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The clinical significance of cerebral atrophy in dementia.

The clinical significance of cortical atrophy is reviewed in relationship to neuropsychological impairment in dementia of the Alzheimer type. The degree of cortical atrophy may vary independent of the degree of cognitive impairment. There is some tendency for greater amounts of cortical atrophy to be associated with greater cognitive deficits, but individual variations limit the linearity of this relationship. On an individual case basis, lateralized atrophy in some patients may be associated with greater lateralization of cognitive impairment. Cortical atrophy patterns do not differ substantially in the pre-senile and senile forms of Alzheimer's disease. Neuropsychological follow-up provides a better index of the speed of deterioration in Alzheimer's disease than does computerized tomography (CT) or magnetic resonance imaging (MRI). Various clinical guidelines are offered for the interpretation of neuropsychological impairment based upon CT or MRI findings of cerebral atrophy.

Clinical Conference↗

Influence of aging, gastric mucosal atrophy and dietary habits on gastric secretion.

BACKGROUND/AIMS: Studies in Japan have reported on the association between gastric secretion and age with consideration given to gastric mucosal atrophy but not pepsin secretion. Though recent reports have shown enhanced gastric secretion in the Japanese, attributed to dietary westernization, the association between diet and gastric secretion is not clear. In this study, the association between gastric secretion and mucosal atrophy, age, and dietary habits was evaluated. METHODOLOGY: The subjects were 47 preoperative patients without upper gastrointestinal disorders. Acid secretion, pepsin secretion, serum pepsinogen level, and serum Helicobacter pylori antibody titer were measured. Dietary habits were investigated by questionnaire. RESULTS: Gastric secretion did not differ among the young, middle, and elderly age groups. Compared with the group without atrophy (pepsinogen I/II > 3.0, 32 subjects), the group with atrophy (I/II < or = 2.5, 11 subjects) showed significantly decreased gastric secretion and a significantly high Helicobacter pyloriseropositive rate. In the group without atrophy, acid and pepsin secretion was significantly correlated with energy intake, pepsin secretion was significantly correlated with glucose intake, and gastric secretion tended to increase with age. CONCLUSIONS: In the absence of gastric mucosal atrophy, gastric secretion does not decrease with age, and is related to dietary habits.

Adult↗

Antibodies to CagA protein are associated with gastric atrophy in Helicobacter pylori infection.

Strains of Helicobacter pylori which express the product of the cytotoxin associated gene A(CagA) are associated with duodenal ulceration. Also there is evidence that the presence of serum IgG antibodies to CagA is associated with an increased risk of gastric cancer of the intestinal type. Gastric atrophy is a precursor of intestinal-type gastric cancer so we have investigated whether antibodies to CagA are associated with gastric atrophy. In H. pylori infected patients, IgG antibodies to CagA were present in 24/38 (63%) of non-ulcer patients with atrophy compared with 13/40 (33%) of patient-controls with neither atrophy nor ulcer (P < 0.02). CagA antibodies were also more prevalent in patients with duodenal ulcers; 15/20 (75%) or gastric ulcers 5/5 (100%) than in the patient-controls (P < 0.005 and < 0.02 respectively). These results show that circulating IgG antibodies to CagA are associated with gastric atrophy, as well as peptic ulcer disease. Atrophy is a precursor of gastric cancer so support the hypothesis that certain strains of H. pylori are more likely to cause gastric cancer.

Adult↗

Supratentorial atrophy in spinocerebellar ataxia type 2: MRI study of 20 patients.

There have been only few studies of brain magnetic resonance imaging (MRI) in spinocerebellar ataxia (SCA) type 2. We investigated 20 SCA2 patients, from 11 Sicilian families, and 20 age-matched control subjects using MRI. Our data confirm that olivopontocerebellar atrophy (OPCA) is the typical pattern in SCA2. We found no significant correlation between infratentorial atrophy, disease duration, or the number of CAG repeats in our SCA2 patients, but there was supratentorial atrophy in 12 patients, with a significant correlation between supratentorial atrophy and disease duration. OPCA appears to represent the "core" of the SCA2: however, central nervous system involvement is not limited to pontocerebellar structures. We therefore consider central nervous system degeneration in SCA2 as a widespread atrophy. MRI is helpful in diagnosing SCA, but it is not diagnostic in the absence of clinical and molecular studies. We suggest that serial MRI may play a role in evaluating "in vivo" the progressive steps of neurodegeneration in SCA2, for a better comprehension of the pathophysiology of this disorder.

Adult↗

Electrocardiographic abnormalities in childhood spinal muscular atrophy.

Tremors of the isoelectric line in routine electrocardiograms have been described in patients with spinal muscular atrophy and have been interpreted as fasciculations of denervated muscles. In order to evaluate this phenomenon, 13 patients with spinal muscular atrophy have been studied (average age: 37.3 months). A first electrocardiogram was recorded routinely; a second tracing was then recorded with double sensitivity and double speed. In addition, all patients were evaluated clinically and had M-mode and cross-sectional echocardiography. Regular and constant spikes on the isoelectric electrocardiographic line were recorded in 12 patients (93.4%); their frequency ranged from 39 to 48 cycles/sec (average: 42.08 +/- 2.64). Contrary to previous reports, we found an "abnormal" electrocardiogram in all our patients with severe spinal muscular atrophy. The only patient with a normal electrocardiogram had a mild and clinically stable form of spinal muscular atrophy. We did not find any significant structural cardiac abnormality by clinical and echocardiographic evaluation. We conclude that continuous tremor on the isoelectric line of electrocardiogram represents a characteristic of spinal muscular atrophy in these patients. It is a result of muscle fasciculations and does not imply any abnormality of the heart.

Adolescent↗

Transcranial magnetic stimulation in multiple system and late onset cerebellar atrophies.

Central motor conduction time (CMCT) after transcranial magnetic stimulation (TMS) of the cortex, electromyography and nerve conduction velocity were performed in 24 patients with multiple system (MSA) and late onset cerebellar atrophy (LOCA) (often olivopontocerebellar atrophy--OPCA -). CMCT was abnormal in 7 patients with OPCA and one with LOCA. CMCT abnormalities (43% of cases) and increased threshold (68%) were more often found within OPCA group than in another multisystem atrophy and LOCA. Reduction in amplitude of the response after TMS was significantly correlated with cerebral hemispheres's atrophy. Increased threshold was correlated with upper vermal hemisphere atrophy and enlargement of the fourth ventricle. Electrophysiologic signs of mixed peripheral neuropathy were found in 8 patients. TMS abnormalities were not related to peripheral nerve involvement. Marked variation in CMCT suggests heterogeneity in these diseases. However, the percentage of CMCT abnormalities in OPCA group suggests that TMS seems to play a role in the neurophysiological diagnosis of these heterogeneous disorders.

Adult↗

Clinical usefulness of magnetic resonance imaging in multiple system atrophy.

OBJECTIVES: To determine the sensitivity, specificity, and positive predictive values of a selection of abnormal findings in the putamen and infratentorial structures on routine magnetic resonance imaging for distinguishing between multiple system atrophy, idiopathic Parkinson's disease, and age matched controls. PATIENTS AND METHODS: Two neuroradiologists blindly and independently rated axial T2 weighted and proton density MRI of 44 patients with multiple system atrophy, 47 patients with idiopathic Parkinson's disease, and 45 controls. High field (1.5 T) scans were available in 16 patients with multiple system atrophy, 15 patients with idiopathic Parkinson's disease, and 16 controls. All other patients had 0.5 T scans. RESULTS: On both 0.5 and 1.5 T scans the following items had high specificity but low sensitivity: putaminal atrophy, a hyperintense putaminal rim, and infratentorial signal change. Finding any infratentorial abnormality gave higher sensitivity but lower specificity. Putaminal isointensity or hypointensity relative to globus pallidus, absolute putaminal hypointensity, and altered size of the olives were not useful discriminators. The overall sensitivity was 73% on 0.5 T and 88% on 1.5 T scans. The specificities of these findings for multiple system atrophy in comparison to idiopathic Parkinson's disease and controls on 0.5 T were 95% and 100% respectively, and on 1.5 T were 93% and 91% respectively. Finding any of the described abnormalities on MRI gave a positive predictive value of 93% on the 0.5 T machine, and 85% on the 1.5 T scanner.

Adult↗

[The cerebral peduncle lesion in multiple system atrophy].

Atrophy of the cerebral peduncle and the pons can be seen on radiologic examination in patients of multiple system atrophy. This radiologic finding is one of the landmarks for the diagnosis of multiple system atrophy, but its detailed pathological background has not been thoroughly assessed. To clarify the pathological features of the cerebral peduncle lesion, samples from 28 autopsied cases (male 16, female 12; age 50-76 yr) were semiquantitatively examined after staining by HE, KB, Holzer, GFAP, Bodian and Gallyas methods. Atrophy of the cerebral peduncle was symmetric in most cases and resulted from the loss of small-sized nerve fibers. The glial cytoplasmic inclusion (GCI) in the cerebral peduncle increased significantly in severe atrophic cases compared with mild atrophic cases. However, in the most severe atrophic cases, in which this tissue was severely damaged, the GCI was decreased. The atrophy of the cerebral peduncle correlated significantly with the degree of degeneration in the olivo-ponto-cerebellar system and tended to correlate with a decrease in brain weight. The duration of disease is significantly longer in severe atrophic cases compared with mild atrophic cases.

Aged↗

A family with Charcot-Marie-Tooth disease and Leber's optic atrophy.

A family has been studied in which members of 4 generations were affected by the hypertrophic type of Charcot-Marie-Tooth disease. The diagnosis was confirmed by electrophysiological studies and by sural nerve biopsy. 10 members of the family, 8 males and 2 females, developed optic atrophy of acute onset with progression over a period of two to six months. The history of visual failure, its maternal inheritance, and the neuro-ophthalmological findings of optic atrophy with bilateral central scotomata were typical of Leber's optic atrophy. 2 members of the family suffered from both Charcot-Marie-Tooth disease and Leber's optic atrophy. There have been a few previous reports of optic atrophy associated with Charcot-Marie-Tooth disease, and in the present family both conditions appeared to have been inherited independently.

Adolescent↗

[Clinical and MRI correlation in multiple system atrophy].

By using magnetic resonance imaging (MRI), we studied 11 patients with multiple system atrophy (MSA): 5 olivo-pontocerebellar atrophy (OPCA), 2 Shy-Drager syndrome (SDS), and 4 striatonigral degeneration (SND). The diagnoses of OPCA, SDS and SND were clinically made. The MR images were performed on 1.5 tesla MRI unit (Siemens Asahi Medical, Magnetom H15), using a T2-weighted spin echo (SE) sequence (TR: 2000-3000ms, TE: 80-90ms), a T1-weighted SE sequence (TR: 550, TE: 15), and a proton density-weighted (PD) SE sequence (TR: 2000-3000, TE: 12-22). In the patients with OPCA, MRI revealed cerebellar and brainstem atrophy and degeneration of pontine transverse fibers more marked than in the patients with SDS and SND. T2-weighted images showed low intensity in posterolateral putamina in one OPCA patient and all of SDS and SND patients. PD images demonstrated the abnormal slit-like high signals in posterolateral putamina in three SND. The degree of cerebellar ataxia was not well correlated with cerebellar and brainstem atrophy and degeneration of pontine transverse fibers. There was a positive correlation between the atrophy of cerebellum and brainstem and the duration of cerebellar ataxia. In most of the patients with parkinsonism, MRI demonstrated abnormal low signals in putamina on T2-weighted images. There were positive correlations between the abnormal low signals putamina and the duration and severity of parkinsonism. Though abnormal low signals in lateral putamina may be seen in normal aging and other disorders on T2-weighted images, it is useful to evaluate parkinsonism in MSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Dominant spinopontine atrophy. Report of two additional members of family W.

In five generations of Anglo-Saxon family W, 28 members were affected with dominant hereditary ataxia. In 1969, two members of this family were reported as prototypes of dominant spinopontine atrophy. We discuss two additional members of the original family, with one postmortem examination, including ultrastructual study. In contrast to previously accepted clinical generalizations, we found abolished tendon reflexes and flexion contractures of the lower extremities in patient 1 and onset of illness at the age of 18 years, palatal myoclonus, and optic atrophy in patient 2. Dementia was observed in both patients. Unlike in previous pathological reports, our patient 1 showed definite involvement of the cerebellum and mild degeneration of the inferior olivary nuclei. We conclude, therefore, that clinical and pathological distinction between dominant spinopontine atrophy and olivopontocerebellar atrophy is not clear and raises the question of the justification for regarding dominant spinopontine atrophy as a nosological entity.

Adult↗

Family with dominantly inherited ataxia, amyotrophy, and peripheral sensory loss. Spinopontine atrophy or Machado-Joseph Azorean disease in another non-Portuguese family?

A family of German extraction with progressive ataxia, eye movement abnormalities, peripheral sensory loss, and spinal muscular atrophy of adult onset is described. Three members came to autopsy, and neuropathologically, the major changes included varying degrees of atrophy of the basis pontis and degeneration of the spinocerebellar tracts, Clarke's columns, anterior horn neurons, and fasciculus gracilis. The dentate nucleus was spared, and there was slight neuron loss from the substantia nigra in one patient. Clinically and neuropathologically, our family resembles that reported by Boller and Segarra as having spinopontine atrophy. However, several kindreds with similar findings have recently been described as having Azorean or Machado-Joseph disease in non-Portuguese families. Comparison of clinical and neuropathological features in spinopontine atrophy and Machado-Joseph disease, both in Portuguese and non-Portuguese families, reveals clinical and pathological similarities and differences between the two. The major differences in our patients include only minor extraocular movement abnormality and absence of protuberant eyes, and muscular rigidity clinically, and the sparing of the substantia nigra and the dentate nucleus neuropathologically. These differences suggest that spinopontine atrophy, as manifested in our family, is distinct from Machado-Joseph disease. Our family showed no linkage to the HLA locus on chromosome 6.

Adult↗

Autoantibodies to glutamate decarboxylase in a patient with cerebellar cortical atrophy, peripheral neuropathy, and slow eye movements.

OBJECTIVE: To study the existence of autoimmunity against the cerebellum in patients with sporadic cortical cerebellar atrophy. DESIGN: The presence of autoantibodies against the cerebellum in the serum and cerebrospinal fluid samples that were obtained from patients with sporadic cortical cerebellar atrophy and control patients was investigated by using immunohistochemical techniques. SETTING: University hospital and research laboratory in Lyons, France. PATIENTS: Eight patients with cortical cerebellar atrophy that was associated with or without other neurological symptoms; 350 patients with various neurological diseases; and 33 normal, healthy subjects. OUTCOME MEASURES: Serum and cerebrospinal fluid anti-cerebellar autoantibodies were investigated by using indirect immunofluorescence techniques in rat cerebellum. To characterize antigen labeled by patient's serum, we used an immunotrapping enzyme activity assay of glutamate decarboxylase. RESULTS: Serum and cerebrospinal fluid samples that were taken from one patient with sporadic cortical cerebellar atrophy associated with peripheral neuropathy and slow eye movements contained anti-glutamate decarboxylase autoantibodies. CONCLUSIONS: These results suggest a participation of autoimmunity in the pathogenesis of some cases of sporadic cerebellar cortical atrophy and the involvement of the cerebellar gamma-aminobutyric acid-ergic system in the pathogenesis of this disease.

Adult↗

Atrophy of the corpus callosum, cortical hypometabolism, and cognitive impairment in corticobasal degeneration.

OBJECTIVE: To investigate whether atrophy of the corpus callosum is associated with cognitive impairment and cerebral cortical hypometabolism in corticobasal degeneration. DESIGN: Prospective clinicoradiological correlation with magnetic resonance imaging and positron emission tomography. SETTING: A university hospital. PATIENTS: Eight right-handed patients with clinically diagnosed corticobasal degeneration (mean+/-SD age, 64+/-8 years). MAIN OUTCOME MEASURES: Midsagittal corpus callosum area-skull area ratio (on T1-weighted magnetic resonance images), the sum of the scaled scores of the 6 subtests on the Wechsler Adult Intelligence Scale-Revised (Digit Span, Arithmetic, Picture Arrangement, Object Assembly, Block Design, and Digit Symbol), and cerebral metabolic rate of glucose (measured with positron emission tomography by using fludeoxyglucose F 18 as a tracer). RESULTS: Compared with 36 age-matched right-handed control subjects, the patients had significantly decreased callosal area-skull area ratio. The reduction in this ratio was greatest in the middle half of the corpus callosum. The atrophy of the corpus callosum was accompanied by a decreased mean cortical glucose metabolic rate with hemispheric asymmetry and a decrease in the sum of the scaled subtest scores of the Wechsler Adult Intelligence Scale-Revised. CONCLUSIONS: Atrophy of the corpus callosum with middle predominance is present in corticobasal degeneration, and this atrophy is associated with cognitive impairment and cerebral cortical hypometabolism with hemispheric asymmetry. Atrophy of the corpus callosum might reflect the severity of the disconnection between cortical regions, and this may be an important factor in the development of cerebral cortical dysfunction in corticobasal degeneration.

Aged↗

Region-specific corpus callosum atrophy correlates with the regional pattern of cortical glucose metabolism in Alzheimer disease.

BACKGROUND: Positron emission tomographic studies of patients with Alzheimer disease (AD) suggest a loss of metabolic functional interactions between different cortical regions. Atrophy of the corpus callosum as the major tract of intracortical connective fibers may reflect decreased cortical functional integration in AD. OBJECTIVES: To investigate whether regional atrophy of the corpus callosum is correlated with regional reductions of cortical glucose metabolism, as shown by positron emission tomography, and whether primary white matter degeneration is a possible cofactor of corpus callosum atrophy in AD. PATIENTS AND METHODS: We measured total and regional cross-sectional areas of the corpus callosum on midsagittal magnetic resonance imaging scans from 12 patients with AD and 15 age-matched control subjects. Regional cerebral metabolic rates for glucose in cortical lobes were measured by positron emission tomography using fludeoxyglucose F 18. White matter hyperintensities were rated in T2-weighted magnetic resonance imaging scans. RESULTS: The total cross-sectional area of corpus callosum was significantly reduced in patients with AD, with the most prominent changes in the rostrum and splenium and relative sparing of the body of the corpus callosum. Frontal and parietal lobe metabolism was correlated with the truncal area of the corpus callosum in AD. The ratios of frontal to parietal and of frontal to occipital metabolism were correlated with the ratio of anterior to posterior corpus callosum area in the group with AD. White matter hyperintensities did not correlate with corpus callosum atrophy in the patients with AD. CONCLUSION: The regional pattern of corpus callosum atrophy correlated with reduced regional glucose metabolism independently of primary white matter degeneration in the patients with AD.

Aged↗

Dopamine metabolism in the cerebrospinal fluid of drug-free schizophrenic patients with and without cortical atrophy.

Cortical atrophy measured with computed tomography was observed in ten of 53 schizophrenic patients. Levels of homovanillic acid, dihydroxyphenyl acetic acid (DOPAC), conjugated DOPAC, and dopamine sulfate (DASO4) were measured in the cerebrospinal fluid of these patients during a drug-free evaluation. Patients with cortical atrophy had lower cerebrospinal fluid levels of homovanillic acid, DOPAC, and conjugated DOPAC but higher DASO4 levels. Combined measures of dopamine utilization were significantly lower in patients with cortical atrophy. We did not find significant clinical or demographic differences between the patients with and without cortical atrophy. Patients without brain atrophy who had dopamine utilization above the mean showed more psychotic symptoms and shorter duration of illness, while those with dopamine below the mean had more negative symptoms. We propose that both state- and trait-dependent variables affect dopamine turnover.

3,4-Dihydroxyphenylacetic Acid↗

DNA plasmid that codes for human Bcl-2 gene preserves axotomized Clarke's nucleus neurons and reduces atrophy after spinal cord hemisection in adult rats.

Spinal cord injury in adult mammals causes atrophy or death of some axotomized neurons. The product of the antiapoptotic gene Bcl-2 prevents neuron death in vivo. We delivered Bcl-2 by intraspinal injection of a DNA plasmid encoding this gene to determine if axotomized neurons destined to undergo retrograde death could be rescued. Axons of the right side Clarke's Nucleus (CN) were cut unilaterally in adult Sprague-Dawley rats by T8 hemisection, leaving the contralateral (left) CN as an intact control. Two months postoperatively, there was approximately 35% loss of total CN neurons in the right L1 segment. Only 15% of large CN neurons (>400 microm2), whose axons project to the cerebellum, survived--indicating atrophy and/or death of 85% of these cells. We injected a DNA plasmid encoding the human Bcl-2 gene and the bacterial reporter gene LacZ, which was complexed with cationic lipids, into the right side of segment T8 of the normal spinal cord, or just caudal to the hemisection site. The reporter gene was expressed in the perikarya of right CN neurons at L1 for up to 7 days, but not 14 days. Two months following T8 hemisection and Bcl-2/LacZ DNA injection, there was no significant loss of CN neurons ipsilateral to the lesion. Surprisingly, 61% of large neurons survived, indicating partial protection from atrophy. In contrast, a DNA plasmid that codes for the LacZ reporter gene, but not Bcl-2, did not prevent CN neuron death or atrophy. Administration of the Bcl-2 gene in adult rats and its expression in these CNS neurons prevents retrograde cell death, and also minimizes atrophy. These results may serve as the basis for developing novel gene therapy strategies for patients with spinal cord injury.

Animals↗

Local oestrogen for vaginal atrophy in postmenopausal women.

BACKGROUND: Vaginal atrophy is a frequent complaint of postmenopausal women; symptoms include vaginal dryness, itching, discomfort and painful intercourse. Systemic treatment for these symptoms in the form of oral hormone replacement therapy is not always necessary. An alternative choice is oestrogenic preparations administered vaginally (in the form of creams, pessaries, tablets and the estradiol releasing ring). OBJECTIVES: The objective of this review is to compare the effectiveness, safety and acceptability of oestrogenic preparations for women who suffer from vaginal atrophy. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group register of trials (searched January 2003), The Cochrane Library (Issue 2, 2003), MEDLINE (1966-January 2003), EMBASE (1980-January 2003), Current Contents (1993-January 2003), Biological Abstracts (1969-2002), Social Sciences Index (1980-January 2003), PsycINFO (1972-February 2003), CINAHL (1982-January 2003) and reference list of articles. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of oestrogenic preparations administered intravaginally in postmenopausal women for the treatment of symptoms resulting from vaginal atrophy or vaginitis. DATA COLLECTION AND ANALYSIS: Twenty nine trials were identified, of these 13 were excluded. Trials were assessed for quality and two reviewers extracted data independently. Ratios for dichotomous and means for continuous outcomes were estimated. Outcomes analysed were included under the headings of efficacy, safety and acceptability. MAIN RESULTS: Sixteen trials with 2129 women were included in this review. The overall quality of the studies was good, although not all trials measured the same outcomes. All trials measured efficacy with various outcome measures. When comparing efficacy of oestrogenic preparations (in the form of creams, pessaries, tablets and the estradiol releasing vaginal ring) with each other in relieving the symptoms of vaginal atrophy, results indicated significant differences favouring the cream, ring, and tablets when compared to placebo and non-hormonal gel. Fourteen trials compared safety. Four looked at hyperplasia, four looked at endometrial overstimulation and six looked at adverse effects. One trial showed significant adverse effects of cream (conjugated equine oestrogen) when compared to tablets (estradiol) which included uterine bleeding, breast pain and perineal pain (1 RCT; OR 0.18, 95% CI 0.07 to 0.50). Two trials showed significant endometrial overstimulation as evaluated by progestagen challenge test in the cream (conjugated equine oestrogen) group when compared to the ring (OR 0.29, 95% CI 0.11 to 0.78). Although not statistically significant there was a 2% incidence of simple hyperplasia in the ring group when compared to cream (conjugated equine oestrogen) and 4% incidence of hyperplasia (one simple, one complex) in the cream group (conjugated equine oestrogen) when compared to the tablet (estradiol). Nine studies compared acceptability to the participants by comparing comfort of product, ease of use, overall product rating, delivery system and satisfaction. Results showed a significant preference for the estradiol releasing vaginal ring. REVIEWER'S CONCLUSIONS: Creams, pessaries, tablets and the estradiol vaginal ring appeared to be equally effective for the symptoms of vaginal atrophy. One trial found significant side effects noted following cream (conjugated equine oestrogen) administration when compared to tablets causing uterine bleeding, breast pain and perineal pain. Another trial found significant endometrial overstimulation following cream (conjugated equine oestrogen) when compared to the ring. As a treatment choice women appeared to favour the estradiol releasing vaginal ring for ease of use, comfort of product and overall satisfaction.

Administration, Intravaginal↗