la arteria cerebral media. Diagnóstico por imagen.

Cervical carotid artery dissections (CCAD) are common in young adults with a mean age of 44 years and may account for as many as 20% of strokes in patients younger than 30 years. Trauma and primary diseases of the arterial wall such as fibromuscular dysplasia are the main predisposing factors. Some CCAD cases are diagnosed solely on clinical history and physical examination, and even imaging tools such as helical/multi-slice computed tomography (CT) and magnetic resonance imaging (MRI) sometimes are not sufficient to reach a diagnosis. We describe the case of an 18-year-old male who presented to our emergency department due to loss of consciousness 18 hours after a car accident. Previously he had been in no acute distress, with fluent speech, and able to follow 3-step commands. Helical CT showed a hypodense lesion in the left-middle cerebral artery territory, as well as hyperdensity of the M1 segment of the middle cerebral artery. Cerebral angiography depicted the left carotid artery dissection in the C1 segment. Physicians should consider this entity in "asymptomatic" patients during their first hours after head injury, among patients who later develop focal neurological symptoms and clinical deficits. Clinical suspicion followed by radiological findings allows early neurovascular treatment, trying to save viable brain tissue in the first hours post injury.

Disección traumática de la arteria carótida interna extracraneal con infarto en el territorio de la arteria cerebral media: diagnóstico por imagen / Traumatic dissection of extracranial internal carotid artery with middle cerebral artery stroke: imaging diagnosis

La disección de la arteria carótida interna (DACI) en su porción extracraneal es más común en adultos jóvenes, con edad de presentación promedio de 44 años y representa hasta 20% de los accidentes vasculares cerebrales en menores de 30. Algunos casos de DACI son de difícil diagnóstico, si se basan únicamente en la clínica y la exploración física; aunado a este hecho, los métodos de imagen como la tomografía computada (TC) helicoidal o multicorte así como la resonancia magnética (RM) pueden no ser suficientes para delinear la patología en cuestión. Presentamos el caso de un paciente masculino de 18 años, quien sufrió accidente automovilístico, sin pérdida del estado de alerta, 18 horas después del accidente presenta deterioro súbito del estado de conciencia, fue trasladado al hospital. La TC identificó una lesión hipodensa en el territorio de la arteria cerebral media izquierda, e hiperdensidad de esta arteria en la fase simple. Se realizó una angiografía cerebral diagnóstica, que mostró DACI izquierda en su segmento C1. Desde el punto de vista clínico-quirúrgico es importante sospechar esta patología en un paciente “asintomático” en las primeras horas postraumatismo y que posteriormente desarrolla déficit neurológico. La sospecha clínica y su comprobación radiológica permiten un tratamiento neuroquirúrgico-vascular para intentar el rescate del tejido cerebral viable en las primeras horas de establecido el daño.

Cervical carotid artery dissections (CCAD) are common in young adults with a mean age of 44 years and may account for as many as 20% of strokes in patients younger than 30 years. Trauma and primary diseases of the arterial wall such as fibromuscular dysplasia are the main predisposing factors. Some CCAD cases are diagnosed solely on clinical history and physical examination, and even imaging tools such as helical/multi-slice computed tomography (CT) and magnetic resonance imaging (MRI) sometimes are not sufficient to reach a diagnosis. We describe the case of an 18-year-old male who presented to our emergency department due to loss of consciousness 18 hours after a car accident. Previously he had been in no acute distress, with fluent speech, and able to follow 3-step commands. Helical CT showed a hypodense lesion in the left-middle cerebral artery territory, as well as hyperdensity of the M1 segment of the middle cerebral artery. Cerebral angiography depicted the left carotid artery dissection in the C1 segment. Physicians should consider this entity in [quot ]asymptomatic[quot ] patients during their first hours after head injury, among patients who later develop focal neurological symptoms and clinical deficits. Clinical suspicion followed by radiological findings allows early neurovascular treatment, trying to save viable brain tissue in the first hours post injury.

Natural rotavirus infection is not associated to intussusception in Mexican children.

AIMS: To determine whether natural rotavirus infection or infection by another enteropathogen is associated to intussusception (IS); and to describe the seasonality of IS compared with severe diarrhea (SD) and rotavirus SD in Mexican children. METHODS: A prospective, observational, multicenter and case-control study was conducted in Mexico City from December 1999 to February 2001. Cases were children younger than 1 year old hospitalized for IS; diagnosis was made by clinical features, radiologic and/or surgery findings. Controls were children younger than 1 year old hospitalized for another disease than a gastrointestinal illness (NGI). Cases and controls were paired by age and date of admission (+/-3 months; for both), in a 1:2 ratio. A surveillance of IS cases, SD and rotavirus SD episodes was conducted during the study period. Stool samples collected soon after IS resolution or at admission were tested for rotavirus, adenovirus, astrovirus, bacteria and parasites. RESULTS: Thirty cases of IS and 60 controls with NGI were studied. Rotavirus was not detected in any case of IS. Adenovirus (17%) was the only enteropathogen detected in IS. Rotavirus (8%), adenovirus (2%), astrovirus (2%) and bacteria (2%) were detected in NGI. Rotavirus infection was not associated with IS (odds ratio, 0; 95% confidence interval, 0-2.9), whereas adenovirus infection was strongly associated as risk factor for IS (odds ratio undefined; P = 0.003), compared with NGI. Seasonal variation in admissions for IS was small, whereas admissions for SD and rotavirus SD showed a marked seasonal increase during fall-winter. CONCLUSIONS: In Mexican children, rotavirus infection was not associated to IS; whereas a significant association was observed between adenovirus and IS. Also there was no increase in IS cases during the sharply defined fall-winter rotavirus outbreak. Observations from this controlled study suggest that natural rotavirus infection is not a risk factor for IS. This information may have implications for development of a safer and effective rotavirus vaccine.

Prevalence and genetic diversity of human astroviruses in Mexican children with symptomatic and asymptomatic infections.

The prevalence and type diversity of human astroviruses (HAstV) in children with symptomatic and asymptomatic infections were determined in five localities of Mexico. HAstV were detected in 4.6 (24 of 522) and 2.6% (11 of 428) of children with and without diarrhea, respectively. Genotyping of the detected strains showed that at least seven (types 1 to 4 and 6 to 8) of the eight known HAstV types circulated in Mexico between October 1994 and March 1995. HAstV types 1 and 3 were the most prevalent in children with diarrhea, although they were not found in all localities studied. HAstV type 8 was found in Mexico City, Monterrey, and Mérida; in the last it was as prevalent (40%) as type 1 viruses, indicating that this astrovirus type is more common than previously recognized. A correlation between the HAstV infecting type and the presence or absence of diarrheic symptoms was not observed. Enteric adenoviruses were also studied, and they were found to be present in 2.3 (12 of 522) and 1.4% (6 of 428) of symptomatic and asymptomatic children, respectively.

Synthesis and antiparasitic activity of albendazole and mebendazole analogues.

Albendazole (Abz) and Mebendazole (Mbz) analogues have been synthesized and in vitro tested against the protozoa Giardia lamblia, Trichomonas vaginalis and the helminths Trichinella spiralis and Caenorhabditis elegans. Results indicate that compounds 4a, 4b (Abz analogues), 12b and 20 (Mbz analogues) are as active as antiprotozoal agents as Metronidazole against G. lamblia. Compound 9 was 58 times more active than Abz against T. vaginalis. Compounds 8 and 4a also shown high activity against this protozoan. Compounds 4b and 5a were as active as Abz. None of the Mbz analogues showed activity against T. vaginalis. The anthelmintic activity presented by these compounds was poor.

Rotavirus diarrhea severity is related to the VP4 type in Mexican children.

This report is of a community-based case control study to assess whether the severity of acute diarrhea by rotavirus (RV) in young children is associated with a particular VP7 (G) or VP4 (P) RV serotype. Five hundred twenty children younger than 2 years of age with diarrhea lasting less than 3 days were age and gender matched with 520 children with no diarrhea. The G and P serotypes were determined with specific monoclonal antibodies, and the VP4 serotype specificity in a subgroup was confirmed by genotyping. Infection with a G3 serotype led to a higher risk of diarrhea than infection with a G1 serotype. Infection with a G3-nontypeable-P serotype was associated with more severe gastroenteritis than infection with a G3 (or G1) P1A[8] serotype. A child with diarrhea-associated dehydration was almost five times more likely to be infected with a G3-nontypeable-P serotype than a child without dehydration (P < 0.001). Moreover, the two predominant monotypes within serotype P1A[8] had significantly different clinical manifestations. In this study, the severity of RV-associated diarrhea was related to different P serotypes rather than to G serotypes. The relationship between serotype and clinical outcomes seems to be complex and to vary among different geographic areas.